The effects of varied extinction procedures on contingent cue-induced reinstatement in Sprague-Dawley rats

Rationale

Cue exposure therapy, which attempts to limit relapse by reducing reactivity to cocaine-paired cues through repeated exposures, has had limited success.

Objectives

The current experiments examined cocaine cue-induced anxiogenesis and investigated whether a model of cue exposure therapy would reduce reinstatement of cocaine seeking in rats with a history of cocaine self-administration.

Methods

Male rats experienced daily intravenous cocaine self-administration. Rats then experienced exposure to either the self-administration context or the context plus noncontingent presentations of cocaine-paired cues. Immediately following exposure, anxiety-like behavior was measured using elevated plus maze and defensive burying tests. In a second group of rats, self-administration was followed by 7 days of exposure to the context, context + noncontingent cue exposure, lever extinction, or cue + lever extinction. All animals then underwent two contingent cue-induced reinstatement tests separated by 7 days of lever extinction.

Results

Exposure to noncontingent cocaine-paired cues in the self-administration context increased anxiety-like behavior on the defensive burying test. Animals that experienced lever + cue extinction displayed the least cocaine seeking on the first reinstatement test, and lever extinction reduced cocaine seeking below context exposure or context + noncontingent cue exposure. All animals had similar levels of cocaine seeking on the second reinstatement test.

Conclusion

Noncontingent cue exposure causes anxiety, and noncontingent cue and context exposure are less effective at reducing contingent cue-induced reinstatement than lever or lever + cue extinction. These data indicate that active extinction of the drug-taking response may be critical for reduction of relapse proclivity in former cocaine users.     

Hypothalamic Neuropeptide S receptor blockade decreases discriminative cue-induced reinstatement of cocaine seeking in the rat

Rationale

Previous studies have shown that activation of brain neuropeptide S receptor (NPSR) facilitates reinstatement of cocaine seeking elicited by environmental cues predictive of drug availability. This finding suggests the possibility that blockade of NPSR receptors may be of therapeutic benefit in cocaine addiction. To evaluate this hypothesis, we investigated the effect of two newly synthetized NPSR antagonists, namely the quinolinone-amide derivative NPSR-QA1 and the NPS peptidic analogue [D-Cys(tBu)⁵]NPS on cocaine self-administration and on discriminative cue-induced relapse to cocaine seeking in the rat.

Methods

Separate groups of rats self-administered food and cocaine 0.25 mg/kg/inf in FR1 and FR5 (fixed ratio reinforcement schedules) for 30-min and 2-h sessions per day. After food and cocaine intake reached baseline levels, the effect of NPSR-QA1 was tested on cocaine and food self-administration. The NPSR-QA1 was injected intraperitoneally and its effect on discriminative cue-induced reinstatement was evaluated, while [D-Cys(tBut)⁵]NPS was injected intracranially, intra-lateral hypothalamus, intra-perifornical area of the hypothalamus, and intra-central amygdala. The effect of the NPSR-QA1 on extinction of cocaine seeking was also assessed.

Results

Intraperitoneal administration of NPSR-QA1 (15–30 mg/kg) did not affect cocaine self-administration. Conversely, NPSR-QA1 (15–30 mg/kg) decreased discriminative cue-induced cocaine relapse. At the lowest dose, this effect was specific, while at the highest dose, NPSR-QA1 also reduced food self-administration. The efficacy of NPSR antagonism on cocaine seeking was confirmed with [D-Cys(tBu)⁵]NPS (10–30 nmol/rat) as it markedly inhibited relapse behavior following site-specific injection into the lateral hypothalamus and the perifornical area of the hypothalamus but not into the central amygdala.

Conclusions

The identification of the NPS/NPSR system as an important new element involved in the physiopathology of cocaine addiction and the discovery of the anti-addictive properties of NPSR antagonists opens the possibility of exploring a new mechanism for cocaine addiction treatment.     

Treatment of cocaine withdrawal anxiety with guanfacine: relationships to cocaine intake and reinstatement of cocaine seeking in rats

Rationale

Successful treatment of cocaine addiction is severely impeded by the propensity of users to relapse. Withdrawal severity may serve as a key predictor of susceptibility to relapse. Therefore, the identification and treatment of cocaine withdrawal symptoms such as anxiety may improve addiction treatment outcome.

Objectives

The current study examined the role of anxiety-like behavior during cocaine withdrawal and anxiolytic treatment in reinstatement of cocaine seeking in an animal model of relapse.

Methods

Male rats experienced daily IV cocaine self-administration. One group of animals received the norepinephrine α-2 agonist, guanfacine, or vehicle prior to anxiety testing 48 h after the last self-administration session. In the second group of rats, relationships between cocaine intake, anxiety-like behavior after withdrawal of cocaine, and reinstatement responding were investigated. The third and fourth groups of animals received guanfacine, yohimbine (norepinephrine α-2 antagonist), or vehicle once per day for 3 days 48 h after cessation of cocaine self-administration, followed by extinction and subsequent reinstatement induced by cocaine injections, cocaine-paired cues, and yohimbine administration.

Results

Cocaine-withdrawn rats at 48 h demonstrated higher levels of anxiety-like behavior as measured on a defensive burying task when compared to yoked saline controls, an effect reversed by guanfacine treatment. Cocaine intake was positively correlated with measures of anxiety-like behavior during early withdrawal, and this anxiety-like behavior was significantly correlated with subsequent cocaine-primed reinstatement. Yohimbine treatment during early withdrawal increased reinstatement to conditioned cues, while guanfacine treatment reduced reinstatement to yohimbine.

Conclusions

These studies suggest an important role for noradrenergic mediation of anxiety-like behavior that emerges after withdrawal of cocaine and potential risk of relapse as modeled by reinstatement, and suggest that treatment of anxiety symptoms during early abstinence may reduce the risk of relapse.     

Time-dependent decreases in nucleus accumbens AMPA/NMDA ratio and incubation of sucrose craving in adolescent and adult rats

Rationale and objective

There is evidence that cue-induced sucrose seeking progressively increases after cessation of oral sucrose self-administration (incubation of sucrose craving) in both adolescent and adult rats. The synaptic plasticity changes associated with this incubation at different age groups are unknown. We assessed whether incubation of sucrose craving in rats trained to self-administer sucrose as young adolescents, adolescents, or adults is associated with changes in 2-amino-3-(3-hydroxy-5-methyl-isoxazol-4-yl)propanoic acid (AMPA)/N-methyl-d-aspartate (NMDA) ratio (a measure of postsynaptic changes in synaptic strength) in nucleus accumbens.

Methods

Three age groups initiated oral sucrose self-administration training (10 days) on postnatal day (P) 35 (young adolescents), P42 (adolescents), or P70 (adults). They were then tested for cue-induced sucrose seeking (assessed in an extinction test) on abstinence days 1 and 21. Separate groups of rats were trained to self-administer sucrose or water (a control condition), and assessed for AMPA/NMDA ratio in nucleus accumbens on abstinence days 1–3 and 21.

Results

Adult rats earned more sucrose rewards, but sucrose intake per body weight was higher in young adolescent rats. Time-dependent increases in cue-induced sucrose seeking (incubation of sucrose craving) were more pronounced in adult rats, less pronounced in adolescents, and not detected in young adolescents. On abstinence day 21, but not days 1–3, AMPA/NMDA ratio in nucleus accumbens were decreased in rats that self-administered sucrose as adults and adolescents, but not young adolescents.

Conclusions

Our data demonstrate age-dependent changes in magnitude of incubation of sucrose craving and nucleus accumbens synaptic plasticity after cessation of sucrose self-administration.     

The effects of the novel DA D3 receptor antagonist SR 21502 on cocaine reward, cocaine seeking and cocaine-induced locomotor activity in rats

Rationale

There is a focus on developing D3 receptor antagonists as cocaine addiction treatments.

Objective

We investigated the effects of a novel selective D3 receptor antagonist, SR 21502, on cocaine reward, cocaine-seeking, food reward, spontaneous locomotor activity and cocaine-induced locomotor activity in rats.

Methods

In Experiment 1, rats were trained to self-administer cocaine under a progressive ratio (PR) schedule of reinforcement and tested with vehicle or one of three doses of SR 21502. In Experiment 2, animals were trained to self-administer cocaine under a fixed ratio schedule of reinforcement followed by extinction of the response. Then, animals were tested with vehicle or one of the SR 21502 doses on cue-induced reinstatement of responding. In Experiment 3, animals were trained to lever press for food under a PR schedule and tested with vehicle or one dose of the compound. In Experiments 4 and 5, in separate groups of animals, the vehicle and three doses of SR 21502 were tested on spontaneous or cocaine (10 mg/kg, IP)-induced locomotor activity, respectively.

Results

SR 21502 produced significant, dose-related (3.75, 7.5 and 15 mg/kg) reductions in breakpoint for cocaine self-administration, cue-induced reinstatement (3.75, 7.5 and 15 mg/kg) and cocaine-induced locomotor activity (3.75, 7.5 and 15 mg/kg) but failed to reduce food self-administration and spontaneous locomotor activity.

Conclusions

SR 21502 decreases cocaine reward, cocaine-seeking and locomotor activity at doses that have no effect on food reward or spontaneous locomotor activity. These data suggest SR 21502 may selectively inhibit cocaine’s rewarding, incentive motivational and stimulant effects.     

Association of time-dependent changes in mu opioid receptor mRNA, but not BDNF, TrkB, or MeCP2 mRNA and protein expression in the rat nucleus accumbens with incubation of heroin craving

Rationale and objectives

Responding to heroin cues progressively increases after cessation of heroin self-administration (incubation of heroin craving). We investigated whether this incubation is associated with time-dependent changes in brain-derived neurotrophic factor (BDNF) and methyl-CpG binding protein 2 (MeCP2) signaling and mu opioid receptor (MOR) expression in nucleus accumbens (NAc), dorsal striatum (DS), and medial prefrontal cortex (mPFC). We also investigated the effect of the preferential MOR antagonist naloxone on cue-induced heroin seeking during abstinence.

Methods

We trained rats to self-administer heroin or saline for 9?C10?days and then dissected the NAc, DS, and mPFC at different abstinence days and measured mRNA and protein levels of BDNF, TrkB, and MeCP2, as well as MOR mRNA (Oprm1). In other groups, we assessed cue-induced heroin seeking in extinction tests after 1, 11, and 30 abstinence days, and naloxone??s (0?C1.0?mg/kg) effect on extinction responding after 1 and 15?days.

Results

Cue-induced heroin seeking progressively increased or incubated during abstinence. This incubation was not associated with changes in BDNF, TrkB, or MeCP2 mRNA or protein levels in NAc, DS, or mPFC; additionally, no molecular changes were observed after extinction tests on day?11. In NAc, but not DS or mPFC, MOR mRNA decreased on abstinence day?1 and returned to basal levels over time. Naloxone significantly decreased cue-induced heroin seeking after 15 abstinence days but not 1?day.

Conclusions

Results suggest a role of MOR in incubation of heroin craving. As previous studies implicated NAc BDNF in incubation of cocaine craving, our data suggest that different mechanisms contribute to incubation of heroin versus cocaine craving.     

Effects of inhibitory GABA-active neurosteroids on cocaine seeking and cocaine taking in rats

Rationale

Several compounds that potentiate GABA-induced inhibitory currents also decrease stress, anxiety and addiction-related behaviors. Because of the well-established connection between stress and addiction, compounds that reduce stress-induced responses might be efficacious in treating addiction. Since endogenous neurosteroids such as allopregnanolone may function in a manner similar to benzodiazepines to reduce HPA axis activation and anxiety following stressful stimuli, we hypothesized that exogenously applied neurosteroids would reduce cocaine reinforcement in two animal models.

Methods

Male Wistar rats were trained to self-administer cocaine and food under a concurrent alternating operant schedule of reinforcement. Two separate groups of rats were trained to self-administer cocaine or food pellets and were then exposed to similar cue-induced reinstatement paradigms. Both groups of rats were pretreated with various doses of neurosteroids.

Results

Allopregnanolone and 3α-hydroxy-3β-methyl-17β-nitro-5α-androstane (R6305-7, a synthetic neurosteroid) were ineffective in selectively decreasing cocaine relative to food self-administration. On the other hand, both allopregnanolone and R6305-7 significantly decreased the cue-induced reinstatement of extinguished cocaine seeking, confirmed by one-way ANOVA.

Conclusions

These results suggest that neurosteroids may be effective in reducing the relapse to cocaine use without affecting ongoing cocaine self-administration.     

Interactions between VTA orexin and glutamate in cue-induced reinstatement of cocaine seeking in rats

Rationale

Glutamate and orexin/hypocretin systems are involved in Pavlovian cue-triggered drug seeking.

Objectives

Here, we asked whether orexin and glutamate interact within ventral tegmental area (VTA) to promote reinstatement of extinguished cocaine seeking in a rat self-administration paradigm.

Methods/results

We first found that bilateral VTA microinjections of the orexin 1 receptor (OX1R) antagonist SB-334867 (SB) or a cocktail of the AMPA and NMDA glutamate receptor antagonists CNQX/AP-5 reduced reinstatement of cocaine seeking elicited by cues. In contrast, neither of these microinjections nor systemic SB reduced cocaine-primed reinstatement. Additionally, unilateral VTA OX1R blockade combined with contralateral VTA glutamate blockade attenuated cue-induced reinstatement, indicating that VTA orexin and glutamate are simultaneously necessary for cue-induced reinstatement. We further probed the receptor specificity of glutamate actions in VTA, finding that CNQX, but not AP-5, dose-dependently attenuated cue-induced reinstatement, indicating that AMPA but not NMDA receptor transmission is required for this type of cocaine seeking. Given the necessary roles of both OX1 and AMPA receptors in VTA for cue-induced cocaine seeking, we hypothesized that these signaling pathways interact during this behavior. We found that PEPA, a positive allosteric modulator of AMPA receptors, completely reversed the SB-induced attenuation of reinstatement behavior. Intra-VTA PEPA alone did not alter cue-induced reinstatement, indicating that potentiating AMPA activity with this drug specifically compensates for OX1R blockade, rather than simply inducing or enhancing reinstatement itself.

Conclusions

These findings show that cue-induced, but not cocaine-primed, reinstatement of cocaine seeking is dependent upon orexin and AMPA receptor interactions in VTA.     

Disrupted social development enhances the motivation for cocaine in rats

Rationale

Early social experiences are of major importance for behavioural development. In particular, social play behaviour during post-weaning development is thought to facilitate the attainment of social, emotional and cognitive capacities. Conversely, social insults during development can cause long-lasting behavioural impairments and increase the vulnerability for psychiatric disorders, such as drug addiction.

Objectives

The aim of this study was to investigate whether a lack of social experiences during the juvenile and early adolescent stage, when social play behaviour is highly abundant, alters cocaine self-administration in rats.

Methods

Rats were socially isolated from postnatal days 21 to 42 followed by re-socialization until adulthood. Cocaine self-administration was then assessed under a fixed ratio and progressive ratio schedule of reinforcement. Next, cue, cocaine and stress-induced reinstatement of cocaine seeking was determined following extinction of self-administration.

Results

Early social isolation resulted in an enhanced acquisition of self-administration of a low dose (0.083 mg/infusion) of cocaine, but the sensitivity to cocaine reinforcement, assessed using a dose–response analysis, was not altered in isolated rats. Moreover, isolated rats displayed an increased motivation for cocaine under a progressive ratio schedule of reinforcement. Extinction and reinstatement of cocaine seeking was not affected by early social isolation.

Conclusions

Early social isolation causes a long-lasting increase in the motivation to self-administer cocaine. Thus, aberrations in post-weaning social development, such as the absence of social play, enhance the vulnerability for drug addiction later in life.     

Persistent reduction of cocaine seeking by pharmacological manipulation of adenosine A1 and A2A receptors during extinction training in rats

Rationale

Adenosine receptor stimulation and blockade have been shown to modulate a variety of cocaine-related behaviors.

Objectives

These studies identify the direct effects of adenosine receptor stimulation on cocaine seeking during extinction training and the persistent effects on subsequent reinstatement to cocaine seeking.

Methods

Rats self-administered cocaine on a fixed ratio one schedule in daily sessions over 3 weeks. Following a 1-week withdrawal, the direct effects of adenosine receptor modulation were tested by administering the adenosine A₁ receptor agonist, N⁶-cyclopentyladenosine (CPA, 0.03 and 0.1 mg/kg), the adenosine A_2A agonist, CGS 21680 (0.03 and 0.1 mg/kg), the presynaptic adenosine A_2A receptor antagonist, SCH 442416 (0.3, 1, and 3 mg/kg), or vehicle prior to each of six daily extinction sessions. The persistent effects of adenosine receptor modulation during extinction training were subsequently tested on reinstatement to cocaine seeking induced by cues, cocaine, and the dopamine D₂ receptor agonist, quinpirole.

Results

All doses of CPA and CGS 21680 impaired initial extinction responding; however, only CPA treatment during extinction produced persistent impairment in subsequent cocaine- and quinpirole-induced seeking. Dissociating CPA treatment from extinction did not alter extinction responding or subsequent reinstatement. Administration of SCH 442416 had no direct effects on extinction responding but produced dose-dependent persistent impairment of cocaine- and quinpirole-induced seeking.

Conclusions

These findings demonstrate that adenosine A₁ or A_2A receptor stimulation directly impair extinction responding. Interestingly, adenosine A₁ receptor stimulation or presynaptic adenosine A_2A receptor blockade during extinction produces lasting changes in relapse susceptibility.     

Effects of combined exercise and progesterone treatments on cocaine seeking in male and female rats

Background

Individually, both treatment with progesterone and concurrent access to an exercise wheel reduce cocaine self-administration under long-access conditions and suppress cocaine-primed reinstatement in female rats. In the present study, wheel running and progesterone (alone and combined) were assessed for their effects on reinstatement of cocaine-seeking primed by yohimbine, cocaine, and cocaine-paired cues.

Methods

Male and female rats were implanted with an intravenous catheter and allowed to self-administer cocaine (0.4 mg/kg/inf, iv) during 6-h sessions for 10 days. Subsequently, the groups of male and female rats were each divided into two groups that were given concurrent access to either a locked or unlocked running wheel under extinction conditions for 14 days. Next, all four groups were tested in a within-subjects design for reinstatement of cocaine-seeking precipitated by separate administration of cocaine-paired stimuli, yohimbine, or cocaine or the combination of yohimbine?+?cocaine-paired stimuli or cocaine?+?cocaine-paired stimuli. These priming conditions were tested in the presence of concurrent wheel access (W), pretreatment with progesterone (P), or both (W?+?P).

Results

In agreement with previous results, females responded more for cocaine than males during maintenance. Additionally, concurrent wheel running attenuated extinction responses and cocaine-primed reinstatement in females but not in males. Across all priming conditions, W?+?P reduced reinstatement compared to control conditions, and for cocaine-primed reinstatement in male rats, the combined W?+?P treatment was more effective than W or P alone.

Conclusion

Under certain conditions, combined behavioral (exercise) and pharmacological (progesterone) interventions were more successful at reducing cocaine-seeking behavior than either intervention alone.     

A randomized, placebo-controlled laboratory study of the effects of d-cycloserine on craving in cocaine-dependent individuals

Rationale

d-Cycloserine (DCS), a partial glutamate N-methyl-d-aspartate (NMDA) receptor agonist, enhances extinction of conditioned fear responding; preliminary data suggest that it may facilitate extinction of drug cue reactivity.

Objective

This study investigates DCS effects on cocaine cue craving and drug use in cocaine-dependent subjects.

Methods

Thirty-two subjects were randomly assigned to receive (1) DCS only, (2) DCS before sessions 1 and 3, placebo (PBO) before session 2, or (3) PBO only 15-min before each of 3 1-h cocaine cue exposure sessions conducted 1 day apart. Craving ratings were obtained before, during, and after sessions. Drug use and cue-induced craving were assessed 1 week after the last cue session.

Results

Repeated presentation of cocaine cues resulted in decreased craving both within and between sessions. DCS did not facilitate extinction learning and may have enhanced craving. The group that received three doses of DCS had significantly higher craving than the PBO group at the baseline ratings taken before sessions 2 and 3, as well as significantly higher cue-induced craving at follow-up. The group that received two doses of DCS did not differ from the PBO group. There were no group differences in postextinction cocaine use.

Conclusions

The reduction of cocaine cue reactivity in the PBO group suggests that the study procedures were sufficient to produce extinction. Under these conditions, DCS did not facilitate extinction and may have enhanced craving. Further studies of glutamatergic agents and extinction in cocaine dependence should include consideration of procedural variables that could have a major impact on study outcomes.     

Attenuation of reinstatement of methamphetamine-, sucrose-, and food-seeking behavior in rats by fenobam, a metabotropic glutamate receptor 5 negative allosteric modulator

Rationale

Methamphetamine (METH) is a highly potent and addictive psychostimulant with severe detrimental effects to the health of users. Currently, METH addiction is treated with a combination of cognitive and behavioral therapies, but these traditional approaches suffer from high relapse rates. Furthermore, there are currently no pharmacological treatment interventions approved by the FDA specifically for the treatment of METH addiction.

Objectives

Metabotropic glutamate receptor 5 (mGluR5) negative allosteric modulators (NAMs) have shown promise in significantly attenuating drug self-administration and drug-seeking in reinstatement paradigms. However, studies assessing the potential efficacy of mGluR5 NAMs that have been tested in human subjects are lacking. The current study sought to assess the effect of the mGluR5 NAM fenobam on METH-seeking behavior.

Methods

Rats were trained to self-administer METH (0.05 mg/kg i.v.), and following extinction, tested for effects of fenobam (5, 10, or 15 mg/kg intraperitoneal) on cue- and drug-induced reinstatement of METH-seeking. To determine if fenobam also alters reinstatement of seeking of natural reinforcers, separate groups of rats were trained to self-administer sucrose or food pellets and were tested for the effects of fenobam on cue-induced reinstatement of sucrose- and food-seeking.

Results

Fenobam attenuated drug- and cue-induced reinstatement of METH-seeking behavior at doses of 10 and 15 mg/kg. Fenobam also attenuated cue-induced reinstatement of sucrose- and food-seeking at all doses tested.

Conclusions

The mGluR5 NAM fenobam attenuates the reinstatement of METH-seeking behavior, but these effects may be due to nonspecific suppression of general appetitive behaviors.     

Attenuated incubation of cocaine seeking in male rats trained to self-administer cocaine during periadolescence

Rationale and objectives  Although onset of drug use during adolescence appears to increase long-term vulnerability to drug dependence in humans, relatively little is known about extinction and reinstatement of drug seeking after periadolescent onset of drug self-administration in laboratory animals. Furthermore, although cue-induced reinstatement of cocaine seeking increases progressively during abstinence from cocaine self-administration in adult subjects, this “incubation of cocaine craving” remains unexplored after adolescent drug intake in animal models. Materials and methods  We allowed periadolescent (postnatal day (PND) 35 at start) and adult (PND 83–95 at start) male Wistar rats to self-administer cocaine (0.36 mg/kg/infusion) in 2-h daily sessions on a fixed ratio 1 schedule of reinforcement over 14 days. Then, we compared extinction and cue-induced or cocaine priming-induced reinstatement (10 mg/kg cocaine, intraperitoneal) of cocaine seeking in both age groups after 30 days of abstinence in home cages. In separate cohorts, we tested for time-dependent increases in cue-induced reinstatement over approximately 1, 14, 30, or 60 days of abstinence in both age groups. Results  Adolescent and adult rats self-administered similar amounts of cocaine. Subsequent cue-induced reinstatement was lower in the adolescent-onset group after a 30-day abstinence period, but cocaine priming-induced reinstatement did not differ across ages. Also, extinction responding and time-dependent increases in cue-induced reinstatement (incubation) were less pronounced in rats that took cocaine as adolescents compared with adults. Conclusions  Surprisingly, these results may reflect resistance among adolescent subjects to some enduring effects of drug self-administration, such as reward learning.     

Effect of wheel-running during abstinence on subsequent nicotine-seeking in rats

Rationale

Exercise appears to be a promising non-pharmacological treatment for nicotine addiction that may be useful for the vulnerable adolescent population.

Objectives

The aim of this study is to determine if wheel-running, an animal model of aerobic exercise, during an abstinence period would decrease subsequent nicotine-seeking in rats that had extended access to nicotine self-administration during adolescence.

Methods

Male adolescent rats (n?=?55) were trained to self-administer saline or nicotine infusions (5 or 10 μg/kg) under a fixed ratio 1 schedule with a maximum of 20 infusions/day beginning on postnatal day 30. After 5 days, access was extended to 23 h/day with unlimited infusions for a total of 10 days. After the last self-administration session, rats were moved to polycarbonate cages for a 10-day abstinence period where they either had access to a locked or unlocked running wheel for 2 h/day. Nicotine-seeking was examined following the 10th day of abstinence under a within-session extinction/cue-induced reinstatement paradigm.

Results

Intake was higher at the 10 μg/kg dose as compared to the 5 μg/kg dose; however, intake did not differ within doses prior to wheel assignment. Compared to saline controls, rats that self-administered nicotine at either dose showed a significant increase in drug-seeking during extinction, and consistent with our hypothesis, exercise during abstinence attenuated this effect. Nicotine led to modest but significant levels of cue-induced reinstatement; however, in this adolescent-onset model, levels were variable and not affected by exercise.

Conclusions

Exercise may effectively reduce relapse vulnerability for adolescent-onset nicotine addiction     

Cue-induced resumption of heroin and cocaine seeking in rats using a conflict model of abstinence and relapse

Rationale and objectives

Most animal research on drug relapse involves the reinstatement model where abstinence is a result of drug removal (extinction). However, abstinence in humans often results from the aversive consequences that accompany drug seeking (conflict situation). This study was aimed at using a conflict-based animal model of abstinence/relapse in rats self-administering heroin or cocaine.

Methods

Rats were trained to self-administer heroin (0.05 mg kg^?1 injection^?1) or cocaine (0.5 mg kg^?1 injection^?1) with each injection paired with a light cue. After stable responding was demonstrated, the floor near the levers was electrified, creating a barrier, in order to model the negative consequences of continued drug seeking. Shock intensities were increased over sessions until no responses occurred for three consecutive sessions. During a relapse test, where shock was maintained,the capacity of noncontingent drug cue presentations to induce active lever pressing was assessed.

Results

Ten of ten heroin animals and three of eight cocaine animals exposed to noncontingent cue presentations resumed responding. During the relapse test, for both drug groups, active lever pressing was significantly higher than during abstinence but only in the heroin group was it significantly higher than inactive lever pressing.

Conclusions

The implementation of negative consequences for drug seeking can result in its cessation just as they might in human addicts. Similarly, exposure to drug cues can lead to resumption of drug seeking. This model may be useful for studying the mechanisms underlying abstinence and relapse and for developing strategies to prevent relapse.     

Bidirectional effects of inhibiting or potentiating NMDA receptors on extinction after cocaine self-administration in rats

Rationale

Extinction of drug seeking is facilitated by NMDA receptor (NMDAr) agonists, but it remains unclear whether extinction is dependent on NMDAr activity.

Objectives

We investigated the necessity of NMDArs for extinction of cocaine seeking and whether extinction altered NMDAr expression within extinction-related neuroanatomical loci.

Methods

Rats were trained to lever press for i.v. infusions of cocaine or sucrose reinforcement prior to extinction training or withdrawal.

Results

Administration of the NMDAr competitive antagonist CPP prior to four brief extinction sessions impaired subsequent extinction retention. In contrast, administration of the NMDAr coagonist D-serine after four brief extinction sessions attenuated lever pressing during subsequent extinction, indicative of facilitated consolidation of extinction. Furthermore, expression of the NMDAr subunits, GluN2A and GluN2B, was not altered in the ventromedial prefrontal cortex. However, both GluN2A and GluN2B subunit expression in the nucleus accumbens increased following cocaine self-administration, and this increased expression was relatively resistant to modulation by extinction.

Conclusions

Our findings demonstrate that extinction of cocaine seeking is bidirectionally mediated by NMDArs and suggest that selective modulation of NMDAr activity could facilitate extinction-based therapies for treatment of cocaine abuse.     

Reinstatement of cocaine seeking induced by drugs, cues, and stress in adolescent and adult rats

Rationale

In human and animal studies, adolescence marks a period of increased vulnerability to the initiation and subsequent abuse of drugs. Adolescents may be especially vulnerable to relapse, and a critical aspect of drug abuse is that it is a chronically relapsing disorder. However, little is known of how vulnerability factors such as adolescence are related to conditions that induce relapse, triggered by the drug itself, drug-associated cues, or stress.

Objective

The purpose of this study was to compare adolescent and adult rats on drug-, cue-, and stress-induced reinstatement of cocaine-seeking behavior.

Methods

On postnatal days 23 (adolescents) and 90 (adults), rats were implanted with intravenous catheters and trained to lever press for i.v. infusions of cocaine (0.4 mg/kg) during two daily 2-h sessions. The rats then self-administered i.v. cocaine for ten additional sessions. Subsequently, visual and auditory stimuli that signaled drug delivery were unplugged, and rats were allowed to extinguish lever pressing for 20 sessions. Rats were then tested on cocaine-, cue-, and yohimbine (stress)-induced cocaine seeking using a within-subject multicomponent reinstatement procedure.

Results

Results indicated that adolescents had heightened cocaine seeking during maintenance and extinction compared to adults. During reinstatement, adolescents (vs adults) responded more following cocaine- and yohimbine injections, while adults (vs adolescents) showed greater responding following presentations of drug-associated cues.

Conclusion

These results demonstrated that adolescents and adults differed across several measures of drug-seeking behavior, and adolescents may be especially vulnerable to relapse precipitated by drugs and stress.     

Age-dependent alterations in reward-seeking behavior after brief nicotine exposure

Rationale

Adolescence is a developmental period that coincides with the onset of tobacco use. Teen smokers are also more likely to abuse other drugs compared to nonsmokers. Previous studies with rats have shown that low-dose nicotine pretreatment enhances initial acquisition of cocaine self-administration when given during early adolescence, but not at later ages. The aim of the present study was to determine whether these nicotine pretreatment effects extend to extinction and reinstatement of reward-seeking behavior.

Methods

Adolescent [postnatal day (P)28] and adult rats (P86) were pretreated for 4 days with nicotine (60 μg/kg, i.v.) or saline. Following pretreatment, rats were allowed to nose poke for cocaine (500 μg/kg/infusion) or sucrose pellets for at least 12 days or until meeting acquisition criterion. Responding was then extinguished for at least 7 days or until extinction criterion was met. The following day, the rats were reinstated with either a priming injection of cocaine (10 mg/kg, i.p.) or sucrose pellets.

Results

Nicotine markedly enhanced extinction of cocaine self-administration in adolescent rats, but not adults. Pretreatment also enhanced the acquisition of cocaine self-administration in adolescents, while reducing discrimination for the reinforced hole in adults. There were no pretreatment or age effects on cocaine-induced reinstatement. In contrast, nicotine induced only minor enhancement of sucrose-taking behavior in adolescents, with no significant impact on extinction or reinstatement at either age.

Conclusions

Nicotine pretreatment affects reward-related behavior in both an age- and reward-dependent manner. These findings show that brief nicotine exposure during early adolescence enhances drug-related learning.     

N-acetylcysteine decreased nicotine self-administration and cue-induced reinstatement of nicotine seeking in rats: comparison with the effects of N-acetylcysteine on food responding and food seeking

Rationale

Chronic nicotine administration decreases the functioning of the cystine–glutamate antiporter system x_c? which is hypothesized to promote nicotine-taking and nicotine-seeking behaviors. N-acetylcysteine (NAC), a cystine pro-drug, increases the activity of the cystine–glutamate antiporter system x_c?. Thus, NAC could potentially reverse nicotine-induced alterations in glutamatergic transmission and decrease nicotine taking and seeking.

Objectives and methods

To test this hypothesis in the present study, the effects of acute NAC treatment (30, 60, and 90 mg/kg, i.p.) on nicotine (fixed- and progressive-ratio schedules) and food (fixed-ratio schedule) self-administration were assessed in rats. In addition, the effects of acute NAC treatment on cue-induced reinstatement of nicotine- and food-seeking behaviors were investigated. Finally, the effects of repeated daily NAC administration (60 mg/kg, i.p., 14 days) on nicotine and food self-administration were assessed.

Results

Acute NAC administration decreased nicotine self-administration but not food responding under a fixed-ratio schedule of reinforcement. In addition, acute NAC administration showed a nonsignificant trend in attenuating nicotine self-administration under a progressive-ratio schedule that was similar to the dose–response function under the fixed-ratio schedule. Furthermore, repeated NAC administration decreased nicotine self-administration from day 6 to 14 compared with vehicle treatment, with no indication of tolerance development. By contrast, repeated NAC administration decreased food responding from day 6 to 8 compared with vehicle treatment and showed rapid development of tolerance. Finally, acute NAC administration attenuated cue-induced reinstatement of nicotine and food seeking.

Conclusions

Altogether, these findings suggest that NAC may be useful in promoting smoking cessation in humans.