Seminars in Neuroscience最新文献

A common conjecture about the basal ganglia holds that these nuclei and their cortical inputs subserve relatively automatic stimulus–response behavior (habits) and other procedural memories. This speculative hypothesis warrants critical reassessment. No unequivocal evidence supports the assignment of this information-processing specialization to the basal ganglia or its cortical afferents.

Recently, molecular cloning has confirmed and extended our knowledge of the heterogeneity of 5-HT receptors. Besides creating some confusion, molecular techniques have provided new tools to study the function of 5-HT receptors. Recent results gained from targeted disruption of the genes encoding the 5-HT_1B and 5-HT_2C receptors have provided confirmation of pharmacological studies as well as unexpected effects. Such ‘constitutive knockouts’ might undergo compensatory changes during their development that could confound the interpretation of the mutant phenotype. New strategies are currently being developed that may enable receptor expression to be turned on and off at will in specific tissues.

Throughout the nervous system the receptors for the neurotransmitter serotonin form an unusually diverse set. Receptor-mediated responses to serotonin utilize a large collection of biochemical second messenger pathways, such as the stimulation or inhibition of adenylate cyclase activity, the hydrolysis of phosphoinositides, the mobilization of calcium and direct gating of ion channels. This diversity of structure and activity has been substantiated by the application of molecular cloning techniques which have now yielded at least 15 distinct molecular entities. The most recent subset of receptors for serotonin to be cloned are those that couple to the stimulation of adenylate cyclase activity. These subtypes: 5-HT₄, 5-HT₆ and 5-HT₇, although sharing a common signal transduction pathway, are remarkably divergent in their amino acid sequences, distribution in the brain and pharmacological properties. This digression from the expected relationships of receptor subtypes based on other serotonin receptors, as well as other biogenic amino receptor families, is unexpected and raises many questions about the extreme diversity of this signaling system.

Ascending and descending efferent pathways from the nuclei of serotonergic neurones located in brainstem raphe nuclei project to all regions of the central nervous system. Therefore, in considering the major physiological roles played by this neurotransmitter system, it is not surprising that serotonin is implicated in the aetiologies of many CNS dysfunctions which underlie psychiatric and neurological disorders. The presynaptic serotonin uptake mechanism and the many receptor subtypes that mediate the neurotransmitter roles of serotonin have been, and continue to be, targeted by drug discovery programmes aimed at identifying improved therapies for CNS disorders. Here we review the radioligands available for the important task of visualizing and characterizing these targets in the living human brain using either positron emission tomography (PET) or single photon emission tomography (SPECT). Such studies are crucial for extending our knowledge of the involvement of serotonin neurotransmission in the aetiologies of these disorders and for the development of new and more effective therapies. Particularly important recent advances in the methodologies for imaging the 5-HT transporter, the 5-HT_2A receptor and the 5-HT_1A receptor will almost certainly lead to important clinical research into the changes occurring in serotonergic neurotransmission during the onset, progression and treatment of affective and neurodegenerative disorders.

Brain serotonin (5-HT) neuronal activity is activated preferentially in association with motor activity. This is especially clear during changes in tonic motor output and during repetitive responses mediated by central pattern generators, such as locomotion, respiration and chewing. These and other data support the hypothesis that the primary function of the brain serotonin system is to facilitate motor output. Concurrently, the system coordinates autonomic and neuroendocrine function with the present motor demand, and inhibits information processing in various sensory pathways. Reciprocally, when the serotonin system is briefly inactivated (e.g. during focussed attention), this disfacilitates motor function and disinhibits sensory information processing.