Nathan Pentkowski

Preclinical animal models are utilized in the study of unconditioned states related to fear and anxiety. They are used to screen novel pharmaceuticals, study behavioral phenomena, and understand underlying etiology. In this chapter, we will present a brief overview of the most prevalently used models, discuss their various applications, and state their main behavioral indices. We will conclude by discussing

Social factors are important determinants of drug dependence and relapse. We reviewed pre-clinical literature examining the role of social experiences from early life through the development of drug dependence and relapse, emphasizing two aspects of these experiences: (1) whether the social interaction is appetitive or aversive and (2) whether the social interaction occurs within or outside of the drug-taking context. The models reviewed include neonatal care, isolation, social defeat, chronic subordination, and prosocial interactions. We review results from these models in regard to effects on self-administration and conditioned place preference established with alcohol, psychostimulants, and opiates. We suggest that in general, when the interactions occur outside of the drug-taking context, prosocial interactions are protective against drug abuse-related behaviors, whereas social stressors facilitate these behaviors. By contrast, positive or negative social interactions occurring within the drug-taking context may interact with other risk factors to enhance or inhibit these behaviors. Despite differences in the nature and complexity of human social behavior compared to other species, the evolving animal literature provides useful models for understanding social influences on drug abuse-related behavior that will allow for research on the behavioral and biological mechanisms involved. The models have contributed to understanding social influences on initiation and maintenance of drug use, but more research is needed to understand social influences on drug relapse.

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.

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.

Addiction to psychostimulants, including cocaine and amphetamine, is associated with dysregulation of dopamine and serotonin (5-HT) neurotransmitter systems. Neuroadaptations in these systems vary depending on the stage of the drug taking-abstinence-relapse cycle. Consequently, the effects of potential treatments that target these systems may vary depending on whether they are given during abstinence or relapse. In this review, we discuss evidence that dopamine D3 receptors (D3Rs) and 5-HT1B receptors (5-HT1BRs) are dysregulated in response to both chronic psychostimulant use and subsequent abstinence. We then review findings from preclinical self-administration models which support targeting D3Rs and 5-HT1BRs as potential medications for psychostimulant dependence. Potential side effects of the treatments are discussed and attention is given to studies reporting positive treatment outcomes that depend on: 1) whether testing occurs during self-administration versus abstinence, 2) whether escalation of drug self-administration has occurred, 3) whether the treatments are given repeatedly, and 4) whether social factors influence treatment outcomes. We conclude that D3/D2 agonists may decrease psychostimulant intake; however, side effects of D3/D2R full agonists may limit their therapeutic potential, whereas D3/D2R partial agonists have fewer undesirable side effects. D3-selective antagonists may not reduce psychostimulant intake during relapse, but nonetheless, may decrease motivation for seeking psychostimulants with relatively few side-effects. 5-HT1BR agonists provide a striking example of treatment outcomes that are dependent on the stage of the addiction cycle. Specifically, these agonists initially increase cocaine's reinforcing effects during maintenance of self-administration, but after a period of abstinence they reduce psychostimulant seeking and the resumption of self-administration. In conclusion, we suggest that factors contributing to dysregulation of monoamine systems, including drug history, abstinence, and social context, should be considered when evaluating potential treatments to better model treatment effects in humans. This article is part of a Special Issue entitled 'NIDA 40th Anniversary Issue'.

The role of serotonin-1B receptors (5-HT(1B)Rs) in modulating cocaine abuse-related behaviors has been controversial due to discrepancies between pharmacological and gene knockout approaches and opposite influences on cocaine self-administration versus cocaine-seeking behavior. We hypothesized that modulation of these behaviors via 5-HT(1B)Rs in the mesolimbic pathway may vary depending on the stage of the addiction cycle. To test this hypothesis, we examined the effects of increasing 5-HT(1B)R production by microinfusing a viral vector expressing either green fluorescent protein and 5-HT(1B)R or green fluorescent protein alone into the medial nucleus accumbens shell of rats either during maintenance of cocaine self-administration (i.e., active drug use) or during protracted withdrawal. 5-HT(1B)R receptor gene transfer during maintenance shifted the dose-response curve for cocaine self-administration upward and to the left and increased breakpoints and cocaine intake on a progressive ratio schedule, consistent with enhanced reinforcing effects of cocaine. In contrast, following 21 days of forced abstinence, 5-HT(1B)R gene transfer attenuated breakpoints and cocaine intake on a progressive ratio schedule of reinforcement, as well as cue- and cocaine-primed reinstatement of cocaine-seeking behavior. This unique pattern of effects suggests that mesolimbic 5-HT(1B)Rs differentially modulate cocaine abuse-related behaviors, with a facilitative influence during periods of active drug use, in striking contrast to an inhibitory influence during protracted withdrawal. These findings suggest that targeting 5-HT(1B)Rs may lead to a novel treatment for cocaine dependence and that the therapeutic efficacy of these treatments may vary depending on the stage of the addiction cycle.

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 ...