Phasic Accumbal Firing May Contribute to the Regulation of Drug Taking during Intravenous Cocaine Self-administration Sessions

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1 Phasic Accumbal Firing May Contribute to the Regulation of Drug Taking during Intravenous Cocaine Self-administration Sessions LAURA L. PEOPLES, a ANTHONY J. UZWIAK, FRED GEE, ANTHONY T. FABBRICATORE, KATHRYN J. MUCCINO, BINAIFER D. MOHTA, AND M.O. WEST Department of Psychology, Rutgers, The State University of New Jersey, New Brunswick, New Jersey 08903, USA INTRODUCTION Recent studies have applied chronic extracellular recording techniques to the intravenous cocaine self-administration paradigm to investigate the neurophysiological mechanisms that contribute to drug taking (e.g., Refs. 1 4). Data of one study suggest that a large percentage of nucleus accumbens (NAcc) neurons exhibit a change in firing during limited-access (fixed-ratio 1) self-administration sessions that is both synchronized to the self-infusion behavior and has a time course comparable to the interval that elapses between successive self-infusions. A firing pattern with such a time course may be involved in the regulation of the self-infusion behavior (cf. Ref. 4). The focus of the present study was to further characterize neurons that exhibit this firing pattern. METHODS AND RESULTS Male Long-Evans rats (n = 32) 5 were implanted with a catheter in the jugular vein and an array of microwires in the NAcc. Intravenous cocaine self-administration sessions were conducted daily (fixed-ratio 1 schedule of 0.7 mg/kg/0.2 ml cocaine infusion). Electrophysiological recording sessions were in most cases conducted on the fifteenth day of self-administration. The recording session consisted of 3 phases: 1) predrug period, 2) self-administration session, and 3) postdrug period. 4,5 Animals exhibited typical self-administration behavior (FIG. 1: 1B,2B). Of 121 neurons, 84 exhibited a phasic change in firing rate during the mins before and after individual self-infusions. Consistent with our previous observations, 4 the most common (58/84, 69%) change consisted of an initial decrease in firing rate during the 1 min after self-infusion and a subsequent reversal of that decrease which occurred progressively during the remaining mins of the interinfusion interval (decrease + progressive reversal) (FIG. 1: 1D,2D). a Corresponding author: Laura L. Peoples, Ph.D., Dept. of Psychology, Busch Science Campus, Rutgers, The State University of New Jersey, New Brunswick, NJ Voice: , -5405; fax: ; llp@psych.rutgers.edu 781

2 782 ANNALS NEW YORK ACADEMY OF SCIENCES FIGURE 1. Neurons that showed the decrease + progressive reversal showed additional changes in firing. Part 1 and Part 2 each shows the behavior of a single animal and the tonic and phasic firing patterns of a single neuron recorded in that animal during one record-

3 PEOPLES et al. : REGULATION OF COCAINE SELF-ADMINISTRATION 783 Neurons that exhibited the decrease + progressive reversal firing pattern showed additional modulations in firing rate. First, almost all (51/58, 87.9%) the neurons showed either a decrease (33/58, 56.9%) (FIG. 1: 1C) or increase (18/58, 31.0%) (FIG. 1: 2C) in tonic firing rate during the self-administration session relative to the presession predrug recording period. Second, about half (27/58, 46.5%) of the neuing session. Each Part consists of six Panels labeled A E. Panel A. An interspike interval histogram shows the total number of interspike intervals in the recording session that were of durations 0.1 msec and 25.0 msec. The ordinate of the interspike interval histogram displays the number of counts (calculated as a function of 0.1 msec bins) and the abscissa displays the length (msec) of the interspike intervals. All neurons exhibited evidence of a minimum interspike interval consistent with the refractory period of a single neuron. To the left of the histogram are overlays of waveform traces (positive voltage is up). The vertical calibration bar on the left side of the waveform traces indicates 0.05 mv (i.e., amplitude of noiseband). Each waveform trace spans 0.64 msec. Panel B. Two functions are shown. At the top is a display of all lever presses made by the animal; underneath the display of lever presses is a graph of normalized calculated (cf. Ref. 12) drug level at the time of each reinforced lever press. Calculated drug level was normalized with respect to the maximum drug level attained in the session. The ordinate displays the percent (0 100%) of maximum drug level present at the time of the lever press (prior to the onset of the infusion). The display of lever presses and the graph of drug level are temporally aligned. Thus, the first and last point on the drug curve indicates the first and last self-infusion of cocaine, respectively. Although actual drug level (not shown) may have differed by some constant amount from that which was calculated, the drug accumulation curve demonstrates the degree to which the rate of self-infusion was likely to have maintained the level of drug in the body within stable limits. Panel C. A stripchart displays the tonic change in firing rate during the self-administration session relative to the presession predrug recording period. The ordinate displays firing rate (Hertz, Hz) and the abscissa displays time (min) during the recording session. The abscissa in Panel C is aligned temporally with the events shown in Panel B. Thus, in Panel C, firing during the self-administration session is shown directly below the drug curve, and firings during the predrug and postdrug recording periods are shown to the left and right of the drug curve, respectively. Panel 1C exemplifies a neuron that showed a decrease in tonic firing rate during the self-administration session, and Panel 2C exemplifies a neuron that showed an increase in tonic firing rate during the self-administration session. Panel D. A histogram shows the decrease + progressive reversal. Time 0 on the abscissa represents the occurrence of the reinforced lever press (i.e., self-infusion). Mins before and after the lever press are shown to the left and right of time 0, respectively. Average firing rate (i.e., average Hz per 0.1 min bin) is shown on the ordinate. Average firing was calculated across all leverpress trials, excluding both the first 8 10 presses and any lever presses bracketed by an interinfusion interval 6.0 min. Above the 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. As shown in the histogram, the firing rate decreased during the 1 min after self-infusion. Within 2 min after the infusion, the firing rate began to increase. The firing rate continued to progressively increase for the remainder of the interinfusion interval, until the firing rate approximated that present at the time of the previous self-infusion and the animal initiated the next self-infusion. Panel E. A histogram shows a phasic increase in firing during the secs before and after self-infusion. Time 0 on the abscissa represents the occurrence of the reinforced lever press. The secs before and after the lever press are shown to the left and right of time 0, respectively. The ordinate shows average firing rate (i.e., average Hz per 0.1 sec bin). Both 1E and 2E demonstrate common phasic changes in firing during the secs before and after self-infusion, i.e., an increase in the firing rate that began within the 3 secs before the cocaine reinforced lever press and ended within the 3 secs after self-infusion. 14 All tonic and phasic changes were statistically significant (Wilcoxon Matched Pairs test, α = 0.05, unidirectional; cf. Refs. 4,5,9).

4 784 ANNALS NEW YORK ACADEMY OF SCIENCES FIGURE 2. Histological localization of neurons. The nucleus accumbens is shown in each of six coronal plates (adapted from Paxinos and Watson 7 ). The rostral-caudal position, relative to bregma is indicated by the number in the upper right of each plate. Black symbols indicate the locations of neurons that exhibited the decrease + progressive reversal; gray symbols indicate the locations of all other neurons. Circles indicate wire tips identified by a lesion mark. Histological procedures were described previously; 4 stars indicate neurons located by interpolation based on lesion marks corresponding to the adjacent rostral and caudal wires. When multiple neurons were recorded from the same location, symbols were slightly offset in order to show all neurons.

5 PEOPLES et al. : REGULATION OF COCAINE SELF-ADMINISTRATION 785 rons exhibited a third type of firing pattern which consisted of a rapid phasic change in firing during the few secs before and/or after self-infusion (e.g., FIG. 1: 1E,2E). Neurons that did not exhibit the decrease + progressive reversal firing pattern rarely exhibited the rapid phasic changes in firing (11/63, 17%). This latter finding is suggestive of a functional and perhaps necessary or limiting relationship between the decrease + progressive reversal pattern and most of the rapid phasic firing patterns. Subterritorial Distribution Neurons along the entire rostral-caudal extent of the NAcc 6,7 exhibited the decrease + progressive reversal firing pattern (FIG. 2). However, neurons of the shell 8 tended to be less likely to show decrease + progressive reversals (4/17, 23.5%) relative to neurons in either the rostral one-fourth of the NAcc (area defined as rostral pole 8 ) (11/21, 52.4%) (χ 2 = 2.17, p >0.05), or the core (33/61,54%) (χ 2 = 3.8, p <0.05). This trend was consistent with the significantly lower likelihood of shell neurons to exhibit any type of phasic change in firing during the mins and/or secs before and after self-infusion (9/17, 52.9%) than either the rostral pole (18/21, 85.7%) (χ 2 = 3.4, p <0.05) or the core (51/61, 83.6%) (χ 2 = 6.13, p <0.05). DISCUSSION The decrease + progressive reversal firing pattern is the most common phasic change in firing time locked to drug self-infusion and is exhibited by a relatively large number of neurons. The firing pattern is unique relative to other phasic changes in exhibiting not only a time-locked synchronicity with the self-infusion behavior but also a time course equal to the interval that separates successive self-infusions 4 (all other phasic changes show only the time-locked synchronicity). Furthermore, the present data suggest that the decrease + progressive reversal firing pattern may be necessary to, or permissive of, other phasic changes. These data suggest that the decrease + progressive reversal pattern may be a particularly important component of the neurophysiological mechanisms that mediate the contribution of the NAcc to self-administration behavior. Self-infusion is importantly regulated by the pharmacokinetic time course of the self-administered drug (cf. Ref. 4). Certain data, some of which include the following (see also Refs. 4,9), indicate that the decrease + progressive reversal may be pharmacologically determined and may contribute to the mediation of the drug-induced regulation of self-administration behavior. First, the firing pattern closely mirrors changes in drug level as well as drug-induced changes in dopamine. 10 Second, a majority of neurons show a general inhibition of tonic firing rate during the selfadministration session. Thus, the decrease + progressive reversal could reflect a repeating pharmacological cycle which consists of an initial inhibition of firing caused by the most recent drug infusion and a subsequent gradual recovery from that inhibition. Other data are suggestive of a potential nonpharmacologic origin and function of the decrease + progressive reversal pattern. First, as noted above, about one third of the neurons show an overall increase in tonic firing during the self-administration session. Decrease + progressive reversal patterns exhibited by tonically excited neu-

6 786 ANNALS NEW YORK ACADEMY OF SCIENCES rons are unlikely to be due entirely to drug actions. Second, approximately half of all neurons that exhibit the decrease + progressive reversal pattern exhibit additional phasic increases in firing rate during the secs before and after self-infusion. 4,5 These rapid changes appear to be nonpharmacological and involved in the motivational (cf. Ref. 11) processing of the cocaine-related appetitive events. 1 3,12 Thus, at least half the decrease + progressive reversal neurons appear to be modulated by behaviorally related excitatory afferent input during the self-administration session. These data are consistent with the conclusion that there may be multiple, perhaps pharmacological and nonpharmacological, determinants of the decrease + progressive reversal firing pattern. The subterritorial topographical distribution of phasic firing patterns observed in the present study (see also Ref. 13) should be viewed as preliminary, given the number of neurons currently included in the analysis. However, a differential distribution of phasic firing is consistent with what one might expect on the basis of other research. The shell shows a number of unique anatomical and neurochemical characteristics relative to the remainder of the NAcc 6,8,14,15 and plays a distinct role in drug reinforcement (e.g., Ref. 16). ACKNOWLEDGMENTS Ms. Linda King, Mr. Patrick Grace, and Dr. Donald McNeil contributed technical support. The research was supported by NIDA Grant DA REFERENCES 1. BOWMAN, E.M., T.G. AIGNER & B.J. RICHMOND Neural signals in the monkey ventral striatum related to motivation for juice and cocaine rewards. J. Neurophysiol. 75: CARELLI, R.M. & S.A. DEADWYLER Cellular mechanisms underlying reinforcement-related processing in the nucleus accumbens: electrophysiological studies in behaving animals. Pharmacol. Biochem. Behav. 57: CHANG, J.-Y., S. F. SAWYER, R.-S. LEE & D.J. WOODWARD Electrophysiological and pharmacological evidence for the role of the nucleus accumbens in cocaine self-administration in freely moving rats. J. Neurosci. 14: PEOPLES, L.L. & M.O. WEST Phasic firing of single neurons in the rat nucleus accumbens correlated with the timing of intravenous cocaine self-administration. J. Neurosci. 16(10): PEOPLES, L.L., A.J. UZWIAK, F.X. GUYETTE & M.O. WEST Tonic inhibition of single nucleus accumbens neurons in the rat: a predominant but not exclusive firing pattern induced by cocaine self-administration sessions. Neuroscience 86: JONGEN-RÊLO, A.L., P. VOORN & H.J. GROENEWEGEN Immunohistochemical characterization of the shell and core territories of the nucleus accumbens in the rat. Eur. J. Neurosci. 6: PAXINOS, G. & C. WATSON The Rat Brain in Stereotaxic Coordinates. Academic Press. New York. 8. ZAHM, D.S. & L. HEIMER Specificity in the efferent projections of the nucleus accumbens in the rat: comparison of the rostral pole projection patterns with those of the core and shell. J. Comp. Neurol. 327: PEOPLES, L.L., F. GEE, R. BIBI & M.O. WEST Phasic firing time locked to cocaine self-infusion and locomotion: dissociable firing patterns of single nucleus accumbens neurons in the rat. J. Neurosci. 18(18):

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