Localization of serotonin subtype 6 receptor messenger RNA in the rat brain by in situ hybridization histochemistry

Ward, Raymond P.; Hamblin, Mark W.; Lachowicz, Jean E.; Hoffman, Beth J.; Sibley, David R.; Dorsa, Daniel M.

doi:10.1016/0306-4522(94)00439-c

Cited by 192 publications

(111 citation statements)

References 14 publications

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“…Our results are consistent with previous studies showing that 5-HT 6 receptors appear restricted to the brain with high levels in the caudate-putamen, nucleus accumbens, and olfactory tubercle and moderate levels in the cerebral cortex hippocampus and amygdala (Monsma et al, 1993;Ruat et al, 1993;Ward et al, 1995;Gerard et al, 1997;Hamon et al, 1999;Roberts et al, 2002).…”

Section: Discussionsupporting

confidence: 93%

Biochemical and Behavioral Evidence for Antidepressant-Like Effects of 5-HT₆Receptor Stimulation

Svenningsson¹,

Tzavara²,

Qi³

et al. 2007

J. Neurosci.

150

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The primary action of several antidepressant treatments used in the clinic raises extracellular concentrations of serotonin (5-HT), which subsequently act on multiple 5-HT receptors. The present study examined whether 5-HT 6 receptors might be involved in the antidepressant-like effects mediated by enhanced neurotransmission at 5-HT synapses. A selective 5-HT 6 receptor antagonist, SB271046, was evaluated for its ability to counteract fluoxetine-induced biochemical and behavioral responses in mice. In addition, biochemical and behavioral effects of the 5-HT 6 receptor agonist, 2-ethyl-5-methoxy-N,N-dimethyltryptamine (EMDT), were assessed in mice to ascertain whether enhancement of 5-HT 6 receptor-mediated neurotransmission engenders antidepressant-like effects. SB271046 significantly counteracted the stimulatory actions of fluoxetine on cortical c-fos mRNA, phospho-Ser845-GluR1, and in the tail suspension antidepressant assay, whereas it had no effect on these parameters by itself. EMDT increased the phosphorylation states of Thr -DARPP-32 and Ser 845-GluR1, both in brain slices and in the intact brain, which were effects also seen with the antidepressant fluoxetine; as with fluoxetine, these effects were demonstrated to be independent of D 1 receptor stimulation. Systemic administration of EMDT increased c-fos mRNA expression in the striatum and cerebral cortex and reduced immobility in the tail suspension test. The antidepressant-like effects of EMDT in the tail suspension test were prevented by SB271046. Our results indicate that 5-HT 6 receptor stimulation may be a mechanism initiating some of the biochemical and behavioral outcomes of 5-HT reuptake inhibitors, such as fluoxetine. These findings also indicate that selective 5-HT 6 receptor agonists may represent a novel antidepressant drug class.

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Section: Discussionsupporting

confidence: 93%

Biochemical and Behavioral Evidence for Antidepressant-Like Effects of 5-HT₆Receptor Stimulation

Svenningsson¹,

Tzavara²,

Qi³

et al. 2007

J. Neurosci.

150

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“…A nonfunctional truncated splice variant of the 5-HT 6 receptor has been identified but appears not to have any physiological significance (Olsen et al, 1999). In situ hybridization and northern blot studies revealed an exclusive distribution of 5-HT 6 mRNA in the rat central nervous system (CNS) with the highest density found in the olfactory tubercle, followed by the frontal and entorhinal cortices, dorsal hippocampus (ie, dentate gyrus and CA1, CA2, and CA3 regions), nucleus accumbens, and striatum (Ward et al, 1995;Gerard et al, 1997). Lower levels were observed in the hypothalamus, amygdala, substantia nigra, and several diencephalic nuclei.…”

Section: Introductionmentioning

confidence: 99%

Neuropharmacological Profile of Novel and Selective 5-HT6 Receptor Agonists: WAY-181187 and WAY-208466

Schechter

Lin

Smith

et al. 2007

Neuropsychopharmacol

200

164

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One of the most recently identified serotonin (5-hydroxytryptamine (5-HT)) receptor subtypes is the 5-HT 6 receptor. Although in-depth localization studies reveal an exclusive distribution of 5-HT 6 mRNA in the central nervous system, the precise biological role of this receptor still remains unknown. In the present series of experiments, we report the pharmacological and neurochemical characterization of two novel and selective 5-HT 6 receptor agonists. WAY-181187 and WAY-208466 possess high affinity binding (2.2 and 4.8 nM, respectively) at the human 5-HT 6 receptor and profile as full receptor agonists (WAY-181187: EC 50 ¼ 6.6 nM, E max ¼ 93%; WAY-208466: EC 50 ¼ 7.3 nM; E max ¼ 100%). In the rat frontal cortex, acute administration of WAY-181187 (3-30 mg/kg, subcutaneous (s.c.)) significantly increased extracellular GABA concentrations without altering the levels of glutamate or norepinephrine. Additionally, WAY-181187 (30 mg/kg, s.c.) produced modest yet significant decreases in cortical dopamine and 5-HT levels. Subsequent studies showed that the neurochemical effects of WAY-181187 in the frontal cortex could be blocked by pretreatment with the 5-HT 6 antagonist, SB-271046 (10 mg/kg, s.c.), implicating 5-HT 6 receptor mechanisms in mediating these responses. Moreover, the effects of WAY-181187 on catecholamines were attenuated by an intracortical infusion of the GABA A receptor antagonist, bicuculline (10 mM), confirming a local relationship between 5-HT 6 receptors and GABAergic systems in the frontal cortex. In the dorsal hippocampus, striatum, and amygdala, WAY-181187 (10-30 mg/kg, s.c.) elicited robust elevations in extracellular levels of GABA without producing similar effects on concentrations of norepinephrine, serotonin, dopamine, or glutamate. In contrast to these brain regions, WAY-181187 had no effect on the extracellular levels of GABA in the nucleus accumbens or thalamus. Additional studies showed that WAY-208466 (10 mg/kg, s.c.) preferentially elevated cortical GABA levels following both acute and chronic (14 day) administration, indicating that neurochemical tolerance does not develop following repeated 5-HT 6 receptor stimulation. In hippocampal slice preparations (in vitro), 5-HT 6 receptor agonism attenuated stimulated glutamate levels elicited by sodium azide and high KCl treatment. Furthermore, in the rat schedule-induced polydipsia model of obsessive compulsive disorder (OCD), acute administration of WAY-181187 (56-178 mg/kg, po) decreased adjunctive drinking behavior in a dose-dependent manner. In summary, WAY-181187 and WAY-208466 are novel, selective, and potent 5-HT 6 receptor agonists displaying a unique neurochemical signature in vivo. Moreover, these data highlight a previously undescribed role for 5-HT 6 receptors to modulate basal GABA and stimulated glutamate transmission, as well as reveal a potential therapeutic role for this receptor in the treatment of some types of anxiety-related disorders (eg OCD).

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“…This is the case for the 5-HT 6 R, a G-protein-coupled receptor that is positively linked to the adenylate cyclase second messenger system (Monsma et al, 1993;Ruat et al, 1993;Kohen et al, 1996;Branchek and Blackburn, 2000). Receptor expression in rats, guinea pigs, and humans appears CNS-limited and most prominent in the caudate-putamen, nucleus accumbens, and olfactory tubercle, with lesser expression in the hippocampus, cortex, and amygdala (Monsma et al, 1993;Ruat et al, 1993;Ward et al, 1995;Kohen et al, 1996;Roberts et al, 2002). Several classes of psychotropic drugs such as atypical antipsychotics, tricyclic antidepressants, and hallucinogens bind with high affinity to 5-HT 6 Rs (Monsma et al, 1993;Roth et al, 1994;Glatt et al, 1995).…”

Section: Introductionmentioning

confidence: 99%

A Null Mutation of the Serotonin 6 Receptor Alters Acute Responses to Ethanol

Bonasera

Chu

Brennan

et al. 2006

Neuropsychopharmacol

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The anatomical distribution and pharmacology of serotonin 6 receptors (5-HT 6 Rs) implicate them as contributors to the serotonergic regulation of complex behavior. To complement the limited range of pharmacological tools available to examine 5-HT 6 R function, we have generated a mouse line bearing a constitutive null mutation of the 5-HT 6 R gene. No perturbations of baseline behavior were noted in a wide array of assays pertinent to multiple neurobehavioral processes. However, 5-HT 6 R mutant mice demonstrated reduced responses to the ataxic and sedative effects of ethanol. No differences in ethanol metabolism were evident between wild-type and 5-HT 6 R mutant mice. These findings implicate 5-HT 6 Rs in the serotonergic modulation of responses to ethanol.

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Localization of serotonin subtype 6 receptor messenger RNA in the rat brain by in situ hybridization histochemistry

Cited by 192 publications

References 14 publications

Biochemical and Behavioral Evidence for Antidepressant-Like Effects of 5-HT₆Receptor Stimulation

Biochemical and Behavioral Evidence for Antidepressant-Like Effects of 5-HT₆Receptor Stimulation

Neuropharmacological Profile of Novel and Selective 5-HT6 Receptor Agonists: WAY-181187 and WAY-208466

A Null Mutation of the Serotonin 6 Receptor Alters Acute Responses to Ethanol

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Localization of serotonin subtype 6 receptor messenger RNA in the rat brain by in situ hybridization histochemistry

Cited by 192 publications

References 14 publications

Biochemical and Behavioral Evidence for Antidepressant-Like Effects of 5-HT6Receptor Stimulation

Biochemical and Behavioral Evidence for Antidepressant-Like Effects of 5-HT6Receptor Stimulation

Neuropharmacological Profile of Novel and Selective 5-HT6 Receptor Agonists: WAY-181187 and WAY-208466

A Null Mutation of the Serotonin 6 Receptor Alters Acute Responses to Ethanol

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Biochemical and Behavioral Evidence for Antidepressant-Like Effects of 5-HT₆Receptor Stimulation

Biochemical and Behavioral Evidence for Antidepressant-Like Effects of 5-HT₆Receptor Stimulation