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Previous Article | Next Article
The Journal of Neuroscience, December 15, 1999, 19(24):11027-11039
Modulation of Basolateral Amygdala Neuronal Firing and Afferent Drive by Dopamine Receptor Activation In Vivo
J. Amiel Rosenkranz and Anthony A. Grace Departments of Neuroscience and Psychiatry, University of Pittsburgh, Pittsburgh, Pennsylvania 15260
ABSTRACT
TOP
ABSTRACT
INTRODUCTION
The basolateral amygdala (BLA) is implicated in responding to affective stimuli. Dopamine (DA) is released in the BLA during numerous conditions; however, the neurophysiological effects of DA in the BLA have not been examined in depth. In this study, the effects of DA receptor manipulation on spontaneous and afferent-driven neuronal firing were examined using in vivo extracellular single-unit recordings in parallel with systemic and iontophoretic drug application, and stimulation of the substantia nigra/ventral tegmental area in the rat. The effects of DA receptor activation in the BLA were found to depend on the characteristics of the BLA neuron examined, causing an increase in the firing rate of putative interneurons and a decrease in the firing of identified projection neurons. Additionally, DA receptor activation attenuated short-latency spikes evoked by electrical stimulation of prefrontal cortical and mediodorsal thalamic inputs to the BLA while potentiating the responses evoked by electrical stimulation of sensory association cortex.
DA receptor activation can thus attenuate BLA projection neuron firing via two mechanisms: (1) by a direct inhibition, and (2) by indirect actions mediated via activation of BLA interneurons. This is hypothesized to lead to a global filtration of weaker inputs. Moreover, DA potentiates sensory inputs and attenuates medial prefrontal cortex inputs to the BLA. Conditions in which DA is released in the BLA, such as during the presentation of an affective stimulus, will lead to a potentiation of the strongest sensory input and a dampening of cortical inhibition over the BLA, thus augmenting the response to affective sensory stimuli.
Key words: dopamine; basolateral amygdala; projection neuron; interneuron; afferent; electrophysiology; iontophoresis; substantia nigra; ventral tegmental area; modulation
INTRODUCTION
The importance of the amygdala in autonomic, endocrine, and motor responses to affective stimuli and affective conditioning has long been recognized (for review, see Aggleton, 1992
; Rolls, 1992
Systemic and direct alterations of dopamine (DA) transmission within the BLA are known to produce significant effects on affective conditioning and responding (Weldon et al., 1991
There is converging evidence that DA plays a significant role in amygdala function. Thus, the elements necessary for functional DA transmission have been shown to be present in the BLA (Swanson, 1982
In this study, we examine the electrophysiological effects of DA receptor activation on afferents to the BLA, such as mediodorsal thalamus (MD), mPFC, and sensory association cortex (Te3). Additionally, the effects of DA receptor activation on the two basic neuronal subtypes of the BLA are examined.
Parts of this paper have been presented in abstract form (Rosenkranz and Grace, 1998
MATERIALS AND METHODS
Materials
DA, the nonselective DA agonist apomorphine, the DA D1 agonist SKF-38393, the D1 antagonist SCH-23390, the D2 agonist quinpirole, and the D2 antagonist raclopride, were purchased from Research Biochemicals (Natick, MA). The nonselective DA antagonist haloperidol was a generous gift from McNeil Laboratories. L-glutamic acid (glutamate) was purchased from Sigma (St. Louis, MO).Electrophysiological recordings
In vivo extracellular single-unit or population field potential electrophysiological recordings were performed in anesthetized male Sprague Dawley rats (250-400 gm). All procedures followed the National Institutes of Health Guide for the Care and Use of Laboratory Animals, and were approved by the Institutional Animal Care and Use Committee at the University of Pittsburgh. Animals were housed in pairs, supplied with food and water ad libitum, and maintained on a 12 hr light/dark cycle. Rats were anesthetized with 8% chloral hydrate (400 mg/kg, i.p). Additional supplemental doses of chloral hydrate were administered intraperitoneally when necessary. Temperature was monitored with a rectal temperature probe (model 4600; Precision Thermometer, Yellow Springs, OH), and maintained at 37-38°C using a heat control unit and heating pad (Fintronics, Orange, CT). The rat was mounted in a stereotaxic device (Narishige, Tokyo, Japan), incisions were made in the scalp to expose the skull, burr holes were drilled into the skull, and the dura was removed in an area overlying the BLA [5.3 lateral (L),
for single-unit recording and 4-8 M
Data collection
Signals from the recording electrode were amplified by a headstage connected to the preamplifier before being fed into a window discriminator (Fintronics discriminator/amplifier) and displayed on an oscilloscope (V-134; Hitachi, Tokyo, Japan) and an audio monitor (AM5; Grass). The data were also stored on video tapes after being digitized (DR-390, Neurocorder; NeuroData, New York, NY). Data were simultaneously collected using a Microstar board for data acquisition and online data monitoring using software developed in this laboratory (Neuroscope), and stored on a personal computer (Gateway 2000, model P5-100XL) for subsequent off-line analysis.Iontophoretic application of drug
Multibarrel microelectrodes (five barrels; Activational Systems, Warren, MI) were constructed using a vertical microelectrode puller (PE-2; Narishige), and the tip was broken back under microscopic control. The central barrel of the microelectrode was filled with 2% Pontamine sky blue in 2 M NaCl for electrophysiological recordings. One of the outer barrels was filled with 4 M NaCl for automatic current balancing, and various drug solutions were used in the remaining barrels. Drug barrels of the multibarrel pipette were filled with 50 or 100 mM DA, pH 4.5, 20-100 mM glutamate, pH 8.0, 20-40 mM NMDA, pH 8.0, 10-30 mM SKF 38393, pH 4.5, 10 mM quinpirole, pH 4.5, or 100-200 mM GABA, pH 4.0. All drugs were dissolved in 10 mM NaCl. Drugs dissolved in solutions of acidic pH were ejected with (+) iontophoretic current, and drugs dissolved in solutions of basic pH were ejected with (Systemic drug administration
Drugs were dissolved in distilled water, or in the case of haloperidol, dilute lactic acid, to a final concentration of 0.5 mg/ml. Drugs were administered via a lateral tail vein (or in a few cases intraperitoneally) in volumes of 0.05-0.4 ml in ascending doses in a dose-response fashion. Saline was administered as a control.Data analysis
The particulars of the data analysis depended on the type of neuronal activity monitored: Spontaneous spike discharge. Single units were isolated (with a signal-to-noise ratio of3:1, and a minimal duration of 1.0 msec was set to exclude spikes that were not of somatodendritic origin; Humphrey, 1979
= 0.05 for significance). If a DA agonist was administered first, antagonists were administered 10-30 min after the final agonist administration, while continuously recording neuronal activity. Additionally, the duration of the action potentials recorded from BLA units was quantified as the time from the initial change from baseline to the return to baseline. The distribution of firing rates was also examined and fit to population curves (Jandel Table Curve). Furthermore, the distribution of firing rates was examined as a function of action potential duration. Using firing rate population distributions and firing rate distributions as a function of action potential duration, a cutoff of 0.5 Hz was used to segregate fast- and slow-firing neurons. Electrically evoked responses. Electrical stimulus pulses were often delivered during electrode penetration to search for units that exhibited evoked responses (0.6 Hz, 0.2-0.7 mA, 0.2 msec duration). Evoked responses consisted of single-unit responses or evoked field potentials. Single units were operationally defined as monosynaptic if their latency was <25 msec; they showed very little shift in latency when increasing the stimulus intensity, yet they showed some range (1-2 msec) in latency distribution ("jitter"), ruling out antidromic activation. Stimulus intensities were varied to determine an evoked spike response probability of ~50% in the case of single units, or half-maximal amplitude in the case of evoked field potentials. The magnitude of the evoked field potential was quantified as the absolute voltage change from baseline to the peak of the positive deflections, or the trough of the negative deflections. After stable baselines were recorded, drugs were administered systemically as above, and drug-induced changes in the evoked spike probability and field potential amplitude were measured. A minimum of 150 sweeps was obtained before and after drug administration at various time points. If the neuron was spontaneously spiking, a minimum of 1-2 min was given after electrical stimulation before basal firing rate was recorded. Substantia nigra/VTA stimulation. After stable baselines were obtained from spontaneously spiking neurons or neurons activated by iontophoretic application of glutamate, the substantia nigra/ventral tegmental area was electrically stimulated to induce dopamine release in the amygdala. The stimulus parameters used consisted of pulse trains of 10-20 Hz, 0.2 msec duration, 0.5-0.6 mA, for a period of 1-2 sec. Prestimulus firing rate values were compared to firing rate values of a 15 sec epoch that immediately followed the SN/VTA stimulation. In many cases, this process was repeated for the same neuron after several minutes had elapsed, and firing had returned to baseline levels. In some of these repeated stimulation trials, haloperidol was administered systemically in an attempt to block the effects of later SN/VTA stimulation trains as a way of confirming dopaminergic mediation of the response. Antidromically evoked activity. Electrical stimulations were performed as above. An antidromic response was defined as the ability of evoked spikes to follow stimulation frequencies of > 250 Hz, displayed constant response latency, display collision with spontaneously occurring spikes when possible, and be evoked from an area receiving BLA projections. In the majority of cases, a test for collision of evoked and spontaneous spikes was not feasible because of the lack of spontaneous spiking in many antidromically activated units. Glutamate-evoked activity. Responses to glutamate were tested in one of two ways: (1) constant glutamate ejection (+10 to +40 nA) was used to maintain a stable baseline of neuronal activity, or (2) glutamate was ejected in pulses, as described above. After obtaining a stable firing rate, or a stable response to pulsed glutamate, DA or DA agonists were co-iontophoresed (as described above), and changes in firing rate that were induced by the iontophoretic application of DA or DA agonists was examined. During constant glutamate iontophoresis, the glutamate-induced spike discharge (minimum 60 sec) was compared to the firing rate during DA co-iontophoresis. Alternatively, when glutamate was applied using 15 or 30 sec duration pulses, several consecutive pulses were averaged, and the responses compared to the effects obtained to pulsed glutamate recorded during DA co-iontophoresis. To examine the statistical significance of the drug effects, Student's t tests were used. A group t test was applied, and if the results were not statistically significant, individual t tests were used on the results from single neurons to determine how many neurons of the particular treatment group displayed a significant change concomitant with the treatment. Post hoc layered Bonferroni was used to maintain multiple comparisons at
Histology
Verification of recording and stimulating electrode sites was obtained histologically. Rats were killed by overdose with anesthetic, decapitated, and the brains were removed and fixed in 10% formalin for a minimum of 24 hr. Brains were cryoprotected with 30% sucrose in 0.1 M phosphate buffer and were then frozen and sliced with a cryostat or with a sliding microtome into 40 µm coronal sections. Mounted sections were then stained with cresyl violet. Recording sites were identified by the blue spot caused by ejection of Pontamine sky blue (see Electrophysiological recordings). Stimulating sites were identified as the end of the stimulating electrode track.
RESULTS
Evidence for two subtypes of BLA neurons
As seen in previous reports, the basal firing rate of most spontaneously spiking neurons in the amygdala was very low (mean ± SEM, 0.91 ± 2.47 Hz; n = 179; range, 0-22.3 Hz), with evidence of a large population of neurons that did not fire spontaneously during the recording period. After closer examination, neurons could be placed into one of two normal distributions (r2 > 0.98) with significantly different mean firing rates (p < 0.05; group t test; Fig. 1): fast-firing (mean, 2.81 ± 0.52 Hz; n = 55; range, 0.51-22.3 Hz) and slow-firing (mean, 0.071 ± 0.013 Hz; n = 124; range, 0-0.50 Hz) neurons. Based on the distribution of neuronal firing rates, a cutoff of 0.5 Hz was used to segregate the two populations. Hence "slow-firing" will be used to indicate neurons that fire at <0.5 Hz, whereas "fast-firing" will be used to denote neurons that fire at >0.5 Hz. This segregation of neuronal types also corresponded to differences in action potential waveform (Fig. 2). The spike durations of a 90 neuron sample were examined (34 fast-spiking neurons, mean, 2.56 ± 0.380 Hz; 56 slow-spiking neurons, mean, 0.18 ± 0.02 Hz; Fig. 2). Slowly firing neurons displayed longer duration action potential waveforms (mean, 2.71 ± 0.10 msec) than fast-firing neurons (mean, 1.64 ± 0.095 msec; p < 0.001; group t test).
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Figure 1. Neuronal firing rate distribution supports the presence of two populations of BLA neurons. A, Firing rate distribution of neurons recorded in the BLA. There is a bimodal distribution that may be separated into two normal populations (p < 0.05; n = 179 neurons) with 0.5 Hz as a cutoff. Representative firing rate histograms of two spontaneously firing neurons, a fast-firing (B) and a slow-firing (C) neuron.
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Figure 2. Parcellation of fast- and slow-firing neurons of the BLA by spike duration. A, Example trace of a fast-spiking neuron that displays a short spike duration (1.2 msec). B, Example trace of a slow-firing neuron that displays a long spike duration (4.0 msec). C, A plot of spike duration by firing rate for a sample of 90 BLA neurons demonstrates that fast-firing neurons (>0.5 Hz) tend to display short spike durations, whereas slow-firing neurons (<0.5 Hz) tend to display longer duration spikes (p < 0.01).
To further validate the parcellation of neuronal subtypes, projection neurons were identified by antidromic activation from either the mPFC or NAc (Fig. 3). Antidromically activated BLA neurons, as defined by a fixed response latency, collision with spontaneously occurring spikes when possible, and the ability to follow high-frequency stimulation, fired spontaneously at slow firing rates (n = 5; mean, 0.263 ± 0.128 Hz) or not at all (n = 16). A sample of antidromically activated neurons also displayed significantly longer spike durations than fast-firing neurons [n = 12; mean, 2.49 ± 0.47 msec; p < 0.001; group t test; there were no differences noted between the spike duration, response latency (mean latency, 12.1 msec; range, 7-20 msec), or projection target of slow-firing and nonspontaneously firing neurons antidromically driven from the mPFC or NAc]. By contrast, none of the fast-firing neurons could be activated antidromically.
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Figure 3. Antidromically activated, slow-firing BLA neurons display an increase in firing rate after DA receptor blockade. A, An example trace of a BLA neuron that follows high-frequency (300 Hz) electrical stimulation of the NAc. Arrows pointing up indicate stimulation, and arrows pointing down indicate spikes, respectively. B, Traces of antidromically evoked spikes in a slow-firing neuron in response to single NAc stimulation. The spikes display constant response latency (1) and collision (2) with a spontaneously occurring spike (3). Arrow indicates stimulus artifact. C, BLA neurons that could be antidromically activated from NAc stimulation display an increase in firing rate after systemic administration of the DA antagonist haloperidol (n = 7; *p < 0.05; Wilcoxon; circles represent neuronal firing rates prehaloperidol and posthaloperidol administration).
DAergic effects on spontaneous or microiontophoretic glutamate-evoked firing
Systemic administration of saline had no substantial effect on neuronal firing rate (two of two neurons). After intravenous drug administration, when significant effects occurred, changes of firing rate could be observed within 2 min. Systemic administration of the dopaminergic agonists apomorphine (n = 10), SKF-38393 (n = 6), or quinpirole (n = 4) had variable effects on the firing rate of spontaneously spiking neurons (10 of 20 neurons increased firing rate, 7 of 20 neurons decreased firing rate). However, the response observed could be differentiated based on the neuronal firing rate. Because of the similarity in responses, all DA agonists were grouped together. Fast-firing (>0.5 Hz) neurons displayed an increase in firing rate after systemic DA agonist administration (Fig. 4; 10 of 11 neurons; 10 rats; p = 0.016; Wilcoxon; mean firing rate ± SEM; pre-DA agonist, 2.57 ± 0.749 Hz; post-DA agonist, 5.44 ± 1.898 Hz; maximum change, >3000% of baseline; mean change, 256% of baseline), whereas the firing rate of slowly firing neurons was attenuated (Fig. 4; seven of nine neurons; eight rats; p = 0.0156; Wilcoxon; pre-DA agonist, 0.371 ± 0.199 Hz; post-DA agonist, 0.191 ± 0.092 Hz; maximum change, 0% of baseline; mean change, 33% of baseline) by similar doses of the same drugs [doses as follows: (1) DA agonists (initial doses of 0.05-0.15 mg): apomorphine, mean initial dose, 0.14 ± 0.016 mg/kg, ranging from 0.09 to 0.31 mg/kg, and a final dose as high as 0.61 mg/kg; SKF-38393, initial dose, 0.05-0.15 mg, corresponding to a mean initial dose 0.12 ± 0.002 mg/kg, ranging from 0.11 to 0.13 mg/kg and a final dose as high as 0.50 mg/kg; quinpirole, initial dose, 0.16 ± 0.03 mg/kg, ranging from 0.13 to 0.290 mg/kg, and a final dose as high as 0.58 mg/kg; (2) DA antagonists (initial doses of 0.1-0.25 mg): haloperidol, initial dose, 0.30 ± 0.050 mg/kg, ranging from 0.13 to 0.65 mg/kg, and a final dose as high as 0.65 mg/kg; raclopride, initial dose, 0.26 ± 0.086 mg/kg, ranging from 0.13 to 0.49 mg/kg, with a final dose as high as 0.58 mg/kg; SCH 23390, initial dose, 0.21 ± 0.017 mg/kg, ranging from 0.13-0.23 mg/kg, with a final dose as high as 0.75 mg/kg]. In several cases, the initial dose was repeated with subsequent injections given at double the previous dose, in a dose-response manner. In the instances in which more than one dose of DA agonist was administered, supplementary doses potentiated the effects of the initial dose or produced an effect when the initial dose was subthreshold for producing a result. In most cases, the effects were reversible after systemic administration of DA receptor antagonists (raclopride, three of four neurons; haloperidol, five of seven neurons; and SCH-23390, three of three neurons). It was also observed in 4 of 11 cases that administration of a DA antagonist after the DA agonist not only reversed the effects of the agonist, but further altered the firing rate beyond baseline levels. This may be attributable to a combination of two factors: (1) removal of DA agonist-induced actions and (2) attenuation of baseline DAergic tone on the neuron. Furthermore, systemic administration of dopamine antagonists alone decreased the firing rate of fast firing neurons (Fig. 5; five of six neurons; six rats; pre-DA antagonist, 2.83 ± 0.92 Hz, post-DA antagonist, 0.93 ± 0.46 Hz; p = 0.040; group t test; maximum change, 2% of baseline; mean change, 18% of baseline) and increased the firing rate of slowly firing neurons (Fig. 4; eight of nine neurons; eight rats; pre-DA antagonist, 0.110 ± 0.077 Hz; post-DA antagonist, 1.21 ± 0.965 Hz; p = 0.0195; Wilcoxon; maximum change, >1000% of baseline; mean change, >1000% of baseline; haloperidol, mean initial dose, 0.10 ± 0.025 mg/kg, ranging from 0.03 to 0.16 mg/kg, with a final dose as high as 0.32 mg/kg).
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Figure 4. Opposite effects of DA receptor activation on fast-firing and slow-firing BLA neurons. A, Firing rate histogram of a fast-firing neuron that displays an increase in firing rate after systemic administration of the DA agonist apomorphine (0.09 mg/kg, i.v.) that is reversed after systemic administration of the DA antagonist haloperidol (0.30 mg/kg, i.v.). B, Firing rate histogram of a slow-firing neuron that displays a decrease in firing rate after systemic administration of apomorphine (0.12 mg/kg, i.v.) that is reversed after systemic administration of the DA antagonist raclopride (0.25 mg/kg, i.v.). Arrows indicate the time of drug administration. C, DA agonist administration has opposite effects on fast-firing (n = 10 of 11 neurons) and slow-firing (n = 7 of 9 neurons) neurons of the BLA (*p < 0.05; error bars indicate mean ± SEM; see Results for dose ranges).
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Figure 5. Opposite effects of DA receptor blockade on fast-firing and slow-firing BLA neurons. A, Firing rate histogram of a fast-firing neuron that displays a decrease in firing rate after systemic administration of the DA antagonist haloperidol (0.32 mg/kg, i.v.). B, Firing rate histogram of a slow-firing neuron that displays an increase in firing rate after systemic administration of haloperidol (0.31 mg/kg, i.v.). Arrows indicate time of drug administration. C, Opposite effects of systemic administration of DA antagonists on fast-firing (5 of 6 neurons) and slow-firing (8 of 9 neurons) neurons of the BLA (*p < 0.05; error bars indicate mean ± SEM; see Results for dose ranges).
Consistent with this, the response of neurons that exhibited antidromic activation from electrical stimulation of the NAc was also qualitatively different from that of the fast-firing neurons. Thus, the firing rates of these neurons increased after systemic administration of haloperidol alone (Fig. 3; seven of seven neurons; six rats; prehaloperidol, 0.27 ± 0.18 Hz; posthaloperidol, 0.52 ± 0.32 Hz; p = 0.016;Wilcoxon; each neuron displayed an increase in firing rate p < 0.05, individual t tests with Bonferroni corrections; haloperidol, mean initial dose, 0.61 ± 0.057 mg/kg, ranging from 0.40-0.85 mg/kg, with a maximal dose of 0.85 mg/kg).
To further demonstrate that the response was dopamine-mediated in the BLA, two strategies were taken: microiontophoresis of DA in the BLA and electrical stimulation of the SN/VTA, which is the locus of the DA cell afferents to the BLA. Electrical stimulation of SN/VTA in three rats yielded results similar to the effects observed with systemic administration of DA agonists. Thus, fast-firing neurons showed an increase in firing after SN/VTA stimulation (Fig. 6; 9 of 10 neurons; pre-SN stimulation, 2.87 ± 0.828 Hz; post-SN stimulation, 4.51 ± 1.242 Hz; p = 0.0091; group t test), whereas slow-firing neurons showed a decrease in firing rate [Fig. 6; four of four neurons; pre-SN stimulation, 0.34 ± 0.097 Hz; post-SN stimulation, 0.11 ± 0.046 Hz; p = 0.066; group t test; however, each individual neuron showed a significant change in firing rate; p < 0.05; individual t tests (with Bonferroni correction)]. The effects of SN/VTA stimulation were attenuated by systemic haloperidol administration (Fig. 6; 0.55-0.68 mg/kg), independent of the effects of haloperidol on basal firing rate. The effects began within seconds of, or during, SN/VTA stimulation and exhibited durations of up to 1 min. Additionally, iontophoretic glutamate-evoked excitation of nonspontaneously spiking neurons was depressed by SN stimulation [Fig. 6; four of four neurons; pre-SN stimulation, 16.1 ± 8.9 Hz; post-SN stimulation, 8.1 ± 4.2 Hz; mean change, 53.6 ± 3.8% of baseline; p > 0.05; group t test; however, each individual neuron displayed a significant (p < 0.05, individual t tests with Bonferroni correction) decrease in firing rate after SN/VTA stimulation].
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Figure 6. Electrical stimulation of the SN/VTA exerts opposite effects on fast-firing and slow-firing neurons. A1, Averaged composites of neuronal responses to SN/VTA stimulations (stimulus time histograms for several neurons were added together and divided by the number of stimulus presentations). SN/VTA stimulation increases the firing rate of fast-firing neurons of the BLA (n = 5; p < 0.05), decreases the firing rate of slow-firing neurons (n = 4; p < 0.05) (2), and attenuates the glutamate-evoked excitation of neurons that did not display spontaneous spike discharge (n = 4; p < 0.05) (3). Arrows indicate onset of electrical stimulation (1-2 sec; 10-20 Hz; 0.5-0.6 mA). B, Example firing rate histogram of the response of a fast-firing neuron to SN/VTA stimulation before (1) and after (2) systemic administration of the DA antagonist haloperidol (0.67 mg/kg, i.v.). Vertical line indicates beginning of 1 sec SN/VTA stimulation at 10 Hz, 0.2 msec durations, 0.6 mA.
Co-microiontophoresis of DA and glutamate produced consistent results. In our iontophoresis recordings, most of the neurons exhibited spontaneous spike discharge only during iontophoresis of glutamate. All but one of the neurons excited by iontophoretic glutamate displayed an attenuation in firing rates during co-iontophoresis of DA (Fig. 7; 20 of 21 neurons; seven rats; p < 0.01; group t test). In the neurons tested with variable iontophoretic currents of DA, the firing rate of the neurons was attenuated in a current-dependent manner (Fig. 7). The effects of iontophoretic DA were attenuated by systemic administration of haloperidol (n = 2 of 2). Iontophoresis of the specific DA agonists SKF-38393 (n = 4 of 5; p = 0.013; group t test) and quinpirole [n = 3 of 4; p = 0.11; group t test; however, three of four neurons displayed significant changes with individual t tests; p < 0.05 (with Bonferroni correction)] also attenuated the firing of BLA neurons induced by glutamate iontophoresis. In no case in which DA or DA agonist was administered alone did a nonfiring neuron begin firing spontaneously. Additionally, a set of neurons antidromically activated from NAc stimulation were induced to fire with iontophoretic glutamate application, and the firing was attenuated by co-iontophoresis of DA (Fig. 7B; n = 3; the firing rate of each neuron was significantly attenuated, p < 0.05; individual t tests with Bonferroni correction).
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Figure 7. Microiontophoretic application of DA attenuates BLA neuronal firing induced by co-microiontophoresis of glutamate. A, Firing rate histogram showing that DA attenuates the neuronal firing induced by iontophoretically applied pulses of glutamate (
DAergic effects on afferent-evoked responses
The BLA receives afferent input from a number of cortical structures, most of which are known to use glutamate as a neurotransmitter (for review, see Somogyi et al., 1998
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Figure 8. DA receptor activation attenuates mPFC- and MD-evoked short-latency responses in BLA neurons. A, An example trace of an MD-evoked short-latency response in a BLA neuron that did not fire spontaneously. Arrow indicates electrical stimulation artifact. B, Repre- sentative PSTHs of the attenuation of MD-evoked responses in a nonspontaneously firing BLA neuron by systemic administration of apomorphine (0.10 mg/kg) and its reversal by systemic administration of haloperidol (0.30 mg/kg). C, MD-evoked short-latency responses are attenuated after systemic administration of DA agonists (6 of 7 neurons; *p < 0.05; error bars indicate mean ± SEM). D, mPFC-evoked short-latency responses are attenuated after systemic administration of DA agonists (5 of 5 neurons; *p < 0.05; error bars indicate mean ± SEM, see Results for dose ranges).
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Figure 9. DA agonist administration has opposite effects on MD-evoked and spontaneous firing recorded from the same neuron. A, PSTH indicating the presence of a short-latency evoked response (arrow) in a spontaneously firing neuron (top). The short-latency evoked response is attenuated, yet the spontaneous firing rate (arrowheads, the prestimulus firing rate) is increased (p < 0.05; bottom) after systemic administration of the DA agonist apomorphine (0.10 mg/kg). B, Graphic representation of the opposite changes in firing rate and MD-evoked short-latency responses recorded in the same neuron displayed in A. Additionally, systemic administration of haloperidol (0.65 mg/kg) reversed the effects of apomorphine and caused a further suppression of neuronal firing rates and potentiation of evoked spike probability to levels that surpassed predrug baseline.
If the activity of these neurons is in fact driven by glutamatergic inputs, one interpretation of these results is a differential modulation of glutamatergic inputs by DA and specifically implies the potentiation of another glutamatergic input, leading to an increased basal firing rate. In light of this, two other inputs were examined; the input from mPFC (infralimbic and prelimbic) and the input from sensory association cortex (Te3). Both send substantial projections to the lateral nucleus of the BLA and represent two classes of inputs to the amygdala: sensory and limbic. Short-latency, presumed monosynaptic evoked responses from mPFC stimulation (mean latency, 17 msec; range, 15-20 msec) were attenuated after systemic apomorphine administration (Fig. 9; 5 of 5 neurons; five rats; pre-DA agonist response probability, 0.52 ± 0.06; post-DA agonist response probability, 0.20 ± 0.10; p = 0.012; group t test; 35 ± 13% of baseline; apomorphine mean initial dose, 0.46 ± 0.052 mg/kg, ranging from 0.19 to 0.61 mg/kg, with a maximal dose of 0.78 mg/kg). By contrast, short-latency evoked responses from Te3 (Fig. 10; mean latency, 11.5 msec; range, 7-13 msec) were potentiated after systemic apomorphine (9 of 10 neurons; nine rats; pre-DA agonist response probability, 0.51 ± 0.07; post-DA agonist response probability, 0.79 ± 0.09; p = 0.001; group t test, 162 ± 12.7% of baseline; apomorphine mean initial dose, 0.28 ± 0.057 mg/kg, ranging from 0.13 to 0.37, with a maximal dose of 0.74 mg/kg). These distinct effects on mPFC and Te3 inputs to the BLA were induced by similar doses of drug and were reversed after systemic administration of haloperidol (mPFC, n = 3 of 4; mean initial dose, 0.55 ± 0.02 mg/kg, ranging from 0.39 to 0.61 mg/kg; Te3, n = 2 of 3; mean initial dose, 0.53 ± 0.035 mg/kg, ranging from 0.49 to 0.60 mg/kg).
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Figure 10. DA receptor activation potentiates Te3-evoked short-latency responses in BLA neurons. A, Representative PSTHs from a nonspontaneously firing BLA neuron that displays potentiation of the Te3-evoked short-latency response after systemic administration of apomorphine (0.37 mg/kg). This effect is reversed after systemic administration of haloperidol (0.49 mg/kg). B, Systemic administration of apomorphine potentiates Te3-evoked short-latency responses in BLA neurons (9 of 10 neurons; *p < 0.05; t test; error bars indicate mean ± SEM; see Results for dose ranges).
Similarly, MD- and mPFC-evoked field potentials (n = 3 of 4, each) were attenuated after systemic DA agonist administration (Fig. 11; MD: apomorphine mean dose, 0.73 ± 0.150 mg/kg; range, 0.58-0.88 mg/kg; mPFC: apomorphine mean dose, 0.72 ± 0.094 mg/kg; range, 0.51-1.0 mg/kg). The field potentials evoked by either MD or mPFC stimulation could be divided into four primary components; two positive and two negative components, labeled P1, P2, N1, and N2, respectively (Fig. 11). The amplitude of MD- and mPFC-evoked responses was dependent on the stimulus intensity. The average ratio of preapomorphine and postapomorphine administration for mPFC-evoked field potentials was: P1, 0.65 ± 0.14, p < 0.05 group t test; P2, 0.62 ± 0.14, p < 0.05 group t test; N1, 0.66 ± 0.20, p > 0.05 group t test; and N2, 0.536 ± 0.18, p < 0.05 group t test. The average ratios of preapomorphine and postapomorphine administration for MD-evoked field potentials were: P1, 0.88 ± 0.12; P2, 0.73 ± 0.15; N1, 0.86 ± 0.21; and N2, 1.04 ± 0.41 (none were significant with group t test, presumably because of the large variance; however, in three of four cases, the MD-evoked field potential displayed a prominent attenuation after apomorphine administration).
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Figure 11. DA receptor activation attenuates MD- and mPFC-evoked population field potentials recorded in the BLA. Traces of mPFC-evoked (A) and MD-evoked population field potentials before (black) and after (gray) systemic administration of apomorphine (mPFC, 0.88 mg/kg; MD, 0.58 mg/kg). Each trace represents 30 averaged recorded field potentials. Arrow (Stim) marks stimulus artifact.
DISCUSSION
This study examined the effects of DA receptor activation on spontaneous activity and afferent drive of BLA neurons. The results indicate that DA receptor activation decreases the spontaneous firing rate of slowly firing neurons but increases the firing rate of fast-firing BLA neurons. Moreover, the effects of DA receptor activation on afferent drive depended on the afferent examined.
BLA neuron subtypes
BLA neurons were parcellated into two types based on their action potential duration, antidromic activation, and their firing rates, with neurons firing at <0.5 Hz comprising one population, and neurons firing at >0.5 Hz belonging to a separate population. This division is consistent with evidence presented here and in other studies showing distinct physiological properties of identified BLA neuronal subtypes (Washburn and Moises, 1992
Effects of DA on spontaneous firing of BLA neuron subtypes
Slow-firing, presumed projection neurons exhibited a decrease in firing rate after systemic administration of DA agonists, which could be reversed after systemic administration of DA antagonists. Furthermore, systemic administration of DA antagonists alone increased the firing of slow-firing and nonfiring neurons, some of which were identified as projection neurons using antidromic activation. Taken together, these results imply that the spontaneous firing of projection neurons is attenuated by DA receptor activation and that there may be a tonic DAergic inhibition on BLA projection neurons.
When using systemic drug administration, it is unclear whether the effects of DA receptor activation are localized to the BLA. Thus, we undertook co-iontophoresis of DA and glutamate in the BLA. When performing glutamate iontophoresis, the probability of recording from projection neurons is increased. These neurons comprise ~80% of BLA neurons (McDonald, 1985
Fast-firing, presumed interneurons display an increase in firing rate after systemic administration of DA agonists that is reversed by DA antagonist administration. Similarly, systemic administration of DA antagonists alone decreases the firing rate of the presumed interneurons. This may provide a mechanism by which DA has indirect inhibitory actions on projection neurons of the BLA. These interneurons display extensive axonal arborization, with many terminals onto the somata of BLA pyramidal neurons (McDonald, 1985
To further test whether this response was a DA-mediated effect, the SN/VTA was electrically stimulated at parameters similar to those shown to evoke DA release in the BLA (Garris and Wightman, 1994
This study indicates that the direction of the effects of DA on neuronal firing rates is neuron subtype-specific, and not firing rate-dependent. Thus, nonfiring neurons, as well as some antidromically activated neurons, could be induced to fire by iontophoretic application of glutamate to rates that in some cases exceeded 10 Hz; nevertheless, DA receptor activation still decreased the firing rate of these neurons.
One puzzling result is that both the D1 and D2 DA receptor agonists produced similar effects on neuronal firing. Further studies are ongoing to determine whether this is the case under other conditions. However, it is conceivable that activation of the two classes of DA receptors may have similar effects but via different substrates (Hoffman and Johnston, 1998
One broad interpretation of results pertaining to DA receptor activation and firing rate is that DA nonspecifically decreases the firing of projection neurons, and by doing so decreases the general excitatory output of the BLA. By modulating the diffuse BLA projection systems, DA may exert broad effects on motoric (NAc) and autonomic (central nucleus of the amygdala and hypothalamus) function, as well as alterations of attention (MD/PFC) and arousal (indirect projections to nucleus basalis, Kretteck and Price, 1977
DA modulation of afferent inputs to the BLA
DA receptor activation appears to exert opposite effects on neuronal responses evoked from Te3 and mPFC (and MD), areas that are representative of sensory and limbic inputs, respectively. Specifically, the sensory input was potentiated by DA, whereas the limbic inputs were attenuated. However, the mechanism of these actions is unclear. For example, these opposite effects may be attributable to presynaptic downmodulation (Maura et al., 1988
Tentative criteria were established to operationally define monosynaptic, polysynaptic, and antidromic responses. However, the possibility of excitation via a collateral of antidromically activated neighboring neurons could not be excluded because of a continuum of antidromic and orthodromic response latencies. Although stimulation of fibers of passage could also not be excluded, it is unlikely to have been the primary source of excitation from cortical areas that send dense projections to the BLA.
Integrated function of DA in the BLA
DA in the BLA appears to exert a dual filtering role: (1) a nonspecific filtering accomplished via GABAergic interneurons that is hypothesized to attenuate the weaker inputs, and (2) a selectivity filter accomplished by modulation of sensory and limbic inputs in opposite directions. Thus, DA may provide a mechanism by which sensory inputs become more capable of driving projection neuron firing than the limbic inputs examined. It is interesting to note that sensory inputs (albeit only sensory thalamus inputs have been examined in depth to date) are potentiated during associative conditioning (McKernan and Shinnick-Gallagher, 1997
Our results indicate that DA plays a powerful modulatory role in the BLA, a site involved in affective learning and affective responding. Thus, DA receptor activation, via cooperative modulation of interneurons, projection neurons, and excitatory inputs, filters particular afferent inputs based on their strength and their source. This study provides the first description of differential effects of DA receptor activation on the projection neurons and presumptive interneurons, as well as on sensory and limbic afferents into the BLA. This provides a neurophysiological substrate for behavioral changes noted under conditions of artificially manipulated DA transmission in the BLA, and more importantly, under conditions in which DA is released in the BLA, such as during the presentation of an aversive sensory stimulus and during some forms of learning.
FOOTNOTES Received July 26, 1999; revised Sept. 10, 1999; accepted Sept. 30, 1999.
This work was supported by National Institutes of Health Grants MH57440, MH45156 (A.A.G.), and NS 07433 (J.A.R.). We acknowledge the excellent technical assistance of Nicole MacMurdo and Brian Lowry.
Correspondence should be addressed to J. Amiel Rosenkranz, Department of Neuroscience, 446 Crawford Hall, University of Pittsburgh, Pittsburgh, PA 15260. E-mail: rosenk{at}bns.pitt.edu.
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