The motor-impairing effects of GABAA and GABAB agonists in γ-hydroxybutyrate (GHB)-treated rats: Cross-tolerance to baclofen but not flunitrazepam

γ-Hydroxybutyrate (GHB) is believed to function as a neurotransmitter in the mammalian brain by binding to a GHB-specific binding site. In addition, GHB may also indirectly enhance the neuroinhibitory actions of γ-aminobutyric acid (GABA) by converting to GABA at neuronal synapses. The purpose of the present study was to examine the effects of representative GABAA and GABAB receptor agonists in rats treated chronically with GHB. Using a rotorod apparatus, the motor-impairing effects of GHB, the indirect GABAA receptor agonist, flunitrazepam, and the direct GABAB receptor agonist, baclofen, were examined before, during and after chronic treatment with 1000 mg/kg GHB, b.i.d. Prior to chronic treatment, all three drugs produced dose-dependent decreases in motor performance at low (8 rpm) and high (32 rpm) rotational speeds. Chronic treatment with GHB significantly decreased the potency of baclofen at both speeds, but did not alter the potency of either GHB or flunitrazepam. Following termination of chronic treatment, the potency of baclofen increased significantly at both speeds and returned to that observed prior to chronic treatment. These data indicate that chronic treatment with GHB confers tolerance to a GABAB receptor agonist under conditions in which tolerance is not conferred to a GABAA receptor agonist. These findings are consistent with the in vivo behavioral profile of GHB, which reveals a greater role for GABAB receptors than for GABAA receptors in its behavioral effects.