Neuropsychopharmacology and molecular pharmacology of the cannabinoid system in the learned helpless model of depression

This study compared and contrasted the neuropsychopharmacological profile of the congenital learned helpless (cLH) and congenital non-learned helpless (cNLH) rat with regard to: (1) responses to the cannabinoid receptor agonist, WIN55212-2, in general and in selective models of depression and anxiety, (2) distribution and binding characteristics of the CB1 receptor in the brain, (3) signal transduction mechanism of the CB1 receptor and (4) CB1 receptor modulation of neurotransmitter release. The cLH rat has been bred for susceptibility to learned helpless behavior as a model of depression. WIN 55212-2 dose-dependently produced hypomotion, antinociception, hypothermia and catalepsy in the cLH and cNLH rats. WIN 55212-2 significantly decreased spontaneous locomotion in the cLH and cNLH rats with similar potency. The hypothermic effect of WIN 55212-2 was greater in the cLH rat whereas the cateleptogenic effect was greater in the cNLH rat. The cLH rat showed greater degree of behavioral despair in the forced swimming test reflecting the learned helpless behavior. WIN 55212-2 dose-dependently decreased immobility and increased swimming of cLH and cNLH rats indicative of antidepressant activity. However, in this regard WIN 55212-2 was less potent in the cLH perhaps reflecting the congenital nature of the model. WIN 55212-2 produced comparable effects on arm entries and time spent in the closed arms in both strains. The CB1 receptor localization via in vitro autoradioghaphy was in accordance with the receptor density defined by [3H]WIN 55212-2 and [3H]SR141716A receptor binding in tissue homogenates. [3H]WIN 55212-2 receptor binding revealed greater Bmax in the hippocampus of the cLH than the cNLH rats, while SR141716A receptor binding revealed greater Bmax in the cNLH striatum. WIN 55212-2 decreased forskolin-stimulated cAMP accumulation in brain slices from hippocampus, striatum and cortex, but increased cAMP accumulation in the cNLH cerebellum. The Emax of WIN 55212-2 stimulated [35S]GTPγS binding was significantly greater in the cLH hippocampus. WIN 55212-2 produced greater increased serotonin accumulation in hippocampal slices in the cLH rat and was antagonized by the CB1 receptor antagonist SR141716A. In conclusion, the neuropsychopharmacological differences between cLH and cNLH rats in response to the cannabinoid agonist WIN 55212-2 may result from the differences in receptor distribution and the signal transduction of the endogenous cannabinoid system mainly in the hippocampus.