Heroin Self-Administration Induces Altered Dopamine Terminal Dynamics in the Nucleus Accumbens

Abstract

Administration of heroin results in the engagement of multiple brain regions and the rewarding and addictive effects are mediated, at least partially, through activation of the mesolimbic dopamine system. However, less is known about dopamine system function following chronic exposure to heroin. Withdrawal from chronic heroin exposure is likely to drive a state of low dopamine in the nucleus accumbens (NAc), as previously observed during withdrawal from other drug classes. Thus, we aimed to investigate alterations in NAc dopamine terminal function following chronic heroin self-administration to identify a mechanism for dopaminergic adaptations. Adult male Long Evans rats were trained to self-administer heroin (0.05 mg/kg/inf, IV) and then placed on a long access (FR1, 6-hrs, unlimited inf, 0.05 mg/kg/inf) protocol to induce escalation of intake. After one day of withdrawal, male rats exhibited lower basal extracellular levels of dopamine as well as reduced dopaminergic responses to a heroin challenge (0.1 mg/kg/inf, IV). Following heroin self-administration, rats had decreased basal extracellular levels of dopamine and blunted dopamine response following a heroin challenge (0.1 mg/kg/inf, IV) in the NAc compared to saline controls. FSCV revealed that heroin-exposed rats have reduced stimulated dopamine release during tonic-like, single-pulse stimulations but increased phasic-like dopamine release during multi-pulse stimulation trains (5 pulses, 5-100Hz) in addition to an altered dynamic range of release stimulation intensities when compared to controls. Further, we found that presynaptic D3 autoreceptor and kappa-opioid receptor activity was increased following heroin self-administration. These results reveal a marked low dopamine state following heroin-exposure and suggest the combination of altered dopamine release dynamics may contribute to increased heroin seeking.