We at the Korpi group have focused on long-term effects of GABAA receptor modulating drugs on the dopamine neurons of the ventral tegmental area, or VTA, and on other drugs that might counteract the effects of the drugs of abuse.
We have found that single ex vivo exposures to addictive, dependence-causing, synaptically active benzodiazepines, diazepam and zolpidem, and to two non-benzodiazepine, extrasynaptically active gaboxadol and ganaxolone, induce glutamate receptor neuroadaptation in mouse VTA dopamine neurons. This process involves cellular plasticity and represents long-lasting neuroadaptation of the glutamatergic system in the VTA, and at the systems level, the mechanism being disinhibition of DA neurons.
Interestingly, these latter drugs do not show rewarding properties in mice or baboons, but induce conditioned place aversion in mice. This result fits with a dichotomous functional/structural organization of VTA dopamine neuron populations in monkeys and mice.
We have recently reviewed the regulation and neuroplasticity of midbrain neurons as the critical part of reward/aversion circuitry for a number of drugs of abuse, and found that the idea of diverse populations of VTA dopamine and GABA neurons is still waiting for more detailed neurobiological and behavioural assessment and verification.
We have also found interesting anti-addictive effects of pregabalin (a presynaptic Ca2+ channel downregulator) and rac-BHFF (a GABAB receptor positive allosteric modulator) on VTA neuroplasticity and behaviours induced by drugs of abuse.
- To establish the cellular heterogeneity and circuitry in the mouse midbrain, with the focus on the ventral tegmental area.
- To link the VTA cellular subtypes to rewarding, emotional and/or cognitive behaviours.