Involvement of brain histamine in delta 9-tetrahydrocannabinol tolerance and withdrawal

The involvement of brain histamine (HA) in delta 9-tetrahydrocannabinol (delta 9-THC) tolerance and dependence was studied in rats. Rats treated for 5 days with delta 9-THC (2-6 mg/kg, IV) developed tolerance to the hypothermic effects of the drug. Tolerance also developed over the 5 day period to the decrease in brain regional HA concentrations observed after an acute injection of delta 9-THC. Administration of the tricyclic antidepressant drug clomipramine hydrochloride to tolerant rats induced a withdrawal-like behavioural syndrome. Accompanying this behaviour was a fall in HA concentrations of the midbrain, cortex, medulla oblongata/pons and the cerebellum. Administration of delta 9-THC, but not of the delta 9-THC vehicle, prior to clomipramine challenge attenuated both the intensity of the withdrawal-like syndrome and the reductions in brain regional HA concentration.