The effect of self-administered methamphetamine on GABAergic interneuron populations and functional connectivity of the nucleus accumbens and prefrontal cortex

Abstract

Introduction Methamphetamine (METH, “ice”) is a potent and addictive psychostimulant. Abuse of METH perturbs neurotransmitter systems and induces neurotoxicity; however, the neurobiological mechanisms which underlie addiction to METH are not fully understood, limiting the efficacy of available treatments. Here we investigate METH-induced changes to neuronal nitric oxide synthase (nNOS), parvalbumin and calretinin-expressing GABAergic interneuron populations within the nucleus accumbens (NAc), prefrontal cortex (PFC) and orbitofrontal cortex (OFC). We hypothesise that dysfunction or loss of these GABAergic interneuron populations may disrupt the excitatory/inhibitory balance within the brain. Methods Male Long Evans rats (N = 32) were trained to lever press for intravenous METH or received yoked saline infusions. Following 14 days of behavioural extinction, animals were given a non-contingent injection of saline or METH (1 mg/kg, IP) to examine drug-primed reinstatement to METH-seeking behaviours. Ninety minutes post-IP injection, animals were culled and brain sections were analysed for Fos, nNOS, parvalbumin and calretinin immunoreactivity in eight distinct subregions of the NAc, PFC and OFC. Results METH exposure differentially affected GABAergic populations, with METH self-administration increasing nNOS immunoreactivity at distinct locations in the prelimbic cortex and decreasing parvalbumin immunoreactivity in the NAc. METH self-administration triggered reduced calretinin immunoreactivity, whilst acute METH administration produced a significant increase in calretinin immunoreactivity. As expected, non-contingent METH-priming treatment increased Fos immunoreactivity in subregions of the NAc and PFC. Conclusion Here we report that METH exposure in this model may alter the function of GABAergic interneurons in more subtle ways, such as alterations in neuronal firing or synaptic connectivity.

Timing of methamphetamine exposure during adolescence differentially influences parvalbumin and perineuronal net immunoreactivity in the medial prefrontal cortex of female, but not male, rats

“…These changes to PV neuronal function may not consistently result in changes to the number or density of PV neurons as results in adult males vary [7,55,56].…”

“…Studies in adult males have shown modifications to inhibitory neurotransmission during exposure to amphetamines [5,53] and long-term modifications to inhibitory neurotransmission after adolescent stimulant exposure [8,40,54], but females were not examined. These changes to PV neuronal function may not consistently result in changes to the number or density of PV neurons as results in adult males vary [7,55,56].…”

“…While we had hypothesized that the development of PV neurons and PNNs in females would be more influenced by METH, the lack of effects in males is notable. To date, only studies assessing PV neuron density (PV neurons/area or volume), not total number per se, have assessed the effects of METH treatment in adult males and mixed results have been reported (Veerasakul et al, 2016;Robinson et al, 2022). Electrophysiologically, METH administration has been shown to increase inhibitory tone in the mPFC of adult male rats (Armenta-Resendiz et al, 2022).…”

Mechanisms of psychiatric disorders induced by amphetamines: A comprehensive review

“…According to magnetic resonance spectroscopy, a reduction in N-acetylaspartate (NAA) was discovered within the basal ganglia, frontal lobe, and anterior cingulate, indicating a reduction in neuronal integrity in these zones (80,81,82). Alteration of GABA function following addiction may be the result of multiple factors, including alterations in neuronal firing or synaptic connectivity (83).…”