CHRONIC BARBITURATES-CNS BIOCHEMISTRY

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We have recently observed that the acute administration of barbiturates produces a marked reduction in cyclic guanosine monophosphate (cyclic GMP) levels in the rat cerebellum. Following long term barbital treatment, cerebellar cyclic GMP levels are only slightly reduced in the presence of acutely anesthetic concentrations of barbital in the cerebellum and in the blood. Upon abrupt barbital withdrawal cyclic GMP levels in the cerebellum are elevated 2-3 fold at a time coincident with the peak in the number of spontaneous convulsions associated with the barbital abstinence syndrome. These data provide strong evidence for the development of tolerance to barbital and for a marked post withdrawal response of cerebellar cyclic GMP. It is hypothesized that the post withdrawal elevations of cyclic GMP in the cerebellum and in other brain areas to be studied are functionally involved in the enhanced excitation associated with the barbital abstinence syndrome. In particular, elevated cerebellar cyclic GMP may be involved in the tonic-extension phase of abstinence convulsions. Cyclic GMP levels in the cerebellum are regulated by [1] extrinsic excitatory inputs which are believed to utilize excitatory amino acids, e.g., glutamate and aspartate, or acetylcholine (ACh) as neurotransmitters and [2] GABAergic cerebellar interneurons. Our recent data suggest that the GABA neurons are of lesser importance. It is therefore hypothesized that the acute and chronic effects of barbiturates on cerebellar cyclic GMP may be mediated via actions on these excitatory amino acid and/or ACh pathways. Since the basic neuronal circuitry as well as the transmitters involved is better understood in the cerebellum as opposed to other brain areas, the cerebellum is proposed as a model to investigate the adaptations of and the functional involvement of the above excitatory transmitters in barbiturate dependence and the manifestation of the abstinence syndrome. Possible presynaptic changes in transmitter synthesis and release and postsynaptic adaptations in receptors will be investigated.