 |
 Previous Article | Next Article 
The Journal of Neuroscience, September 15, 1998, 18(18):7588-7598
Phasic Firing Time Locked to Cocaine Self-Infusion and
Locomotion: Dissociable Firing Patterns of Single Nucleus Accumbens
Neurons in the Rat
Laura L.
Peoples,
Fred
Gee,
Racquel
Bibi, and
Mark O.
West
Department of Psychology, Rutgers University, New Brunswick, New
Jersey 08903
 |
ABSTRACT |
The activity of single nucleus accumbens (NAcc) neurons of rats was
extracellularly recorded during intravenous cocaine self-administration sessions (0.7 mg/kg per infusion, fixed ratio 1). We reported previously that NAcc neurons showed a change, usually a decrease, in
firing rate during the first 1 min after the cocaine-reinforced lever
press. This postpress change was followed by a progressive reversal of that change, which began within the first 2 min
after the press and was not complete until the last 1 min before the next lever press (termed the change + progressive reversal firing pattern). In the present study we documented a regular pattern of
locomotion that occurred in parallel with the change + progressive reversal firing pattern. This observation suggested that discharges time locked to locomotion may determine the change + progressive reversal firing pattern. However, 55% of the neurons failed to show
firing time locked to locomotion that could have contributed to the
change + progressive reversal firing pattern. Moreover, for all
neurons, the change + progressive reversal firing pattern was apparent
even if the calculation of firing rate excluded all periods of
locomotion. The present data showed that the change + progressive
reversal firing pattern is not solely attributable to phasic changes in
firing time locked to the execution of locomotion. The change + progressive reversal firing pattern closely mirrors changes in drug
level and dopamine overflow observed by previous researchers and may
thus be a component of the neurophysiological mechanism by which drug
level regulates drug-taking behavior during an ongoing
self-administration session.
Key words:
addiction; self-administration; drug; cocaine; psychomotor stimulant; nucleus accumbens; neuron; electrophysiology; reinforcement; reward; incentive motivation; locomotion; stereotypy
| |
INTRODUCTION |
Lesion and microinjection studies in
the rat have shown that neurons of the nucleus accumbens (NAcc) are
necessary for cocaine self-administration (Phillips et al.,
1983 ; Zito et al., 1985; Robledo et al., 1992; McGregor and
Roberts, 1993). Consistent with this observation, single NAcc neurons
show phasic changes in firing time locked to intravenous cocaine
self-administration (Carelli et al., 1993; Carelli and Deadwyler, 1994,
1996a,b; Chang et al., 1994, 1996, 1998; Peoples et al., 1994,
1996, 1997, 1998; Bowman et al., 1996; Uzwiak et al., 1997). One of the
most common changes in firing occurs during the interval that elapses
between successive cocaine self-infusions. Firing rate decreases during the first 1 min after cocaine self-infusion, relative to the last 1 min
before self-infusion. The postinfusion change in firing is followed by
a progressive reversal of that change, which begins within 2 min after
the infusion and is not complete until the last 1 min before the next
self-infusion (termed change + progressive reversal firing pattern)
(Peoples and West, 1996).
We have hypothesized that this NAcc firing pattern contributes to
cocaine self-administration. However, casual observation of behavior
during the interinfusion interval suggests an alternative interpretation of the firing pattern. During the interinfusion interval, animals engage in a regular pattern of locomotion that parallels the change + progressive reversal firing pattern. Research of
other investigators has shown that the NAcc contributes to locomotion
(Lorens et al., 1970; Pijnenburg and van Rossum, 1973; Costall and
Naylor, 1975; Jackson et al., 1975; Kelly et al., 1975; Kelly and
Iversen, 1976; Iversen and Koob, 1977; Watchtel et al., 1979;
Makanjuola et al., 1980; Jones et al., 1981; Mogenson and Nielsen,
1984; Evenden and Carli, 1985; Kafetzopoulos, 1986; Delfs et al., 1990;
Weissenborn and Winn, 1992; Wu et al., 1993; Maldonado-Irizarry
and Kelley, 1995; Brudzynski and Gibson, 1997). In addition, the tonic
firing rate of some NAcc neurons is modulated by locomotion (Peoples
and West, 1990; Callaway and Henriksen, 1992; Chang et al.,
1994, 1998; Peoples et al., 1994; Kiyatkin and Rebec, 1996).
These data suggest that the change + progressive reversal firing
pattern potentially reflects locomotor-related discharges rather than,
or in addition to, self-administration-related firing.
The extent to which locomotor-related firing may contribute to the
change + progressive reversal firing pattern was evaluated in the
present study. Extracellular recordings of single NAcc neurons were
conducted in rats intravenously self-administering cocaine. The
sessions were videotaped to document the behaviors that occur during
the interinfusion interval, as well as to analyze the activity of
individual neurons with respect to those behaviors. The video and
neural analyses were used to test the following predictions. If the
"locomotor interpretation" of the change + progressive reversal
firing pattern is correct, the time course of the change + progressive
reversal firing pattern should be highly correlated with the time
course of the changes in locomotion. In addition, neurons that show the
change + progressive reversal firing pattern should also show phasic
changes in firing time locked to specific locomotion events. Finally,
the change + progressive reversal firing pattern should be disrupted by
the exclusion of all periods of locomotion from the calculation of
firing rates during the minutes before and after cocaine
self-infusion.
Parts of this paper have been published previously in abstract form
(Peoples et al., 1997).
| |
MATERIALS AND METHODS |
The procedures used for surgery, postoperative maintenance of
animals, self-administration, extracellular recording, and histology were described in a previous report (Peoples and West, 1996). Thus,
only a brief description of each is provided here.
Subjects and neuron sample. Subjects of the present study
were a subset of animals (8 of 14) included in a previous study (Peoples and West, 1996). No neurons were included other than those of
the previous study. Inclusion of each subject in the present study was
dictated by two electrophysiological criteria. First, at least one of
the neural recordings made for that subject had to exhibit a minimum
interspike interval consistent with the refractory period of a
discriminated single neuron. Second, at least one of the recordings
that met the first criterion had to show additionally the phasic firing
pattern of primary interest, i.e., the change + progressive reversal
pattern. One subject had to be excluded because of a damaged videotape
that precluded most of the analyses conducted in the present study.
Surgery. Long-Evans rats (300-350 gm; Charles River,
Wilmington, MA) were anesthetized with sodium pentobarbital. A catheter was implanted in the jugular vein, and an array of 12-16 Teflon-coated stainless steel microwires was implanted in the NAcc (microwire arrays
purchased from Dr. David Shapiro).
Experimental procedures
Cocaine self-administration session. Before the start
of each self-administration session, a nonretractable Plexiglas
response lever was mounted on a side wall (henceforth referred to as
the lever wall) of the chamber. Onset of the session
was signaled by illumination of a stimulus light above the lever. Each
lever press was immediately followed by a 0.2 ml intravenous infusion of cocaine solution (0.24 mg/0.2 ml infusion), a 7.5 sec tone that
corresponded with the operation of a syringe pump, and a 40 sec
time-out during which the stimulus light was turned off and lever
presses had no programmed consequence.
Video recording. During each recording session, behavior was
videotaped using a Sony Super VHS videocassette recorder. Each video
frame (30 frames/sec) was sequentially time-stamped by a computer
coupled with a video frame counter (Thalner Electronics VC-436). Frames
were time stamped according to the same computer clock that time
stamped each neural discharge. The camera viewed the animal through one
of the Plexiglas chamber walls that was perpendicular to the lever
wall. The entire chamber was visible; thus the rat was always visible.
As the rat locomoted to the lever and then faced the lever to press it,
the right flank of the rat was the typical view of the camera. As the
rat locomoted away from the lever to the opposite side of the chamber,
the left flank of the rat was in view of the camera. The side view of
the rat facilitated detection of both forepaw and hindpaw movements as well as head movements.
Electrophysiological procedures. During each experiment,
electrophysiological recording began 1 hr before the start of the self-administration session and continued for 1 hr after the session. Using software and hardware of DataWave Technologies (Longmont, CO),
electrical signals were stored for off-line analysis. Only one
recording session per microwire contributed to the final data set.
After a population of neural waveforms was isolated by the post
hoc discrimination procedures (DataWave Common Processing Module,
DataWave Inc.), that population was subjected to an interspike interval
analysis to confirm that it corresponded to a discriminated single
neuron (Moore et al., 1966; Perkel et al., 1967; Kosobud et al., 1994).
When more than a single population of neural waveforms appeared to have
been recorded from a given wire, cross-correlation analysis was used to
confirm that the populations corresponded to distinct neurons.
Histological procedures. All wire tips from which neurons
were recorded were verified to have been located in the NAcc.
Histological procedures have already been discribed (Peoples and West,
1996). Given the number of neurons that were included in the present analyses, we did not compare the firing patterns of neurons located in
different areas of the NAcc.
Analysis of behavior during the interinfusion interval
The video system allowed us to document, off-line, the timing of
behaviors completed in any area of the chamber with a temporal resolution of 33 msec. After the recording session, in off-line frame-by-frame analysis, time stamps associated with the onsets or
offsets of particular behaviors were read from the video frames displayed on a video monitor. Frames in which the same type of behavioral event occurred were compiled and input as nodes into the
computer (Chapin et al., 1980; West et al., 1997) for subsequent histogram analysis of neural firing in relation to specific behaviors. The use of video procedures in conjunction with strict operational definitions of behavior provided a more reliable characterization of
the occurrence of specific behaviors than would have been
possible using automated procedures. This is because the latter can
potentially fail to discriminate between topographically distinct motor
behaviors (Kehne et al., 1981; Kelly and Roberts, 1983; O'Dell
et al., 1996). The video analysis of behavior was limited to
those lever-press trials included in the analysis of neural firing (see
below).
Operational definitions of behavior. Focused
stereotypy was defined as a period in which the rat made
repetitive head movements and/or repetitive forepaw movements while
maintaining hindpaws stationary. The absence of hindpaw movements was
associated with the rat remaining fixed (and behaviorally focused) in
one area of the chamber. Locomotion was defined by a
sequence of forepaw and hindpaw steps and thus involved traversal of
the animal across the floor of the chamber. The presence versus absence
of traversal maximally differentiated locomotion events from stereotypy
events (i.e., differentiated major large movements from small
repetitive movements, which is important for distinguishing between
behaviors that are potentially mediated by the NAcc vs the lateral
striatum) (see Kelly and Roberts, 1983; Wise and Bozarth, 1987).
Mixed behavior consisted of some locomotive behavior,
involving at least one hindpaw movement that occurred in conjunction
with stereotypic head movement directed toward the floor of the
chamber.
Onset and offset latencies of particular behaviors. Onset of
locomotion equaled the time at which the paw that made the first step
was lifted from the floor and offset of locomotion equaled the time at
which the paw that made the last step contacted the floor. Nearly all
focused stereotypy events were bracketed by either locomotion or mixed
behavior. Therefore, the onset time of a stereotypy event was defined
with respect to the last step of the locomotion or mixed event that
preceded stereotypy. Similarly, the offset time of a stereotypy event
was defined with respect to the first step of the locomotion or mixed
behavior event that followed the stereotypy event.
Direction of locomotion. Each locomotion event was
classified as either (1) toward the lever wall or (2) toward nonlever
walls. Locomotion toward the lever wall was defined as
forward locomotion that moved the animal in the direction of the lever
wall and terminated with at least the head and shoulders of the rat
inside the half-portion of the chamber that contained the lever.
Forward or side-to-side locomotion that moved the animal from one
portion of the lever wall to the other, with at least the head and
shoulders of the rat in the quarter portion of the chamber containing
the lever, was also classified as locomotion toward the lever wall. The
remaining locomotion was defined as locomotion toward nonlever
walls.
Analysis of the change + progressive reversal firing pattern
Histograms displaying firing of single neurons. The
initial 5-10 irregularly spaced self-infusions of the loading phase
were excluded from analysis. All other reinforced lever presses
bracketed by interinfusion intervals of a minimum length (i.e., 1 min
less than the modal interinfusion interval) were included in the
histogram. Offset of the reinforced lever press (0.1 msec resolution)
was the histogram node.
Quantitative and statistical analysis of the change + progressive
reversal firing pattern. The procedures used to statistically analyze phasic changes in firing rate during the minutes before and
after the press were described previously (Peoples and West, 1996). The
procedures used to analyze decreases in firing rate are briefly
described below. Comparable procedures were used to analyze increases
in firing rate.
Significance was evaluated by using a one-tailed Wilcoxon matched pairs
test ( = 0.05, unidirectional; Siegel and Castellan, 1988). To
conduct the test, firing rate before and after the reinforced lever
press was calculated using a sliding window procedure (Schultz et al.,
1992); the measure of firing rate, number of discharges, was determined
as a function of 0.5 min time windows using a step time equal to 0.1 min. For each lever-press trial that was included in a Wilcoxon matched
pairs test, the discharges in two time windows, or in two 0.1 min
steps, were input as a matched pair into the test.
Postpress change in firing rate. A postpress decrease
in firing rate was defined as a significant decrease in firing
rate that occurred during the first 2 min after the reinforced lever press, relative to firing during the last 2 min before the reinforced lever press. In analyzing a postpress decrease, the number of discharges in the 0.5 min time window with the minimum discharges after
the press was compared with the number of discharges in the 0.5 min
window with the maximum discharges before the press. The latency to
culmination of the postpress decrease was defined as the 0.1 min step
in which firing decreased to its minimum during the 2 min
postpress.
Progressive reversal of postpress change. After culmination
of the postpress decrease, firing rate began to revert toward prepress
rates. The latency to onset of the reversal was defined as
the first 0.1 min step in which firing reverted significantly from the
culminant (minimum) firing rate of the postpress decrease. The latency
to culmination of the reversal was defined as the 0.1 min step with the
maximum discharges during the 2 min prepress.
Relationship between the time course of the change + progressive
reversal firing pattern and the timing of locomotion
After the lever press, subjects typically locomoted away from
the lever wall and then engaged in stereotypy. After some time elapsed
the animal reinitiated locomotion. The length of time that elapsed
before locomotion was reinitiated appeared to vary positively with the
duration of the progressive reversal phase of the change + progressive
reversal firing pattern. To test this possibility, a Pearson
product-moment correlation was calculated between this latency to
reinitiate locomotion and the duration of the progressive reversal. The
reinitiation of locomotion was defined as the first postinfusion
locomotion event that met the following two criteria: (1) occurred
after the 40 sec time-out period, and (2) did not consist of the
initial locomotion away from the response lever after the
cocaine-reinforced lever press. This definition was based on the
following. Preliminary characterization of locomotion patterns
indicated that locomotion typically decreased to minimum within the
first 40 sec and/or after the initial locomotion away from the lever
wall after self-infusion. Locomotion subsequently increased in
frequency. The latency from the lever press to this increase in
locomotion was the dependent variable of interest.
Duration of the postpress change and the progressive
reversal. The change + progressive reversal firing pattern was
divided into three phases: the postpress change, the reversal, and the postreversal period. The first two phases were defined above. The
third, the postreversal period, was the number of minutes that elapsed
between culmination of the reversal and the time of the next
self-infusion. The combined duration of these three phases equaled the
duration of the interinfusion interval. The duration of the postpress
change equaled the onset latency for the reversal (defined above). The
duration of the reversal was defined as: [interinfusion interval  (duration of postpress change + duration of postreversal period)].
Pearson product-moment correlations ( = 0.05) were calculated
between the various phases of the firing pattern and the duration of
the interinfusion interval.
Does NAcc firing concomitant with locomotion engender the change + progressive reversal firing pattern?
Do neurons show a phasic change in firing rate time locked
to locomotion? Histograms were constructed to display firing rate time locked to locomotion events that were preceded by focused stereotypy events. Each of the locomotion events used as a node to
construct these histograms (1) was preceded by a focused stereotypy event, and (2) did not occur within ±10 sec of the reinforced lever
press. The histogram node equaled the onset of locomotion. The average
duration of focused stereotypy ranged from 2.3 to 11.6 sec. The average
duration of locomotion ranged from 0.8 to 2.2 sec. Given the above
criteria, the onset of locomotion necessarily corresponded to the end
of the immediately preceding stereotypy event. A change in firing rate
to the right of the histogram node, relative to the left, was
indicative of a phasic change in firing associated with the transition
from stereotypy to locomotion. Using the Wilcoxon matched pairs test,
firing rate during the first 0.5 sec of locomotion was compared with
firing rate during a 0.5 sec period of focused stereotypy (i.e., 1.0
to 0.5 sec before the onset of the locomotion) ( = 0.05, unidirectional; Siegel and Castellan, 1988). Histograms were
constructed to display firing during the following: (1) locomotion
toward the lever wall, (2) locomotion toward nonlever walls, and (3)
locomotion toward all walls. Directionally opposed locomotion events
that contributed to the histograms were temporally matched with respect
to cocaine self-infusion. Differences in the phasic firing apparent in
histograms of firing time locked to locomotion toward the lever wall
versus locomotion toward nonlever walls could therefore not be
attributed to differences in drug level. There were no EMG recordings.
However, given that the locomotion events were comparably defined
except for direction, differences in these histograms were also
unlikely to reflect any movement parameter other than direction.
Effect on the progressive reversal firing pattern of excluding
all periods of locomotion from the calculation of firing rate. Histograms that display firing during the minutes before and after the
press were reconstructed using only periods in which the animal was
engaged in focused stereotypy. The following procedures were used to
construct the histograms. Each stereotypy event was subdivided into 1 sec subunits. The last 1 sec subunit of stereotypy was discarded. For
each lever-press trial, the 1.0 sec subunits were grouped according to
time before and after the press in bins of 0.5 min. The discharges that
occurred during the 1.0 sec subunits were summed within each 0.5 min
bin for a given lever-press trial. Discharges per 0.5 min bin were then
summed across all lever-press trials and plotted as a function of time
before and after the press. Note that before summation of discharges
across lever-press trials, the 0.5 min bins were equated for total
number of 1.0 sec subunits. This was accomplished by first determining
the minimum number of subunits within any of the 0.5 min bins and then
reducing the number of subunits in all other 0.5 min bins to equal that minimum. The deletions were distributed equally across trials and
across portions of the 0.5 min bin. Thus comparison of firing rate
during different 0.5 min bins before and after the press was not
confounded by different sample sizes. This analysis is comparable to
behavioral clamping techniques (c.f., Rank et al., 1983) used to
discriminate between firing patterns that reflect a primary drug effect
and firing patterns that instead reflect feedback from drug-induced
behaviors (e.g., West et al., 1992, 1997; Haracz et al., 1993; Peoples
et al., 1994).
| |
RESULTS |
Neuron sample
Recordings of 18 neurons in eight animals met all the criteria for
inclusion in the present study. One subject contributed four neurons.
Each of the remaining seven subjects contributed between one and three
neurons. The recordings of the 18 change + progressive reversal neurons
were made during nine recording sessions using 17 microwires. Nine of
the neurons were located in the core; the remaining neurons were in the
shell and shell-core border areas. Each neuron exhibited a stable
waveform throughout the recording session and exhibited a minimum
interspike interval of 3-5 msec (Fig.
1). For 15 of the 18 neurons, the change + progressive reversal pattern consisted of a decrease in firing after
the press followed by a progressive increase (abbreviated as decrease + progressive increase) (Fig. 2, neuron
B). For the remaining neurons, it consisted of an increase
in firing after the press followed by a progressive decrease
(abbreviated as increase + progressive decrease) (Fig. 2, neuron
F). Ten additional neurons, which were not considered
further in the present analyses, exhibited either a phasic change in
firing during the minutes before and after the press that was other
than the change + progressive reversal firing pattern (5 of 10) or
failed to show any phasic change in firing during the minutes before
and after the press (i.e., were nonresponsive).
View larger version (30K):
[in this window]
[in a new window]
|
Figure 1.
Interspike interval histograms. Each of the two
rows shows an interspike interval histogram for a single neuron. Each
histogram plots the total number (0.1 msec bin width) of interspike
intervals (ordinate) exhibited by the neuron during the
entire recording session that were of durations,  0.1 msec and  25.0
msec (abscissa). To the left of each
histogram is a sample of the corresponding neural waveform. The sample
consists of the first 500 consecutively recorded waveforms of the
recording session. Positive voltage is up. The vertical
calibration bar to the left of each waveform sample
indicates 0.05 mV; each waveform trace spans 0.64 msec. In all figures,
letters at top left of histograms
correspond to identifying labels in other figures representing the same
neurons.
|
|
View larger version (25K):
[in this window]
[in a new window]
|
Figure 2.
Examples of the change + progressive reversal
firing pattern. Each histogram displays the firing pattern of one
neuron during the minutes before and after the press. The
ordinate of each histogram displays average firing rate
(i.e., average hertz calculated as a function of 0.1 min bins); Time
0 on the abscissa represents the
occurrence of the reinforced lever press. Minutes before and after the
press are shown to the left and right of
time 0, respectively. Above each histogram is a raster
display that shows firing of the neuron on a trial-by-trial basis.
Lever-press trials are shown chronologically from the bottom
row to the top row. The figure shows examples of
both types of change + progressive reversal firing patterns. A decrease + progressive increase pattern is shown at the top; an
increase + progressive decrease pattern is shown at the
bottom.
|
|
The qualitative and quantitative characteristics of the change + progressive reversal firing patterns of the neurons in the present
study were comparable to those of the larger group of neurons from
which the present subset was drawn (Peoples and West, 1996). They were
also comparable to those of a larger and separate sample of NAcc
neurons (see Peoples et al., 1998). Animals' self-administration behavior was consistent with that typically observed in limited-access (fixed ratio 1) cocaine self-administration studies. The present neural and behavioral data are thus likely to be representative.
Self-administration behavior
Animals had various amounts of self-administration experience
(i.e., 2-6 weeks) and thus exhibited, to varying degrees, regular rates of self-infusion. The rates of infusion maintained a calculated drug level within correspondingly stable limits, assuming constant pharmacokinetics (Fig. 3).
View larger version (28K):
[in this window]
[in a new window]
|
Figure 3.
Patterns of lever presses and calculated drug
level. Each of the two rows shows the self-administration behavior of a
single animal during a single self-administration session. For each
behavioral display, the following is shown. The abscissa
shows time (minutes) during the self-administration phase of the
recording session; Time 0 corresponds to time of the
first lever press. The pattern of reinforced lever presses is shown at
the top. Each tick represents the
occurrence of one cocaine reinforced lever press. Underneath the
display of lever presses is a graph of the normalized calculated drug
level present at the time of the self-infusion behavior (i.e., before
the onset of the infusion) (c.f., Peoples et al., 1997). Calculated
drug levels were normalized within each session relative to the maximum
calculated drug level attained in the session. Although the calculated
drug level (data not shown) may have differed from the actual drug
level by some constant amount, the relative stability of the calculated
drug level across the self-administration session demonstrates the
degree to which the rate of self-infusion was likely to have maintained
body levels of drug within stable limits (c.f., Yokel and Pickens,
1974). The patterns of behavior shown are representative of the range
of regularity in self-administration behavior exhibited by subjects in
the present study.
|
|
Behavior during the interinfusion interval
Locomotion
Behavior consistent with the definition of locomotion accounted
for a relatively low percentage of behavior exhibited during the
interinfusion interval. Nevertheless, there were regular changes over
the course of the interinfusion interval in the percent time that
animals spent in locomotion as opposed to other behaviors. Within the
first 1-1.5 min after the press, time spent in locomotion decreased to
minimum (eight of eight animals) (Figs.
4, 5),
which was typically (five of eight animals) maintained for several
minutes and consisted of the complete absence of locomotion.
Thereafter, animals reinitiated locomotion (average latency, 4.5 ± 0.5 min after the press). Percent time spent in locomotion
progressively increased as the interval elapsed such that locomotion
was at maximum during the ±0.5 min of the lever press. The patterns of locomotion toward the lever and nonwall walls were comparable (Fig.
6).
View larger version (52K):
[in this window]
[in a new window]
|
Figure 4.
Percent time spent by individual subjects in
locomotion and stereotypy. Each of the two columns shows the percent of
time (ordinate) that a single animal spent in either
stereotypy (top row) or locomotion (bottom
row) during all the lever-press trials combined (i.e., all
lever-press trials included in histogram analysis of firing). Time
0 on the abscissa represents occurrence
of the reinforced lever press. Minutes before and after the press are
shown to the left and right of time
0, respectively. Subjects 1 and
2 correspond to neurons D and
B shown in other figures.
|
|
View larger version (14K):
[in this window]
[in a new window]
|
Figure 5.
Average percent time spent in locomotion and
stereotypy exhibited by all subjects. Each behavioral histogram shows
the average percent of total time spent in a particular behavior by all
animals combined.
|
|
View larger version (31K):
[in this window]
[in a new window]
|
Figure 6.
Average percent time spent in locomotion toward
the lever and nonlever walls. Each of the two columns displays the
percent of total time that an individual animal spent engaged in either
locomotion toward the lever wall (top row) or locomotion
toward nonlever walls (bottom row). The two animals
represented in this figure are the same animals represented in Figure
4.
|
|
Mixed behavior
Most of the behavior that did not meet the strict definition
of either stereotypy or locomotion consisted of mixed behavior. Changes
in mixed behavior that occurred over the course of the interinfusion
interval were comparable to the changes in locomotion (Fig. 5). The
patterns of both locomotion and mixed behavior, which included
locomotion, were similar in form to the change + progressive reversal
firing pattern.
Stereotypy
Stereotypy was the predominant behavior during the interinfusion
interval. Total percent time spent in stereotypy was >70% for each
animal. Time spent in stereotypy showed a regular pattern during the
interinfusion interval that was opposite the pattern of locomotion
(Figs. 4, 5).
Relationship between the time course of the change + progressive
reversal firing pattern and the time course of locomotion
Firing rates of NAcc neurons and percent time spent in locomotion:
Latency to minimum and maximum during the interinfusion interval
For the progressive reversal neurons that showed a postpress
decrease in firing, the minimum firing rate (i.e., culminant of the
postpress change) occurred, on average, 0.85 ± 0.12 min after the
press. The maximum firing rate (i.e., culminant of the progressive
reversal) occurred, on average, 0.43 ± 0.16 min before the press.
These latencies to minimum and maximum firing rate corresponded to the
times at which minimum and maximum locomotion occurred during the
interinfusion interval. Neurons that showed a postpress increase in
firing showed culminant latencies (i.e., latencies to maximum firing
rate after the press and minimum firing rate before the press) that
were comparably synchronized to locomotion.
Time course of the progressive reversal and reinitiation of
locomotion during the interinfusion interval
Average latency to onset of the progressive reversal equaled
1.4 ± 0.2 min after the press. The latency to reinitiate
locomotion averaged 4.5 min after the press. Thus, the progressive
reversal was typically under way for several minutes before animals
reinitiated locomotion. Despite the lag time between the onset of the
progressive reversal and the onset of locomotion, both firing rate (of
most neurons) and locomotion showed a progressive increase during the minutes before the press. Moreover, the duration of the progressive reversal was significantly positively correlated with both the latency
to reinitiate locomotion toward the lever wall and the latency to
reinitiate locomotion toward nonlever walls (Fig.
7). These correlations showed that the
longer the period over which firing rate progressively reversed,
perhaps recovered, from the postpress change in firing, the longer the
animal waited after the preceding infusion to reinitiate
locomotion.
View larger version (22K):
[in this window]
[in a new window]
|
Figure 7.
Duration of the progressive reversal phase of the
change + progressive reversal firing pattern was correlated with the
latency to reinitiate locomotion. Each of the four scatter plots
corresponds to one Pearson product-moment correlation analysis. Each
point in a scatter plot represents a single neuron. Points that
correspond to the same subject are indicated by a unique geometric
shape (total of 8 shapes). The ordinates display the
duration (minutes) of either the progressive reversal (top
row) or the postpress change (bottom row). The
abscissas in all scatter plots show the modal postpress
time (i.e., minutes after the press) at which locomotion was
reinitiated during the interinfusion interval. Correlations were
calculated separately for locomotion toward the lever wall
(left scatter plot) and locomotion toward nonlever walls
(right scatter plot). The Pearson product-moment
correlations are shown in the top left corners of the
scatter plots. The latency to reinitiate locomotion was significantly
correlated with the duration of the progressive reversal regardless of
locomotion direction (p < 0.5).
Correlations with the duration of the postpress change were not
significant (p > 0.5).
|
|
Did NAcc firing concomitant with locomotion engender the change + progressive reversal firing pattern?
Phasic changes in firing rate time locked to locomotion
A total of 10 (55%) of the 18 neurons showed a significant phasic
change in firing rate time locked to locomotion. These 10 neurons were
distributed among the two types of change + progressive reversal
neurons as follows. Of the 15 decrease + progressive increase neurons, 7 showed a significant increase
in firing rate time locked to locomotion relative to stereotypy (Fig.
8, neuron D). The increase in firing
time locked to locomotion was consistent with the change in firing that
would have been expected if firing associated with locomotion
contributed to the change + progressive reversal firing pattern. The
remaining 8 of the 15 decrease + progressive reversal neurons showed no
change in firing time locked to locomotion. Of the three increase + progressive decrease neurons, one showed a small but
significant decrease in firing rate time locked to
locomotion compared with stereotypy (Fig. 8, neuron E). For
that neuron, the phasic change in firing time locked to locomotion was
consistent with that which could have potentially contributed to the
change + progressive reversal firing pattern. The remaining two
increase + progressive decrease neurons showed a significant increase
in firing time locked to locomotion (Fig. 9, neuron
F). The increase in firing time locked to locomotion exhibited by those neurons would have been expected to actually oppose
the change + progressive reversal firing pattern. Taken together, these
data showed that phasic changes in firing time locked to locomotion
were unlikely to have engendered the change + progressive reversal
firing pattern of 55% of the 18 neurons (i.e.,  decrease + progressive reversal neurons and  increase + progressive
reversal neurons). The same data left open the possibility that firing
time locked to locomotion determined the change + progressive reversal
firing pattern for the remaining 45% of the neurons (i.e.,  decrease + progressive reversal neurons and  increase + progressive reversal neurons).
View larger version (32K):
[in this window]
[in a new window]
|
Figure 8.
Neurons that showed locomotor-related firing
consistent with the change + progressive reversal firing pattern. Each
histogram shows a phasic change in firing time locked to the
onset of locomotion. The top histogram
shows the phasic change in firing time locked to locomotion that was
exhibited by one decrease + progressive increase neuron (neuron
D); the bottom histogram shows the same
for one increase + progressive decrease neuron (neuron
E). The following are shown for each neuron. Time
0 represents the onset of locomotion. Seconds before and
after the onset of locomotion are shown to the left and
right of time 0, respectively. Firing
during locomotion is thus shown on the right, and firing
during focused stereotypy is shown on the left. At the
top of the histogram is a raster display that shows
firing on a trial-by-trial basis. The horizontal bar
above the raster indicates the average duration of the locomotion
events used to construct the histograms (exceeded 1.0 sec). The average
duration of the focused stereotypy events that preceded the locomotion
events exceeded the time base of the histograms. Letters
at the top left correspond to identifying labels in
other figures representing the same neurons.
|
|
View larger version (40K):
[in this window]
[in a new window]
|
Figure 9.
Phasic changes in firing rate time locked to
locomotion were directionally specific for most neurons. Each histogram
shows firing time locked to the onset of locomotion.
Data are shown for two neurons, one decrease + progressive reversal
neuron (left column) and one increase + progressive
reversal neuron (right column). The neuron represented
in the left column showed a change in firing time locked
to locomotion that was specific for locomotion toward the nonlever
walls. The neuron shown in the right column exhibited a
change in firing time locked to locomotion that was specific for
locomotion toward the lever wall. For each neuron, firing is shown
during all locomotion (top row), locomotion toward the
lever wall (middle row), and locomotion toward nonlever
walls (bottom row). The horizontal bar at
the top of each column indicates the
average duration of the locomotion events (i.e., all locomotion toward
lever and nonlever walls combined) used to construct the histograms.
The average duration of the focused stereotypy events that preceded the
locomotion events exceeded the time base of the histograms.
|
|
Phasic changes in firing time locked to locomotion tended to be
specific for locomotion of a given direction
Further analysis of the 10 neurons that fired phasically during
locomotion showed that for 9 (90%) of them firing was not uniform
among all locomotion events. Rather, the firing tended to vary
depending on the direction of locomotion. For six neurons this
"directional specificity" consisted of either (1) a change in
firing time locked to locomotion toward the lever wall that was
opposite in sign to the change in firing time locked to locomotion toward nonlever walls, or (2) a change in firing that occurred during
locomotion of one direction, with no change in firing occurring during
the locomotion of the other direction (Fig. 9, neurons K,
F). For three neurons, the directional specificity
was quantitative rather than qualitative. Specifically, firing rate was
elevated during all locomotion; however, the increase in firing was
more robust and tightly time locked to locomotion toward the lever wall
than to locomotion toward nonlever walls. The directional specificity
of firing during locomotion indicated that even if firing time locked
to locomotion contributed to the change + progressive reversal firing
pattern of some neurons, the contribution was unlikely to have
reflected an influence of general locomotor processing.
Effect of excluding all periods of locomotion from the calculation
of firing rate
For all 18 neurons, the progressive reversal firing
pattern persisted when firing rates were calculated using only periods of focused stereotypy. This finding is demonstrated for four individual neurons in Figure 10 (see group mean
histograms in Fig. 11). Each of the
four neurons showed a phasic change in firing time locked to locomotion
that was of a sign consistent with that which would have been expected
if locomotor firing determined the change + progressive reversal firing
pattern (e.g., Figs. 8, 10, neuron D). The results of this
analysis did not completely exclude the possibility of a minor
contribution of firing time locked to locomotion to the absolute firing
rate of some neurons (Fig. 10, neuron D). However, it
demonstrated that for all neurons in the present study, the
change + progressive reversal firing pattern could not have been
determined solely by the differential occurrence of locomotion during
the interinfusion interval.
View larger version (16K):
[in this window]
[in a new window]
|
Figure 10.
The change + progressive reversal firing pattern
persisted when all locomotion was excluded from calculations of firing
rate. Each histogram shows the phasic change in firing time
locked to the cocaine reinforced lever press. Data are shown
for four neurons. Each column corresponds to a single neuron. The
top row displays histograms constructed by calculating
firing rate during all behaviors (i.e., shows the normal change + progressive reversal firing pattern). The bottom row
shows histograms constructed by calculating firing rate during periods
of only focused stereotypy. For each histogram the
abscissa displays minutes before and after the press
(Time 0 represents occurrence of the lever press.) The
ordinate shows average firing rate (hertz).
|
|
View larger version (26K):
[in this window]
[in a new window]
|
Figure 11.
The change + progressive reversal firing pattern
persisted when all locomotion was excluded from calculations of firing
rate. Each histogram shows phasic firing time locked to the
cocaine-reinforced lever press. Histograms shown in the
left column correspond to all decrease + progressive
reversal neurons combined (n = 15); Histograms in
the right column correspond to all increase + progressive reversal neurons (n = 3). For each
column, the top histogram displays firing during all
behaviors, and the bottom histogram displays firing of
the same neurons exclusively during stereotypy. Each histogram displays
average normalized firing rate during the minutes before and after the
press (ordinate). Firing rates within the histogram of
each neuron were normalized by dividing hertz in each 0.5 min bin by
the hertz in the 0.5 min bin showing the maximum firing rate in that
histogram.
|
|
| |
DISCUSSION |
Relationship between firing of NAcc neurons and the occurrence
of locomotion
A number of previous studies showed that NAcc neurons exhibit
changes in overall firing rate during periods of locomotion (Peoples
and West, 1990; Peoples et al., 1994; Callaway and Henriksen, 1992; Chang et al., 1994; Kiyatkin and Rebec, 1996). The present study extended these previous electrophysiological observations and
showed that a substantial number of NAcc neurons exhibit a phasic change in firing time locked to locomotion. Moreover,
the present data suggest that phasic firing tends to be specific for locomotion that is of a particular direction. The directional specificity indicates that locomotion and NAcc firing are not related
in a one-to-one manner as if NAcc discharges cause the efferent signals
mediating the execution of locomotor movements or process somatosensory
feedback associated with its execution. These new data regarding phasic
firing time locked to locomotion are consistent with the findings of
numerous studies that have led researchers to propose that the NAcc
does not directly mediate the execution of movements. Instead, the NAcc
may have a motivational function that facilitates
certain types of approach behaviors (Iversen and Koob, 1977;
Mogenson et al., 1980; Robbins and Everitt, 1982; Kelley and Stinus,
1985; Fibiger and Phillips, 1986; Wise and Bozarth, 1987; Everitt et
al., 1989; Mogenson and Yim, 1991; Phillips et al., 1991;
Apicella et al., 1992; Blackburn et al., 1992; DiChiara et al.,
1992; Salamone, 1992; Robinson and Berridge, 1993; Floresco et
al., 1997).
Discharges time locked to locomotion: contribution to NAcc firing
patterns that occur in relation to cocaine self-administration
Present findings
In the present study, during the minutes before and after
self-infusion, animals engaged in a predictable pattern of behavior in
which stereotypy predominated and locomotion increased over the course
of the interinfusion interval. These present data corroborated and
quantified previous qualitative observations regarding the behavior of
animals during cocaine self-administration sessions (e.g., Pickens et
al., 1978; Peoples and West, 1990; Woolverton and Johnson, 1992;
Carelli et al., 1993; Chang et al., 1994). In the present study
the pattern of locomotion was comparable in form to the change + progressive reversal firing pattern. These data suggested that the
change + progressive reversal firing pattern might have been determined
by firing time locked to locomotion. Further analysis showed that this
was not so. First, the onset of the progressive increase in locomotion
after the press lagged behind the onset of the progressive increase in
firing. Second, >50% of the neurons failed to show firing time locked
to locomotion that could have potentially contributed to the
progressive reversal pattern. Third, for all neurons, the change + progressive reversal firing pattern persisted when firing rates were
calculated using only periods of stereotypy and thus when all locomotor
firing was factored out. Given that the firing pattern persisted with both amount and type of behavior held constant across all time points
(0.5 min resolution), this latter finding also largely ruled out the
possibility that the change + progressive reversal firing pattern was
determined by firing during any other specific behavior.
Previous findings
In addition to exhibiting changes in firing during the minutes
before and after the press, such as the change + progressive reversal
firing pattern (Peoples and West, 1996), NAcc neurons show phasic
changes in firing during the seconds before and after the press (Chang
et al., 1990, 1994, 1996, 1998; Carelli et al., 1993; Carelli
and Deadwyler, 1994, 1996a,b; Peoples et al., 1997; Uzwiak et al.,
1997). Neurons additionally exhibit changes in firing during the entire
self-administration session relative to presession nondrug baseline
recording periods (referred to as tonic changes in firing) (Peoples and
West, 1990; Peoples et al., 1994, 1998; West et al., 1992; Chang
et al., 1998; for a related finding see Carelli and Deadwyler, 1994,
1996a). Like the change + progressive reversal firing pattern, the
phasic changes in firing during the seconds before and after the press,
as well as the tonic changes in firing, are associated with regular
patterns of locomotion and thus potentially reflect discharges time
locked to locomotion. However, on close examination, Chang et al.
(1994) found that the phasic changes in firing during the
seconds before and after the press are not completely synchronized
with, and thus not entirely attributable to, the pattern of locomotion. Moreover, preliminary analysis of the tonic changes in firing showed
that the differences in overall firing rate between the nondrug and
self-administration period are not likely to be attributable solely to
the differences in locomotion between those two conditions (Peoples and West, 1990; Peoples et al., 1994; West et
al., 1992). In total, evidence that is currently available indicates
that the changes in firing exhibited by NAcc neurons in temporal
relation to cocaine self-administration are not determined solely by
phasic changes in firing time locked to locomotion. Current data
do not, however, show that firing during (certain) locomotion and
firing time locked to self-administration are completely unrelated (see below).
Firing time locked to locomotion and firing time locked to
self-infusion may be temporally dissociable but nevertheless
functionally related
The present study showed that there are individual NAcc neurons
that show both phasic firing time locked to self-administration and
phasic firing time locked to locomotion of a specific direction. It is
possible that the phasic firing patterns are functionally distinct.
However, it is also possible that the firing patterns are functionally
related. Specifically, both may facilitate movements regardless of
form whether it be walking, running, rearing, or lever pressingas
long as the movements are consistent with the same motivational end
point. For example, the firing may facilitate any movement associated
with approach toward a cocaine-related stimulus. Although speculative,
this interpretation is consistent with the Hebbian concept of motor
equivalence (Hebb, 1949). Moreover, it is consistent with many previous
findings regarding the influence of the NAcc on behavior (see citations
in first section of Discussion).
Psychomotor stimulant theory
Wise and Bozarth (1987) proposed that the psychomotoric
locomotor-activating effects and reinforcing effects of drugs of abuse may be homologous and, moreover, may be commonly mediated, at least in
part, by the NAcc. Other researchers have made similar proposals (e.g.,
Pulvirenti et al., 1991). The data supportive of this hypothesis are
mixed (Wise and Bozarth, 1987; Burns et al., 1993; Robledo et al.,
1993; Wise and Munn, 1993; Whitelaw et al., 1996; Gong et al., 1997).
However, the finding of the present study that individual neurons show
both phasic firing time locked to locomotion and phasic firing time
locked to self-administration is consistent with the psychomotor
stimulant theory. In fact, the neurons that exhibit both types of
firing are neurons that could theoretically underlie such a common
contribution of the NAcc to locomotor activating and reinforcing
effects of drugs of abuse.
Possible contributions of the change + progressive reversal neurons
to cocaine self-administration
Phasic changes in firing time locked to cocaine self-infusion
potentially contribute to drug-taking behavior. However, phasic firing
in and of itself does not provide definitive evidence of a functional
relationship between the activity of a recorded neuron and
self-administration behavior. Numerous pharmacological, behavioral, and
stimulus events are highly synchronized during the self-administration session. Careful step-by-step experimental discrimination of the potential contribution of these variables to the firing patterns is
necessary to identify firing patterns that may contribute specifically to cocaine self-administration. The present study showed that the
change + progressive reversal firing pattern is not attributable solely
to phasic changes in firing time locked to locomotion (or to any other
specific behavior) that occurs in parallel with the firing pattern.
This finding eliminated one of the simplest alternative interpretations
of the change + progressive reversal firing pattern and thereby added
credence to the hypothesis that the firing pattern may be specifically
related to drug self-administration.
The change + progressive reversal firing pattern is correlated with the
timing of cocaine self-infusion (Peoples and West, 1996) and
closely mirrors the changes in cocaine and dopamine that occur over the
course of the interinfusion interval (e.g., Pettit and Justice, 1989;
Wise et al., 1995). The latter are believed to regulate cocaine
self-administration behavior during the self-administration session. It
is thus possible that the change + progressive reversal firing pattern
is determined in large part by the oscillations in cocaine and dopamine
and that the firing pattern in turn contributes to the transduction
mechanisms by which mesoaccumbens drug and dopamine levels regulate
drug taking. We have hypothesized that the rise and fall of drug level
in the NAcc that occurs as a function of drug absorption and metabolism
after each successive cocaine self-infusion lead to concomitant changes
in accumbal throughput of afferent signals, perhaps including those
that typically influence instrumental behavior. These changes in
throughput may contribute to the bias of the animal to engage in
drug-taking behavior as opposed to other behaviors over the course of
the interinfusion interval (c.f., Peoples and West, 1996; Peoples et
al., 1998).
| |
FOOTNOTES |
Received March 12, 1998; revised July 2, 1998; accepted July 7, 1998.
This work was supported by National Institute on Drug Abuse Grant DA
06886. Ms. Sejal Vyas and Ms. Binaifer Mohta contributed to
video and data analysis. Ms. Linda King conducted the histological procedures, and Mr. Bruno Molino assisted in surgical procedures.
Correspondence should be addressed to Dr. L. L. Peoples,
Department of Psychology, Rutgers University, New Brunswick, NJ 08903.
| |
REFERENCES |
-
Apicella P,
Scarnati E,
Ljungberg T,
Schultz W
(1992)
Neuronal activity in monkey striatum related to the expectation of predictable environmental events.
J Neurphysiol
68:945-960[Abstract/Free Full Text].
-
Blackburn JR,
Pfaus JG,
Phillips AG
(1992)
Dopamine functions in appetitive and defensive behaviors.
Prog Neurobiol
39:247-279[Web of Science][Medline].
-
Bowman EM,
Aigner TG,
Richmond BJ
(1996)
Neural signals in the monkey ventral striatum related to motivation for juice and cocaine rewards.
J Neurophysiol
75:1061-1073[Abstract/Free Full Text].
-
Brudzynski SM,
Gibson CJ
(1997)
Release of dopamine in the nucleus accumbens caused by stimulation of the subiculum in freely moving rats.
Brain Res Bull
42:303-308[Web of Science][Medline].
-
Burns LH,
Robbins TW,
Everitt BJ
(1993)
Differential effects of excitotoxic lesions of the basolateral amygdala, ventral subiculum, and medial prefrontal cortex on responding with conditioned reinforcement and locomotor activity potentiated by intra-accumbens infusions of d-amphetamine.
Behav Brain Res
55:167-183[Web of Science][Medline].
-
Callaway CW,
Henriksen SJ
(1992)
Neuronal firing in the nucleus accumbens is associated with the level of cortical arousal.
Neuroscience
51:547-553[Web of Science][Medline].
-
Carelli RM,
Deadwyler SA
(1994)
A comparison of nucleus accumbens neuronal firing patterns during cocaine self-administration and water reinforcement in rats.
J Neurosci
14:7735-7746[Abstract].
-
Carelli RM,
Deadwyler SA
(1996a)
Cellular mechanisms underlying reinforcement-related processing in the nucleus accumbens: electrophysiological studies in behaving animals.
Pharmacol Biochem Behav
57:495-504.
-
Carelli RM,
Deadwyler SA
(1996b)
Dual factors controlling activity of nucleus accumbens cell-firing during cocaine self-administration.
Synapse
24:308-311[Web of Science][Medline].
-
Carelli RM,
King VC,
Hampson RE,
Deadwyler SA
(1993)
Firing patterns of nucleus accumbens neurons during cocaine self-administration in rats.
Brain Res
626:14-22[Web of Science][Medline].
-
Chang J-Y,
Sawyer S-F,
Lee R-S,
Maddux BN,
Woodward DJ
(1990)
Activity of neurons in nucleus accumbens during cocaine self-administration in freely moving rats.
Soc Neurosci Abstr
16:252.
-
Chang J-Y,
Sawyer SF,
Lee R-S,
Woodward DJ
(1994)
Electrophysiological and pharmacological evidence for the role of the nucleus accumbens in cocaine self-administration in freely moving rats.
J Neurosci
14:1224-1244[Abstract].
-
Chang J-Y,
Paris JM,
Sawyer SF,
Kirillov AB,
Woodward DJ
(1996)
Neuronal spike activity in rat nucleus accumbens during cocaine self-administration under different fixed-ratio schedules.
Neuroscience
74:483-497[Web of Science][Medline].
-
Chang J-Y,
Janak PH,
Woodward DJ
(1998)
Comparison of mesocorticolimbic neuronal responses during cocaine and heroin self-administration in freely moving rats.
J Neurosci
18:3098-3115[Abstract/Free Full Text].
-
Chapin JK,
Loeb GE,
Woodward DJ
(1980)
A simple technique for determination of footfall patterns of animals during treadmill locomotion.
J Neurosci Methods
2:97-102[Medline].
-
Costall B,
Naylor RJ
(1975)
The behavioral effects of dopamine applied intracerebrally to areas of the mesolimbic system.
Eur J Pharmacol
32:87-92[Medline].
-
Delfs JM,
Schreiber L,
Kelly AE
(1990)
Microinjection of cocaine into the nucleus accumbens elicits locomotor activation in the rat.
J Neurosci
10:303-310[Abstract].
-
DiChiara G,
Morelli M,
Acquas E,
Carboni E
(1992)
Functions of dopamine in the extrapyramidal and limbic systems.
Drug Res
42:231-237[Medline].
-
Evenden JL,
Carli M
(1985)
The effects of 6-hydroxydopamine lesions of the nucleus accumbens and caudate nucleus of rats on feeding in a novel environment.
Behav Brain Res
15:63-70[Web of Science][Medline].
-
Everitt BJ,
Cador M,
Robbins TW
(1989)
Interactions between the amygdala and ventral striatum in stimulus-reward associations: studies using a second-order schedule of sexual reinforcement.
Neuroscience
30:63-75[Web of Science][Medline].
-
Fibiger HC,
Phillips AG
(1986)
Reward, motivation, cognition: psychobiology of mesotelencephalic dopamine systems.
In: Handbook of physiology-the nervous system: intrinsic regulatory systems of the brain, Vol IV, Sect I (Bloom FE,
ed), pp 647-675. Bethesda, MD: American Physiological Society.
-
Floresco SB,
Seamans JK,
Phillips AG
(1997)
Selective roles for hippocampal, prefrontal cortical, and ventral striatal circuits in radial-arm maze task with or without a delay.
J Neurosci
17:1880-1890[Abstract/Free Full Text].
-
Gong W,
Justice Jr JB,
Neill D
(1997)
Dissociation of locomotor and conditioned place preference responses following manipulation of GABAA and AMPA receptors in ventral pallidum.
Prog Neuropsychopharmacol Biol Psychiatry
21:839-852[Medline].
-
Haracz JL,
Tschanz JT,
Wang Z,
White IM,
Rebec GV
(1993)
Striatal single-unit responses to amphetamine and neuroleptics in freely moving rats.
Neurosci Biobehav Rev
17:1-12[Web of Science][Medline].
-
Hebb DO
(1949)
In: The Organization of behavior: a neuropsychological theory. New York: Wiley.
-
Iversen SD,
Koob GF
(1977)
Behavioral implications of dopaminergic neurons in the mesolimbic system.
In: Advances in biochemical psychopharmacology, Vol 16 (Costa E,
Gessa GL,
eds), pp 209-214. New York: Raven.
-
Jackson DM,
Andén N-E,
Dahlström A
(1975)
A functional effect of dopamine in the nucleus accumbens and in some other dopamine-rich parts of the rat brain.
Psychopharmacologia
45:139-149.
-
Jones DL,
Mogenson GJ,
Wu M
(1981)
Injections of dopaminergic, cholinergic, serotonergic, and gabaergic drugs into the nucleus accumbens. Effects on locomotor activity in the rat.
Neuropharmacology
20:29-37[Medline].
-
Kafetzopoulos E
(1986)
Effects of amphetamine and apomorphine on locomotor activity after kainic acid lesion of the nucleus accumbens septi in the rat.
Psychopharmacology
88:271-274[Medline].
-
Kehne JH,
Sant WW,
Sorenson CA
(1981)
The effects of radio-frequency lesions of the nucleus accumbens on d-amphetamine-induced locomotor rearing behavior in rats.
Psychopharmacology
75:363-367[Medline].
-
Kelley AE,
Stinus L
(1985)
Disappearance of hoarding behavior after 6-hydroxydopamine lesions of the mesolimbic dopamine neurons and its reinstatement with l-dopa.
Behav Neurosci
99:531-545[Web of Science][Medline].
-
Kelly PH,
Iversen SD
(1976)
Selective 6-OHDA induced destruction of mesolimbic dopamine neurons: abolition of psychostimulant-induced locomotor activity in rats.
Eur J Pharmacol
40:45-56[Web of Science][Medline].
-
Kelley PH,
Roberts DC
(1983)
Effects of amphetamine and apomorphine on locomotor activity after 6-OHDA and electrolytic lesions of the nucleus accumbens septi.
Pharmacol Biochem Behav
19:137-143[Medline].
-
Kelly PH,
Seviour PW,
Iversen SD
(1975)
Amphetamine and apomorphine responses in the rat following 6-OHDA lesions of the nucleus accumbens septi and corpus striatum.
Brain Res
94:507-522[Web of Science][Medline].
-
Kiyatkin EA,
Rebec GV
(1996)
Dopaminergic modulation of glutamate-induced excitations of neurons in the neostriatum and nucleus accumbens of awake, unrestrained rats.
J Neurophysiol
75:142-153[Abstract/Free Full Text].
-
Kosobud AEK,
Harris GC,
Chapin JK
(1994)
Behavioral associations of neuronal activity in the ventral tegmental area of the rat.
J Neurosci
14:7117-7129[Abstract].
-
Lorens SA,
Sorensen JP,
Harvey JA
(1970)
Lesions in the nuclei accumbens septi of the rat: behavioral and neurochemical effects.
J Comp Physiol Psychol
73:284-290[Web of Science][Medline].
-
Makanjuola ROA,
Dow RC,
Ashcroft GW
(1980)
Behavioral responses to stereotactically controlled injections of monoamine neurotransmitters into the accumbens and caudate-putamen nuclei.
Psychopharmacology
71:227-235[Medline].
-
Maldonado-Irizarry CS,
Kelley AE
(1995)
Excitotoxic lesions of the core and shell subregions of the nucleus accumbens differentially disrupt body weight regulation and motor activity in rat.
Brain Res Bull
38:551-559[Web of Science][Medline].
-
McGregor A,
Roberts DCS
(1993)
Dopaminergic antagonism within the nucleus accumbens or the amygdala produces differential effects on intravenous cocaine self-administration under fixed and progressive ratio schedules of reinforcement.
Brain Res
14:69-97.
-
Mogenson GJ,
Nielsen M
(1984)
A study of the contribution of hippocampal accumbens-subpallidal projections to locomotor activity.
Behav Neural Biol
42:38-51[Medline].
-
Mogenson GJ,
Yim CC
(1991)
Neuromodulatory functions of the mesolimbic dopamine system: electrophysiological and behavioral studies.
In: The mesolimbic dopamine system: from motivation to action (Willner P,
Scheel-Kruger J,
eds), pp 105-131. New York: Wiley.
-
Mogenson GJ,
Jones DL,
Yim CY
(1980)
From motivation to action: functional interface between the limbic system and the motor system.
Prog Neurobiol
14:69-97[Web of Science][Medline].
-
Moore GP,
Perkel D,
Segundo JP
(1966)
Statistical analysis and functional interpretation of neuronal spike data.
Annu Rev Physiol
28:493-522[Web of Science][Medline].
-
O'Dell LE,
Khroyan TV,
Neisewander JL
(1996)
Dose-dependent characterization of the rewarding and stimulant properties of cocaine following intraperitoneal and intravenous administration in rats.
Psychopharmacology
123:144-153[Medline].
-
Peoples LL,
West MO
(1990)
Effects of intravenous cocaine on single unit activity in the nucleus accumbens of freely moving rats.
Soc Neurosci Abstr
16:252.
-
Peoples LL,
West MO
(1996)
Phasic firing of single neurons in the rat nucleus accumbens correlated with the timing of intravenous cocaine self-administration.
J Neurosci
16:3459-3473[Abstract/Free Full Text].
-
Peoples LL, Bibi R, West MO (1994) Effects of intravenous
self-administered cocaine on single cell activity in the nucleus
accumbens of the rat. In: Problems of drug dependence, 1993:
proceedings of the 55th annual scientific meeting. The College on
Problems of Drug Dependence, Inc. Vol II, (Harris L, ed), pp 326. Washington, D.C.: Superintendent of Documents, United States Government
Printing Office. National Institute on Drug Abuse Research Monograph
141.
-
Peoples LL, Gee F, West MO (1997) Activity of neurons
in the nucleus accumbens correlated with cocaine self-infusion:
relationship to behavior during the interinfusion interval. In:
Problems of drug dependence, 1996: proceedings of the 58th annual
scientific meeting. The College on Problems of Drug Dependence, Inc.
(Harris LS, ed), pp 228. Washington, D.C.: Superintendent of
Documents, United States Government Printing Office. National Institute
on Drug Abuse Research Monograph 174.
-
Peoples LL,
Uzwiak AJ,
Gee F,
West MO
(1997)
Operant behavior during sessions of intravenous cocaine infusion is necessary and sufficient for phasic firing of single nucleus accumbens neurons.
Brain Res
757:280-284[Web of Science][Medline].
-
Peoples LL,
Uzwiak AJ,
Guyette FX,
West MO
(1998)
Tonic inhibition of single nucleus accumbens neurons in the rat: a predominant but not exclusive firing pattern induced by cocaine self-administration.
Neuroscience
86:13-22[Web of Science][Medline].
-
Perkel DH,
Gerstein GL,
Moore GP
(1967)
Neuronal spike trains and stochastic point processes. I. The single spike train.
Biophys J
7:391-418.
-
Pettit HO,
Justice Jr JB
(1989)
DA in the NAcc during cocaine self-administration as studied by in vivo microdialysis.
Pharmacol Biochem Behav
34:899-904[Web of Science][Medline].
-
Phillips AG,
Broekkamp CLE,
Fibiger HC
(1983)
Strategies for studying the neurochemical substrates of drug reinforcement in rodents.
Prog Neuropsychopharmacol Biol Psychiatry
7:585-590[Medline].
-
Phillips AG,
Pfaus JG,
Blaha CD
(1991)
Dopamine and motivated behavior: insights provided by in vivo analyses.
In: The mesolimbic dopamine system: from motivation to action (Willner P,
Scheel-K J,
eds), pp 199-224. New York: Wiley.
-
Pickens R,
Meisch A,
Thompson T
(1978)
Drug self-administration: an analysis of the reinforcing effects of drugs.
In: Handbook of psychopharmacology, Vol 12 (Iversen LL,
Iversen SD,
Snyder SH,
eds), pp 1-37. New York: Plenum.
-
Pijnenburg AJJ,
van Rossum JM
(1973)
Stimulation of locomotor activity following injection of dopamine into the nucleus accumbens.
J Pharm Pharmacol
25:1003-1005[Web of Science][Medline].
-
Pulvirenti L,
Swerdlow NR,
Hubner CB,
Koob GF
(1991)
The role of limbic-accumbens pallidal circuitry in the activating and reinforcing properties of psychostimulant drugs.
In: The mesolimbic dopamine system: from motivation to action (Willner P,
Scheel-Kruger,
eds), pp 131-140. New York: Wiley.
-
Rank Jr JB,
Kubie JL,
Fox SE,
Wolfson S,
Muller RU
(1983)
Single neuron recording in behaving mammal: bridging the gap between neuronal events and senory-behavioral variables.
In: Behavioral approaches to brain research (Robinson TE,
ed), pp 5-62. New York: Oxford UP.
-
Robbins TW,
Everitt BJ
(1982)
Functional studies of the central catecholamines.
In: International review of neurobiology, Vol 23 (Smythies JR,
Bradley RJ,
eds), pp 303-365. New York: Academic.
-
Robinson TE,
Berridge KC
(1993)
The neural basis of drug craving: an incentive-sensitization theory of addiction.
Brain Res Rev
18:247-291[Medline].
-
Robledo P,
Maldonado-Lopez R,
Koob GF
(1992)
Role of dopamine receptors in the nucleus accumbens in the rewarding properties of cocaine.
In: The neurobiology of drug and alcohol addiction. Annals of the New York Academy of Sciences, Vol. 654 (Kalivas PW,
Samson HH,
eds), pp 509-512. New York: Academy Science.
-
Robledo P,
Maldonado R,
Koob GF
(1993)
Neurotensin injected into the nucleus accumbens blocks the psychostimulant effects of cocaine but does not attenuate cocaine self-administration in the rat.
Brain Res
622:105-112[Medline].
-
Salamone JD
(1992)
Complex motor and sensorimotor functions of striatal and accumbens dopamine: involvement in instrumental behavior processes.
Psychopharmacology
107:160-174[Medline].
-
Schultz W,
Apicella P,
Scarnati I,
Ljungberg T
(1992)
Neuronal activity on monkey ventral striatum related to the expectation of reward.
J Neurosci
12:4595-4610[Abstract].
-
Siegel S,
Castellan Jr S
(1988)
In: Nonparametric statistics for the behavioral sciences. New York: McGraw-Hill.
-
Uzwiak AJ,
Guyette FX,
West MO,
Peoples LL
(1997)
Neurons in accumbens subterritories of the rat: phasic firing time-locked within seconds of intravenous cocaine self-infusion.
Brain Res
767:363-369[Web of Science][Medline].
-
Watchtel H,
Ahlenius S,
Andén N-E
(1979)
Effects of locally applied dopamine in the nucleus accumbens on the motor activity of normal rats and following -methyltyrosine or reserpine.
Psychopharmacology
63:203-206[Medline].
-
Weissenborn R,
Winn P
(1992)
Regulatory behavior, exploration, and locomotion following NMDA or 6-OHDA lesions in the rat nucleus accumbens.
Behav Brain Res
51:127-137[Medline].
-
West MO, Peoples LL, Wolske M, Dworkin SI (1992) Psychomotor
stimulant effects on single neurons in awake, behaving rats. In:
Neurobiological approaches to brain-behavior. (Frascell J, Brown RM,
eds), pp 57-72. Washington, D.C.: Superintendent of Documents, United
States Government Printing Office. Interaction National Institute on
Drug Abuse Research Monograph Series 124.
-
West MO,
Peoples LL,
Michael A,
Chapin JK,
Woodward DJ
(1997)
Low-dose amphetamine elevates movement-related firing of rat striatal neurons.
Brain Res
745:331-335[Medline].
-
Whitelaw RB,
Markou A,
Robbins TW,
Everitt BJ
(1996)
Excitotoxic lesions of the basolateral amygdala impair the acquisition of cocaine-seeking behaviour under a second-order schedule of reinforcement.
Psychopharmacology
127:213-224[Medline].
-
Wise RA,
Bozarth MA
(1987)
A psychomotor stimulant theory of addiction.
Psychol Rev
94:469-492[Web of Science][Medline].
-
Wise RA,
Munn E
(1993)
Effects of repeated amphetamine injections on lateral hypothalamic brain stimulation reward and subsequent locomotion.
Behav Brain Res
55:195-201[Medline].
-
Wise RA,
Newton P,
Leeb K,
Burnette B,
Pocock D,
Justice Jr JB
(1995)
Fluctuations in nucleus accumbens dopamine concentration during intravenous cocaine self-administration in rats.
Psychopharmacology
120:10-20[Medline].
-
Woolverton WL,
Johnson KM
(1992)
Neurobiology of cocaine abuse.
Trends Pharmacol Sci
13:193-200[Medline].
-
Wu M,
Brudzynski SM,
Mogenson GJ
(1993)
Functional interaction of dopamine and glutamate in the nucleus accumbens in the regulation of locomotion.
Can J Physiol Pharmacol
71:407-413[Web of Science][Medline].
-
Yokel RA,
Pickens R
(1974)
Drug level of d- and l-amphetamine during intravenous self-administration.
Psychopharmacologia
34:255-264.
-
Zito KA,
Vickers G,
Roberts DCS
(1985)
Disruption of cocaine and heroin self-administration following kainic acid lesions of the nucleus accumbens.
Pharmacol Biochem Behav
23:1029-1036[Web of Science][Medline].
Copyright © 1998 Society for Neuroscience 0270-6474/98/18187588-11$05.00/0
This article has been cited by other articles:
|
|
|
|
 
C. C. Tang, D. H. Root, D. C. Duke, Y. Zhu, K. Teixeria, S. Ma, D. J. Barker, and M. O. West
Decreased Firing of Striatal Neurons Related to Licking during Acquisition and Overtraining of a Licking Task
J. Neurosci.,
November 4, 2009;
29(44):
13952 - 13961.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
P. W. German and H. L. Fields
Rat Nucleus Accumbens Neurons Persistently Encode Locations Associated With Morphine Reward
J Neurophysiol,
March 1, 2007;
97(3):
2094 - 2106.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
X. Wan and L. L. Peoples
Firing Patterns of Accumbal Neurons During a Pavlovian-Conditioned Approach Task
J Neurophysiol,
August 1, 2006;
96(2):
652 - 660.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. A. Taha and H. L. Fields
Inhibitions of Nucleus Accumbens Neurons Encode a Gating Signal for Reward-Directed Behavior
J. Neurosci.,
January 4, 2006;
26(1):
217 - 222.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
U. E. Ghitza, A. T. Fabbricatore, V. F. Prokopenko, and M. O. West
Differences Between Accumbens Core and Shell Neurons Exhibiting Phasic Firing Patterns Related to Drug-Seeking Behavior During a Discriminative-Stimulus Task
J Neurophysiol,
September 1, 2004;
92(3):
1608 - 1614.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. M. Nicola, I. A. Yun, K. T. Wakabayashi, and H. L. Fields
Cue-Evoked Firing of Nucleus Accumbens Neurons Encodes Motivational Significance During a Discriminative Stimulus Task
J Neurophysiol,
April 1, 2004;
91(4):
1840 - 1865.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. M. Nicola, I. A. Yun, K. T. Wakabayashi, and H. L. Fields
Firing of Nucleus Accumbens Neurons During the Consummatory Phase of a Discriminative Stimulus Task Depends on Previous Reward Predictive Cues
J Neurophysiol,
April 1, 2004;
91(4):
1866 - 1882.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
L. L. Peoples, K. G. Lynch, J. Lesnock, and N. Gangadhar
Accumbal Neural Responses During the Initiation and Maintenance of Intravenous Cocaine Self-Administration
J Neurophysiol,
January 1, 2004;
91(1):
314 - 323.
[Abstract]
[Full Text]
|
|
|
|
|
|
|
R. M. Carelli and J. Wondolowski
Selective Encoding of Cocaine versus Natural Rewards by Nucleus Accumbens Neurons Is Not Related to Chronic Drug Exposure
J. Neurosci.,
December 3, 2003;
23(35):
11214 - 11223.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
L. L. Peoples and D. Cavanaugh
Differential Changes in Signal and Background Firing of Accumbal Neurons During Cocaine Self-Administration
J Neurophysiol,
August 1, 2003;
90(2):
993 - 1010.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
R. M. Carelli
The nucleus accumbens and reward: neurophysiological investigations in behaving animals.
Behav Cogn Neurosci Rev,
December 1, 2002;
1(4):
281 - 296.
[Abstract]
[PDF]
|
|
|
|
|
|
|
S. B. Floresco, C. D. Blaha, C. R. Yang, and A. G. Phillips
Dopamine D1 and NMDA Receptors Mediate Potentiation of Basolateral Amygdala-Evoked Firing of Nucleus Accumbens Neurons
J. Neurosci.,
August 15, 2001;
21(16):
6370 - 6376.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
W. Schultz
Book Review: Reward Signaling by Dopamine Neurons
Neuroscientist,
August 1, 2001;
7(4):
293 - 302.
[Abstract]
[PDF]
|
|
|
|
|
|
|
S. M. Nicola and S. A. Deadwyler
Firing Rate of Nucleus Accumbens Neurons Is Dopamine-Dependent and Reflects the Timing of Cocaine-Seeking Behavior in Rats on a Progressive Ratio Schedule of Reinforcement
J. Neurosci.,
July 15, 2000;
20(14):
5526 - 5537.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
R. M. Carelli, S. G. Ijames, and A. J. Crumling
Evidence That Separate Neural Circuits in the Nucleus Accumbens Encode Cocaine Versus "Natural" (Water and Food) Reward
J. Neurosci.,
June 1, 2000;
20(11):
4255 - 4266.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S.-P. Onn and A. A. Grace
Amphetamine Withdrawal Alters Bistable States and Cellular Coupling in Rat Prefrontal Cortex and Nucleus Accumbens Neurons Recorded In Vivo
J. Neurosci.,
March 15, 2000;
20(6):
2332 - 2345.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
Top
Abstract
Introduction
