Synergistic interactions between 'club drugs': Gamma-hydroxybutyrate and phencyclidine enhance each other's discriminative stimulus effects

Gamma-hydroxybutyrate (GHB) is often abused together with other 'club drugs', such as the N-methyl-D-aspartate (NMDA) receptor antagonists ketamine and phencyclidine (PCP). We recently found that the NMDA antagonist dizocilpine markedly enhanced GHB-induced catalepsy in rats. The present studies explored the generality of this interaction. Different groups of rats were trained to discriminate 2 mg/kg PCP or 3.2 mg/kg of the γ-aminobutyric acid B receptor agonist baclofen from saline. In the PCP-trained rats, the dose-response (DR) curve for the discriminative stimulus (DS) effects of PCP was shifted 2.5-fold to the left by 178 mg/kg GHB, but not by baclofen. In the baclofen-trained rats, 2 mg/kg PCP shifted the DR curve for the baclofen-like DS effects of GHB 2.2-fold to the left, but did not shift the DR curve for baclofen. These results suggest that (i) NMDA antagonists potentiate not only the cataleptic effects of high doses of GHB, but also the DS effects of low doses, (ii) PCP and GHB enhance one another's DS effects, and (iii) this enhancement might be specific for GHB, because it did not occur with PCP and baclofen. These findings suggest that NMDA antagonists might potentiate the subjective effects of GHB in humans, and are further evidence that glutamatergic systems modulate effects of drugs of abuse.