Alcopop consumption and a sex dependent predisposition for methamphetamine use: brain and behavioural effects

Alcopop beverages are well known for their high levels of both sugar and alcohol, and they are generally the first alcoholic beverage that young people drink. The over-consumption of these drinks may encourage alcohol co-administration with other drugs later in life, and the prevalence of methamphetamine (METH) co-use is high. Despite this co-morbidity, little is known about the behavioural changes and neurochemical consequences of alcohol-METH interaction in preclinical animal models.

The main aims of this thesis were to develop binge-drinking models of alcopop consumption and to determine the impact on METH locomotor behaviour, METH intravenous self-administration (IVSA), cue-induced relapse behaviour, and the neurobiological correlates. 

In the first experimental chapter of this thesis (Chapter 2) adolescent female rats were exposed to a chronic alcopop (ALCP) binge drinking model, and during alcohol withdrawal, they were tested for anxiety-like behaviour and later received acute METH administration. In addition, GFAP-astrocyte density was analysed via immunohistochemistry in reward-related brain regions after 2-weeks of alcohol withdrawal. Overall, ALCP rats consumed more ethanol compared to the controls but showed no signs of anxiety-like behaviour after 1-week of alcohol withdrawal, nor cross sensitization to METH or changes to astrocyte density in brain areas at 2 weeks of withdrawal in adulthood.

The second experiment (Chapter 3) investigated sex differences in the behavioural effects of prior alcohol self-administration during adolescence on the acquisition of chronic METH IVSA when adults, exploring METH-taking behaviour while under the influence of alcohol, and the effect on cue-induced relapse to alcohol or METH. Altogether, prior alcohol exposure during adolescence seemed to partially affect only female rats as they took more METH at low dose compared with male rats. While under the influence, ALCP females increased METH intake in the sequential access paradigm when compared to water controls and ALCP males. Further ALCP treated females had higher rates of relapse to ALCP or METH related cues than their male counterparts. Thus, these data suggest a possible sex-dependent difference in sensitivity to the effect of low dose METH, and it seems that ALCP may be affecting the drinking behaviour and alcohol-METH cue relapse in female rats greater than males.

These ALCP and METH behavioural findings informed a third investigation (Chapter 4) and more targeted study, using an in situ hibridyzation RNAscope assay to evaluate the quantity and proportion of mRNA expression of excitatory and inhibitory cells in the amygdala of both male and female rats after 1-month of alcohol-METH withdrawal. RNAscope results showed that female rats had greater expression of vGluT-1 mRNA cells in the CeA compared to male rats, except in the water control group, with increases in glutamate and GABA cells in the BLA of ALCP when compared to ETOH rats, independent of sex.

Overall, this thesis has demonstrated that exposure to alcopops in adolescence may impact on future drug use in adult female rats to a greater extent than in males and highlights the importance of investigating sex diferences in addiction-related research.