Ketamine reduces alcohol seeking in female but not male rats, including in a model of stress combined with cues that trigger relapse. A dose of 10 mg/kg ketamine selectively lowered alcohol self-administration and stress-plus-cue-induced reinstatement of alcohol seeking in females. The same dose reduced reinstatement of saccharin seeking in both sexes. The NMDA receptor antagonist memantine reduced alcohol seeking in both sexes, while the ketamine metabolite hydroxynorketamine had no effect. These findings suggest that NMDA receptor antagonism may broadly reduce stress-related alcohol seeking, but ketamine has unique properties producing female-specific effects on alcohol-motivated behaviors.
Cannabis use is more common among people with schizophrenia than the general population, partly due to shared genetic risk. Beyond overlapping risks, cannabis pharmacologically worsens an already altered cortical system. Cannabis use dose-dependently increases the likelihood of a schizophrenia diagnosis, acutely worsens symptoms, and leads to poorer long-term outcomes. The psychoactive component, Δ9-tetrahydrocannabinol, acts on the cannabinoid CB1 receptor (CB1R), a G protein-coupled receptor. This review examines recent advances in understanding CB1R biology, sex differences, alterations in schizophrenia, and the impact of comorbid cannabis use. Cell type-specific findings reconcile past discrepancies, and new knowledge of GPCR pharmacology and biased ligands offers opportunities for CB1R-targeted therapeutics for schizophrenia, especially with comorbid cannabis use.
Acute restraint stress and THC did not impair working memory in rats. However, a 3 mg/kg dose of THC disrupted motivation-related task engagement in some rats, while others were unaffected. Those that stopped responding had higher plasma THC and metabolite concentrations than those that continued. Individual differences in THC metabolism may explain why some people experience adverse cognitive or motivational effects after cannabis use, while others do not.