c-Fos and deltaFosB expression are differentially altered in distinct subregions of the nucleus accumbens shell in cocaine-sensitized rats.

Repeated cocaine administration in rats can lead to sensitization as evidenced by an increased locomotor response to a subsequent exposure (challenge) dose of cocaine even after a drug-free period. Expression of the immediate early gene product, c-Fos, differs among distinct subregions of the nucleus accumbens shell. This would suggest that these subregions may be differentially involved in sensitization. The present study quantified c-Fos- and deltaFosB-immunoreactive nuclei in subterritories of the nucleus accumbens in animals behaviorally sensitized to cocaine. Rats received a sensitization-inducing regimen of cocaine (twice-daily injections of 15 mg/kg i.p. for five consecutive days). Fourteen days following the last injection, rats were given a challenge injection of cocaine (15 mg/kg i.p.), and killed 2 h later. Sections through the nucleus accumbens were processed for tyrosine hydroxylase and either c-Fos or deltaFosB. The number of immunoreactive nuclei was quantified in five subregions of the nucleus accumbens shell: the vertex, arch, cone, intermediate zone and ventrolateral zone, which can be identified by differential histological staining for tyrosine hydroxylase. Repeated cocaine administration resulted in robust sensitization that was associated with more deltaFosB in the vertex, arch, and cone compared with saline-treated controls. As previously reported, c-Fos immunoreactivity was increased in the intermediate zone in cocaine-sensitized rats. deltaFosB was significantly elevated in rats that did not receive a cocaine challenge, attesting to the long half-life of this transcription factor. These results provide further evidence suggesting distinct anatomical neuroadaptations within the nucleus accumbens shell that may play a functional role in psychomotor-stimulant sensitization.

Differential distribution of parvalbumin immunoreactive neurons in the striatum of cocaine sensitized rats.

Intermittent administration of psychostimulants such as cocaine and amphetamine can result in behavioral sensitization, which is believed to model the onset of drug addiction, as well as possible neural adaptations that lead to addictive behaviors. The dorsal striatum and the nucleus accumbens (NAc) have been shown to play an integral role in this phenomenon. However, these structures comprise a complex neuroanatomical organization, and few studies have correlated anatomical differentiation within these brain regions with functional (i.e. behavioral) outcome, particularly after psychostimulant exposure. Parvalbumin (PV)-containing GABAergic interneurons are a key neuronal cell population that can significantly regulate input-output functions in these brain regions. The present study quantified parvalbumin-immunoreactive cells in subterritories of the striatum and NAc in animals behaviorally sensitized to cocaine. Rats received a sensitization-inducing regimen of cocaine (twice-daily injections of 15 mg/kg i.p. for 5 consecutive days). Two or 14 days following the last injection, rats were given a challenge injection of cocaine (15 mg/kg i.p.), and killed 2 h later. Sections through the striatum (including the NAc) were processed for parvalbumin immunoreactivity, and the number of immunoreactive neurons was quantified. Repeated cocaine administration resulted in robust sensitization that correlated with transient increases in the number of PV immunoreactive neurons in the ventrolateral, dorsolateral and dorsomedial striatum. After a 2-week withdrawal period, sensitized animals showed a significant decrease in the number of PV+ neurons in the ventrolateral shell of the NAc and dorsomedial striatum, and no significant difference in any other area examined. These data suggest a dichotomous role for PV interneurons in different subterritories of the striatum and NAc during the short-term (induction) vs. long-term (expression) phases of cocaine sensitization.

Withdrawal duration differentially affects c-fos expression in the medial prefrontal cortex and discrete subregions of the nucleus accumbens in cocaine-sensitized rats.

Intermittent administration of cocaine can result in behavioral sensitization, which is indicated by an augmented behavioral response to a subsequent administration of cocaine. This increase in behavior can be seen after various periods of abstinence from the drug, and is believed to model the cravings of drug users and the onset of drug addiction. It is believed that behavioral sensitization is mediated by activity of the mesocorticolimbic dopamine system. In particular, the nucleus accumbens and prefrontal cortex have been shown to play integral roles in this phenomenon. Recently, it has been demonstrated that the shell portion of the nucleus accumbens can no longer be considered a homogeneous structure, and can be subdivided into five separate regions. The present study was designed to assess the activation of key neuronal populations in subdivisions of the accumbens and subdivisions of the medial prefrontal cortex in cocaine-sensitized rats, using the expression of the immediate early gene, c-fos, as a marker of neuronal activation. Repeated cocaine administration resulted in robust sensitization that correlated with a significant decrease in the density of c-fos nuclei in all three subdivisions of the medial prefrontal cortex, and two subdivisions of the nucleus accumbens only in animals challenged after a 2-day withdrawal period. After a 2-week withdrawal period, sensitized animals no longer showed any differences in the density of c-fos nuclei in any of the areas examined, with the exception of a significant increase in the intermediate zone of the shell. The results indicate that distinct adaptations in neural activation take place in cocaine-sensitized rats that have been drug-free for various lengths of time. Furthermore, while specific subregions of brain areas known to play a role in drug abuse can be uniquely involved in the manifestations of cocaine sensitization, the functional roles of these subregions may differ depending on the time at which the behavior is assessed.

Effects of isolation-rearing on intracranial self-stimulation reward of the lateral hypothalamus: baseline assessment and drug challenges.

There is evidence that isolation rearing produces down-regulation of the dopamine D2 receptor. Therefore, isolation rearing should also modify the effects of D2 antagonists on intracranial self-stimulation (ICSS) reward. This study investigated the effect of isolation rearing on ICSS reward, and modulation of that reward by SCH23390, Raclopride and MK-801. Sprague-Dawley rats were reared alone (isolates) or in pairs from day 21 postnatal to day 75 postnatal. At this time, all rats were implanted with monopolar stimulating electrodes in the lateral hypothalamus. The ICSS rate-frequency curve-shift method was used to assess reward and operant motor function at baseline and after administration of SCH-23390 (D1 antagonist: 0.02, 0.06, 0.2 mg/kg), Raclopride (D2 antagonist: 0.01, 0.025, 0.06 mg/kg), and MK-801 (non-competitive NMDA receptor antagonist: 0.1, 0.2 mk/kg). Isolation-reared rats displayed similar measures of both basal reward and motor function when compared to socially reared controls. Isolation-reared rats were subsensitive to the reward decreasing effects of Raclopride. Socially reared rats were observed to have more variant baseline reward measures, and could be divided into distinctly different groups with different basal reward function. Isolation-rearing down-regulates D2 function but does not affect basal reward function, but some unknown factor in the social rearing environment did have a substantial effect on basal reward function.

Neither ibotenic acid nor volkensin lesions of the nucleus accumbens shell affect the expression of cocaine sensitization.

Studies have shown that the nucleus accumbens shell plays an integral role in the expression of psychostimulant-induced behavioural sensitization. Dopaminergic regulation of excitatory amino acid inputs in this region of the brain could be a key factor in the neural influence of this phenomenon. Alterations in the dopaminergic innervation patterns in the shell have been demonstrated in rats that received repeated cocaine injections. Furthermore, lesions of brain regions that send projections to the shell alter psychostimulant-induced locomotion, both acutely and in sensitization paradigms. A previous study from our laboratory demonstrated that lesions of the shell before repeated cocaine treatment decrease the locomotor response to cocaine during the induction phase of behavioural sensitization. To better understand the role of this brain region during the expression phase of behavioural sensitization, the present study examined the effects of two forms of cytotoxic lesions of the shell. Rats received a sensitization-inducing regimen of cocaine (bi-daily injections of 15 mg/kg i.p. for 5 consecutive days). Two days after the last injection, rats demonstrating behavioural sensitization received one of three bilateral microinjections into the shell: (i) 0.5 micro L 0.9% saline; (ii) 2.5 micro g/0.5 micro L ibotenic acid (which lesions the cell bodies at the injection site); or (iii), 0.5 ng/0.2 micro L of volkensin (a retrograde suicide transport lectin). Upon challenge with cocaine (15 mg/kg) 12 days after surgery, neither ibotenic acid- nor volkensin-lesioned rats showed any difference in their locomotor response compared with sham controls. These data indicate that bilateral shell lesions do not affect the long-term expression of behavioural sensitization in cocaine-sensitized rats.

CGP 44532, a GABAB receptor agonist, is hedonically neutral and reduces cocaine-induced enhancement of reward.

Drugs that alter the function of gamma-aminobutyric acid (GABA) neurotransmission seem to reduce cocaine reinforcement, and as such may be useful in pharmacologically treating cocaine addiction. In the present experiment, the anti-cocaine effects of CGP 44532, a phosphinic acid analogue of GABA, and a highly selective GABA(B) receptor agonist were examined in male Sprague-Dawley rats using brain stimulation reward (BSR) paradigm. In this method, the relationship between the rate of bar pressing and the frequency of stimulation pulses was analyzed in two measures: the maximum rate of responding (MAX) and the frequency necessary to sustain half maximal rate of responding known as the locus of rise (LOR). CGP 44532 was found to be hedonically neutral without producing any measurable effects on performance (MAX). It also dose-dependently reduced cocaine-induced BSR enhancement, in the order of 15-31%, as shown by progressive shifts in LOR towards baseline. Thus, in theory, administration of CGP 44532 might reduce cocaine's hedonic effects, while also maintaining patient compliance. Whether this agent would also be effective at curbing craving, a long-term consequence of drug abuse, remains to be determined.

The dorsomedial shell of the nucleus accumbens facilitates cocaine-induced locomotor activity during the induction of behavioral sensitization.

The mesolimbic dopamine system has been intensely studied as the neural circuit mediating the locomotor response to psychostimulants and behavioral sensitization. In particular, the dopaminergic innervation of the nucleus accumbens has been implicated as a site responsible for the manifestations of behavioral sensitization. Previous studies have demonstrated an augmented release of dopamine in the nucleus accumbens upon a systemic injection of a psychostimulant. In addition, alterations in the dopaminergic innervation patterns in this brain region have been demonstrated in animals that received repeated injections of cocaine. Furthermore, lesions of projection sites that have terminations in the nucleus accumbens have demonstrated alterations in psychostimulant induced locomotion, both acutely, as well as in sensitization paradigms. Since dopamine in the nucleus accumbens is believed to regulate several excitatory amino acid inputs, the present study examined the effects of a localized electrolytic lesion in the dorsomedial shell of the nucleus accumbens in order to better understand the functional role this brain region has in behavioral sensitization. All animals received bi-daily injections of 15 mg/kg i.p. cocaine. Only those demonstrating behavioral sensitization after a subsequent challenge dose were included in the analysis. Following acute exposure to cocaine, lesioned animals did not show any difference in their locomotor response when compared with sham controls. However, after repeated exposure to cocaine, sensitized animals demonstrated a significant attenuation in locomotor behavior when compared with sensitized sham controls. This decrease in horizontal locomotion persisted 2 days into withdrawal, yet dissipated in the sensitized animals that were challenged 2 weeks following their last injection. The data presented here demonstrate that the dorsomedial shell of the nucleus accumbens plays an important role in the initial stages of behavioral sensitization to cocaine.

Electrophysiological and behavioral output of the rat basal ganglia after intrastriatal infusion of d-amphetamine: lack of support for the basal ganglia model.

Dopamine, by acting upon D1 and D2 dopamine receptors located on striatonigral and striatopallidal neurons, respectively, has been postulated to inhibit output from the substantia nigra pars reticulata (SNpr) and internal pallidal segment (GPi). The inhibition of the SNpr/GPi should, in turn, disinhibit the thalamus to facilitate movement. The present study tests this prediction in intact (unlesioned) rats by attempting to correlate changes in the single unit activities of SNpr neurons with motor (i.e. behavioral) responses in the 20-30 min after infusions of d-amphetamine into the striatum. Unilateral injections of amphetamine (20 microg/microl) into either the dorsal-rostral, central, or ventral-lateral striatum failed to appreciably alter behavior and, in parallel electrophysiological studies, failed to consistently or significantly alter the activities of SNpr neurons in either chloral hydrate-anesthetized rats or awake locally anesthetized rats. However, when amphetamine was infused bilaterally into the ventral-lateral striatum (VLS; 20 microg/microl per side), a robust behavioral activation ensued (increased locomotor activity, oral movements, and sniffing) with an onset ranging from immediate to 20 min post-infusion and persisting for at least 40 min. In parallel studies, bilateral amphetamine infusions into VLS also caused changes in the firing frequency of a majority of SNpr neurons. However, the changes in firing were extremely variable and, contrary to expectation, the net population response of SNpr neurons was an increase in firing which corresponded in time with the period of peak behavioral activation. These results show that (i) bilateral but not unilateral activation of striatal dopamine receptors is needed to elicit behavioral and electrophysiological output from the basal ganglia, and (ii) motor activation is apparently not signaled by a generalized inhibition of SNpr firing, as is predicted by the basal ganglia model.

Repeated exposure to rewarding brain stimulation downregulates GluR1 expression in the ventral tegmental area.

There is considerable evidence that drug reward and brain stimulation reward (BSR) share common neural substrates. Although it is known that exposure to drugs of abuse causes a variety of molecular changes in brain reward systems, little is known about the molecular consequences of BSR. We report that repeated exposure to rewarding stimulation of the medial forebrain bundle (MFB) selectively decreases expression of GluR1 (an AMPA receptor subunit) in the VTA, without effect on expression of several other proteins (GluR2, NMDAR1, tyrosine hydroxylase). This effect of BSR on GluR1 expression is opposite of that caused by intermittent exposure to cocaine and morphine, which are known to elevate GluR1 expression in the VTA. Considering that elevated GluR1 expression in the VTA has been associated with increased sensitivity to drug reward, the finding that BSR and drugs of abuse have opposite effects on GluR1 expression in this region may provide an explanation for why the reward-related effects of many drugs (cocaine, morphine, amphetamine, PCP, nicotine) do not sensitize with repeated testing in BSR procedures that quantify reward strength.

Effects of repeated GBR 12909 administration on brain stimulation reward.

Male rats were trained at three separate currents to bar press for intracranial self-stimulation. On days 1 and 15, all subjects were given 1-(2-bis(4-fluorophenyl)-methoxy)-ethyl-4-(3-phenylpropyl) piperazine, also known as GBR 12909 (10 mg/kg, i.p.), prior to test session. Between these days, the paired Chronic-before group was injected (every other day) with GBR 12909 prior to intracranial self-stimulation, while unpaired, Chronic-after group was given the drug just after the end of the session. A third group (Control) received saline injections (i.p.) 20 min following the session. Although GBR 12909 was found to be reward enhancing, neither sensitization nor tolerance developed to the rewarding and performance/motor effects regardless of the injection regimen. In addition, the rewarding effects of intracranial self-stimulation were found to be independent of both current and environment-specific pairing. The present data obtained for GBR 12909 agree with previous observations of the effects of repeated administration of drugs of abuse on intracranial self-stimulation.

Novel monoamine transporter ligands reduce cocaine-induced enhancement of brain stimulation reward.

Six novel monoamine reuptake inhibitors were screened for their intrinsic effects on brain stimulation reward (BSR), as well as for their potential to reduce cocaine-induced reward-enhancement in that paradigm. Two of the compounds, nocaine-3B and 5-ara-74A (disubstituted piperidines) significantly reduced locus of rise (LOR), threshold measure of reward, at some doses. One compound, 1-RV-96A (a hybrid of the GBR and WIN-like agents) significantly reduced reward (increased LOR), but only at the highest dose tested. No effect of dose was found for MC9-20 (a GBR-like acyclic analogue of the N-bisarylmethoxyethyl-N'-phenylpropyl piperazine), nocaine-250B or 4-ara-42C (disubstituted piperidines). When cocaine (10 mg/kg, ip) and selected, hedonically neutral doses of novel compounds were combined, the following findings were obtained: MC9-20 (2.5 mg/kg, ip) showed a significant increase in cocaine-induced reward enhancement (0.2 log units or 53%). In contrast, nocaine-250B and 1-RV-96A (both at 10 mg/kg, ip) demonstrated a significant reduction (0.13 log units or 41%) in cocaine-induced reward enhancement (P<.01 and P<.05, respectively), as measured by changes in LOR. There were no differences in the maximum behavioral output (MAX) at either dose of each of the six drugs, or when selected doses were combined with cocaine. These results indicate that nocaine-250B and 1-RV-96A constitute two potential anticocaine compounds worthy of further behavioral and biochemical evaluation.

Assessment of tyrosine hydroxylase immunoreactive innervation in five subregions of the nucleus accumbens shell in rats treated with repeated cocaine.

To explore the effects of behavioral sensitization on the anatomy of the nucleus accumbens shell, we employed a typical cocaine dosing paradigm and assessed tyrosine hydroxylase immunoreactive varicosities in five different areas of the shell, as well as the core of the nucleus accumbens. Rats were given bidaily injections of either saline (1 ml/kg i.p.) or cocaine (15 mg/kg i.p.) for 5 consecutive days, and sacrificed either 2 or 14 days from the last injection. Sections of the nucleus accumbens were processed for tyrosine hydroxylase immunoreactivity and the number of immunoreactive varicosities in contact with neuronal cell bodies was quantified in each of the subregions of the shell, as well as the core of the nucleus accumbens. Compared to saline controls, the cocaine-treated animals showed a significant augmentation in tyrosine hydroxylase immunoreactivity in two of the five subregions after 2 days of withdrawal in the shell, but not in the core. No differences were found in any region tested after 14 days of withdrawal. These data are the first to suggest that increases in nucleus accumbens presynaptic tyrosine hydroxylase may play a role in the development of behavioral sensitization, but not in the long-term expression of this phenomenon.

Repeated cocaine treatment alters tyrosine hydroxylase in the rat nucleus accumbens.

To determine whether repeated exposure of cocaine affects the dopaminergic innervation of the nucleus accumbens, we employed a typical cocaine-dosing regimen in adult male Sprague-Dawley rats followed by an immunocytochemical analysis of tyrosine hydroxylase (TH). Treatment consisted of bi-daily injections of saline or 15 mg/kg cocaine for 5 consecutive days. After 2 or 14 days of withdrawal, sections of the nucleus accumbens (NAc) were processed for tyrosine hydroxylase and the number of immunoreactive varicosities in the core and shell were quantified. Two days after treatment, the core demonstrated a decrease, while after 14 days of treatment, the shell was found to contain significantly more TH immunoreactive varicosities. Additionally, 2 days post-cocaine treatment, core-shell differences were found, however moderate differences were also found in the saline treatment group, making the absolute effects of cocaine difficult to separate from injection and handling effects at this time point. These results suggest that the shell of the NAc may undergo alterations that could be involved with behavioral sensitization that typically results from such cocaine treatment regimens.

An examination of glutamate decarboxylase(65) immunoreactive puncta with respect to rat ventral pallidum neurons after repeated cocaine administration.

The ventral pallidum is known to have topographically organized reciprocal gamma-aminobutyric acid-ergic projections with the nucleus accumbens, and changes in these connections may play a role in mediating the behavioral sensitizing effect of repeated exposure to cocaine. The present study investigated glutamate decarboxylase-65 (GAD(65)) immunoreactivity in the rat ventral pallidum after repeated cocaine administration. Male Sprague-Dawley rats were administered bi-daily injections of 15 mg/kg cocaine or saline vehicle for 5 consecutive days. After 2 or 14 days of withdrawal, ventral pallidal sections were immunocytochemically processed for GAD(65) immunoreactive puncta and counts were made. In both groups, there were no statistically significant differences in the number or density of GAD(65) puncta in medial or lateral portions either in contact with neuronal cell bodies or in the neuropil after 2 or 14 days of withdrawal. The results suggest that there is no alteration in the number of GABAergic boutons expressing GAD(65) immunoreactivity in the ventral pallidum after repeated exposure to cocaine.

A simple design for a small fixed four-electrode brain stimulation array.

Anatomical studies of intracranial self-stimulation (ICSS) reward in rats often use the lesion method and, therefore, require repeated behavioral testing before and after the lesion. Other anatomical studies on unlesioned rats use a moveable electrode to permit testing at a number of ICSS sites. Combining these methods would yield still more information, but repeated testing is not possible due to the damage created by lowering the electrode. To meet this need, an array of 4 fixed vertically-spaced electrodes was devised. Electrodes are constructed from strands of 0.14-mm (0.0045'') Teflon-insulated stainless-steel wire, 4 of which are glued into an implantable bundle. A 4-channel IC rotary switch is implanted on the rat's head to permit the use of an inexpensive 2-channel electrode lead and commutator. In our laboratory, electrodes were vertically spaced at 0.3 mm, spanning the dorsoventral extent of the lateral hypothalamus and yielded stable rate-frequency curves over the usual 3-4 month period of behavioral testing.

A simple and reliable method for delivering small fluid volumes to the brain of a freely moving rat.

A stepper motor-powered micropump for making intracerebral microinjections in freely moving animals is described. The micropump is capable of delivering fluid volumes of up to 20 microl in steps of 17 nl The system does not require a fluid swivel, delivers injections rapidly, maintains long-term calibration accuracy and is not susceptible to blockage of the cannula.

NMDA-induced lesions of the nucleus accumbens or the ventral pallidum increase the rewarding efficacy of food to deprived rats.

The role of the nucleus accumbens (NAC) and ventral pallidum (VP) in food reward modulation was investigated using Heyman's [24] curve fitting approach in food deprived rats. All rats were maintained at 80% normal body weight, and trained to lever press for food reinforcement. Each rat was tested daily with a series of four variable-interval (VI) reinforcement schedules (80, 40, 20, and 10 s) designed to approximate an exponential distribution, and randomly administered in ascending or descending order. The maximum response rate (Rmax) and the reinforcement rate required to maintain half-maximal responding (Re50) were recorded for each rat's daily test session. Following the establishment of baseline responding, the excitotoxin N-methyl-D-aspartic acid (NMDA) was bilaterally administered into the NAC (30 micrograms per side) or VP (20 micrograms per side) over a 10 min period. Both groups displayed substantial damage to the intended structure, with the lateral regions typically sustaining more damage than medial regions, and minor damage to surrounding areas. When tested at three weeks post-lesion, a suppression of motor activity was evident in all animals when compared to pre-lesion baseline. Moreover, in almost all rats, Re50 decreased, suggesting that the rewarding efficacy of food had increased. These data are surprising, given the extensive literature on the relationship between damage in the NAC and loss of reward efficacy. However, based on pharmacological and anatomical findings, both brain regions have been divided into several subregions. Behavioral studies suggest that these subregions may differentially regulate reward and motor functions. The results from the present study suggest that (1) both the NAC and VP are involved in the modulation of food reward, (2) that lateral subregions in each structure may function to dampen food reward efficacy, and (3) that medial subregions may enhance food reward.

Measurement issues in curve-shift analysis of apomorphine effects on rewarding brain stimulation.

The direct dopamine agonist apomorphine has been reported to reduce the rewarding efficacy of lateral hypothalamic (LH) self-stimulation. This effect has been claimed to support the notion that dopamine mediates the rewarding effects of LH self-stimulation. Using a standard rate-frequency curve-shift paradigm with ascending order of frequency presentation, we also found that apomorphine (0.1-0.8 mg/kg, SC) appeared to decrease LH self-stimulation reward. These apparent rightward curve shifts were exacerbated by shortening the test duration, which also produced a number of sessions in which the subjects did not respond at all. When the presentation order of stimulation frequencies was reversed, apomorphine did not produce large reward decreases. These results suggest that the previously reported effects of apomorphine on LH self-stimulation were the result of artifact, perhaps related to apomorphine-induced stereotypical behavior combined with rapid pharmacological recovery.

Reward shifts and motor responses following microinjections of opiate-specific agonists into either the core or shell of the nucleus accumbens.

Differences in pharmacology, anatomical connections, and receptor densities between the "core" and "shell" of the nucleus accumbens suggest that behavioral activity normally modulated by the accumbens, such as reward and motor functions, may be differentially regulated across the mediolateral axis. This study investigated the effects of opiate receptor-specific agonists on reward and motor functions in either the accumbens core or shell, using the intracranial self-stimulation (ICSS) rate-frequency curve-shift method. Microinjections of the mu opiate receptor-specific agonist, DAMGO (vehicle, 0.03 nmol, and 0.3 nmol), or the delta opiate receptor-specific agonist DPDPE (vehicle, 0.3 nmol, 3.0 nmol), were administered bilaterally in a random dose order with a minimum of 3 days between injections. Rats were tested over three consecutive 20-min rate-frequency curves immediately following a microinjection to investigate the time course of drug effects. Both opiate agonists decreased the ICSS frequency necessary to maintain half-maximal response rates when injected into the medial and ventral shell region of the accumbens. However, DAMGO microinjections into the lateral accumbens core or the control site of the caudate increased the frequency necessary to elicit half-maximal response rates, while DPDPE microinjections into these regions had no effect. Evaluation of motor effects show that administration of DAMGO resulted in a suppression of activity in all locations. In contrast, DPDPE microinjections resulted in little or no effect on lever pressing activity at any location.

Comparison of delta opiate receptor agonist induced reward and motor effects between the ventral pallidum and dorsal striatum.

The role of the ventral pallidum and the dorsal striatum in mediating the rewarding effects of the delta receptor specific agonist [2-D-penicillamine, 5-D-penicillamine]enkephalin (DPDPE) were evaluated in the rat using the intracranial self-stimulation paradigm. Reward shifts were indicated by the change in frequency required to maintain half-maximal responding while motor/performance changes were identified by increases or decreases in the maximum responding. Each hour-long test session consisted of three identical, consecutive 20 min rate-frequency curves. In an effort to ascertain possible heterogeneity of function along the rostrocaudal axis, DPDPE (0.0 nmol = saline dose, 0.3 nmol = low dose, 1.0 nmol = medium dose, 3.0 nmol = high dose) was microinjected into either the rostral or caudal region of the two structures. Microinjections into the caudate were positioned directly above the ventral pallidum placements resulting in centromedial or caudomedial caudate placements. DPDPE microinjections into the rostral ventral pallidum resulted in a significant reward increase (28% increase or -0.14 log Hg shift) only at the high dose. In contrast, caudal ventral pallidal DPDPE microinjections showed a dose-response effect with reward increases of 19, 22 and 31% (-0.09, -0.11 and -0.16 log Hz) for the low, medium and high dose, respectively. DPDPE microinjections into the centromedial caudate resulted in a large reward increase (29% or -0.15 log Hz) at the high dose, while caudomedial caudate DPDPE microinjections had no effect on reward. Motor/performance effects tended to follow the pattern of reward effects, with most regions showing motor increases ranging from 25 to 75% over baseline activity. The only exception was found in the caudomedial caudate, where microinjections of the high dose of DPDPE resulted in an approximate 20% suppression of motor/performance activity. These results demonstrate that the ventral pallidum and the mediocentral caudate play a role in modulating opiate rewards, and adds to the growing body of literature regarding the regional heterogeneity within the caudate and ventral pallidum.