Identification of a GABA(A) receptor-mediated opiate addiction switch in the mammalian ventral tegmental area

A fundamental question in the neurobiological study of drug reward and addiction is how the organism switches from the drug-naive, non-dependent state, to a state of drug dependence and addiction. In this thesis, I identify a neural substrate within the mammalian ventral tegmental area (VTA) that serves as a molecular switching substrate for the transmission of reward signals through separate, dopaminergic (DA) and DA-independent neural systems.; I report that a GABA_A receptor substrate within the VTA serves as a switching mechanism between a DA-independent and a DA-dependent neural motivational system as a function of the opiate state of the organism. In opiate naive animals, agonist activation of VTA GABA_A receptors produces a DA-dependent reward effect while antagonist blockade of these receptors produces a DA-independent effect. Remarkably, once animals are in a state of opiate-dependence and withdrawal, agonist activation of VTA GABA_A receptors produces a DA-independent effect, while antagonist blockade of these receptors produces a DA-dependent reward effect. This switching mechanism is mediated by molecular alterations occurring at the level of the GABA _A receptor that switches the membrane conductance properties of the receptor from an inhibitory, hyperpolarizing conductance in the opiate-naive state, to an excitatory, depolarizing conductance in the opiate withdrawn state. This phenomenon depends upon the efflux of HC0₃− through the GABA_A ionophore, as intra-VTA administration of the carbonic anhydrase inhibitor, acetazolamide (10–50 μM) prevents the observed opiate withdrawal-induced switch in the molecular valence of VTA GABA_A receptors and restores the functional activity of the VTA GABA_A receptor substrate to the opiate-naive state. Furthermore, excitotoxic lesions of the brainstem tegmental pedunculopontine nucleus (TPP) selectively block the DA-independent, GABA_A receptor reward signal in the VTA, but have no effect on the DA-dependent VTA GABA_A receptor reward signal, suggesting that the neural substrates responsible for transmission of DA-dependent and DA-independent reward signals associated with opiate or GABA_A receptor signalling, act through a common neural mechanism. The studies described in this thesis suggest that the neurobiological mechanism(s) responsible for the switch from a non-dependent to a dependent and drug-addicted state, involve a dynamic boundary between pharmacologically and anatomically distinct neural motivational systems.