Kenneth J. Thiel

Social Reward-Conditioned Place Preference: A Model Revealing an Interaction between Cocaine and Social Context Rewards in Rats

A recent thrust in drug abuse research is the influence of social interactions on drug effects. Therefore, the present study examined conditioned place preference (CPP) as a model for assessing interactions between drug and social rewards in adolescent rats. Parameters for establishing social reward-CPP were examined, including the number of conditioning sessions/day (1 or 2), the total number of sessions (2, 8, or 16), and the duration of sessions (10 or 30 min). Subsequently, the effects of cocaine or dextromethorphan on social reward-CPP and play behavior were examined. The results demonstrate that social reward-CPP (i.e., preference shift for an environment paired previously with a rat) was similar using either 1 or 2 conditioning sessions/day and either 10 or 30 min sessions; however, social reward-CPP increased as the number of social pairings increased. Additionally, a low dose of cocaine (2 mg/kg, IP) and a low number of social pairings (2 pairings) failed to produce CPP when examined alone, but together produced a robust CPP, demonstrating an interaction between these rewards. The non-rewarding drug, dextromethorphan (30 mg/kg, IP), failed to enhance social reward-CPP, suggesting that drug-enhanced social reward-CPP is specific to rewarding drugs. Surprisingly, there was no relationship between play behaviors and preference shift in drug-naïve animals. Furthermore, cocaine inhibited play behavior despite enhancing social reward-CPP, suggesting that aspects of social interaction other than play behavior likely contribute to social reward. The findings have important implications for understanding the influence of social context on cocaine reward during adolescence.

Anti-craving effects of environmental enrichment

We hypothesized that environmental enrichment in rats may reduce cocaine-seeking behaviour elicited by cocaine-priming injections and by cocaine-associated cues. Rats trained to self-administer cocaine while housed in isolated conditions were then assigned to live in isolation or an enriched environment for 21 d of forced abstinence. Subsequently, extinction and reinstatement of cocaine-seeking behaviour (operant responses without cocaine available) were assessed. Expt 1 showed that enrichment resulted in less cocaine-seeking behaviour during extinction and cue-elicited reinstatement compared to continued isolation housing, but had no effect on cocaine-primed reinstatement. A subsequent experiment, which included a pair-housed group to control for potential isolation stress, again demonstrated that enrichment attenuated cocaine seeking during extinction, but not cocaine-primed reinstatement, relative to both isolation and pair-housed conditions. The findings suggest that enrichment reduces the impact of cocaine-associated environmental stimuli, and hence it may be a useful intervention for attenuating cue-elicited craving in humans.

c-Fos expression associated with reinstatement of cocaine-seeking behavior by response-contingent conditioned cues

The capability of cocaine cues to generate craving in cocaine‐dependent humans, even after extended abstinence, is modeled in rats using cue reinstatement of extinguished cocaine‐seeking behavior. We investigated neural activity associated with incentive motivational effects of cocaine cues using c‐fos mRNA and Fos protein expression as markers. Unlike preceding studies, we used response‐contingent presentation of discrete cues to elicit cocaine seeking. Rats were first trained to press a lever, resulting in cocaine reinforcement and light and tone cues. Rats then underwent extinction training, during which lever presses decreased. On the test day, rats either received response‐contingent cocaine cues or received no cues. The cues reinstated extinguished cocaine‐seeking behavior on the test day. In general, cue‐elicited c‐fos mRNA and protein expression were similar and both were enhanced in the prefrontal cortex, ventral tegmental area (VTA), dorsal striatum, and nucleus accumbens. Cues elicited more widespread Fos protein expression relative to our previous research in which cues were presented noncontingently without prior extinction training, including increases in the VTA, substantia nigra, ventral subiculum, and lateral entorhinal cortex. We also observed a correlation between cocaine‐seeking behavior and Fos in the agranular insula (AgI) and basolateral amygdala (BLA). The findings suggest that connections between BLA and AgI play a role in cue‐elicited incentive motivation for cocaine and that reinstatement of cocaine seeking by response‐contingent cues activates a similar corticolimbic circuit as that observed with other modes of cue presentation; however, activation of midbrain and ventral hippocampal regions may be unique to reinstatement by response‐contingent cues. Synapse 63:823–835, 2009.

Limited physical contact through a mesh barrier is sufficient for social reward-conditioned place preference in adolescent male rats

Adolescence is a period of enhanced sensitivity to social influences and vulnerability to drug abuse. Social reward in adolescent rats has been demonstrated with the conditioned place preference (CPP) model, but it is not clear whether limited contact with another rat without play is sufficient to produce reward. We investigated this issue using an apparatus containing two main compartment, each with a wire mesh barrier that allowed rats placed on either side of the barrier to have limited physical contact. Adolescent male rats were given two conditioning sessions/day for 2 or 8 days following baseline preference tests. Rats were placed into their preferred side alone for one daily 10-min session and into their initially non-preferred side (i.e., CS) for the other session during which they either had restricted or unrestricted physical access to another rat (Rat/Mesh or Rat/Phys, respectively) or to a tennis ball (Ball/Mesh or Ball/Phys, respectively) unconditioned stimulus (US). Only the Rat/Phys group exhibited CPP after 2 CS-US pairings; however, after 8 CS-US pairings, the Rat/Mesh and Ball/Phys groups also exhibited CPP. During conditioning, the rat US elicited more robust approach and contact behavior compared to the ball, regardless of physical or restricted access. The incidence of contact and/or approach increased as the number of exposures increased. The results suggest that the rank order of US reward efficacy was physical contact with a rat>limited contact with a rat>physical contact with a ball, and that rough-and-tumble play is not necessary to establish social reward-CPP. The findings have important implications for emerging drug self-administration models in which two rats self-administering drug intravenously have limited physical contact via a mesh barrier shared between their respective operant conditioning chambers.

Stimulation of Medial Prefrontal Cortex Serotonin 2C (5-HT 2C ) Receptors Attenuates Cocaine-Seeking Behavior

Serotonin 2C receptor (5-HT2CR) agonists administered systemically attenuate both cocaine-primed and cue-elicited reinstatement of extinguished cocaine-seeking behavior. To further elucidate the function of these receptors in addiction-like processes, this study examined the effects of microinfusing the 5-HT2CR agonist MK212 (0, 10, 30, 100 ng/side/0.2 μl) into the medial prefrontal cortex (mPFC) on cocaine self-administration and reinstatement of extinguished cocaine-seeking behavior. Male Sprague–Dawley rats were trained to self-administer cocaine (0.75 mg/kg, i.v.) paired with light and tone cues. Once responding stabilized, rats received MK212 microinfusions before tests for maintenance of cocaine self-administration. Next, extinction training to reduce cocaine-seeking behavior, defined as responses performed without cocaine reinforcement available, occurred until low extinction baselines were achieved. Rats then received MK212 microinfusions before tests for reinstatement of extinguished cocaine-seeking behavior elicited by cocaine-priming injections (10 mg/kg, i.p.) or response-contingent presentations of the cocaine-associated cues; operant responses during cocaine-primed reinstatement tests produced no consequences. MK212 microinfusions into the prelimbic and infralimbic, but not anterior cingulate, regions of the mPFC dose-dependently attenuated both cocaine-primed and cue-elicited reinstatement of extinguished cocaine-seeking behavior, but did not reliably affect cocaine self-administration. A subsequent experiment showed that the effects of MK212 (100 ng/side/0.2 μl) on reinstatement of extinguished cocaine-seeking behavior were blocked by co-administration of the 5-HT2CR antagonist SB242084 (200 ng/side/0.2 μl). MK212 administered alone into the mPFC as a drug prime produced no discernable effects on cocaine-seeking behavior. These findings suggest that stimulation of 5-HT2CRs in the mPFC attenuates the incentive motivational effects produced by sampling cocaine or exposure to drug-paired cues.

The interactive effects of environmental enrichment and extinction interventions in attenuating cue-elicited cocaine-seeking behavior in rats.

Cues associated with cocaine can elicit craving and relapse. Attempts have been made to employ extinction therapy, which is aimed at attenuating the incentive motivational effects of cocaine cues, as a treatment for cocaine addiction; however, this approach has been largely unsuccessful perhaps due to the inability to extinguish all cues associated with cocaine use while in a clinic. Recently, environmental enrichment (EE) during abstinence has been proposed as a strategy to attenuate cue-elicited cocaine craving. The present study used an animal model to examine whether the utility of extinction toward attenuating cue-elicited cocaine-seeking behavior could be enhanced by also providing EE. All rats were trained to self-administer cocaine while housed in isolated conditions and then subsequently underwent 17 days of forced abstinence, during which they were either housed in pairs or under EE and they either received daily 1-h extinction sessions or similar handling without exposure to the self-administration environment. Following this intervention period, all rats were tested for cue-elicited cocaine-seeking behavior. To examine whether effects of these interventions persist, all rats were subsequently single-housed for an additional 7-day forced abstinence period, followed by a second test for cue-elicited cocaine-seeking behavior. We found that although daily extinction training and EE each attenuated subsequent cue-elicited cocaine-seeking behavior, the combined treatment of extinction training+EE completely prevented it. However, once these interventions were discontinued, their protective effects diminished. These findings suggest that combining behavioral therapy approaches may improve outcomes; however, future work is needed to improve the longevity of these strategies beyond their implementation.

Environmental enrichment counters cocaine abstinence-induced stress and brain reactivity to cocaine cues but fails to prevent the incubation effect.

Environmental enrichment (EE) during a period of forced abstinence attenuates incentive motivational effects of cocaine‐paired stimuli. Here we examined whether EE during forced abstinence from cocaine self‐administration would prevent time‐dependent increases in cue‐elicited cocaine‐seeking behavior (i.e. the incubation effect). Rats were trained to self‐administer cocaine, which was paired with light/tone cues, for 15 days while living in isolated conditions (IC). Controls received yoked saline infusions. Subsequently, rats were assigned to live in either continued IC or EE for either 1 or 21 days of forced abstinence prior to a test for cocaine‐seeking behavior. During testing, responding resulted only in presentation of the light/tone cues. Contrary to our prediction, cocaine‐seeking behavior increased over time regardless of living condition during abstinence; however, EE attenuated cocaine‐seeking behavior relative to IC regardless of length of abstinence. Brains were harvested and trunk blood was collected immediately after the 60‐minute test and later assayed. Results indicated that short‐term EE elevated hippocampal brain‐derived neurotrophic factor and reduced plasma corticosterone compared with IC. Furthermore, 21 days of EE during forced abstinence prevented increases in the cue‐elicited amygdala phosphorylated extracellular signal‐regulated kinase expression that was observed in IC rats. These findings suggest that EE attenuates incentive motivational effects of cocaine cues through a mechanism other than preventing the incubation effect, perhaps involving reduction of stress and neural activity in response to cocaine‐paired cues during acute withdrawal.

Effect of schedule of reinforcement on cue-elicited reinstatement of cocaine-seeking behavior.

Cocaine-associated cues can elicit incentive motivational effects that drive cocaine-seeking behavior and contribute to relapse. The extinction/reinstatement model is commonly used to measure these effects in animals. This study examined the influence of training and testing schedules of reinforcement on cue-elicited reinstatement. Lever presses during training resulted in cues and cocaine (0.75 mg/kg/IV) on either continuous or partial reinforcement schedules [fixed ratio (FR) 1 or 11, variable ratio (VR) 5 or 11]. Animals then underwent extinction training, followed by a test for cue-elicited reinstatement of extinguished cocaine-seeking behavior by response-contingent cue presentations on either a continuous (FR 1) or a partial reinforcement schedule (FR 11). Partial reinforcement during training resulted in higher response rates during cue-elicited reinstatement relative to continuous reinforcement. In contrast, delivery of cues on a continuous reinforcement schedule during testing yielded higher response rates relative to delivery on a partial reinforcement schedule. Finally, the shift from a partial to a continuous reinforcement schedule across training and testing phases did not alter response rates. These findings provide important information for choosing parameters for reinstatement of drug-seeking behavior that would allow the most sensitive method to detect changes in response rate after an experimental manipulation.

Stimulation of dopamine D2/D3 but not D1 receptors in the central amygdala decreases cocaine-seeking behavior

Alterations in dopamine output within the various subnuclei of the amygdala have previously been implicated in cocaine reinforcement, as well as cocaine-seeking behavior. To elucidate the potential for increased stimulation of D1- and D2-like receptors (D1Rs and D2Rs, respectively) specifically in the central nucleus of the amygdala (CeA) to modulate cue- and cocaine-elicited reinstatement of cocaine-seeking behavior, we infused either the D1R agonist, SKF-38393 (0-4.0 microg/side) or the D2R agonist, 7-OH-DPAT (0-4.0 microg/side) into the CeA immediately prior to tests for cue and cocaine-primed reinstatement. We also examined the effects of 7-OH-DPAT on cocaine self-administration as a positive behavioral control. 7-OH-DPAT decreased cue-and cocaine-primed reinstatement, and reduced the number of cocaine infusions obtained during self-administration; SKF-38393 produced no discernable effects. The results suggest that enhanced stimulation of D2Rs, but not D1Rs, in the CeA is sufficient to inhibit expression of the incentive motivational effects of cocaine priming and cocaine-paired cues. Together with previous findings that D1R blockade attenuates reinstatement of cocaine-seeking behavior, the results suggest that D1R stimulation may be necessary, but not sufficient, to modulate the incentive motivational effects of cues and cocaine priming.

Novel cues reinstate cocaine-seeking behavior and induce Fos protein expression as effectively as conditioned cues.

Cue reinstatement of extinguished cocaine-seeking behavior is a widely used model of cue-elicited craving in abstinent human addicts. This study examined Fos protein expression in response to cocaine cues or to novel cues as a control for activation produced by test novelty. Rats were trained to self-administer cocaine paired with either a light or a tone cue, or received yoked saline and cue presentations, and then underwent daily extinction training. They were then tested for reinstatement of extinguished cocaine-seeking behavior elicited by response-contingent presentations of either the cocaine-paired cue or a novel cue (that is, tone for those trained with a light or vice versa). Surprisingly, conditioned and novel cues both reinstated responding and increased Fos similarly in most brain regions. Exceptions included the anterior cingulate, which was sensitive to test cue modality in saline controls and the dorsomedial caudate-putamen, where Fos was correlated with responding in the novel, but not conditioned, cue groups. In subsequent experiments, we observed a similar pattern of reinstatement in rats trained and tested for sucrose-seeking behavior, whereas rats trained and tested with the cues only reinstated to a novel, and not a familiar, light or tone. The results suggest that novel cues reinstate responding to a similar extent as conditioned cues regardless of whether animals have a reinforcement history with cocaine or sucrose, and that both types of cues activate similar brain circuits. Several explanations as to why converging processes may drive drug and novel cue reinforcement and seeking behavior are discussed.