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When stimulated, what is the activity associated with serotonin receptor site 5-HT2?

When stimulated, what is the activity associated with serotonin receptor site 5-HT2?

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Expert Solution

The 5-HT2 receptor family mediates a large array of physiological and behavioral functions in humans via three distinct subtypes: 5-HT2A, 5-HT2B, and 5-HT2C.

In spinal cord and brain stem motor nuclei, motoneurons have a high density of 5-HT2 receptor binding sites. Serotonin applied microiontophoretically does not by itself induce firing in the normally quiescent facial motoneurons but does facilitate the subthreshold and threshold excitatory effects of glutamate. Intracellular recordings from facial motoneurons in vivo or in brain slices in vitro show that serotonin induces a slow, subthreshold depolarization associated with an increase in input resistance, indicating a decrease in a resting K+ conductance. Selective 5-HT2antagonists are able to selectively block the excitatory effects of serotonin in facial motoneurons. The facilitation of motoneuron excitability contributes to the role of serotonin as a ‘wake-on’ system to promote activity during the waking state

In brain slices of the medial pontine reticular formation, serotonin induces depolarizing responses that have a 5-HT2pharmacology and are associated with a decrease in membrane conductance resulting from a decrease in an outward K+current. In brain slices of the substantia nigra pars reticulata, a majority of neurons are excited by serotonin via 5-HT2receptors, possibly of the 5-HT2C rather than 5-HT2A subtype. Neurons in the inferior olivary nucleus are excited by serotonin via 5-HT2A receptors, thereby altering the oscillatory frequency of input to cerebellar Purkinje cells. In the nucleus accumbens, the great majority of neurons are depolarized by serotonin, inducing them to fire. This depolarization is associated with an increase in input resistance due to a reduction in an inward rectifier K+ conductance. In addition, GABAergic neurons within a number of regions (e.g., dorsal raphe nucleus, medial septal nucleus, hippocampus, cerebral cortex) are also excited by serotonin via 5-HT2 receptors, suggesting that in multiple locations within the CNS there are subpopulations of interneurons that are excited by serotonin via 5-HT2 receptors, giving rise to indirect inhibitory effects.

The electrophysiological effects of serotonin have been studied in several cortical regions. In vitro studies in the brain slice preparation have shown that pyramidal cells in various cortical regions respond to serotonin by either a small hyperpolarization, depolarization, or no change in potential. Depending on the region of cortex under study, as described below, the depolarizations appear to be mediated by 5-HT2A or 5-HT2C receptors. In addition to these postsynaptic effects, serotonin induces an increase in ‘spontaneous’ (nonelectrically evoked) postsynaptic potentials or currents (PSPs/PSCs) recorded in brain slices from various cortical regions. These may originate from the activation of intracortical pathways or through interactions with subcortical inputs such as the thalamus. Activation of 5-HT2A receptors also enhances late components of evoked responses in cerebral cortex . These late responses (also termed UP states) are generated by sustained recurrent network activity. The UP states rely on glutamate spillover onto extrasynaptic NMDA receptors. Interestingly, these UP states are characteristic of alert waking and are enhanced by psychedelic hallucinogens which are known to be 5-HT2A/2C partial agonists. It has been proposed that the hallucinogenic drugs produce their characteristic aberrations in perception, cognition, and affect by driving cortical UP states beyond normal limits. It is significant that the facilitation of UP states by 5-HT2A receptors is opposed by 5-HT1A receptors which tend to suppress UP states. This damping effect of 5-HT1A receptors on UP states may explain why selective 5-HT2A agonists are hallucinogenic, whereas serotonin, the natural transmitter, is not. This example further illustrates how serotonin, rather than having a monolithic action, exercises numerous checks and balances at a cellular and systems level via its diverse receptor subtypes


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