HT2CRMediated Regulation of Ascending Serotonergic Neurotransmission

Serotonergic neurotransmission effects CNS systems through the binding of serotonin to one of 14 currently described receptors. Discussion of the known properties of these receptors is beyond the scope of this text, and the reader may enjoy many excellent reviews for further information (Gordon and Hen 2004; Bockaert et al. 2008; Roth 2006; Di Giovanni et al. 2006; Hedlund and Sutcliffe 2004; Thomas 2006; Woolley et al. 2004; Barnes and Sharp 1999). Mouse models engineered to lack a specific serotonin receptor are ideal for studying that receptor's effect on serotonergic function spanning molecular to behavioral scales. This statement is particularly true if parallel studies treating intact mice with specific antagonists or inhibitors of the targeted receptor replicate the mutant phenotype. In this manner, studies using 5-HT2CR transgenic mouse models have provided important insights regarding how these receptors interact with other components of the serotonergic system.

Despite the key regulatory role of 5-HT2CRs in many serotonin related behaviors, constitutive loss of 5-HT2CR function evokes no compensatory increase in the expression of 5-HT1A, 5-HT1B/1D, 5-HT1F, 5-HT2A, 5-HT4, and 5-HT7 receptors or in 5-HT transporter protein expression (as measured by quantitative receptor autoradiography; see Lopez-Gimenez et al. 2002). Consistent with these findings was the observation that microiontophoretic application of serotonin to neurons within either the orbitofrontal cortex or the striatum led to similar inhibition of neuronal firing rates in both wild-type and constitutive 5-HT2CR /Y mice (Rueter et al. 2000). However, loss of 5-HT2CRs evoked a more global change in regulation of pyramidal neuron excitability in these two regions, as suggested by the finding that one could activate neurons from 5-HT2CR /Y mice with less quisqualate-evoked excitation. Pyramidal cells from 5-HT2CR /Y mice also fired at higher frequencies compared with cells from wild-type mice when excited with equivalent doses of quisqualate.

These findings suggest that loss of 5-HT2CR function increases the excitability of cortical pyramidal cells in a currently undetermined manner independent of serotonergic neurotransmission. As will be discussed throughout this chapter, this global change in 5-HT2CR-mediated neuron excitability may underlie a number of specific behavioral phenotypes observed in 5-HT2CR mutant mice.

Defeat Drugs and Live Free

Defeat Drugs and Live Free

Being addicted to drugs is a complicated matter condition that's been specified as a disorder that evidences in the obsessional thinking about and utilization of drugs. It's a matter that might continue to get worse and become disastrous and deadly if left untreated.

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