Locomotor activity and cocaine-seeking behavior during acquisition and reinstatement of operant self-administration behavior in rats

Recent studies indicate that administration of dopamine D2-like receptor agonists reinstates drug-seeking behavior in rodents, whereas dopamine D1-like receptor agonists do not. These effects have been related to the ability of these agonists to facilitate the expression of sensitized locomotor activity. Presently, we describe experiments in which locomotor activity was assessed concomitantly with operant performance during acquisition, extinction and reinstatement. We report that locomotor activity was inversely related to drug-seeking behavior during acquisition of cocaine self-administration under a Fixed Ratio (FR) 1 schedule of reinforcement. During a single trial extinction session, animals that had acquired cocaine self-administration exhibited a conditioned increase in drug-seeking behavior, but there was no evidence of a conditioned locomotor response. During reinstatement, cocaine (20 mg/kg) significantly increased both locomotor activity and drug-seeking behavior. The dopamine D2-like receptor agonist quinpirole (0.5 mg/kg) increased drug-seeking behavior, but did not significantly increase locomotor activity. In contrast, the dopamine D1-like receptor agonist SKF 81297 (0.5 mg/kg) failed to reinstate drug-seeking behavior, but produced significant locomotor activation. To determine whether the inability of SKF 81297 to promote reinstatement is related to the strength of operant conditioning, additional rats were trained to self-administer cocaine using an FR-3 schedule of reinforcement. Despite achieving response rates during training almost four times higher compared to the FR-1 condition, administration of SKF 81297 again failed to significantly increase drug-seeking behavior during reinstatement testing. These results extend previous findings, confirming the important role of D2-like, but not D1-like receptor activation in the reinstatement of drug-seeking behavior. An understanding of the mechanisms by which D1- and D2-like agonists differentially influence locomotor activation and drug-seeking behavior in cocaine-experienced rodents may prove critical to the development of increasingly effective pharmacotherapies for substance abuse.     

Role of GluR1 expression in nucleus accumbens neurons in cocaine sensitization and cocaine-seeking behavior

Chronic cocaine use reduces glutamate levels in the nucleus accumbens (NAc), and is associated with experience-dependent changes in (+/-)-alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) glutamate receptor membrane expression in NAc neurons. These changes accompany behavioral sensitization to cocaine and increased susceptibility to cocaine relapse. The functional relationship between neuroplasticity in AMPA receptors and the behavioral manifestation of cocaine addiction remains unclear. Thus, we examined the behavioral effects of up- and downregulating basal AMPA receptor function in the NAc core and shell using viral-mediated gene transfer of wild-type glutamate receptor 1 (wt-GluR1) or a dominant-negative pore-dead GluR1 (pd-GluR1), respectively. Transient increases in wt-GluR1 during or after cocaine treatments diminished the development of cocaine sensitization, while pd-GluR1 expression exacerbated cocaine sensitization. Parallel changes were found in D2, but not D1, receptor-mediated behavioral responses. As a correlate of the sensitization experiments, we overexpressed wt- or pd-GluR1 in the NAc core during cocaine self-administration, and tested the effects on subsequent drug-seeking behavior 3 weeks after overexpression declined. wt-GluR1 overexpression during self-administration had no effect on cocaine intake, but subsequently reduced cocaine seeking in extinction and cocaine-induced reinstatement, whereas pd-GluR1 facilitated cocaine-induced reinstatement. When overexpressed during reinstatement tests, wt-GluR1 directly attenuated cocaine- and D2 agonist-induced reinstatement, while pd-GluR1 enhanced reinstatement. In both experimental procedures, neither wt- nor pd-GluR1 expression affected cue-induced reinstatement. Together, these results suggest that degrading basal AMPA receptor function in NAc neurons is sufficient to facilitate relapse via sensitization in D2 receptor responses, whereas elevating basal AMPA receptor function attenuates these behaviors.     

Acute administration of SB-277011A, NGB 2904, or BP 897 inhibits cocaine cue-induced reinstatement of drug-seeking behavior in rats: role of dopamine D3 receptors

Recent studies have shown that the novel dopamine (DA) D3 receptor antagonists SB-277011A and NGB 2904 inhibit cocaine- and/or stress-induced reinstatement of drug-seeking behavior. The present study sought to determine if SB-277011A, NGB 2904, or BP-897 (a mixed D3 agonist/antagonist) similarly inhibit cocaine-associated cue-induced reinstatement of drug-seeking behavior. Long-Evans rats were allowed to self-administer cocaine. Each cocaine infusion was paired with discrete conditioned cue-light and tone. Subsequently, drug-seeking (i.e., lever-pressing) behavior was extinguished in the absence of cocaine and cocaine-associated cues. Rats were then tested for cue-induced reinstatement of drug-seeking. We found that cocaine-associated cues evoked robust reinstatement of lever-pressing. Acute intraperitoneal (i.p.) administration of SB-277011A (6, 12, or 24 mg/kg) produced a dose-dependent inhibition of cue-induced reinstatement of drug-seeking behavior by 35, 65, and 85%, respectively, compared to vehicle-treated animals. Acute i.p. administration of NGB 2904 (0.1, 1.0, or 5.0 mg/kg) produced a 45, 30, and 70% inhibition of cue-induced reinstatement, respectively, compared to vehicle-treated animals. Acute i.p. administration of either 0.1 or 1 mg/kg of BP 897 did not produce a significant effect on cue-induced reinstatement, whereas a dose of 3 mg/kg produced a 70% inhibition of cue-induced reinstatement. These findings, combined with previous data, suggest that DA D3 receptor antagonism may underlie the inhibitory effects of SB-277011A and NGB 2904 on cocaine cue-induced reinstatement, while the effects of BP 897 may involve D3 and non-D3 receptor mechanisms.     

Adenosine A2A receptors in the nucleus accumbens bi-directionally alter cocaine seeking in rats

Repeated cocaine administration enhances dopamine D(2) receptor sensitivity in the mesolimbic dopamine system, which contributes to drug relapse. Adenosine A(2A) receptors are colocalized with D(2) receptors on nucleus accumbens (NAc) medium spiny neurons where they antagonize D(2) receptor activity. Thus, A(2A) receptors represent a target for reducing enhanced D(2) receptor sensitivity that contributes to cocaine relapse. The aim of these studies were to determine the effects of adenosine A(2A) receptor modulation in the NAc on cocaine seeking in rats that were trained to lever press for cocaine. Following at least 15 daily self-administration sessions and 1 week of abstinence, lever pressing was extinguished in daily extinction sessions. We subsequently assessed the effects of intra-NAc core microinjections of the A(2A) receptor agonist, CGS 21680 (4-[2-[[6-amino-9-(N-ethyl-b-D-ribofuranuronamidosyl)-9H-purin-2-yl]amino]ethyl]benzenepropanoic acid hydrochloride), and the A(2A) receptor antagonist, MSX-3 (3,7-dihydro-8-[(1E)-2-(3-methoxyphenyl)ethenyl]-7-methyl-3-[3-(phosphonooxy)propyl-1-(2-propynyl)-1H-purine-2,6-dione disodium salt hydrate), in modulating cocaine- and quinpirole-induced reinstatement to cocaine seeking. Intra-NAc pretreatment of CGS 21680 reduced both cocaine- and quinpirole-induced reinstatement. These effects were specific to cocaine reinstatement as intra-NAc CGS 21680 had no effect on sucrose seeking in rats trained to self-administer sucrose pellets. Intra-NAc treatment with MSX-3 modestly reinstated cocaine seeking when given alone, and exacerbated both cocaine- and quinpirole-induced reinstatement. Interestingly, the exacerbation of cocaine seeking produced by MSX-3 was only observed at sub-threshold doses of cocaine and quinpirole, suggesting that removing tonic A(2A) receptor activity enables behaviors mediated by dopamine receptors. Taken together, these findings suggest that A(2A) receptor stimulation reduces, while A(2A) blockade amplifies, D(2) receptor signaling in the NAc that mediates cocaine relapse.     

Attenuation of cocaine-seeking by progesterone treatment in female rats

Clinical research suggests that gender differences exist in cocaine dependence. Similarly, preclinical studies have shown that female rats exhibit higher response rates during cocaine self-administration, early extinction, and cocaine-primed reinstatement of drug-seeking. These effects are also estrous cycle dependent and inversely related to plasma progesterone, in that proestrus females (high progesterone) exhibit less cocaine-seeking, while estrous females (low progesterone) show the greatest cocaine-seeking. Based on these findings, we hypothesized that progesterone would attenuate cocaine-seeking behavior in intact, freely cycling animals. The role of the estrous cycle on cocaine-seeking behavior during early (first acquisition day) versus late (last maintenance day) cocaine self-administration was also examined. Female, Sprague-Dawley rats self-administered cocaine (0.5 mg/kg/infusion, IV) along a FR1 schedule, followed by daily extinction sessions in the absence of cocaine reinforcement. Once responding was extinguished, rats received an injection of cocaine (10 mg/kg, IP) immediately prior to reinstatement testing. Progesterone (2 mg/kg, SC) or vehicle was administered 20 and 2h prior to the first day of extinction (early cocaine withdrawal) and the reinstatement trials. To determine estrous cycle phase, we assessed vaginal cytology prior to the first acquisition and last maintenance days of cocaine self-administration, the first day of extinction training, and each reinstatement test. During early and late cocaine self-administration, proestrus and estrous females exhibited the greatest levels of active lever responding, respectively. A significant increase in responding also occurred during cocaine-primed reinstatement for estrous versus nonestrous females, an effect that was selectively attenuated by progesterone. However, progesterone was not effective at reducing cocaine-primed reinstatement for females in other phases of the estrous cycle, nor was it effective at reducing cocaine-seeking during early withdrawal. Taken together, these results suggest that progesterone may be a useful therapeutic for preventing relapse in abstinent female cocaine users, especially when the likelihood of relapse is greatest.     

Prazosin, an alpha-1 adrenergic antagonist, reduces cocaine-induced reinstatement of drug-seeking.

BACKGROUND: Norepinephrine is implicated in cocaine's behavioral effects. In this study, we tested the effect of prazosin, an alpha1-adrenergic receptor antagonist, on cocaine-induced reinstatement of drug-seeking behavior. METHODS: Rats were trained to self-administer cocaine intravenously under a fixed-ratio 3 schedule of reinforcement. After behavior was established, cocaine was replaced with saline and behavior extinguished. The ability of cocaine (0, 5-20 mg/kg) alone or combined with prazosin (.3 mg/kg) to reinstate lever press responding was tested. The effects of prazosin on lever press responding for food was examined in another set of rats. RESULTS: Cocaine induced a dose-dependent reinstatement of drug-seeking behavior that was significantly attenuated by prazosin. This dose of prazosin did not alter lever press response rates for food. CONCLUSIONS: The attenuation in drug-induced reinstatement is likely not due to prazosin-induced suppression of activity. These results suggest alpha1-adrenergic mechanisms contribute to reinstatement in rats and perhaps, to relapse in addicts.     

Aripiprazole: pharmacology, efficacy, safety and tolerability

Aripiprazole is a recently released antipsychotic medication which differs from other atypical antipsychotic agents by its partial agonist activity at postsynaptic D2 receptors. It is administered orally and is distinguished by a long elimination phase half-life relative to other antipsychotic medications. Randomized studies have demonstrated the efficacy of aripiprazole relative to placebo in the treatment of acute relapse of schizophrenia and schizoaffective disorder, maintenance treatment of schizophrenia, and treatment of acute bipolar mania. Aripiprazole is generally well tolerated relative to other antipsychotic medications, although commonly reported side effects include worsening extrapyramidal symptoms and motoric activation similar to akathisia. Further studies and postmarketing data will be helpful in providing additional information about the comparative safety, efficacy and tolerability of aripiprazole.     

Stimulation of D1-like or D2 dopamine receptors in the shell, but not the core, of the nucleus accumbens reinstates cocaine-seeking behaviour in the rat

Although increases in dopamine transmission in the brain are clearly involved in the reinstatement of cocaine seeking, the role of nucleus accumbens dopamine in cocaine priming-induced reinstatement remains controversial. The goal of these experiments was to evaluate the relative contributions of D1-like and D2-like dopamine receptors in the nucleus accumbens core and shell in the reinstatement of cocaine-seeking behaviour. Initially, rats were trained to press a lever for cocaine (0.25 mg, i.v.) using a fixed-ratio 5 (FR5) schedule of reinforcement. Responding was then extinguished by substituting saline for cocaine. During the reinstatement phase, subtype-specific dopamine receptor agonists were microinjected into the nucleus accumbens core or medial shell in order to assess their ability to induce cocaine seeking. Administration of the D1/D5 dopamine receptor agonist SKF-81297 (1.0 microg) into the nucleus accumbens shell, but not core, reinstated drug-seeking behaviour. Similarly, microinjection of quinpirole (3.0 microg), a D2/D3 dopamine receptor agonist, into the nucleus accumbens shell and not core reinstated drug-seeking behaviour. In contrast, administration of the D3- or D4-preferring dopamine receptor agonists PD 128,907 (1.5 and 3.0 microg) and PD 168,077 (0.3 and 3.0 microg), respectively, did not promote reinstatement when administered into either the core or the shell. Taken together, these results indicate that activation of D1/D5 or D2 dopamine receptors, in the limbic shell subregion of the nucleus accumbens but not the basal ganglia-orientated accumbens core, promotes the reinstatement of cocaine-seeking behaviour.     

Mirtazapine attenuates cocaine seeking in rats

BackgroundRelapse to cocaine use is a major problem in the clinical treatment of cocaine addiction. Antidepressants have been studied for their therapeutic potential to treat cocaine use disorder. Research has suggested that antidepressants attenuate both drug craving and the re-acquisition of drug-seeking and drug-taking behaviors. This study examined the efficacy of mirtazapine, an antidepressant/anxiolytic, in decreasing cocaine seeking in rats.MethodsWe used the cocaine self-administration paradigm to assess the effects of mirtazapine on rats trained to self-administer cocaine or food under a fixed-ratio schedule. Mirtazapine (30 mg/kg, i.p.) was administered during extinction.ResultsMirtazapine significantly attenuated non-reinforced lever-press responses during extinction. Moreover, the mirtazapine dosed for 30 days during extinction produced sustained attenuation of lever-press responses during re-acquisition of cocaine self-administration, without changing food-seeking behavior. Our results showed that mirtazapine attenuated the re-acquisition of cocaine-seeking responses.ConclusionOur study pointed to the efficacy of mirtazapine in reducing the risk of drug relapse during abstinence, suggesting for its potential use as a novel pharmacological agent to treat drug abuse.     

Drug‐induced reinstatement of heroin‐ and cocaine‐seeking behaviour following long‐term extinction is associated with expression of behavioural sensitization

The present study was designed to evaluate the relationship between reinstatement of drug-seeking behaviour following long-term extinction of intravenous (i.v.) drug self-administration (an animal model for craving) and long-term behavioural sensitization. Rats were allowed to self-administer heroin (50 μg/kg per inj., 14 daily sessions), cocaine (500 μg/kg per inj., 10 daily sessions) or saline. Following a 3-week extinction period, reinstatement tests were performed to evaluate priming effects of amphetamine, cocaine and heroin on non-reinforced drug-seeking behaviour. In addition, the occurrence of long-term behavioural sensitization in rats with a history of heroin or cocaine self-administration was determined. Heroin-seeking behaviour was reinstated by heroin (0.25 mg/kg), amphetamine (1.0 mg/kg) and cocaine (10 mg/kg). In addition, animals with a history of heroin self-administration displayed locomotor sensitization to both heroin and amphetamine. Cocaine-seeking behaviour was reinstated by cocaine and amphetamine, but not by heroin. Interestingly, locomotor sensitization to amphetamine, but not heroin, was observed in animals with a history of cocaine self-administration. In other words, the induction of drug-seeking behaviour following a prolonged drug-free period was found to be associated with the expression of long-term behavioural sensitization. These data provide experimental evidence for a role of behavioural sensitization in the incentive motivation underlying drug-seeking behaviour. If drug hyperresponsiveness would indeed be a crucial factor in drug-induced craving in human addicts, pharmacological readjustment of the neuroadaptations underlying drug sensitization may prevent relapse to drug use long after detoxification.     

Context-dependent prefrontal cortex regulation of cocaine self-administration and reinstatement behaviors in rats

Evidence of stimulus attribute-specificity within the prefrontal cortex (PFC) suggests that different prefrontal subregions may contribute to cocaine addiction in functionally distinct ways. Thus, the present study examined the effects of lidocaine-induced inactivation of two distinct PFC subregions, the prelimbic (PL) or dorsal agranular insular (AId) cortices, on drug-seeking and drug-taking behaviors under cocaine maintenance and reinstatement testing conditions in rats trained to self-administer 1 mg/kg cocaine under a second-order schedule of drug delivery. Throughout maintenance and reinstatement phases, rats were exposed to conditioned light cues and contextual odor or sound cues. Results showed that PL inactivation during maintenance test sessions significantly reduced drug-seeking and drug-taking behaviors, and disrupted patterns of responding in rats exposed to light-sound, but not light-odor, cues. Moreover, lidocaine-induced inactivation of the PL significantly attenuated drug-seeking behavior during cue-induced and cocaine prime-induced reinstatement in rats exposed to light-sound cues only. In contrast, AId inactivation significantly attenuated cue-induced reinstatement of drug-seeking behavior in rats exposed to light-odor cues only. Drug-seeking and drug-taking behaviors in these rats were not disrupted during maintenance and cocaine prime-induced reinstatement testing regardless of the type of contextual cues used. Together, these data suggest that PL and AId subregions play separate yet overlapping roles in regulating cocaine addiction in rats in ways that are dependent on the presence or absence of cocaine and on the types of contextual cues present in the cocaine self-administration environment.     

The novel antipsychotic aripiprazole is a partial agonist at short and long isoforms of D2 receptors linked to the regulation of adenylyl cyclase activity and prolactin release

Aripiprazole is a novel antipsychotic with a unique mechanism of action, which differs from currently marketed typical and atypical antipsychotics. Aripiprazole has been shown to be a partial agonist at the D(2) family of dopamine (DA) receptors in biochemical and pharmacological studies. To demonstrate aripiprazole's action as a partial D(2) agonist in pituitary cells at the molecular level, we retrovirally transduced the short (D(2S)) and the long (D(2L)) form of the human DA D(2) receptor gene into a rat pituitary cell line, GH4C1. [(3)H]-raclopride saturation binding analyses revealed a B(max) value approximately four-fold higher at D(2S) receptor-expressing GH4C1 cells than at D(2L) receptor-expressing GH4C1 cells, while a K(d) value was similar. Aripiprazole inhibited forskolin-stimulated release of prolactin in both D(2S) and D(2L) receptor-expressing GH4C1 cells, whereas the maximal inhibition of prolactin release was less than that of DA. Similarly, aripiprazole partially inhibited forskolin-induced cAMP accumulation in both D(2) receptor-expressing cells. Aripiprazole antagonized the suppression attained by DA (10(-7) M) in both D(2) receptor-expressing cells and, at the maximal blockade of cAMP, yielded residual cAMP levels equal to those produced by aripiprazole alone. These results indicate that aripiprazole acts as a partial agonist at both D(2S) and D(2L) receptors expressed in GH4C1 cells. These data may explain, at least in part, the observations that aripiprazole shows a novel antipsychotic activity with minimal potential for adverse events including no significant increase of serum prolactin levels in clinical studies.     

Aripiprazole,an antipsychotic with a novel mechanism of action,and risperidone vs placebo in patients with schizophrenia and schizoaffective disorder

BACKGROUND: Aripiprazole is a dopamine D2 receptor partial agonist with partial agonist activity at serotonin 5HT1A receptors and antagonist activity at 5HT2A receptors. This multicenter trial examined the efficacy, safety, and tolerability of aripiprazole in patients with acute exacerbation of schizophrenia or schizoaffective disorder. METHODS: In this 4-week double-blind study, 404 patients were randomized to 20 mg/d (n = 101) or 30 mg/d (n = 101) of aripiprazole, placebo (n = 103), or 6 mg/d of risperidone (n = 99). Efficacy assessments included Positive and Negative Syndrome Scale (PANSS) scores and Clinical Global Impression scores. Safety and tolerability evaluations included extrapyramidal symptoms and effects on weight, prolactin, and corrected QT (QTc) interval. RESULTS: Aripiprazole (20 and 30 mg/d) and risperidone (6 mg/d) were significantly better than placebo on all efficacy measures. Separation from placebo occurred at week 1 for PANSS total and positive scores with aripiprazole and risperidone and for PANSS negative scores with aripiprazole. There were no significant differences between aripiprazole and placebo in mean change from baseline in the extrapyramidal symptom rating scales. Mean prolactin levels decreased with aripiprazole but significantly increased 5-fold with risperidone. Mean change in QTc interval did not differ significantly from placebo with any active treatment group. Aripiprazole and risperidone groups showed a similar low incidence of clinically significant weight gain. CONCLUSIONS: Aripiprazole is effective, safe, and well tolerated for the positive and negative symptoms in schizophrenia and schizoaffective disorder. It is the first non-D2 receptor antagonist with clear antipsychotic effects and represents a novel treatment development for psychotic disorders.     

Neural circuit competition in cocaine-seeking: roles of the infralimbic cortex and nucleus accumbens shell

Following cocaine self-administration and extinction training, activity in the infralimbic cortex (IL) suppresses cocaine-seeking behavior. IL inactivation induces cocaine-seeking whereas activation suppresses cocaine-reinstated drug-seeking. We asked how the suppression of cocaine-seeking induced by IL activation integrates with the circuitry promoting reinstated cocaine-seeking. Following cocaine self-administration and extinction training, rats underwent cue-induced reinstatement. In order to activate IL projections, microinjections of PEPA, a positive allosteric modulator of AMPA receptors, were made into the IL in combination with microinjections into a variety of nuclei known to regulate cocaine-seeking. Intra-IL PEPA administration suppressed cue-induced reinstatement without affecting locomotor activity. The suppression of cocaine-seeking was reversed by activating dopamine neurons in the ventral tegmental area with microinjections of the μ-opioid receptor agonist DAMGO, and was partially reversed by dopamine microinjections into the prelimbic cortex or basolateral amygdala. Previous evidence suggests that the nucleus accumbens shell both promotes and suppresses cocaine-seeking. The suppression of cue-induced cocaine seeking by PEPA in the IL was reversed by intra-shell microinjections of either dopamine or the AMPA receptor antagonist CNQX, suggesting that the accumbens shell bidirectionally regulates cocaine-seeking depending on whether dopamine input is mimicked or glutamate input is inhibited. Together, these findings indicate that the IL acts 'upstream' from structures promoting cocaine-seeking, including from the mesolimbic dopamine projections to the prelimbic cortex and basolateral amygdala, and that the accumbens shell may be a crucial point of integration between the circuits that promote (ventral tegmental area) and inhibit (IL) reinstated cocaine-seeking.     

The novel mGluR2/3 agonist LY379268 attenuates cue-induced reinstatement of heroin seeking

In humans, drug-associated stimuli can provoke heroin relapse during abstinence. In rats, cues paired with heroin self-administration reinstate heroin seeking in a relapse model. The neurobiological mechanisms involved in this reinstatement, however, are largely unknown. Here, we determined the effect of LY379268, an mGluR2/3 agonist that decreases evoked glutamate release, on cue-induced reinstatement of heroin seeking. Systemic injections of LY379268 attenuated reinstatement of heroin seeking induced by exposure to a discrete tone-light cue that was previously paired with heroin infusions during self-administration training. In contrast, LY379268 had no effect on heroin self-administration. Results indicate that glutamate plays an important role in cue-induced reinstatement of heroin seeking and suggest that mGluR2/3 agonists should be considered for the treatment of opiate relapse.     

The limbic circuitry underlying cocaine seeking encompasses the PPTg/LDT

The direct glutamatergic projection from the medial prefrontal cortex (mPFC) to the nucleus accumbens plays a critical role in mediating the reinstatement of cocaine seeking behavior. The mPFC also sends glutamatergic projections to the pedunculopontine tegmental nucleus (PPTg) and laterodorsal tegmental nucleus (LDT), which in turn send glutamatergic and cholinergic efferents to the ventral tegmental area (VTA) where they synapse on dopaminergic cells that innervate limbic structures including the nucleus accumbens. The goal of these experiments was to examine a potential role for the PPTg/LDT in the reinstatement of cocaine seeking. All rats were trained to self-administer cocaine (0.25 mg, i.v.) on a fixed-ratio 5 schedule of reinforcement. Cocaine self-administration behavior was extinguished and a series of subsequent pharmacological experiments were performed to assess the potential role of the mPFC, PPTg/LDT and VTA in the reinstatement of cocaine seeking. Administration of the D1-like dopamine receptor agonist SKF-81297 (1.0 μg) directly into the mPFC produced a small, but statistically significant, increase in cocaine seeking behavior. Furthermore, microinjection of the ionotropic glutamate receptor antagonist CNQX (0.3 μg) into the PPTg/LDT attenuated the reinstatement of drug seeking induced by a priming injection of cocaine (10 mg/kg, i.p.). Intra-VTA administration of CNQX, the nicotinic receptor antagonist mecamylamine (10.0 μg) or the muscarinic receptor antagonist scopolamine (24.0 μg) also blocked cocaine seeking. Taken together, these results suggest that cocaine priming-induced reinstatement of drug seeking is mediated in part by a serial polysynaptic limbic subcircuit encompassing the mPFC, PPTg/LDT and VTA.     

Activation of D₂-like receptors in rat ventral tegmental area inhibits cocaine-reinstated drug-seeking behavior

Relapse is a hallmark of cocaine addiction. Cocaine‐induced neuroplastic changes in the mesocorticolimbic circuits critically contribute to this phenomenon. Pre‐clinical evidence indicates that relapse to cocaine‐seeking behavior depends on activation of dopamine neurons in the ventral tegmental area. Thus, blocking such activation may inhibit relapse. Because the activity of dopamine neurons is regulated by D₂‐like autoreceptors expressed on somatodendritic sites, this study, using the reinstatement model, aimed to determine whether activation of D₂‐like receptors in the ventral tegmental area can inhibit cocaine‐induced reinstatement of extinguished cocaine‐seeking behavior. Rats were trained to self‐administer i.v. cocaine (0.25 mg/infusion) under a modified fixed‐ratio 5 schedule. After such behavior was well learned, rats went through extinction training to extinguish cocaine‐seeking behavior. The effect of quinpirole, a selective D₂‐like receptor agonist microinjected into the ventral tegmental area, on cocaine‐induced reinstatement was then assessed. Quinpirole (0–3.2 μg/side) dose‐dependently decreased cocaine‐induced reinstatement and such effects were reversed by the selective D₂‐like receptor antagonist eticlopride when co‐microinjected with quinpirole into the ventral tegmental area. The effect appeared to be specific to the ventral tegmental area because quinpirole microinjected into the substantia nigra had no effect. Because D₂‐like receptors are expressed on rat ventral tegmental area dopamine neurons projecting to the pre‐frontal cortex and nucleus accumbens, our data suggest that these dopamine circuits may play a critical role in cocaine‐induced reinstatement. The role of potential changes in D₂‐like receptors and related signaling molecules of dopamine neurons in the vulnerability to relapse was discussed.     

Decrease in basal dopamine levels in the nucleus accumbens shell during daily drug-seeking behaviour in rats

Accumbal dopamine (DA) is generally accepted to participate in the neural mechanisms underlying drug dependence. Recently the involvement of accumbal DA in drug-seeking behaviour has gained more experimental attention. To study an involvement of accumbal DA in drug-seeking behaviour within and between daily self-administration behaviour, changes in extracellular DA concentration in the nucleus accumbens (NAc) shell were measured during the daily dynamics of intravenous heroin and cocaine self-administration. Groups of drug naive rats were allowed to intravenously self-administer heroin (30 microg/infusion) and cocaine (30 microg/infusion) during five consecutive daily 3 h sessions. Extracellular DA concentrations in the NAc were measured before and after a single 3 h session (acute) and before and after 5 consecutive 3 h sessions (repeated). Following acute and repeated heroin and cocaine self-administration the extracellular DA concentration in the NAc shell was increased by two-fold to three-fold over baseline. These changes in DA concentrations are thought to reflect a direct effect of heroin and cocaine on DA neurotransmission in the NAC shell. Measurement of basal DA concentrations before the self-administration sessions revealed that just before the scheduled 5th self-administration session the (absolute) basal DA levels in the NAc in heroin or cocaine self-administering animals were decreased by approximately halve, as compared to drug-naive animals. It is assumed that just before a scheduled next session the (daily) desire for the drug is high. This decrease in basal DA neurotransmission in the NAc shell may, therefore, reflect an involvement of accumbal DA in drug-seeking behaviour during daily self-administration behaviour. The results demonstrate that initiation of i.v. heroin and cocaine self-administration is linked with changes in extracellular levels of DA in the NAc shell. Moreover, the present data suggest that accumbal DA might be involved in processes underlying the motivational aspects involved in daily drug-seeking behaviour, and that neuroadaptive changes in the mesolimbic DA system due to repeated drug intake lead to an tonic decrease in overall DA activity in the NAc.     

Hippocampal memory system function and the regulation of cocaine self-administration behavior in rats

There is considerable interest in elucidating neurocognitive mechanisms of cocaine addiction. This report focuses on the hippocampal memory system. Using food reward, two cognitive tasks were examined after lidocaine inactivation of the dorsal (dSUB) or ventral (vSUB) subiculum, the primary hippocampal output regions in rats. These tasks were conducted to first identify functionally relevant stereotaxic coordinates within the hippocampal memory system, in order to then examine its role in regulating drug-seeking and drug-taking behavior studied under a contextually discriminable FI 5-min(FR5:S) second-order schedule of cocaine and brief stimulus delivery. Inactivation of the dSUB and vSUB with 10microg lidocaine impaired hippocampal-dependent win-shift performance. Amygdalar-dependant conditioned cue preference, used as a test for behavioral specificity of lidocaine, was not affected following inactivation of either site. Inactivation of the dSUB with 100 microg lidocaine significantly reduced drug-seeking and drug-taking behavior studied during the cocaine self-administration maintenance phase. Following extinction, inactivation of neither the dSUB nor vSUB influenced reinstatement of drug-seeking behavior induced by drug-paired cues presented alone or with a cocaine priming injection. The impairments in win-shift performance are consistent with the spatial processing functions of the dSUB and vSUB, and the reduction in drug-taking behavior is consistent with the non-spatial temporal processing functions of the dSUB. The lack of an effect of dSUB and vSUB inactivation on reinstatement of drug-seeking behavior may relate to the fact that the contextual associations with cocaine were well-practiced at the time of cue reinstatement testing, and therefore, drug-seeking behavior was likely regulated by nonhippocampal-dependent mechanisms.     

Evaluation of the relationship between anxiety during withdrawal and stress-induced reinstatement of cocaine seeking

The initial termination of cocaine consumption in human addicts is associated with heightened anxiety states and low levels of craving. Craving, however, tends to increase progressively over time, remains high for extended periods of time, and can be exacerbated by stressors, leading to relapse. Laboratory rats, likewise, exhibit heightened states of anxiety after withdrawal from drug, and follow a time course of cocaine seeking that parallels the time course of craving reported in humans. In addition, laboratory rats show heightened susceptibility to relapse when exposed to stressors after extended periods of withdrawal, and exhibit persistent and heightened expressions of stress-induced anxiety. The general objective of this paper is to consider the relationship between anxiety states after withdrawal from cocaine and stress-induced reinstatement of cocaine seeking in laboratory rats, and to identify the neural substrates involved. The focus of the review is on studies addressing the roles of corticotropin-releasing factor (CRF) and noradrenaline pathways of the extended amygdala circuitry, and their direct or indirect interactions with the mesocorticolimbic dopamine system, in anxiety after withdrawal from cocaine and stress-induced reinstatement of cocaine seeking. Furthermore, the effects of time after withdrawal from cocaine and amount of cocaine exposure during self-administration on the activity of CRF, noradrenaline, and dopamine pathways of the extended amygdala and mesocorticolimbic systems will be considered. The review will highlight how changing levels of activity within these systems may serve to alter the nature of the relationship between anxiety and stress-induced reinstatement of cocaine seeking at different times after withdrawal from cocaine.