Cannabinoid pharmacological properties common to other centrally acting drugs

Cannabinoids produce a characteristic profile of in vivo effects in mice, including suppression of spontaneous activity, antinociception, hypothermia, and catalepsy. Measurement of these four properties, commonly referred to as the tetrad test, has played a key role in establishing the structure-activity relationship of cannabinoids acting at cannabinoid CB(1) receptors. The purpose of this study was to determine whether drugs acting at noncannabinoid CB(1) receptors produced a similar pharmacological profile. Mice were tested in this paradigm after being injected with Delta(9)-tetrahydrocannabinol and selected drugs from other drug classes. Delta(9)-Tetrahydrocannabinol dose-dependently produced all four effects with reversal by the cannabinoid CB(1) receptor antagonist N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide hydrochloride (SR 141716A). Amphetamine, scopolamine, morphine, desipramine, pimozide, pentobarbital, ethanol, and diazepam were not fully active in at least one of the tests. Antipsychotics showed the greatest similarity to those of cannabinoids in the tetrad tests, although there were also distinct differences. Clozapine, haloperidol, thioridazine, and chlorpromazine (but not pimozide) were fully active in all four tests; however, unlike with Delta(9)-tetrahydrocannabinol, their effects were not blocked by SR 141716A. Further, whereas antipsychotics produced nearly 100% catalepsy, maximal catalepsy produced by Delta(9)-tetrahydrocannabinol was 60%. The mechanism through which antipsychotics produce these effects in mice is uncertain, but it differs from cannabinoid CB(1) receptor activation that mediates the effects of cannabinoids. While results of previous research suggest that the tetrad tests are a useful tool in examination of structure-activity relationships of cannabinoid CB(1) receptor agonists, the present results suggest that they must be used cautiously in the search for novel cannabinoid receptors.