Investigating the neural circuitry of methamphetamine addiction, and prelimbic cortex GABA involvement in the treatment effect of Oxytocin
Creators: name: Robinson, Katherine Jane
Publisher: name: Macquarie University
Year: 2022
Subjects: Other education not elsewhere classified

description: Abuse of methamphetamine (METH), a potent psychostimulant, elicits dysfunction of reward-associated brain regions such as the nucleus accumbens (NAc) and prefrontal cortex (PFC). Additionally, it is thought that METH disrupts the balance of excitation and inhibition in the brain, perturbing neurotransmitter systems and inducing neurotoxicity. Current pharmacotherapies act to reduce the acute rewarding effects of METH, however, existing treatments are largely ineffective with most abstinent users relapsing to drug-taking behaviour. Ineffective pharmacotherapies can, in part, be attributed to our limited understanding of the neurobiological mechanisms which underlie METH addiction. Preclinical models of addiction have evidenced the therapeutic potential of oxytocin, an endogenous neuropeptide, which may act to restore METH-induced disruptions to the excitatory/inhibitory balance. The present thesis utilized the intravenous drug-self administration model of reinstatement to investigate METH-induced neuroadaptations and the mechanistic action of oxytocin. Existing published literature suggests increased neuronal activation in reward-associated brain regions following administration of addictive drugs or drug-associated cues. However, it is unknown precisely which neuronal populations are activated and how this may impact on functional connectivity. Chapter 2 investigated alterations to neuronal activity as indicated by Fos immunoreactivity and immunoreactivity of neuronal nitric oxide synthase (nNOS) and parvalbumin (PV), two populations of GABAergic interneurons. Injection of METH significantly increased Fos immunoreactivity in the NAc and many subregions of the PFC. Analysis also revealed reduced correlated activity between these regions in METH-exposed animals. Analysis of nNOS immunoreactivity revealed increased number and activation of nNOS+ neurons at discrete areas of the NAc in chronic METH-exposed animals, suggesting increased activation of the nitrergic system. In contrast, no significant differences were noted in PV immunoreactivity. Furthermore, the lack of colocalisation of Fos with GABAergic markers suggests activation was most likely confined to excitatory populations. This study presents the first investigation of altered correlated activity following relapse to METH use in the intravenous self-administration paradigm, evidencing aberrant activation of excitatory neurons within subregions of the NAc and PFC. It is hypothesized that oxytocin treatment interacts with GABA systems within the brain to restore the imbalance of excitation and inhibition, yet the precise mechanisms for this interaction are unknown. Chapter 3 used a chemogenetic approach to investigate the interaction between GABAergic neurons and oxytocin in the PFC during relapse. DREADDs were used to inactivate GABAergic neurons in the prelimbic subregion of the PFC (PrL) prior to pretreatment with systemic oxytocin. It was hypothesised that inactivation of GABAergic neurons would blunt the effect of systemic oxytocin treatment, eliciting robust reinstatement. While this study demonstrated attenuation of cue-induced and METH-primed reinstatement behaviours following treatment with systemic oxytocin, chemogenetic inactivation of GABAergic neurons did not reduce the efficacy of systemic oxytocin treatment. This suggests that oxytocin is not interacting with GABAergic neurons within the PrL to attenuate drug-seeking behaviours. The present thesis reveals new insights relating to the neurobiological mechanisms underlying METH addiction and enhances knowledge about the mechanistic actions of oxytocin which facilitates attenuatuation of drug-associated behaviours.