Differential Sensitivity of GABAA Receptor-Mediated IPSCs to Cannabinoids in Hippocampal Slices From Adolescent and Adult Rats

1 Departments of Psychiatry and 2 Pharmacology, Duke University Medical Center and 3 Neurobiology Research Laboratory, Durham Veterans Affairs Medical Center, Durham, North Carolina The impairment of learning and memory is one of the most powerful and least understood effects of marijuana although the hippocampal formation appears to be one CNS region mediating these effects. We have shown that systemic injection of 9 -tetrahydrocannabinol (THC), an active component of marijuana, impairs spatial learning more efficaciously in adolescent rats, compared with adult rats, but there have been no studies of the cellular mechanisms underlying this developmental sensitivity. In this study, we examined cannabinoid-mediated activity in hippocampal area CA1 neurons in brain slices from adolescent and adult rats. The magnitude of endocannabinoid-mediated synaptic functions such as long-term depression of inhibition was greater in the hippocampal slices from adolescent rats than in those from adults. The effect of R -(+)-(2,3-dihydro-5-methyl-3-[(4-morpholinyl)methyl]pyrrolo[1,2,3-de]-1,4-benzoxazine-6-yl)(1-naphtalenyl) methanone mesylate (WIN55,212-2), an exogenous cannabinoid agonist, to suppress GABA A receptor-mediated synaptic responses was also greater in the hippocampal slices from adolescent rats than in those from adults. However, tonic endocannabinoid effects, shown as an increase of the spontaneous IPSC frequency by N -(piperidin-1-yl)-5-(4-iodophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide (AM251), a specific CB1 receptor antagonist, were greater in CA1 neurons from adult rats than in those from adolescent rats. On the other hand, WIN55,212-2 suppressed glutamate-mediated excitatory neurotransmission in CA1 pyramidal cells from adolescent and adult rats with similar efficacy. These results indicate that inhibitory synaptic function in the adolescent hippocampus is more sensitive to cannabinoid effects and may account, in part, for the greater sensitivity of adolescent animals to THC-induced memory impairment. Address for reprint requests and other correspondence: M.-H. Kang-Park, 508 Fulton St. VAMC, Bldg. 16, Rm. 31, Durham, NC 27705 (E-mail: mhk{at}duke.edu )