Article Figures & Data
Figures
- Fig. 1.
Different categories of neuronal responses in mPFC and NAc during cocaine and heroin self-administration.A, Raster and perievent histogram plots show excitatory anticipatory and post-cocaine inhibitory responses by a mPFC neuron. Each dot in the raster plot (top) represents a neuronal spike, and each row represents an individual trial. The perievent histogram (bottom) depicts the average neuronal activity of the individual trials within the raster around the lever press event (50 sec before and 100 sec after lever press in this case). The zero point corresponds to the behavioral event of the lever press for cocaine self-administration. An increase in spike activity was found a few seconds before the lever press (excitatory anticipatory response), and a decrease in neuronal activity was observed after cocaine self-infusion (post-cocaine inhibitory response). B, Example of an excitatory anticipatory response during a heroin self-administration session by a NAc neuron. C, Inhibitory anticipatory neuronal response recorded from the mPFC during cocaine self-administration. Note a decrease in firing rate before the lever press. D, Excitatory post-heroin response recorded from a mPFC neuron during a heroin self-administration session. An increase in spike activity after heroin infusion is evident.
- Fig. 2.
Comparison of NAc neuronal activity during a single heroin and cocaine self-administration session.A, This rate meter record shows the spike activity of a NAc neuron during a heroin-first, cocaine-second self-administration session. ♦, Lever press events. The initial eight lever presses were for heroin self-administration and were followed by 11 presses for cocaine self-administration. Cocaine self-administration resulted in an increase in neuronal activity. B, Raster and perievent histogram for the heroin self-administration trials. Note the increase in firing rate before the lever press (excitatory anticipatory response). C, Same neuron as inB during the cocaine self-administration period. In contrast to B, no significant alteration of neuronal activity was observed before the lever press for cocaine self-administration.
- Fig. 3.
Comparison of mPFC neuronal activity during a cocaine-first, heroin-second self-administration session using the same plot as in Figure 2. A, This rate meter plot demonstrates the firing rate of a mPFC neuron during the entire cocaine–heroin self-administration session. In this case, heroin self-administration caused general inhibition. B, Raster and perievent histogram for cocaine self-administration trials. A decrease in firing rate occurred ∼2 sec before the lever press (inhibitory anticipatory response). C, Raster and perievent histogram for heroin self-administration trials. The inhibitory anticipatory response observed during cocaine self-administration trials (B) was absent during heroin selfadministration.
- Fig. 4.
Different anticipatory neuronal responses across alternating daily cocaine and heroin sessions recorded from the same NAc neuron. A, NAc neuron exhibited inhibitory anticipatory responses before the lever press for cocaine self-administration in session 1. B, Same neuron depicted in A showed no response during the heroin self-administration session of the following day. C, An identical inhibitory anticipatory response was observed by the same neuron on the third day when cocaine self-administration was repeated.D, No alteration of neuronal activity of this same neuron was found when the subject was switched back to heroin self-administration for the session of the fourth day.
- Fig. 5.
Comparison of post-drug infusion responses in simultaneously recorded mPFC and NAc neurons. A, Raster and perievent histogram plots for a mPFC neuron during the heroin self-administration trials of a heroin–cocaine self-administration session. An increase in firing rate was observed after heroin self-administration that occurred at 0 sec. B, Same neuron depicted in A during the cocaine self-administration period of the same session. No significant change in firing rate was found during cocaine self-administration.C, This NAc neuron did not change its firing rate after the lever press during the heroin self-administration trials.D, Same NAc neuron as in Cdisplayed an inhibitory response after cocaine self-administration during the same session. This neuron also exhibited an excitatory anticipatory response immediately before the lever press at 0 sec.
- Fig. 6.
Multiple regression analysis of the neuronal responses to cocaine and heroin self-administration from cocaine–heroin and heroin–cocaine sessions. A, Anticipatory responses recorded from the mPFC during the self-administration of cocaine and heroin in the same session. The responses were measured as a percentage change of neuronal activity. Two sessions were plotted in this figure: the cocaine-first, heroin-second session (n = 39, ○) and the heroin-first, cocaine-second session (n = 53, •). The correlation coefficient values (r) for cocaine-first and heroin-first sessions were 0.37 and 0.46, respectively. Both correlations were significant (p < 0.05). B, Same plot as in A for the NAc. The correlations between cocaine and heroin responses are not significant (p > 0.05) for either cocaine-first (r = 0.27;n = 43) or heroin-first sessions (r = 0.14; n = 40).C, Regression analysis for post-drug infusion responses recorded from the mPFC. The regression lines were nearly flat and parallel for cocaine and heroin self-administration in both cocaine-first (r = 0.06; n = 38) and heroin-first (r = 0.03;n = 29) conditions, and there were no significant correlations between cocaine and heroin responses. D, Same plot as in C for NAc. No significant correlations were observed between cocaine (r = 0.05;n = 48) and heroin (r = 0.12;n = 43) post-drug infusion responses.
- Fig. 7.
Behavioral correlations of an anticipatory neuronal response recorded from a NAc neuron. Behavioral nodes (raising head, lever press) were created by video analysis and used as reference points for the creation of the raster and perievent histogram plots. A, C, Plot of data during cocaine self-administration period. Note the increase in firing rate at the onset of the raising head behavioral episode as indicated by the arrow in A. The increased firing rate continued until the lever press.B, D, Same neuron during heroin self-administration within the same session. In contrast to cocaine self-administration, the identical raising head behavior during heroin self-administration was associated with a decrease in firing rate as indicated by the arrow inB. The decreased neuronal activity persisted until thelever press episode as depicted inD.
- Fig. 8.
Behavioral correlations of the anticipatory neuronal activity recorded from a mPFC neuron. A, Fromtop to bottom, the panels demonstrate the behavioral sequence of raising head, lever press, andback to floor during cocaine self-administration trials. Note the onset of a decrease in spike activity at the raising head behavior episode (top panel). The decreased activity continued through the lever press episode (middle panel) and until the subject returned its paws back to the floor (bottom panel). B, The same neuron during heroin self-administration trials during the same session. No significant change in firing rate was detected during raising head, lever press, and return back to floor behavioral episodes.
- Fig. 9.
Baseline neuronal activity changes during a heroin–cocaine self-administration session. This rate meter record shows 19 neurons simultaneously recorded from the mPFC and from the NAc (mPFC neurons are indicated by 1–16 in theparentheses along the right y-axis; NAc neurons are indicated by 17–32). Neurons with changes in baseline neuronal activity are marked by an asterisk. Note that many of the changes after the switch to the cocaine reinforcer (vertical line) are inhibitory.
- Fig. 10.
Comparison of baseline neuronal activities between self and passive administering heroin–cocaine.A, Twenty neurons recorded simultaneously in the mPFC and the NAc during heroin–cocaine self-administration session (see Fig. 9 for neuron identification). Alteration of neuronal activity induced by switching from heroin to cocaine, indicated by avertical line, was observed in several neurons (*).B, The next day, a computer-controlled, passive administration of heroin–cocaine was performed in the same animal with the same dose of cocaine (1 mg/kg per infusion) and heroin (30 μg/kg per infusion) used in self-administration sessions. The interinfusion interval was randomly selected by computer using the range of mean ± SE calculated from self-administration session in A. Note that the same pattern of neuronal activity changes occurred in comparison to the neurons marked in A. ♦, Bar press inA and passive drug infusion in B.
- Fig. 11.
Scatter plots of the overall firing rates of mPFC and NAc neurons during cocaine and heroin self-administration and the control period. All the plots are constructed from heroin-first, cocaine-second sessions. A, Comparison of the firing rates recorded from the mPFC during cocaine and heroin self-administration conditions with the control period of that session. The ordinate depicts the firing rate (spikes per second) during cocaine and heroin self-administration trials, and theabscissa depicts the firing rate (spikes per second) for the control condition. Inhibitory responses elicited by cocaine (○) and heroin (•) are under the line that represents the control responses (□), whereas excitatory responses induced by cocaine (▵) and heroin (▴) are above the controlline. B, Same plot as Afor NAc. C, Comparison of the firing rates recorded from the mPFC during cocaine and heroin self-administration periods. Firing rates (spikes per second) during the cocaine self-administration period are represented along the ordinate, and the firing rates during the heroin self-administration trials are represented along theabscissa. Inhibitory responses (•) are defined as a decrease in firing rate under the cocaine self-administration condition in comparison with the heroin self-administration condition. Excitatory responses (▵) are defined as an increase in firing rate under cocaine self-administration in comparison with the heroin self-administration condition. Note that more neurons exhibited inhibitory responses under the cocaine self-administration condition. D, Same plot as in C for the NAc.
- Fig. 12.
Histological location of recording sites in mPFC (A) and NAc (B) revealed by potassium ferricyanide staining of iron deposited by current applied to recording microwires. Cg1, Cingulate cortex area 1;Cg2, cingulate cortex area 2; Cg3, cingulate cortex area 3; IL, infralimbic cortex;mo, medial orbital cortex; vlo, ventrolateral orbital cortex; Fr1, frontal cortex area 1; Fr2, frontal cortex area 2; AcbC, nucleus accumbens core; AcbSh, nucleus accumbens shell.
Tables
- Table 1.
Classification of neuronal responses during cocaine and heroin self-administration
AE AI PI PE NR n % of total n % of total n % of total n % of total n % of total Cocaine mPFC 11 10 9 8.2 20 18.2 4 3.6 80 72.7 NAc 27 24.3 6 5.4 30 27.0 8 7.2 61 54.9 Heroin mPFC 20 18.2 9 8.2 14 12.7 3 2.7 69 62.7 NAc 18 16.2 6 5.4 20 18.0 6 5.4 68 61.3 Number and distribution of different types of neuronal responses in mPFC and NAc during separate cocaine and heroin self-administration sessions. Different categories of neuronal responses are displayed at the top of table (AE, anticipatory excitatory response; AI, anticipatory inhibitory response; PI, post-drug inhibitory response; PE, post-drug excitatory response; NR, no response). Number of neuron(n) and percentage of total are indicated in each category. A total of 110 mPFC and 111 NAc neurons were tested across cocaine and heroin sessions. A single neuron sometimes exhibited more than one type of response so it could be counted in multiple categories.
Distribution of neuronal responses during cocaine and heroin self-administration trials during cocaine-first, heroin-second sessions from 110 mPFC and 111 NAc neurons. A, Data from mPFC; the horizontal direction displays different types of responses for cocaine self-administration. Vertical direction shows the responses for heroin self-administration. Fifty-two (47.3% of 110) neurons exhibited no response to either the cocaine or heroin sessions. A single neuron may have more than one attribute by exhibiting more than one response in different categories. The 58 (of 110) neurons that did respond exhibited 75 neuron response cases across the different categories. Of these there were only 14 instances (18.7% of 75) when similar responses to both cocaine and heroin were observed. The dark shaded blocks in the diagonal show the neurons that share the same response during both cocaine and heroin self-administration segments. Light shaded blocks represent the neuron-response cases having different responses during cocaine and heroin self-administration. Sixty-one neuron response cases (81.3% of 75) responded differently during cocaine and heroin self-administration phases. B, Comparison of neuronal responses of the NAc during cocaine and heroin self-administration as in A. Only 25% of neurons exhibited the same response to both cocaine and heroin whereas 75% of neurons responded differently to cocaine and heroin self-administration.
Comparison of neuronal activity during cocaine and heroin self-administration in the heroin-first, cocaine-second sessions. The format of the table is the same as Table 2. A, Comparison of mPFC neuronal activity during heroin and cocaine self-administration trials. Similar to what was observed in cocaine-first, heroin-second sessions in Table 2, most neuron-response cases responded to heroin and cocaine self-administration differently (84.1%), whereas only 15.9% of neuron-response cases shared the same response during heroin and cocaine self-administration trials. B, Comparison of the data obtained from NAc. Again, only 22.4% of neurons responded in the same way to both heroin and cocaine self-administration; the majority of neuron-response cases (77.6%) responded differently during heroin and cocaine self-administration trials.
Comparison of mPFC and NAc neuronal responses to cocaine and heroin self-administration in separate sessions in which cocaine and heroin were self-administered first (same format as in Table 2). A, Data obtained from the mPFC; similar to the results obtained from cocaine and heroin self-administration in the same session (Tables 2, 3) the majority of neuron-response cases with a significant response responded to cocaine and heroin self-administration differently (80.5%); only 19.5% of neuron-response cases shared the same response to cocaine and heroin. B, Data obtained from NAc; only 20.4% of neuron-response cases responded in the same way to cocaine and heroin whereas 79.6% of neuron response cases responded differently to cocaine and heroin self-administration.
- Table 5.
Comparing the average neuronal activity during cocaine and heroin self-administration in the same session
Type of responses Cocaine vs control Heroin vs control Cocaine vs heroin (n = 58) % changes in firing rate n % of total % Changes in firing rate n % of total % Changes in firing rate n % of total mPFC Heroin first, cocaine second n = 49 Excitatory 115.2 ± 24.9 7* 14.3 167.3 ± 47.0 14 28.6 92.3 ± 18.8 9a 15.5 Inhibitory −62.6 ± 3.5 28* 57.1 −55.1 ± 3.7 17 35.3 −56.2 ± 3.9 30 51.7 Cocaine first, heroin second n = 40 Excitatory 171.0 ± 63.4 7 17.5 187.5 ± 38.9 13 32.5 164.5 ± 101.6 10 25.0 Inhibitory −51.7 ± 3.7 21 52.5 −50.3 ± 4.2 16 40.0 −47.2 ± 5.6 19 47.5 NAc Heroin first, cocaine secondn = 67 Excitatory 158.5 ± 24.3 15* 22.4 103.9 ± 20.9 22 32.8 220.2 ± 54.6 17b 25.4 Inhibitory −64.7 ± 3.1 42* 62.7 −49.5 ± 3.3 23 34.3 −64.7 ± 3.1 42 62.7 Cocaine first, heroin second n = 52 Excitatory 414.1 ± 77.3 9 17.3 294.5 ± 88.6 17 32.6 265.9 ± 59.2 17 32.6 Inhibitory −62.0 ± 4.3 29 55.7 −66.7 ± 3.6 26 50.0 −58.3 ± 3.8 26 50.0 Comparison of overall firing rates during cocaine and heroin self-administration within the same session. The neuronal activity during the entire period of either cocaine or heroin self-administration was compared with each other and with the control period (200 sec at the beginning of the session). The comparisons were made in heroin-first, cocaine-second and cocaine-first, heroin-second sessions for the mPFC (top panel) and the NAc (bottom panel). The comparison between cocaine and heroin self-administration trials is expressed as percentage change as follows: [(cocaine firing rate-heroin firing rate)/heroin firing rate] × 100. χ22 × 2 contingency table tests were used to test whether different numbers of neurons showed excitatory and inhibitory responses under conditions of cocaine and heroin self-administration. Significant differences were observed in heroin first, cocaine second sessions in both the mPFC and NAc (*significantly different number of neurons having excitatory and inhibitory responses as compared to heroin self-administration phase, p < 0.05). χ2goodness of fit test was used to determine whether significantly different numbers of neurons showed excitatory and inhibitory responses when compared between drug conditions. More neurons were inhibited than excited during cocaine self-administration in comparison with heroin self-administration phase (ap < 0.05, bp < 0.01).
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