Glutamate and Addiction

National Institute On Drug Abuse

Investigators

Linked publications, trials & patents

Abstract

In one of our recent reports (Zhan et al., 2018), we used wild-type (WT) and DA D3R-KO mice, to study whether D3R loss alters heroin-taking and heroin-seeking behaviors in different stages of the drug addiction cycle. We found that D3-KO mice learned to self-administer heroin faster and took more heroin than wild-type mice during acquisition and maintenance of self-administration. D3R-KO mice also displayed higher motivation to work to obtain heroin reward during self-administration under progressive-ratio reinforcement, as well as elevated heroin-seeking during extinction and reinstatement testing. In addition, deletion of the D3R induced higher baseline levels of extracellular dopamine (DA) in the nucleus accumbens (NAc), higher basal levels of locomotion, and reduced NAc DA and locomotor responses to lower doses of heroin. These findings suggest that the D3R is critically involved in regulatory processes that normally limit opioid intake via DA-related mechanisms. Deletion of D3R augments opioid-taking and opioid-seeking behaviors. Therefore, low D3R availability in the brain may represent a risk factor for the development of opioid abuse and addiction. In another report by Li et al., (2018), we investigated whether and how mGluR5 antagonists inhibit drug-taking and drug-seeking behavior in experimental animals. In this study, we found that systemic or intra-nucleus accumbens (NAc) administration of the mGluR5 antagonist MPEP dose-dependently reduced cocaine self-administration and cocaine-induced reinstatement of drug-seeking behavior. The reduction in cocaine-taking and cocaine-seeking was associated with a reduction in cocaine-enhanced extracellular glutamate, but not cocaine-enhanced extracellular DA in the NAc. MPEP alone, when administered systemically or locally into the NAc, elevated extracellular glutamate, but not DA. A series of follow up experiments indicate that a cannabinoid CB1 receptor mechanism underlies MPEP-induced glutamate release and the antagonism of cocaine self-administration. In the report by Han et al (2017), we found that VTA glutamatergic neurons play an important role in mediating cannabis aversion. In this study, we used transgenic and optogenetic approaches to dissect the role of VTA GABAergic neurons and glutamatergic neurons in cannabis reward versus aversion. We found that optical activation of VTA glutamatergic neurons produced robust intracranial self-stimulation (ICSS) behavior, which was dose-dependently blocked by DA receptor antagonists 9-THC (the major psychoactive component of cannabis), but enhanced by cocaine or other drugs of abuse. In addition, 9-THC also produced dose-dependent conditioned place aversion in WT control mice, but not in glutamate-CB1-cKO mice. These findings suggest that activation of CB1Rs in VTA glutamate neurons produces aversive effects that might explain why cannabinoid is not rewarding in rodents and might also account for individual differences in the hedonic effects of cannabis in humans.