The role of the ventral hippocampus in an animal model of methamphetamine-induced behavioural sensitisation: implications for chronic methamphetamine use and psychoses

Methamphetamine (METH) is a potent psychostimulant capable of inducing persistent psychosis in both chronic and recreational users. This METH-induced psychosis closely resembles schizophrenia, both clinically and neurobiologically. The shared characteristics of the two pathologies can be partly explained in the context of behavioural sensitisation and critical dependence on the mesocorticolimbic dopamine system. However, knowledge of the modulatory mechanisms of this dopamine system remain limited. Accumulating literature has implicated the rodent ventral hippocampus (vHipp; analogous to the anterior hippocampus in humans) as a potential modulator of mesocorticolimbic circuitries in psychostimulant-induced psychosis and schizophrenia, but research findings remain mixed. A synthesis of experimental approaches could allow for important insights into the complex aetiology of these debilitating illnesses. Therefore, the aim of this thesis was to further elucidate the role of the vHipp in METH-induced behavioural sensitisation, as an animal model of psychoses, at a proteomic, behavioural, and cellular level.

First, an explorative proteomic approach allowed for the identification of unique changes to protein expression within the rat vHipp following METH sensitisation. Shotgun proteomic analysis revealed 370 proteins that were uniquely expressed in the vHipp of METH-sensitised rats, compared with controls. Of particular interest was the identification of several key proteins involved in γ-aminobutyric acid (GABA) transmission, implicating dysfunctional inhibitory drive from the vHipp in the hyperdopaminergic state associated with sensitisation and psychoses.

These proteomic findings informed a second and more targeted study, which examined the effects of vHipp microinjections of GAD67 inhibitor, L-allylglycine (L-AG), and selective GABAA receptor δ-subunit agonist, 4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol (THIP), on sensitised behaviour. A pilot experiment showed promising findings, however the primary study demonstrated no effect on sensitised behaviour following L-AG or THIP microinjections into the CA3 subregion of the vHipp. These results were interpreted in the context of likely functional and molecular differences between vHipp subregions, and highlighted the need for a comparative study of GABA substrates across subregions and specific cell populations.

In the third study, immunofluorescent analyses were conducted to compare expression of key GABAergic substrates, GAD67 and parvalbumin, in vHipp subregions following METH sensitisation, acute METH treatment, and chronic METH treatment. Findings showed that chronic METH exposure was associated with significant cellular changes in the CA1 subfield of the vHipp, including increased parvalbumin immunoreactivity, and increased co-expression of GAD67 and cFos within parvalbumin interneurons. There were no changes to GAD67 or parvalbumin expression in the CA3 or the dentate gyrus. Importantly, findings did not differ between chronic METH-treated animals that were sensitised and those that were not. Therefore, implications were discussed in the context of both METH dependence and psychoses.

Overall, the findings of this thesis demonstrate that behavioural sensitisation to METH is associated with significant alterations to GABA transmission in the vHipp, and particularly the CA1 subregion. Notably however, several of these alterations are discrepant to findings in the existing psychoses and schizophrenia literature, which highlights the need for further subregion-specific studies of GABA cell populations in the vHipp and related circuitries. The clinical and methodological implications of these findings are discussed throughout the thesis.