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In this study, the expression patterns of zif268 and activity-regulated cytoskeleton-associated gene (arc) were investigated in the basolateral amygdala (BLA) and dorsal hippocampal (dHPC) subregions during context-induced drug-seeking following 22 h or 15 d abstinence from cocaine self-administration. Arc and zif/268 mRNA in BLA and dHPC increased after re-exposure to the cocaine-paired chamber at both timepoints; however, only the BLA increases (with one exception-see below) were differentially affected by the presence or absence of the cocaine-paired lever in the chamber. Following 22 h of abstinence, arc mRNA was significantly increased in the BLA of cocaine-treated rats re-exposed to the chamber only with levers extended, whereas following 15 d of abstinence, arc mRNA in the BLA was increased in cocaine-treated rats returned to the chamber with or without levers extended. In contrast, zif268 mRNA in the BLA was greater in cocaine-treated rats returned to the chamber with levers extended vs. levers retracted only after 15 d of abstinence. In the dentate gyrus (DG) following 22 h of abstinence, zif268 mRNA was greater in rats returned to the chamber where levers were absent regardless of drug treatment whereas arc mRNA was increased in CA1 (cell bodies and dendrites) and CA3 only in cocaine-treated groups. Following 15 d of abstinence, arc mRNA was significantly greater in CA1 and CA3 of both cocaine-treated groups returned to the chamber than in those placed into a familiar, non-salient alternate environment; however, only in CA1 cell bodies the cocaine context-induced increases significantly greater than in yoked-saline controls. In contrast, zif/268 mRNA in all dHPC regions was significantly greater in both cocaine-treated groups returned to the cocaine context than in the cocaine-treated group returned to an alternative environment or saline-treated groups. These data suggest that the temporal dynamics of arc and zif268 gene expression in the BLA and dHPC encode different key elements of drug context-induced cocaine-seeking., (Copyright 2010 IBRO. Published by Elsevier Ltd. All rights reserved.)

Reinstatement of extinguished drug-seeking has been utilized in the study of the neural substrates of relapse to drugs of abuse, particularly cocaine. However, limited studies have examined the circuitry that drives the reinstatement of heroin-seeking behavior in the presence of conditioned cues, or by heroin itself. In order to test the hypothesis that the circuitry underlying reinstatement in heroin-experienced animals would show overlapping, yet distinct differences from cocaine-experienced animals, we used transient inhibition of several cortical, striatal, and limbic brain regions during reinstatement of heroin-seeking produced by heroin-paired cues, or by a single priming dose of heroin. Rats lever pressed for i.v. heroin discretely paired with a conditioned stimulus (CS) during daily 3-h sessions for a period of 2 weeks, followed by daily extinction of lever responding. Subsequent reinstatement of heroin-seeking was measured as lever responding in the absence of heroin reinforcement. The first set of reinstatement tests involved response-contingent CS presentations following bilateral intracranial infusion of either a combination of GABA receptor agonists (baclofen-muscimol, B/M) or vehicle (saline) into one of 13 different brain regions. The second set of reinstatement tests involved a single heroin injection (0.25 mg/kg, s.c.) following either B/M or vehicle infusions. Our results showed that vehicle-infused animals reinstated to both CS presentations and a priming injection of heroin, while B/M inactivation of several areas known to be important for the reinstatement of cocaine-seeking also attenuated heroin-seeking in response to CS presentations and/or a priming dose of heroin. However, as predicted, inactivation of areas previously shown to not affect cocaine-seeking significantly attenuated heroin-seeking, supporting the hypothesis that the circuitry underlying the reinstatement of heroin-seeking is more diffusely distributed than that for cocaine.

The basolateral amygdala complex has been implicated in the formation and utilization of cocaine-cue associations in rat models of cue-induced reinstatement to cocaine-seeking behavior. We have previously demonstrated the importance of dopamine inputs to the basolateral amygdala complex in the reinstatement of cocaine-seeking behavior following chronic cocaine self-administration. Here we show that selective blockade of amygdalar dopamine D1 and D2 receptors during acquisition of cocaine-cue associations has distinctive effects on subsequent conditioned-cued cocaine-seeking behavior. Male, Sprague-Dawley rats were first trained to self-administer i.v. cocaine on a fixed ratio 1 schedule for 5 days. Subjects then received bilateral, intra-basolateral amygdala complex infusions of a dopamine D1 receptor antagonist (SCH23390, 0.25-2.0 microg/side; experiment 1), a dopamine D2 receptor antagonist (raclopride, 0.625-5.0 microg/side; experiment 2), or vehicle just prior to a single classical conditioning session, during which a light+tone cue was discretely paired with passive infusions of cocaine in the absence of lever responding. Following five additional days of cocaine self-administration and 7-10 days of extinction training, animals underwent multiple tests for cue-induced reinstatement. SCH23390 (2.0 microg/side), administered at the time of cocaine-cue association only, produced an attenuation of reinstatement to cue-induced cocaine-seeking behavior. In contrast, low doses of raclopride potentiated, while a higher dose of raclopride attenuated cue-induced reinstatement. These results demonstrate unique contributions of D1 vs. D2 receptors in mediating dopamine inputs within the basolateral amygdala complex during the formation of cocaine-stimulus associations that are critical for cue-induced reinstatement.

Recent evidence has demonstrated a critical role for the basolateral amygdala complex in the reinstatement of extinguished drug-seeking behavior produced by drug-paired cues. In the current study, we utilized a model of the acquisition and expression of cocaine-stimulus associative pairing in order to study the role of cholinergic input to the basolateral amygdala in mediating conditioned-cued reinstatement. Male, Sprague-Dawley rats were first trained daily to self-administer i.v. cocaine on a fixed ratio 1 schedule of reinforcement. The muscarinic acetylcholine receptor antagonist, scopolamine, was directly infused into the basolateral amygdala prior to: a) classically conditioned pairing of a tone+light stimulus with cocaine infusions (acquisition), or b) testing of conditioned-cued reinstatement following a period of withdrawal from cocaine and extinction of cocaine-paired lever responding. Infusion of scopolamine just prior to the classical conditioning trial produced a dose-dependent disruption of cocaine-seeking behavior maintained by cocaine-paired cues during the reinstatement test. In contrast, infusion of scopolamine prior to the reinstatement test had no effect on conditioned-cued reinstatement of cocaine-seeking behavior. These results indicate a crucial role for cholinergic innervation of muscarinic acetylcholine receptors in the basolateral amygdala during the formation, but not the expression, of stimulus-reward associations that mediate cue-induced cocaine-seeking behavior.

Using dual probe microdialysis, assessment of extracellular neurotransmitter levels in the corpus striatum and globus pallidus was performed in ovariectomized and gonadally intact female, Sprague-Dawley rats following chronic (24 weeks) oral haloperidol administration. Vacuous chewing movements, an animal analog of orofacial dyskinesia, were also recorded at several time points during haloperidol administration and throughout the dialysis sampling session. Basal GABA levels were significantly elevated in the globus pallidus of haloperidol-treated rats compared with vehicle animals. Injection of the dopamine D(1) agonist dihydrexidine (3mg/kg, s.c.) decreased striatal dopamine levels in both vehicle and haloperidol-treated rats, with a larger decrease seen in haloperidol-treated rats. Furthermore, dihydrexidine reduced striatal 3,4-dihydroxyphenylacetic acid and homovanillic acid levels only in haloperidol-treated rats. Gonadal status had no effect on any neurochemical measure. Vacuous chewing movements were significantly elevated in haloperidol-treated groups by the sixth week of treatment, with higher counts seen in gonadally intact rats. Vacuous chewing movements were significantly elevated above baseline in all groups following dihydrexidine, with no differential effect of prior haloperidol treatment or gonadal status. These results indicate a tonic increase in pallidal GABA levels and a hypersensitivity of D(1)-mediated striatal dopamine and dopamine metabolite decreases following chronic haloperidol treatment. While not found to be correlated with neurochemical measures, the heightened vacuous chewing movements in gonadally intact vs ovariectomized rats may serve as a model of hormone-mediated differences in neuroleptic-induced oral dyskinesia.

Parameters of cocaine self-administration behavior and vaginal cytological changes were assessed in ovariectomized rats during and after chronic self-administration. Response to novelty as measured by locomotor activity was found to correlate with cocaine self-administration on both fixed ratio (FR) and progressive ratio (PR) schedules of reinforcement. Chronic 17-beta estradiol (E2) replacement did not affect cocaine self-administration on FR or PR schedules of reinforcement. Acute E2 administration decreased cocaine self-administration on a PR schedule of reinforcement on the day of and on the two days following hormone treatment. Finally, the proliferation of vaginal epithelia following acute E2 was potentiated in rats both during cocaine self-administration and 30 days into withdrawal when compared with non-drug-exposed animals. These results identify response to novelty as a behavioral index predictive of cocaine self-administration liability in female rats and additionally provide evidence of psychostimulant-hormonal interactions highly relevant to female behavior and physiology.

Chronic neuroleptic administration has been shown to selectively increase striatal extracellular glutamate concentration. In the current study, age-matched female rats were administered chronic oral fluphenazime or no drug via their drinking water for 3 or 32 weeks. Microdialysis probes were inserted into the ventrolateral caudate putamen and the medial nucleus accumbens and dialysis samples were analyzed for glutamate and gamma-aminobutyric acid (GABA) concentrations Glutamate levels were significantly increased only in the ventrolateral caudate putamen after 32 weeks. No significant effects were seen for GABA levels. Neuroleptic-induced enhancement of striatal glutamate levels thus appears to increase with chronic exposure and this increase may relate to late onset motor side effects.

The effects of unique profile antipsychotic drugs on dopamine D2 receptors and D2 receptor messenger RNA were assessed following subchronic administration in rats. Male, Sprague-Dawley rats were administered oral haloperidol, clozapine, metoclopramide or no drug for three weeks via their drinking water. Tissue from the medial nucleus accumbens and dorsolateral caudate-putamen was dissected and analyzed by Northern blot analysis for levels of dopamine D2 receptor messenger RNA and binding assays conducted with [3H]spiperone for dopamine D2 receptors. Haloperidol and metoclopramide, but not clozapine, significantly increased [3H]spiperone in the caudate-putamen, but not the nucleus accumbens. Clozapine significantly decreased D2 messenger RNA levels in the caudate-putamen and the nucleus accumbens, while metoclopramide and haloperidol had no significant effect in either brain region. The finding of decreased D2 receptor messenger RNA levels produced by subchronic clozapine may account for the lack of striatal D2 receptor up-regulation, which was robustly observed after subchronic haloperidol and metoclopramide. Furthermore, since haloperidol and metoclopramide have a high liability for motor side effects, the current results relate favorably to the low motor side effect profile of clozapine.

Rats administered chronic haloperidol or clozapine in their drinking water for 6 months were monitored for changes in oral movements using a computerized video analysis system. Haloperidol-treated animals exhibited late onset increases in small amplitude oral movements and an increase in the percentage of oral movements in the 1-2 Hz range, accompanied by a decrease in oral movements in the higher frequency range (> 6 Hz) as determined by fast fourier analysis. In contrast, clozapine-treated rats showed a decrease in medium-sized amplitude oral movements, but did not demonstrate significant changes in the distribution of oral movements across frequencies. Extracellular concentrations of gamma-aminobutyric acid (GABA) and glutamate in the ventrolateral striatum were then assessed by intracranial microdialysis during oral drug administration and 3 days after drug withdrawal. Extracellular GABA and glutamate levels were not significantly different between groups during drug administration. However, 3 days after drug withdrawal, there was a significant increase in glutamate in the haloperidol-treated rats. No changes were noted for glutamate levels in clozapine-treated rats or for GABA levels in either group following withdrawal. These results confirm the atypical profile of clozapine in an animal model of tardive dyskinesia and suggest that alterations in striatal glutamatergic function follow typical, but not atypical, antipsychotic drug administration.

The extracellular levels of dopamine (DA) and DA metabolites in the caudate-putamen (CPu) and the nucleus accumbens (NA) of rats following administration of haloperidol (HAL) decanoate and fluphenazine (FLU) decanoate for 8 months were assessed using intracranial microdialysis 1 month after final injection. Both HAL- and FLU-treated animals showed persisting plasma neuroleptic levels at time of sacrifice. Extracellular basal levels of homovanillic acid (HVA) in the CPu were significantly elevated in the FLU-treated animals, while basal levels of 3,4-dihydroxyphenylacetic acid (DOPAC) in the CPu were significantly elevated in the HAL-treated animals. Basal levels of DA and the serotonin metabolite, 5-hydroxyindoleacetic acid (5HIAA) in the CPu were not significantly different between groups. No significant between-group differences were found for basal levels of any of the analytes in the NA. Neuroleptic-treated animals showed an enhanced response to direct infusion through the dialysis probe of amphetamine (1 microM) and nomifensine (10 microM) in the CPu but not the NA. These results suggest that chronic neuroleptic treatment produces enhanced extracellular DA activity in nigrostriatal, but not mesolimbic DA pathways.

Rats were administered haloperidol, clozapine, raclopride, or no drug for either 28 days or 8 months and then withdrawn from drug treatment for 3 weeks. Oral movements were repeatedly recorded, both by a human observer and by a computerized video analysis system which determined mouth openings and closings, or computer-scored movelets (CSMs). Four weeks of neuroleptic administration produced no changes in CSMs in any drug-treated group. Long-term administration induced distinctively different patterns of oral activity in the three drug groups, both in number of CSMs and the form of these movements. The oral movements which developed in the haloperidol-treated rats fit a previously described syndrome of late-onset oral dyskinesias which increased upon drug withdrawal. The clozapine- and raclopride-treated rats did not show the increased oral movements seen in the haloperidol animals, but each exhibited uniquely different CSM characteristics compared to controls. The results from this rodent model imply that haloperidol, but not clozapine or raclopride, produces late-onset oral dyskinesias in rats that fit the pattern expected for tardive dyskinesia.