Glutamatergic Systems and Memory Mechanisms Underlying Opioid Addiction

Abstract

Glutamate is the main excitatory neurotransmitter in the brain and is of critical importance for the synaptic and circuit mechanisms that underlie opioid addiction. Opioid memories formed over the course of repeated drug use and withdrawal can become powerful stimuli that trigger craving and relapse, and glutamatergic neurotransmission is essential for the formation and maintenance of these memories. In this review, we discuss the mechanisms by which glutamate, dopamine, and opioid signaling interact to mediate the primary rewarding effects of opioids, and cover the glutamatergic systems and circuits that mediate the expression, extinction, and reinstatement of opioid seeking over the course of opioid addiction.

Prolonged Withdrawal From Escalated Oxycodone Is Associated With Increased Expression of Glutamate Receptors in the Rat Hippocampus

“…Nevertheless, it will be important to investigate the effects of prolonged drug withdrawal in the absence of drug seeking tests. In any case, our results are consistent with the proposal that glutamatergic and memory systems might play important roles in the manifestations and clinical course of opioid use disorders ( Heinsbroek et al, 2020 ). The present observations broadened our insight into potential ways that glutamate receptors might act to promote incubation of oxycodone seeking after prolonged withdrawal.…”

Alterations in Excitatory and Inhibitory Synaptic Development Within the Mesolimbic Dopamine Pathway in a Mouse Model of Prenatal Drug Exposure

“…Glutamatergic signaling has been shown to be critical to many different aspects of opioid abuse and addiction ( 37 ). Previous studies have shown that morphine-induced activation of dopaminergic neurons cannot occur within the VTA without glutamatergic modulation ( 38 ), and glutamate release within the NAC has been shown to be associated with heroin addiction and reinstatement of heroin-seeking behavior in rats ( 39 ).…”

“…Taken together, these results indicate a net increase in excitatory glutamatergic signaling capability within the mesolimbic dopamine pathway of mice prenatally exposed to buprenorphine and gabapentin. Glutamatergic neurotransmission is heavily implicated in many aspects of drug use, including acute effects, consolidation, craving/seeking, withdrawal, and relapse [reviewed in Heinsbroek et al ( 37 )]. Whether the synaptic population shifts observed in this study result in greater dopamine release in response to rewarding stimuli, such as drugs of abuse, or a greater risk for developing substance abuse disorder later in life remains to be elucidated.…”

Role of Cannabidiol in the Therapeutic Intervention for Substance Use Disorders

“…Drugs of abuse trigger critical adaptive changes in the reward system by inducing widespread modifications of glutamatergic synapses. The NAcc receives glutamatergic projections from the VTA ( Yamaguchi et al, 2011 ) and other regions involved in the addictive process such as PFC, amygdala, and HIPP ( Koob and Volkow, 2010 ; Floresco, 2015 ; Heinsbroek et al, 2020 ). The acquisition of drug reward associations depends on the convergence of dopaminergic and glutamatergic signaling in the NAcc ( Neuhofer et al, 2019 ).…”