Salvinorin A, the active compound in the hallucinogenic herb Salvia divinorum, does not directly interact with the endocannabinoid system. Although some earlier studies suggested a link, this work shows that salvinorin A does not bind to or activate CB1 cannabinoid receptors. In laboratory tests, it caused reduced movement and pain relief, effects blocked by a kappa-opioid receptor antagonist but not by a CB1 antagonist. Salvinorin A also did not substitute for THC in drug discrimination tests. The results indicate that similarities between salvinorin A and cannabinoid effects stem from its activation of kappa-opioid receptors, and previous findings of CB1 antagonist reversal may be due to that antagonist also dampening kappa-opioid receptor activation.
Phencyclidine (PCP) and other high-affinity NMDA receptor channel blockers disrupt prepulse inhibition (PPI) of acoustic startle in rats, a model of sensorimotor gating relevant to attentional deficits in schizophrenia. This study tested NMDA channel blockers with varying affinities in Sprague-Dawley rats. High-affinity drugs dizocilpine and dextrorphan disrupted PPI at doses that did not alter startle responses alone. Low-affinity drugs showed mixed results: dextromethorphan and memantine disrupted PPI, while orphenadrine, amantadine, desipramine, and alaproclate did not. Ibogaine disrupted PPI only at doses that severely reduced startle. Not all NMDA channel blockers share PCP's PPI-disrupting effect, and caution is warranted for supratherapeutic doses and vulnerable populations.