The psychoactive ingredient in marijuana, delta9-tetrahydrocannabinol (THC), produces euphoria in humans. THC activates cannabinoid receptors that modulate ion channels and second messenger systems. In order to link molecular studies to behavioral experiments, it is essential to know the effects of these drugs on synaptic networks. Cannabimimetics inhibited glutamatergic synaptic transmission but failed to affect inhibitor neurotransmission between cultured rat hippocampal neurons. Anatomical evidence suggests that cannabinoid receptors are located on gamma- aminobutyric acid (GABA) containing striatal projections to the substantia nigra. Experiments are proposed to determine the effects of the cannabimimetic drugs on synaptic transmission between cells cultured from the rat striatum and substantia nigra. The first objective is to determine whether activation of cannabinoid receptors inhibit GABAergic neurotransmission. Neurons from striatum and substantia nigra will be grown together in primary tissue culture and synaptic activity recorded. The whole-cell configuration of the patch clamp technique will be used to record inhibitory and excitatory postsynaptic currents (IPSCs & EPSCs) evoked by stimulation of the presynaptic neuron with an extracellular electrode. The mechanism of cannabinoid-mediated effects in striatonigral co-vultures will be determined. Anatomical data, previous work with hippocampal synapses, and cannabinoid-mediated effects on ion channels, all suggest that cannabinoid receptors participate in presynaptic inhibition. A presynaptic site of action predicts that cannabinoid receptor agonists will increase the coefficient of variation of evoked postsynaptic currents, increase the number of synaptic failures, and not affect responses elicited by direct application of agonist. The pharmacology of cannabinoid-mediated effects in striatonigral co-cultures will be characterized. Pharmacologic properties to be evaluated include the potency of agonists, the intrinsic activity of partial agonists and the rate of desensitization to agonists. These studies will enhance our understanding of now cannabinoids affect synaptic transmission. Effects on inhibitory systems have not previously been examined. If the pharmacological effects of the cannabinoids are specific to particular brain regions it might be possible to separate their abuse potential from their clinically useful attributes.
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