Administration of an extrasynaptic δ-subunit GABA A receptor agonist in the prelimbic cortex attenuates methamphetamine sensitisation and relapse to methamphetamine-seeking behaviour in male rats

Aims: Chronic methamphetamine (METH) intake is associated with a high risk of psychosis and high susceptibility to relapse following abstinence. Prelimbic cortex (PLC) extrasynaptic GABA A receptors containing the δ-subunit may be involved in the long-term effects of METH. We therefore investigated the effects of intra-PLC injection of the δ-subunit GABA A receptor agonist 4,5,6,7-tetrahydroisoxazolo (5,4-c)pyridine-3(-ol) (THIP), on METH sensitisation, a model of METH psychosis, or relapse to METH seeking behaviour following extinction of intravenous self-administration. Methods and results: In Experiment 1, male rats received 1 week of chronic treatment with METH (1 mg/kg days 1 and 7, 5 mg/kg days 2–6) or saline, followed by 14 days withdrawal. THIP (0, 0.1, 0.3 or 1.0 μg per hemisphere) was then micro-injected into the PLC prior to challenge with METH (1 mg/kg) or saline. Acute METH challenge enhanced locomotor hyperactivity in METH-pretreated rats, confirming sensitisation. THIP administration into the PLC dose-dependently reduced the effect of acute METH challenge in METH-pretreated rats. In Experiment 2, rats were trained to intravenously self-administer METH, followed by 2 weeks of extinction. Rats were then given a METH priming injection or exposed to cues associated with METH self-administration, both of which reinstated responding on the lever previously paired with METH delivery. At the 0.3 µg dose, injection of THIP into the PLC reduced reinstatement responding in both paradigms. Conclusion: Selective activation of extrasynaptic PLC δ-subunit GABA A receptors reduced METH sensitisation and drug primed or cue-induced METH-seeking behaviour. These findings may aid development of effective pharmacotherapies for treating chronic METH use.