Ly T.L. Tran-Nguyen

Time-Dependent Changes in Cocaine-Seeking Behavior and Extracellular Dopamine Levels in the Amygdala during Cocaine Withdrawal

Cocaine and cocaine-associated cues elicit craving in addicts and reinstate cocaine-seeking behavior in rats. Craving and cocaine-seeking behavior may be mediated by withdrawal-induced changes in dopamine (DA) neurotransmission in the amygdala. To examine whether there are concomittant changes in cocaine-seeking behavior and extracellular DA levels during withdrawal, experimental rats were trained to self-administer cocaine (0.75 mg/kg IV). After 14 daily 3-hour training sessions, animals underwent either a 1-day, 1-week, or 1-month withdrawal period. Extracellular DA levels were assessed during baseline, extinction, cue reinstatement, and cocaine (15 mg/kg IP) reinstatement of cocaine-seeking behavior (i.e., defined as the difference in nonreinforced lever presses on an active minus inactive lever). Cocaine-seeking behavior became more intense during the course of cocaine withdrawal. Additionally, basal and cocaine-induced extracellular DA levels were enhanced after the 1-month withdrawal period. We suggest that the former may reflect a persistent elevation in tonic extracellular DA levels in the amygdala, whereas the latter may reflect a persistent elevation in phasic extracellular DA levels.

Dopamine Overflow in the Nucleus Accumbens during Extinction and Reinstatement of Cocaine Self-Administration Behavior

Both cocaine and cocaine-associated stimuli can reinstate extinguished self-administration behavior in animals. It has been suggested that reinstatement of drug-seeking behavior may be mediated by enhanced dopamine (DA) neurotransmission. To examine this hypothesis, DA overflow was measured in the nucleus accumbens (NAc) of rats during both extinction and cocaine-induced reinstatement of self-administration behavior. Rats were either allowed to self-administer cocaine for 3 hours daily for 14 days, or they received yoked administration of saline. A stimulus light above the lever was illuminated during drug delivery. Baseline DA overflow was measured in the NAc, using in vivo microdialysis 7 to 8 days after the last self-administration session. The rats were then placed into the operant chambers and allowed to respond in extinction for 90 minutes, during which responses resulted in presentation of the stimulus light. The rats then received a cocaine injection that reinstated self-administration behavior. Contrary to our hypothesis, cocaine-experienced animals exhibited less DA overflow in the NAc relative to controls during both extinction and reinstatement.

Predictive validity of the extinction/reinstatement model of drug craving

Abstract The effects of chronic desmethylimipramine (DMI) treatment on measures of incentive motivation for cocaine were assessed in order to investigate the predictive validity of the extinction/reinstatement model of drug craving. Rats were trained to respond for cocaine infusions (0.75 mg/kg per 0.1 ml IV) or received yoked-saline infusions during daily 3-h sessions. A light and tone were presented with the infusions. Following self-administration training, each group received daily injections of either saline or DMI (10 mg/kg, IP) for 21 days of withdrawal from the self-administration regimen. On days 12–21 of withdrawal, rats were allowed to respond in the absence of cocaine reinforcement (extinction phase). After reaching an extinction criterion of no responses for 1 h, the cocaine-paired stimuli were repeatedly presented to reinstate responding (reinstatement phase). In the control group, DMI treatment did not alter responding during either test phase, but increased the response latency during the extinction phase. In contrast, DMI treatment in the cocaine group decreased responding and increased the response latency during both test phases, and decreased the extinction latency during the extinction phase. Overall, the effects of DMI were consistent with a reduction of incentive motivation for cocaine, lending support for the predictive validity of the extinction/reinstatement model of drug craving.

Increases in dopamine D3 receptor binding in rats receiving a cocaine challenge at various time points after cocaine self-administration: implications for cocaine-seeking behavior.

Previous research suggests that cocaine dysregulates dopamine D3 receptors. The present study examined the time course of changes in dopamine D3 receptor binding after terminating a cocaine self-administration regimen. [125I]-7-hydroxy-2-[N-propyl-N-(3′-iodo-2′-propenyl)-amino]-tetralin was used to label dopamine D3 receptors in rats that had undergone testing for cocaine-seeking behavior reinstated by a cocaine priming injection (15 mg/kg, i.p.; the behavior results have been previously published), and were killed 24 h after the test at time points that were either 2, 8, or 31–32 days after their last cocaine self-administration session. The results indicated a time-dependent increase in D3 receptor binding relative to controls that received saline yoked to the delivery of cocaine in an experimental animal. Specifically, there was no significant change in D3 receptor binding in cocaine-experienced rats killed at the 2- or 8-day time points relative to controls, but there was an increase in D3 receptor binding in the nucleus accumbens core and ventral caudate-putamen in rats killed at the 31- to 32-day time point. In a subsequent experiment, we replicated the increase in D3 receptor binding in rats that underwent a less extensive self-administration regimen, then were tested for cocaine-primed reinstatement of cocaine-seeking behavior, and then were killed 24 h later at a time point of 22 days after their last self-administration session. Furthermore, the increase in binding was attenuated by repeated 7-hydroxy-N,N-di-n-propyl-2-aminotetralin administration (1 mg/kg/day, s.c. for 14 days), a regimen that also reduces cocaine-seeking behavior in animals when tested in a nondrug state. Collectively, the findings suggest that regulatory responses of D3 receptors may be functionally related to changes in propensity for cocaine-seeking behavior.

Serotonin depletion attenuates cocaine-seeking behavior in rats.

Abstract Rationale: Alterations in serotonin (5-HT) neurotransmission during cocaine withdrawal may be involved in incentive motivation for cocaine. Objective: The present study examined the effects of 5-HT depletion on cocaine- and food-seeking behavior (i.e., non-reinforced operant responding). Methods: Separate groups of rats were trained to lever press for cocaine infusions (0.33 mg/kg/0.1 ml, i.v.) or for food pellets (45-mg Noyes food pellets) on a fixed-ratio one schedule of reinforcement during 14 daily 2-h sessions. Half of each group then received treatment with either saline or the tryptophan hydroxylase inhibitor para-chlorophenylalanine (p-CPA; 100 mg/kg, i.p.) on post-training day 5 and day 6. Twenty-four hours after their last treatment, rats were tested for cocaine- or food-seeking behavior by measuring operant responding in the absence of reinforcement until they reached an extinction criterion of no responses for 30 min. Animals were sacrificed 24 h after testing and brain 5-HT levels in various regions were quantified. Results: In cocaine-trained animals, p-CPA treatment significantly decreased cocaine-seeking behavior and produced a trend toward a decrease in extinction latency relative to saline treatment. In food-trained animals, p-CPA treatment failed to alter any of the behavioral measures during testing, suggesting that p-CPA treatment did not alter the animals’ memory or ability to perform an operant response. p-CPA significantly depleted 5-HT by 73–85% in every brain region examined. Conclusion: The results suggest that decreasing 5-HT neurotransmission may decrease incentive motivation for cocaine.

The role of the striatum in organizing sequences of play fighting in neonatally dopamine-depleted rats

Juvenile rats sustaining dopamine depletions by intraventricular injections of 6-hydroxydopamine (6-OHDA) as neonates were used to study the role of the striatum in controlling play fighting. As juveniles, the rats exhibited all the behavior elements typical of play fighting. However, they were more likely to use defensive tactics that shortened the playful contact between partners; and when contacting the partner, they were more likely to switch to other behaviors, such as allogrooming and sexual mounting, rather than continue with the play sequence. It is suggested here that the striatum is important for maintaining sequential organization of play fighting.

Making two movements at once: Impairments of movement, posture, and their integration underlie the adult skilled reaching deficit of neonatally dopamine-depleted rats

Adult rats depleted bilaterally of dopamine in infancy display a profound impairment in skilled forelimb use in reaching for food. This impairment was investigated using end-point measures of reaching success, movement analysis, and kinematic measures. The rats made few successful reaches in either an easy or a difficult reaching test. Their reaches were characterized by many attempts in which trajectories of the limb were irregular and the movements were slow. Their lack of success was related in part to an impairment in making component movements of the reach, including aiming, pronating, grasping, and supinating the paw and in releasing the food pellet. It was also related to an inability to adjust posture as the limb was voluntarily moved toward the food. The results are consistent with the hypotheses that the basal ganglia, including its dopamine innervation, is important for enabling voluntary movements and postural adjustments and perhaps also the simultaneous performance of two movements at the same time.

Effects of 7-OH-DPAT on cocaine-seeking behavior and on re-establishment of cocaine self-administration.

Effects of the D2-like dopamine agonist, 7-hydroxy-N,N-di-n-propyl-2-aminotetralin (7-OH-DPAT), on cocaine-seeking behavior and re-establishment of cocaine self-administration were examined. Rats were trained to lever press for cocaine infusions (0.25 mg/kg iv). Some were then tested for cocaine-seeking behavior (i.e., lever presses in the absence of cocaine re-inforcement) immediately following acute 7-OH-DPAT (0.001, 0.01, 0.1, or 1.0 mg/kg sc) or saline administration. Others were tested immediately or 2-23 h following repeated daily 7-OH-DPAT (1.0 mg/kg sc) or saline administration for extinction of cocaine-seeking behavior, cocaine re-instatement of cocaine-seeking behavior, and re-establishment of cocaine self-administration following extinction. 7-OH-DPAT-induced changes in locomotion were also assessed. Cocaine-experienced animals exhibited cross-tolerance to the transient hypoactivity produced by acute 7-OH-DPAT administration. Acute administration of low doses (0.01-0.1 mg/kg) of 7-OH-DPAT attenuated cocaine-seeking behavior, whereas the highest dose (1.0 mg/kg) initially attenuated, then increased, cocaine-seeking behavior. In animals tested immediately following one of the repeated administrations, 7-OH-DPAT did not alter cocaine self-administration, but sensitized locomotion. Repeated 7-OH-DPAT administration also increased cocaine-seeking behavior when administered 0 h, but not 2 or 4 h, before cocaine priming (15 mg/kg ip) and testing. In animals tested 17-23 h following one of the repeated administrations, cocaine-seeking behavior and re-establishment of cocaine self-administration were attenuated, but maintenance of self-administration following re-establishment, cocaine re-instatement of extinguished cocaine-seeking behavior, and spontaneous locomotion were unaltered. The findings suggest that following repeated administration, 7-OH-DPAT produces a transient increase (<2 h) in incentive motivation for cocaine that is followed by a protracted decrease in incentive motivation for cocaine.

Acute reserpine administration elicits long-term spontaneous oral dyskinesia.

Chronic reserpine administration produces persistent oral dyskinesia accompanied by severe dopamine depletion in the caudate-putamen. The present study examined whether these behavioral and neurochemical effects would persist following acute reserpine administration. Acute administration of reserpine (1 mg/kg, s.c.) produced spontaneous oral dyskinesia that persisted above control levels for at least 84 days. Reserpine also produced a 74% depletion of dopamine in the caudate-putamen relative to vehicle treatment at 3 days post-injection, but did not significantly alter dopamine in the caudate-putamen at 84 days post-injection. The finding that reserpine-induced oral dyskinesia persisted despite repletion of dopamine in the caudate-putamen suggests that the persistent neuropathological change underlying this behavior occurs in a neural pathway other than the dopaminergic nigrostriatal pathway.

Amphetamine Infused Into the Ventrolateral Striatum Produces Oral Stereotypies and Conditioned Place Preference

The effects of amphetamine infused into the ventrolateral striatum (VLS) on locomotion, stereotypies, and conditioned place preference (CPP) were investigated. Five 2-day conditioning trials were conducted over 10 consecutive days. On 1 day of each trial, animals received an infusion of amphetamine (0, 2.5, 5, 10, or 20 mg/0.5 ml/side) and were placed into a distinct compartment for 30 min. On the other day, animals received sham intracranial infusions and were placed into a different compartment for 30 min. Locomotion and stereotypies were assessed following the first and last amphetamine infusions. CPP was assessed the day following the last conditioning trial. Intra-VLS infusions of amphetamine did not alter sniffing or locomotion. Acute administration of amphetamine into the VLS dose dependently produced oral stereotypies, however, tolerance developed to this effect following repeated administrations. Also, intra-VLS infusions of amphetamine dose dependently produced CPP. These results suggest that the VLS is involved in amphetamine-induced oral stereotypies and reward.