Serotonin Receptor Subtypes: Regulation and Interaction

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DESCRIPTION (provided by applicant): 5-HT1A receptors have been implicated in psychiatric illnesses, such as affective disorders and schizophrenia, as well as alcoholism, impulsivity and aggression. In brain, the 5-HT1A receptor is present in high density in serotonergic cell body areas, where it functions as the somatodendritic autoreceptor and therefore plays a key role in regulating serotonergic neuronal firing. The 5-HT1A receptor is also present in high density in cortical and limbic areas where it is located postsynaptically. Agonists at the 5-HT1A receptor have both anxiolytic and antidepressant-like effects, and are of great interest in the treatment of schizophrenia. It is well known that the sensitivity of pre- and postsynaptic 5-HT1A receptors is decreased following chronic administration of 5-HT1A receptor agonists, or a variety of antidepressant drugs. The interaction between norepinephrine (NE) and serotonin (5-HT) neurons may serve as a significant site of action for drugs used to treat affective disorders. Indeed, there is abundant evidence of functional interactions between NE and 5-HT in brain. For example, serotonergic neuronal firing is increased via excitatory postsynaptic alpha1-adrenergic receptors on serotonergic cell bodies, and decreased by activation of alpha2 autoreceptors on noradrenergic terminals. Our overall goal is to examine adrenergic modulation of the regulation of 5-HT1A receptor function by antidepressants or 5-HT1A receptor agonists. Because the use of selective 5-HT/NE re-uptake inhibitors in the clinic has increased dramatically over the last two years, these studies address an important and timely issue. We hypothesize that a reduction in NE input to serotonergic cell bodies, as a result of chronic inhibition of both NE and 5-HT re-uptake, alpha1-adrenergic receptor blockade, or activation of alpha2-adrenergic autoreceptors, prevents desensitization of somatodendritic 5-HT1A receptors at the level of receptor-G protein interaction. We will examine the regulation of 5-HT1A receptor function at the level of receptor-G protein interaction using [35S]GTPgammaS autoradiography. We will assess changes in somatodendritic and postsynaptic 5-HT1A receptor sensitivity using behavioral measures, physiological responses and neurochemical assays. Studies of the regulation of 5-HT1A receptor function may have important implications for our understanding the role of this receptor in the therapeutic action of drugs used to treat mental illness