The objectives of the proposed research are to extend our studies of the excitatory properties of delta-9-THC to its interaction with excitatory states caused by other drugs of abuse, and to investigate further the electrophysiological mechanisms of the cannabinoids' excitatory and depressant actions. The interactions will be assessed with the increased locomotor activity in animals acutely treated with cocaine, morphine or amphetamine, and on the enhanced or kindling-like locomotor responses after chronic treatment with these drugs. The kindling-like responses will be described in detail to compare their characteristics to those of classical kindled states and to evaluate the influence of delta-9-THC on the development of the responses. In addition, the relationship of changes in receptor density, affinity and distribution to these reactions will be investigated. The receptors to be studied include the muscarinic receptor for electrical and the picrotoxin-sensitive, benzodiazepine-GABA receptor ionophore for picrotoxin kindling; and for the kindling-like reactions, opioid receptors for morphine and dopamine receptors for cocaine and amphetamine. The mechanism studies are designed to provide an electrophysiological basis for effects observed previously at different organizational levels of the nervous system. E.g., because delta-9-THC can enhance both electrical and pharmacological kindling, studies will be conducted in conscious rats with chronically implanted electrodes to determine the relationship of the cannabinoid changes in the afterdischarge to the drug enhancement of kindling. At single cat spinal motoneurons, our study of potential synaptic mechanisms of delta-9-THC will include the principal metabolite, the 11-hydroxy derivative, and cannabidiol, an anticonvulsant with therapeutic possibilities as an antiepileptic. Their actions will be evaluated on synaptic potentials. Finally, the mechanism studies will include an examination of the actions of delta-9-THC on postsynaptic membrane conductances, which may account for some of the drug's synaptic effects; the influence of delta-9-THC on transmitter- and electrically evoked conductances and their ionic bases will be investigated in isolated synaptic preparations.
