Daniel F. Manvich, Ph.D. - US grants

DESCRIPTION (provided by applicant): Despite substantial efforts, there are currently no FDA-approved pharmacotherapies available for the treatment of cocaine abuse or dependence. A prominent feature of cocaine use is the high rate of relapse among addicted individuals. Cocaine craving is thought to serve as an important event preceding relapse and can be elicited in human addicts via presentation of cocaine-associated cues. Similarly, cocaine-paired cues are capable of reinstating previously-extinguished cocaine-seeking behavior in experimental animals trained to self-administer cocaine. Recent evidence obtained in rodents has suggested that activation of group II metabotropic glutamate receptors (mGluRs) is capable of attenuating the ability of cocaine cues to induce reinstatement. Group II mGluRs include the mGluR2 and mGluRS subtypes and are Gi/o-coupled presynaptic receptors whose activation results in decreased synaptic release of glutamate, dopamine, and other neurotransmitters. These receptors are localized in brain regions known to be involved in the reinforcing effects of cocaine, such as the caudate nucleus, nucleus accumbens (NAcc), prefrontal cortex, and amygdala. The proposed experiments seek to translate and extend earlier findings from rodents to nonhuman primate models of cocaine use and relapse. Squirrel monkeys will be trained to self-administer intravenous cocaine in the presence of distinct environmental stimuli. Presentation of these stimuli during saline substitution tests will thus result in cocaine-seeking behavior initiated and maintained solely by the presentation of cocaine-paired cues and not by the direct pharmacological effects of cocaine itself. Animals will be pretreated with the highly-selective and potent group II mGluR agonist LY379268 prior to cue- presentation tests to determine if activation of these receptors can attenuate cue-induced drug-seeking behavior in primates with extensive histories of cocaine self-administration. Subsequently, animals will be implanted with guide cannulae targeting both the dorsal and ventral (NAcc) portions of the striatum. Cue- presentation test sessions will be conducted concurrently with microdialysis to assess any possible correlations between LY379268 effects on cocaine-seeking and its neuropharmacological effects on extracellular dopamine or glutamate levels within the dorsal and ventral striatum. The goal of this research is to better understand the mechanism(s) by which drug-associated cues are capable of eliciting drug-craving in cocaine-addicted individuals. As craving is a major factor preceding relapse to drug use, the results of these experiments may help identify new targets for anticraving and relapse-prevention medications development.

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The purpose of this project is to better understand the mechanisms by which drug-associated cues are capable of eliciting drug-seeking behavior in cocaine abusers, as well as to identify pharmacotherapeutic targets for the treatment of cocaine addiction and relapse. We proposed to train nonhuman primates on a novel operant-conditioning procedure whereby environmental stimuli are predictive of either intravenous cocaine (S+) or saline (S-) infusions. Early experiments demonstrated that the group II metabotropic glutamate receptor agonist LY479268 selectively reduced responding elicited by drug-associated stimuli. However, this behavioral schedule proved difficult to entrain in an adequate number of experimental subjects due to its inherent complexity, and we have therefore modified our experimental procedures. A full cohort of subjects are now trained according to a more traditional schedule of second-order cocaine self-administration that lacks the S+/S- contingency, and we will use the reinstatement procedure as our model of cue- or drug-induced relapse. Additionally, we have halted our work with LY379268 due to the appearance of adverse side effects as well as its reported actions at dopamine D2 receptors. We have begun pilot studies investigating other pharmacological targets, specifically the serotonin (5-HT) 2a and 2c receptors. To date, we have demonstrated that systemic administration of the 5-HT 2c receptor agonists mCPP or Ro 60-0175 attenuates the behavioral-stimulant and relapse-inducing effects of cocaine. Current studies are investigating the effects of these compounds on the reinforcing effects of cocaine using self-administration procedures.

? DESCRIPTION (provided by applicant): A prominent feature of cocaine abuse and dependence disorders is the frequent occurrence of relapse episodes often caused by psychological distress and/or negative emotional affect. Relapse to drug use is commonly modeled in experimental animals using the reinstatement procedure. In this paradigm, animals are first trained to self-administer drugs of abuse via operant responding (e.g. lever-press), and then this responding is extinguished by withholding drug infusions. Once extinguished, responding can be reinstated by exposing the animal to various stimuli, including stress. However, the stressors typically used to reinstate cocaine-seeking behavior in animals are physical or pharmacological in nature, whereas psychosocial stressors more closely resemble the types of stress that typically induce craving and provoke relapse in humans. This is of great concern because numerous studies have indicated that the brain circuitry mediating responses to psychosocial stress may be different from those that mediate responses to other forms of stress. To address this gap in drug abuse research, I developed a novel reinstatement procedure in which cocaine-seeking behavior in rats is triggered by psychosocial, rather than physical or pharmacological, stress. The psychosocial stressor employed in this paradigm is conspecific social defeat, which can be engendered by placing an intruder rat into the home cage of a larger resident territorial rat. The resident will quickly threaten and ultimately foce the intruder to submit. Importantly, the distress experienced by the intruder is thought to closely mirror the types of psychosocial stress that drug abusers experience prior to a relapse episode. I hypothesize that psychosocial stress-induced cocaine seeking is mediated by distinct neural circuitry as compared to other stressors, and likely includes components of a highly- conserved defensive system in the brain. In Aim 1 (K99 phase), I will use c-fos immunohistochemical techniques to map the brain activation patterns produced by cocaine seeking in response to psychosocial or physical stress to identify those regions selectively activated during psychosocial stress-induced reinstatement. In Aims 2 and 3 (R00 phase), I will use the training I acquired during the K99 phase to apply chemical genetic approaches (site-specific expression of designer receptors, DREADDs) to determine whether components of the defensive circuit are causally linked to the observed drug-seeking response. The results of these studies could have a profound impact on our understanding of the interaction between stress and addiction processes, and will lay the foundation for future work aimed at further characterizing the neurobiology underlying psychosocial stress-induced drug-seeking behavior. The ultimate goal of these studies is to identify novel behavioral and/or pharmacotherapeutic treatment strategies to prevent stress-induced drug relapse.