Reinstatement Of Cocaine Seeking Research Articles

Rapid extinction of cocaine craving: toward a novel cue exposure therapy

AbstractCocaine does not only evoke intense rewarding sensations but also induces craving for more cocaine. This latter effect is especially obvious in addicted individuals and is thought to contribute together with other factors to trigger relapse after abstinence. Cocaine-induced craving can be studied in animals in the drug reinstatement model. In this model, responding for the drug (e.g., pressing a lever) is first extinguished by discontinuing drug reinforcement and then reinstated by drug priming (i.e., non-contingent re-exposure to the drug) or stress. Importantly, during reinstatement testing, responses continue to be unrewarded as during extinction and, therefore, reflect genuine drug seeking. Here we show that reinstatement of cocaine seeking can be rapidly extinguished with daily repeated cocaine priming. The extinction of cocaine seeking fully generalized to stress, another major trigger of drug craving and relapse. These findings suggest that cocaine and stress induce drug craving by generating similar conditioned interoceptive effects. The targeted extinction of these effects by repeated drug priming under medical supervision may represent a novel behavioral therapy against relapse in abstinent cocaine addicts.

Reinstatement of Cocaine Seeking by Hypocretin (Orexin) in the Ventral Tegmental Area: Independence from the Local Corticotropin-Releasing Factor Network

Hypocretin (Hcrt), an arousal- and feeding-associated peptide, is expressed in lateral hypothalamic neurons that project to the ventral tegmental area (VTA). Intra-VTA Hcrt reinstates morphine-conditioned place preferences, and intracerebroventricular and intra-VTA corticotropin-releasing factor (CRF) reinstate cocaine seeking. Each is presumed to act, at least in part, through actions local to the VTA. Here, we examined the possibility that VTA perfusion of Hcrt reinstates cocaine seeking and, if so, whether it does so through the VTA mechanism that is implicated in reinstatement by CRF. Rats were trained to lever-press for intravenous cocaine (2 weeks) and then underwent extinction training (saline substituted for cocaine: 3 weeks). Reinstatement behavior was tested and VTA dialysates were collected and assayed for glutamate or dopamine following footshock or perfusion of Hcrt or CRF, with or without Hcrt or CRF antagonists, into the VTA. Ventral tegmental area perfusion of Hcrt-1 or footshock stress reinstated cocaine seeking and caused release of VTA glutamate and dopamine. The effects of Hcrt-1 were blocked by a selective Hcrt-1 antagonist, but not a CRF antagonist, and were not mimicked by Hcrt-2. The Hcrt-1 antagonist did not block CRF-dependent footshock-induced reinstatement or glutamate or dopamine release. The behavioral and neurochemical effects of Hcrt-1 were attenuated but not blocked by kynurenic acid, an ionotropic glutamate antagonist that blocks footshock-induced reinstatement and glutamate release. While Hcrt and CRF are known to interact in some area of the brain, in the VTA proper they appear to have largely independent actions on the mesolimbic dopamine mechanisms of cocaine seeking.

Alprazolam and oxazepam block the cue-induced reinstatement of extinguished cocaine seeking in rats

We have previously reported that pretreatment with benzodiazepines reduces intravenous cocaine self-administration in rats. This experiment was designed to investigate whether or not benzodiazepines would also inhibit the reinstatement of cocaine seeking induced by the presentation of a conditioned reinforcer. Adult male rats were implanted with jugular catheters and trained to self-administer cocaine (0.25 mg/kg/infusion) during daily 2-h sessions. During training, cocaine delivery was paired with the presentation of a tone and the illumination of a houselight. Once a stable baseline of cocaine self-administration was observed, lever pressing was extinguished to less than 20% of baseline rates. During reinstatement testing, responding resulted in the presentation of the conditioned reinforcer (i.e., the houselight and tone previously paired with self-administered cocaine). The response-contingent presentation of the conditioned reinforcer reliably reinstated cocaine seeking. Pretreatment with alprazolam (2 or 4 mg/kg, ip) or oxazepam (20 or 40 mg/kg, ip) reversed the conditioned reinforcer-induced reinstatement of extinguished cocaine-seeking behavior at doses that did not reliably affect the conditioned reinforcer-induced reinstatement of extinguished food seeking, suggesting that benzodiazepines may not have reduced reinstatement responding due to non-specific reductions in behavior. These data suggest that benzodiazepines may be useful in blocking the ability of environmental cues to stimulate cocaine seeking.

Acetylcholine release in the mesocorticolimbic dopamine system during cocaine seeking: conditioned and unconditioned contributions to reward and motivation.

Microdialysis was used to assess the contribution to cocaine seeking of cholinergic input to the mesocorticolimbic dopamine system in ventral tegmental area (VTA). VTA acetylcholine (ACh) was elevated in animals lever pressing for intravenous cocaine and in cocaine-experienced and cocaine-naive animals passively receiving similar "yoked" injections. In cocaine-trained animals, the elevations comprised an initial (first hour) peak to approximately 160% of baseline and a subsequent plateau of 140% of baseline for the rest of the cocaine intake period. In cocaine-naive animals, yoked cocaine injections raised ACh levels to the 140% plateau but did not cause the initial 160% peak. In cocaine-trained animals that received unexpected saline (extinction conditions) rather than the expected cocaine, the initial peak was seen but the subsequent plateau was absent. VTA ACh levels played a causal role and were not just a correlate of cocaine seeking. Blocking muscarinic input to the VTA increased cocaine intake; the increase in intake offset the decrease in cholinergic input, resulting in the same VTA dopamine levels as were seen in the absence of the ACh antagonists. Increased VTA ACh levels (resulting from 10 microM VTA neostigmine infusion) increased VTA dopamine levels and reinstated cocaine seeking in cocaine-trained animals that had undergone extinction; these effects were strongly attenuated by local infusion of a muscarinic antagonist and weakly attenuated by a nicotinic antagonist. These findings identify two cholinergic responses to cocaine self-administration, an unconditioned response to cocaine itself and a conditioned response triggered by cocaine-predictive cues, and confirm that these cholinergic responses contribute to the control of cocaine seeking.

Erratum: Corrigendum: CaMKII: a biochemical bridge linking accumbens dopamine and glutamate systems in cocaine seeking

Nat. Neurosci. 11, 344–353 (2008); published online 17 February 2008; corrected after print 1 April 2008 In the version of this article initially published, Thr286 was substituted for Ser831 in the second sentence of the concluding paragraph. The sentence should read: “The reinstatement of cocaine seeking is also associated with an increase in GluR1 phosphorylated on Ser831, a CaMKII phosphorylation site, and enhanced cell-surface expression of GluR1-containing AMPA receptors in the accumbens shell.

Progesterone metabolite allopregnanolone attenuates the reinstatement of cocaine‐seeking behavior in female not male rats

Previous research indicates that progesterone decreased cocaine‐seeking in female rats. The attenuating effects of progesterone may be, in part, due to its metabolite, allopregnanolone (ALLO). ALLO, is a neurosteroid that is also a positive modulator of GABA A receptors. ALLO has been shown to decrease the sensitizing effects of cocaine and reduce lethality associated with cocaine overdose in mice. The purpose of the present study was to examine the effects of ALLO on the reinstatement of cocaine‐seeking in female and male rats. Rats were trained to lever press for i.v. infusions of cocaine during 2‐hour sessions. Once acquisition criteria were met, they continued cocaine self‐administration for 14 days. Cocaine was then replaced with saline, and lever‐pressing was allowed to extinguish over 21 days. After the extinction phase rats received ALLO (15 mg/kg or 30 mg/kg) or vehicle pretreatment 30 min prior to the session for 3 days. Rats were then tested during reinstatement with 3 randomly administered doses of cocaine (5, 10 and 15 mg/kg, i.p.), each separated by one day of saline treatment. The results of the study indicate that ALLO, administered to females at the 15 and 30 mg/kg dose, decreased cocaine‐seeking. However, ALLO did not effect cocaine‐seeking behavior in male rats. These findings suggest that ALLO may provide a novel approach for preventing relapse in female cocaine‐abusers.

CaMKII: a biochemical bridge linking accumbens dopamine and glutamate systems in cocaine seeking

Increases in dopamine and glutamate transmission in the nucleus accumbens independently promote the reinstatement of cocaine seeking, an animal model of relapse. Here we have tested whether cocaine reinstatement in rats depends on interactions between accumbal dopamine and glutamate systems that are mediated by Ca(2+)/calmodulin-mediated kinase II (CaMKII). We show that stimulation of D1-like dopamine receptors in the nucleus accumbens shell reinstates cocaine seeking by activating L-type Ca(2+) channels and CaMKII. Cocaine reinstatement is associated with D1-like dopamine receptor-dependent increases in accumbens shell CaMKII phosphorylated on Thr286 and glutamate receptor 1 (GluR1) phosphorylated on Ser831 (a known CaMKII phosphorylation site), in addition to increases in cell-surface expression of GluR1-containing AMPA receptors in the shell. Consistent with these findings, cocaine reinstatement is attenuated by intra-shell administration of AAV10-GluR1-C99, a vector that impairs the transport of GluR1-containing AMPA receptors. Thus, CaMKII may be an essential link between accumbens shell dopamine and glutamate systems involved in the neuronal plasticity underlying cocaine craving and relapse.

Aripiprazole Blocks Reinstatement of Cocaine Seeking in an Animal Model of Relapse

Aripiprazole Blocks Reinstatement of Cocaine Seeking in an Animal Model of Relapse

A comparison of the effects of different operant training experiences and dietary restriction on the reinstatement of cocaine-seeking in rats

Studies on the reinstatement of drug-seeking after withdrawal from chronic drug self-administration have varied in terms of the procedures by which animals are initially trained to self-administer the drug. The current study directly compared whether prior operant training for food pellet reinforcement and/or maintained dietary restriction significantly altered the reinstatement of extinguished cocaine-seeking in the presence of cocaine-paired cues, a priming injection of cocaine (10 mg/kg; i.p.), and the pharmacological stressor, yohimbine (1.25 or 2.5 mg/kg, i.p.). Male Long Evans rats were divided into four groups as follows: a) trained to lever press for food pellets prior to cocaine self-administration and then maintained on a restricted diet, b) trained to lever press for food pellets prior to cocaine self-administration and then placed on an ad libitum diet, c) untrained and maintained on a restricted diet, or d) untrained and placed on ad libitum feeding. All rats readily self-administered cocaine (0.2 mg/50 μl/infusion) and were subsequently extinguished in the absence of cocaine or previously cocaine-paired cues (light + tone). Following extinction, rats experienced cue-, cocaine-, and yohimbine-induced reinstatement testing. No significant differences were seen between groups for lever responding during the maintenance phase and during extinction. Likewise, reinstatement of cocaine-seeking did not vary across groups for cue-, cocaine-, or yohimbine-induced reinstatement. Under these specific parameters, operant training prior to cocaine self-administration and/or dietary restriction do not significantly alter reinstatement of cocaine-seeking. The results arguably support the approach of not using prior lever training with a non-drug reinforcer and to limit the use of dietary restriction only to the acquisition phase of drug self-administration.

Footshock stress reinstates cocaine seeking in rats after extended post-stress delays

Exposure to footshock stress reinstates drug seeking in rats when tests for reinstatement are conducted immediately after termination of the stressor. It is not known, however, whether footshock is effective in inducing reinstatement if a post-stress delay is imposed before testing for reinstatement. The objectives of the study were to determine for how long footshock remains effective in inducing the reinstatement of cocaine seeking if testing is delayed after termination of the stressor and to determine whether the context in which a post-stress delay is carried out influences the magnitude of reinstatement. Rats self-administered cocaine (1.0 mg/kg per infusion) for 8-10 days. After extinction, tests for reinstatement by intermittent footshock (20 min; 0.8 mA) were conducted after post-stress delays of up to 60 min. Although footshock was always administered in the self-administration (SA) chamber, delays were given either in the SA chamber or home cage (HC). Footshock induced reinstatement after post-stress delays of up to 40 min. No differences in responding during tests for reinstatement were observed between animals in the SA chamber and under HC conditions. Within a limited time window, footshock is effective in reinstating cocaine seeking, when testing is delayed after termination of the stressor. Together with previous work from this laboratory, the findings are consistent with the idea that stress can induce the reinstatement of drug seeking by conditioning excitation to the context in which it is administered and that this conditioned excitation can overcome the inhibitory processes maintaining extinction responding, even after a post-stress delay.

NMDA receptor blockade in the basolateral amygdala disrupts consolidation of stimulus-reward memory and extinction learning during reinstatement of cocaine-seeking in an animal model of relapse

Previous research from our laboratory has implicated the basolateral amygdala (BLA) complex in the acquisition and consolidation of cue–cocaine associations, as well as extinction learning, which may regulate the long-lasting control of conditioned stimuli (CS) over drug-seeking behavior. Given the well established role of NMDA glutamate receptor activation in other forms of amygdalar-based learning, we predicted that BLA-mediated drug–cue associative learning would be NMDA receptor dependent. To test this hypothesis, male Sprague–Dawley rats self-administered i.v. cocaine (0.6 mg/kg/infusion) in the absence of explicit CS pairings (2-h sessions, 5 days), followed by a single 1-h classical conditioning (CC) session, during which they received passive infusions of cocaine discretely paired with a light + tone stimulus complex. Following additional cocaine self-administration sessions in the absence of the CS (2-h sessions, 5 days) and extinction training sessions (no cocaine or CS presentation, 2-h sessions, 7 days), the ability of the CS to reinstate cocaine-seeking on three test days was assessed. Rats received bilateral intra-BLA infusions (0.5 μl/hemisphere) of vehicle or the selective NMDA receptor antagonist, 2-amino-5-phosphonovalerate (AP-5), immediately prior to the CC session (acquisition), immediately following the CC session (consolidation), or immediately following reinstatement testing (consolidation of conditioned-cued extinction learning). AP-5 administered before or after CC attenuated subsequent CS-induced reinstatement, whereas AP-5 administered immediately following the first two reinstatement tests impaired the extinction of cocaine-seeking behavior. These results suggest that NMDA receptor-mediated mechanisms within the BLA play a crucial role in the consolidation of drug–CS associations into long-term memories that, in turn, drive cocaine-seeking during relapse.

Prenatal Stress Enhances Responsiveness to Cocaine

Early environmental events have profound influences on a wide range of adult behavior. In the current study, we assessed the influence of maternal stress during gestation on psychostimulant and neurochemical responsiveness to cocaine, cocaine self-administration, and reinstatement of cocaine-seeking in adult offspring. Pregnant, female Sprague-Dawley rats were subjected to either no treatment or to restraint stress three times per day for the last 7 days of gestation and cocaine-related behavior was assessed in offspring at 10 weeks of age. Relative to controls, a noncontingent cocaine injection elevated locomotor activity as well as nucleus accumbens levels of extracellular dopamine and glutamate to a greater extent in both cocaine-naive and cocaine-experienced prenatal stress (PNS) rats and elevated prefrontal cortex dopamine in cocaine-experienced PNS rats. To assess the impact of PNS on cocaine addiction-related behavior, rats were trained to lever press for intravenous (i.v.) infusions of cocaine (0.25, 0.5, or 1 mg/kg/infusion), with each infusion paired with a light+tone-conditioned stimulus. Lever-pressing was extinguished and cocaine-seeking reinstated by re-exposure to the conditioned cues or by intraperitoneal cocaine-priming injections (5 or 10 mg/kg). PNS elevated active lever responding both during extinction and cocaine-primed reinstatement, but not during self-administration or conditioned-cued reinstatement. PNS also did not alter intake during self-administration. These findings demonstrate that PNS produces enduring nervous system alterations that increase the psychomotor stimulant, motivational, and neurochemical responsiveness to noncontingent cocaine. Thus, early environmental factors contribute to an individual's initial responsiveness to cocaine and propensity to relapse to cocaine-seeking.

Stress-induced relapse to cocaine seeking: roles for the CRF2 receptor and CRF-binding protein in the ventral tegmental area of the rat

Footshock reinstates cocaine seeking in cocaine-experienced rats by inducing corticotropin-releasing factor (CRF) and glutamate release in the ventral tegmental area (VTA) and thus activating VTA dopaminergic neurons. Footshock-induced VTA glutamate release, dopamine activation and reinstatements are blocked by VTA administration of a alpha-helical CRF, a nonselective CRF receptor antagonist. The effects of selective CRF antagonists have not yet been reported. The present studies were designed to explore the roles of VTA CRF receptor subtypes and CRF-BP in these effects induced by footshock. Rats were first trained to lever-press for intravenous cocaine (1 mg/infusion/0.13 ml, FR-1 schedule), and then tested under extinction conditions until response rates returned to the pretraining baseline. Reinstatements, VTA glutamate and dopamine levels [microdialysis with high performance liquid chromatography (HPLC)] were then assessed, under various pharmacological conditions, after mild inescapable footshock. Footshock-induced reinstatement of cocaine seeking and release of VTA glutamate and dopamine were blocked by selective blockade of VTA CRF(2) receptors (CRF(2)Rs) but not CRF(1)Rs. VTA perfusion of CRF or CRF(2)R agonists that have strong affinity for CRF-BP mimicked the effects induced by footshock while CRFR agonists that do not bind CRF-BP were ineffective. CRF(6-33), which competes for the CRF binding site on CRF-BP, attenuated the effects of CRF or urocortin I on VTA glutamate and dopamine release and on reinstatement of cocaine seeking. The present studies revealed a role of VTA CRF-BP and suggest an involvement of CRF(2)R in the effectiveness of stress in triggering glutamate and dopamine release and cocaine seeking in drug-experienced animals.

Selective inactivation of the ventral hippocampus attenuates cue-induced and cocaine-primed reinstatement of drug-seeking in rats

Recent evidence suggests that the hippocampus may have a functional role in mediating relapse to cocaine-seeking behavior. Based on the importance of the ventral CA subfields in mediating reward, the present experiment determined the effects of temporary inactivation of the ventral hippocampus on reinstatement of cocaine-seeking in a rodent model of relapse. Male, Sprague–Dawley rats self-administered i.v. cocaine (0.6 mg/kg/infusion) in the presence of discrete conditioned cues (tone + light) in daily 2-h sessions for ten days. Following seven days of extinction sessions in which neither cues nor drug were available, rats underwent four reinstatement tests in a counterbalanced, within-subjects design. Bilateral microinjections of GABA receptor agonists (baclofen/muscimol—0.1/1.0 mM) into the ventral hippocampus significantly attenuated cue-induced and cocaine-primed reinstatement compared with vehicle microinjections in the same rats. In contrast, injections just outside the ventral hippocampus did not block either form of reinstatement. Furthermore, inactivation failed to affect responding for food reinforcement, baseline extinction responding, or locomotor activity. These data indicate that the ventral hippocampus plays an important role in the relapse to cocaine-seeking behavior and may interact with key limbic structures previously implicated in cocaine addiction.

Diverse effects of GABA-mimetic drugs on cocaine-evoked self-administration and discriminative stimulus effects in rats

Recent data indicate that gamma-aminobutyric acid (GABA) is a modulator of behavioral responses to cocaine. The efficacy of gabapentin (a cyclic GABA analogue), tiagabine (a GABA reuptake inhibitor), or vigabatrin (an inhibitor of GABA transaminase and reuptake) to alter cocaine-seeking behavior and discriminative effects was examined in rats. Rats were trained to press a lever for cocaine (0.5 mg/kg per infusion) paired with a cue (light + tone) using a fixed ratio (FR) 5 schedule of reinforcement. After extinction, the cocaine-seeking behavior was reinstated by cocaine priming (10 mg/kg). Another group of rats was trained to discriminate cocaine (10 mg/kg) from saline in a two-lever FR 20 task. Vigabatrin (150-250 mg/kg) decreased cocaine-maintained responding, whereas tiagabine (10 mg/kg) significantly reduced responses on the "active" lever. Vigabatrin (150-250 mg/kg) significantly decreased responding to the cocaine-priming dose and a nonsignificant attenuation of cocaine-induced reinstatement was seen after tiagabine (5-10 mg/kg). Gabapentin (10-30 mg/kg) failed to alter maintenance of cocaine self-administration or drug-induced reinstatement. Pretreatment with either gabapentin, tiagabine, or vigabatrin resulted in neither reinstatement of cocaine seeking nor alterations in cocaine discrimination. Our study demonstrates that vigabatrin (only at the 150 mg/kg dose) exerted inhibitory actions on cocaine-maintained responding and attenuated the reinstatement of extinguishing responding more effectively than gabapentin or tiagabine and with less evidence of motor impairment than the latter drugs. Present findings do not support a role for gabapentin or tiagabine for the possible treatment of cocaine relapse, whereas albeit limited effects of vigabatrin may be seen.

Systemic administration of a dopamine, but not a serotonin or norepinephrine, transporter inhibitor reinstates cocaine seeking in the rat

Reinstatement of cocaine-seeking behavior can be elicited by a systemic priming injection of cocaine or a non-selective biogenic amine transporter inhibitor. In order to determine which biogenic amine is responsible for this effect, selective dopamine (GBR 12909), serotonin (fluoxetine) or norepinephrine (nisoxetine) transporter inhibitors were systemically administered in order to assess their ability to induce cocaine seeking in rats. Administration of GBR 12909, but not nisoxetine or fluoxetine, dose-dependently reinstated cocaine seeking in rats. Furthermore, administration of the non-selective dopamine receptor antagonist flupenthixol into the nucleus accumbens shell attenuated GBR 12909-induced reinstatement of cocaine seeking. These results suggest that increases in extracellular concentrations of dopamine, specifically in the nucleus accumbens shell, are primarily responsible for promoting cocaine priming-induced reinstatement of drug seeking in rats.

Cooperative activation of D1-like and D2-like dopamine receptors in the nucleus accumbens shell is required for the reinstatement of cocaine-seeking behavior in the rat

Activation of D1-like (D1, D5) or D2-like (D1, D3, D4) dopamine receptors in the nucleus accumbens shell is sufficient to reinstate cocaine-seeking behavior in rats. The goal of these experiments was to assess whether cooperative activation of D1-like and D2-like dopamine receptors in the accumbens shell is required to promote cocaine reinstatement. Rats were initially trained to self-administer cocaine (0.25 mg, i.v.) using a fixed-ratio schedule of reinforcement for approximately 21 days. Animals subsequently underwent an extinction phase during which saline was substituted for cocaine. Once cocaine self-administration behavior was extinguished (defined as <15% of the total responses maintained during self-administration), dopamine receptor agonist-induced reinstatement of cocaine seeking was assessed. Administration of the selective D1/5 agonist R-(+)-6-chloro-7,8-dihydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrobromide (SKF-81297) (1.0 μg) or the D2/3 receptor agonist trans-(−)-(4aR)-4,4a,5,6,7,8,8a,9-octahydro-5-propyl-1H-pyrazolo[3,4-g]quinoline hydrochloride (quinpirole) (3.0 μg) directly into the nucleus accumbens shell promoted reinstatement of cocaine seeking. In order to determine if endogenous dopamine tone in the accumbens shell is required for dopamine receptor agonist-induced reinstatement of cocaine seeking, D1/5 or D2/3 dopamine receptor antagonists were administered into the nucleus accumbens shell prior to a selective dopamine receptor agonist. Microinfusion of the D2/3 dopamine receptor antagonist sulpiride (( S)-5-aminosulfonyl-N-[(1-ethyl-2-pyrrolidinyl)methyl]-2-methoxybenzamide) (1.0 μg) into the nucleus accumbens shell 10 minutes prior to SKF-81297 (1.0 μg) blocked the ability of this D1-like dopamine receptor agonist to reinstate cocaine seeking. Similarly, administration of the selective D1/5 dopamine receptor antagonist R(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride (SCH-23390) (1.0 μg) into the nucleus accumbens shell prior to quinpirole (3.0 μg) blocked reinstatement of drug-seeking behavior elicited by this D2/3 dopamine receptor agonist. Moreover, intra-accumbal shell co-administration of subthreshold doses of quinpirole (1.5 μg) and SKF-81297 (0.1 μg) promoted cocaine-seeking behavior. Collectively, these results indicate that cooperative activation of D1-like and D2-like dopamine receptors in the nucleus accumbens shell is necessary to reinstate cocaine seeking in rats.

Central injections of CRF reinstate cocaine seeking in rats after postinjection delays of up to 3 h: an influence of time and environmental context

In drug addicts, the induction of drug craving is not always associated with an immediate opportunity to take drugs again. It is, therefore, important to study how delays in opportunity for drug seeking affect the time-course of relapse. Intracerebroventricular (i.c.v.) injection of corticotropin-releasing factor (CRF) is a stressor that reinstates heroin and alcohol seeking in rats, when administered just before tests for reinstatement. It is not known whether CRF reinstates cocaine seeking; moreover, the effect of delaying testing for reinstatement, after CRF injection, has not been studied. To determine whether i.c.v. CRF induces reinstatement of cocaine seeking after postinjection delays of up to 3 h and to determine whether the context in which a delay is experienced influences the time-course of CRF-induced reinstatement. Rats self-administered cocaine (1.0 mg/kg per infusion) for 8-10 days. Subsequently, responding for drug was extinguished and testing for reinstatement by i.c.v. CRF (0.5 microg) was conducted. Animals were tested after postinjection delays of up to 3 h; the delays were experienced either in the self-administration (SA) chamber or home cage (HC). When delays were spent in the SA chambers, CRF induced reinstatement in all delay groups. When delays were spent in the HC, CRF did not induce reinstatement after a 2-h delay. We argue that the effects we observed are consistent with a contextual conditioning account of reinstatement, whereby CRF that was experienced in the context of the SA chamber served to elicit a conditioned excitatory response developed to that context during training.

Cocaine Increases Actin Cycling: Effects in the Reinstatement Model of Drug Seeking

Addiction to cocaine is associated with persistent changes in synaptic function. The cycling of actin between polymerized [F (for filamentous)] and depolymerized forms contributes to synaptic plasticity, and acute and withdrawal from repeated cocaine administration produced reversible and enduring elevations, respectively, in F-actin in the nucleus accumbens. Increased F-actin after 3 weeks withdrawal from repeated cocaine resulted from changes in the content or phosphorylation state of actin binding proteins (ABPs) that cosediment with F-actin. The profile of altered APBs was consistent with filopodia formation, including increased mammalian Enabled, phosphorylated (p)-cortactin, and p-vasodilator-stimulated phosphoprotein, and increased actin depolymerization [e.g., reduced LIM (Lin11/Isl-1/Mec3)-kinase and p-cofilin]. In contrast to repeated cocaine, the increase in F-actin after acute cocaine administration resulted from reduced depolymerization and actin cycling. The potential involvement of chronic cocaine-induced increases in actin cycling in cocaine addiction was examined using the reinstatement of cocaine seeking in rats previously trained to self-administer cocaine by inhibiting actin polymerization with intra-accumbens latrunculin A or by accelerating actin depolymerization with a LIM-kinase inhibitor. Disrupting actin cycling via either mechanism augmented cocaine-induced reinstatement of drug seeking but did not affect the locomotor response to acute cocaine administration. Thus, withdrawal from repeated cocaine induces a restructuring of actin-ABP complexes, which increases actin cycling and may modulate cocaine-induced reinstatement of drug seeking.

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.