Our co IP data show that HT A or
Our co-IP data show that 5HT1A or 5HT2A receptors do not heterodimerize with mGluR1α receptors. Given that both 5-HT and mGlu receptors are GPCRs and produce anxiolytic effects, a degree of cooperativity via a functional cross-talk may still exist between these receptors . In addition to the functional and/or physical interactions of 5-HT receptors, agonist effects in the hippocampus vary depending on how these neurons co-express individual 5-HT receptor subtypes. While our studies reveal that sleep deprivation differentially affects the expression of 5-HT1A and 5-HT2A receptors, examining how it affects other subtypes is equally important. As mentioned elsewhere, 5-HT receptors differ not only in agonist sensitivity but also in the net effect they produce (excitatory vs. inhibitory). So, selective alterations in the function or expression of individual 5-HT subtypes may flip this delicate balance in opposing ways with significant implications for people under medications targeting 5-HT receptors. Therefore, as subtype specific drugs and HPF become readily available, these studies must be continued further to get a better understanding of how sleep deprivation affects the 5-HT system.
Conclusion A 12h period of sleep deprivation increases 5-HT1A receptor expression in the rat hippocampus. This effect subsides 48h post sleep recovery, indicating that sleep deprivation induced changes to the 5-HT1A receptors are temporary. Furthermore, the greater depressant effect of 5-HT on pEPSPs from hippocampal CA1 neurons could be related to alterations in receptor expression.
Acknowledgement This work was supported by Canadian Institutes of Health Research Grant TGS-109219.
Introduction Painful conditions constitute a major public health challenge. In the USA alone, the annual cost of pain disorders (comprising direct health care costs and lost productivity) is estimated at between $560 and $635 billion (2010 equivalent US$), that is approximately as much as the costs of heart disease ($309 billion), cancer ($243 billion) and diabetes ($188 billion) combined (Gaskin and Richard, 2012). Although there are numerous therapeutic options (opioids, antidepressants, gabapentin-likes, NaV channel blockers, etc.), available to alleviate painful conditions (including acute, tonic and neuropathic pain), none offers the combined advantages of high efficacy and minimal side-effects, and there remain large unmet medical needs for improved therapy. Amongst the 14 subtypes of serotonin (5-hydroxytryptamine, 5-HT) receptors, the 5-HT1A receptor occupies a prominent place as a target for treatment of various neuropsychiatric and neurological disorders, in particular pain (Avila-Rojas et al., 2015, Colpaert et al., 2002, Lindstedt et al., 2012, Sagalajev et al., 2015, Salat et al., 2017) and depression (Chilmonczyk et al., 2015). This double action is of considerable interest, as painful conditions are often associated with co-morbid mood deficits/depression (Burke et al., 2015). Although several 5-HT1A receptors agonists have been clinically tested (e.g. buspirone, tandospirone, gepirone, eltoprazine, sarizotan and flesinoxan), these compounds have yielded somewhat unimpressive results when investigated as therapeutics for various indications, including pain and depression. The reasons for this include their lack of selectivity and their activity at other (off targets) sites: for example, azapirone drugs such as buspirone also exhibit marked affinity for the dopamine D2 receptor (Peroutka, 1985). Also, these agonists display only modest agonist efficacy (several of the above compounds only partially activate 5-HT1A receptors) (Newman-Tancredi et al., 2003) and/or poor metabolic profile, including generation of active metabolites targeting other receptors (Myers et al., 2004, Wong et al., 2007, Zuideveld et al., 2002). These considerations therefore suggest that a highly selective and efficacious 5-HT1A receptor agonist could represent an improved therapeutic strategy for targeting pain and its associated depressive states.