The Dopamine D3 Receptor Antagonist VK4-40 Attenuates Morphine-Induced Hyperactivity But Not Cocaine-Induced Hyperactivity in Mice

In light of the increasing rates of opioid abuse in the US, the search for viable medications to treat opioid abuse disorder (OUD) has become ever more urgent. Opioids exert their abuse-related effects in part by indirectly increasing dopamine (DA) neurotransmission in the mesolimbic system, a dopaminergic projection arising in the ventral tegmental area and terminating in the nucleus accumbens. The DA D3 receptor (D3R), which belongs to the D2 family of dopamine receptors (D2, D3 , D4 receptor subtypes), is highly expressed in these brain regions and has shown strong potential as a pharmacotherapeutic target for the treatment of OUD. More specifically, D3R antagonists have been shown by us and others to attenuate the abuse-related behavioral effects of opioids without producing adverse side effects associated with nonselective D2-like receptor antagonists. We previously examined the effects of the selective D3R antagonist PG01037 (133-fold selectivity for D3R vs. D2R) using drug-induced hyperactivity as a behavioral proxy for DA release within the nucleus accumbens. Interestingly, we found that PG01037 enhances cocaine-induced hyperlocomotion while it attenuates morphine-induced hyperlocomotion in mice. The potentiation of psychostimulant effects could confound the potential use of D3R antagonists for the treatment of OUD, since many opioid users co-abuse stimulants such as cocaine. However, recent studies with more selective D3R antagonists found that they do not enhance certain effects of cocaine while still reducing opioid effects. It is currently unknown what impact these highly-selective D3R antagonists will have on cocaine-induced hyperactivity and/or dopamine neurotransmission. The purpose of this study was to examine the impact of pretreatment with the novel and highly selective D3R antagonist VK4-40 (250-fold selectivity for D3R vs. D2R) on cocaine- and morphine-induced hyperlocomotion in mice

Neuroactivational and Behavioral Correlates of Psychosocial Stress-Induced Cocaine Seeking in Rats

A prominent feature of cocaine abuse is a high risk of relapse even despite prolonged periods of abstinence. Psychosocial stress is thought to be a major contributor to the onset of cocaine craving and relapse in human substance abusers, yet most preclinical models of stress-induced relapse employ physical stressors (e.g., unpredictable footshock) or pharmacological stressors (e.g., yohimbine to elicit a drug seeking response) and do not rely upon psychosocial stress per se. Importantly, social stressors are well known to activate distinct neural circuits within the brain as compared to other stressors. It is therefore possible that currently available animal models of stress-induced drug relapse do not fully engage the neuroanatomical, neurochemical, and/or molecular substrates that are recruited specifically by psychosocial stressors to produce drug-seeking behavior. Social defeat stress has been proposed as an ethologically valid psychosocial stressor in rodents that more closely models the forms of psychosocial stress that precede relapse episodes in drug abusers. We previously developed a model of psychosocial stress-induced reinstatement in rats in which cocaine seeking is elicited via exposure to a cue signaling impending social defeat stress. Using this model, we discovered that predilection towards displaying active coping behaviors during prior social defeat stress exposures was positively correlated with levels of psychosocial stress-induced cocaine seeking. The present study aimed to expand upon these initial findings by assessing and comparing patterns of neural activation in key brain areas during stress induced cocaine seeking that is triggered by psychosocial or footshock stress predictive cues