Serotonin axons appear to regulate beta-adrenergic receptor number and function in brain. The objective of this study is to test the hypothesis that serotonin neurons influence noradrenergic neurotransmission in brain by affecting beta-adrenergic receptor number and function, and to determine the nature of the underlying mechanisms that lead to these receptor changes.
The specific aims are: 1) to determine the time course of the onset of up-regulation of beta-adrenergic receptors following lesions of serotonin neurons; 2) to determine the specific location of the serotonin lesion necessary to increase beta-adrenergic receptor binding and function (production of cyclic AMP) in brain; 3) to determine whether the administration of a serotonin precursor or receptor agonists will prevent the increase in beta-adrenergic receptor binding and function seen after lesions of serotonin neurons; 4) to determine whether beta-adrenergic receptors are altered by chronic administration of drugs which affect pre- and post-synaptic serotonin function without lesioning serotonin axons; 5) to determine whether the turnover and/or synthesis of norepinephrine is affected by lesions of serotonin neurons and to determine whether changes in these pre-synaptic processes are linked to the up-regulation of central beta-adrenergic receptors seen after specific lesions of serotonin neurons; 6) to determine the pharmacological characteristics and quanyl nucleotide sensitivity of beta-adrenergic receptor binding after up-regulation of the receptor by a lesion of serotonin neurons; and 7) to determine whether serotonin-1 or serotonin-2 receptor binding or function is affected by alteration in noradrenergic neurotransmission. These studies should provide a strong test of the hypothesis that serotonin neurons can directly influence noradrenergic neurotransmission, and should clarify the functional link between two neurotransmitters that have been implicated in mood, sleep, arousal, learning, and neuroendocrine and autonomic nervous system regulation. Since norepinephrine axons are anatomically intact following these lesions of the serotonin system, this model may prove useful in testing and understanding the effects of antidepressant treatments on the regulation of increased numbers of beta-adrenergic receptors in brain.
