The overall aim of this project is to investigate the actions of psychotogenic drugs within the framework of the basic electrophysiological and anatomical properties of central serotonergic and noradrenergic systems. This work has mental health relevance in terms of promoting an understanding of brain systems that may be disturbed in naturally occurring psychoses. Specific research proposals are: 1. To study the ionic mechanisms underlying pacemaker properties of serotonergic dorsal raphe neurons. Ionic conductances in the pacemaker cycle are to be studied in brain slices and the effects of LSD, serotonin, and alpha-1-agonists will be tested. 2. To study the effects of L-tryptophan infusions on autoreceptor regulation of serotonergic neurons in brain slices. Light and electron immunohistochemical as well as electrophysiological experiments are planned in conjunction with L-tryptophan infusions. 3. To investigate intrinsic and extrinsic factors in the regulation of noradrenergic locus coeruleus in brain slices. The regulatory role of intrinsic ionic conductances, extrinsic transmitter inputs, and the effects of hallucinogenic drugs are to be explored. 4. To investigate the ionic mechanisms underlying the facilitatory effects of alpha-1-adrenoceptors. The effects of indoleamine and phenethylamine hallucingens on alpha-1-receptor mediated effects are to be investigated in various brain regions. 5. To study the interaction of hallucinogenic drugs with putative serotonin-2 receptors in prefrontal. The effects of serotonin-2 antagonists on hallucinogenic drug responses will be examined by iontophoretic techniques in vivo. 6. To study cellular mechanisms of tolerance and sensitization to hallucinogenic drugs. Receptor effects are to be examined by means of in vitro recordings following a tolerance schedule of in vivo drug injection.
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