The effects of pharmacological blockade of the 5-HT6 receptor on formalin-evoked nociceptive behaviour, locomotor activity and hypothalamo–pituitary–adrenal axis activity in rats

Finn, David P.; Fone, Kevin C. F.; Beckett, Simon; Baxter, Jonathan A.; Ansell, Lucy; Marsden, C.A.; Chapman, Victoria

doi:10.1016/j.ejphar.2007.05.020

Cited by 24 publications

(12 citation statements)

References 26 publications

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“…Yet, in the current study, the agonists did not attenuate freezing when administered before or immediately after training and the antagonist did not attenuate freezing when given before retention, so an acute anxiolytic action is unlikely to explain why only the antagonist decreased contextual freezing when given pre‐training. The 5‐HT 6 antagonist is antinociceptive in a formalin‐evoked pain behaviour (Finn et al ., 2007), and such an action would reduce the effectiveness of the US–CS association if drug was present during training, but not if given before the retention task (as observed herein). However the effect of 5‐HT 6 receptor agonists has not been examined in such paradigms.…”

Section: Discussionmentioning

confidence: 99%

5‐HT₆ receptor agonists and antagonists enhance learning and memory in a conditioned emotion response paradigm by modulation of cholinergic and glutamatergic mechanisms

Woods

Clarke

Layfield

et al. 2012

British J Pharmacology

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BACKGROUND AND PURPOSE5-HT6 receptors are abundant in the hippocampus, nucleus accumbens and striatum, supporting their role in learning and memory. Selective 5-HT6 receptor antagonists produce pro-cognitive effects in several learning and memory paradigms while 5-HT6 receptor agonists have been found to enhance and impair memory. EXPERIMENTAL APPROACHThe conditioned emotion response (CER) paradigm was validated in rats. Then we examined the effect of the 5-HT6 receptor antagonist, EMD 386088 (10 mg·kg KEY RESULTSPairing unavoidable foot shocks with a light and tone cue during CER training induced a robust freezing response, providing a quantitative index of contextual memory when the rat was returned to the shock chamber 24 h later. Pretreatment (-20 min pre-training) with scopolamine or MK-801 reduced contextual freezing 24 h after CER training, showing production of memory impairment. Immediate post-training administration of 5-HT6 receptor antagonist, SB-270146, and agonists, EMD 386088 and E-6801, had little effect on CER freezing when given alone, but all significantly reversed scopolamine-and MK-801-induced reduction in freezing. CONCLUSION AND IMPLICATIONSBoth the 5-HT6 receptor agonists and antagonist reversed cholinergic-and glutamatergic-induced deficits in associative learning. These findings support the therapeutic potential of 5-HT6 receptor compounds in the treatment of cognitive dysfunction, such as seen in Alzheimer's disease and schizophrenia.

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Section: Discussionmentioning

confidence: 99%

5‐HT₆ receptor agonists and antagonists enhance learning and memory in a conditioned emotion response paradigm by modulation of cholinergic and glutamatergic mechanisms

Woods

Clarke

Layfield

et al. 2012

British J Pharmacology

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“…Rats ( n = 11 per group) received a total of six injections of vehicle, 5 or 10 mg/kg SB-399885 (lower dose in isolates only) over the course of 13 days (40–52 post-weaning), with a single injection on the days that locomotor activity, NOD, PPI and acquisition, retention and extinction of CFR were assessed, using a previously described test battery and methods with the tasks ordered from least to most aversive [ 37 , 41 ]. Treatments were administered 30 min prior to each behavioral test, or immediately after CFR acquisition to preclude confounding drug effects on nociception [ 42 ] or affective state [ 38 ]. In all cases, the experimenter was unaware of the treatment received.…”

Section: Methodsmentioning

confidence: 99%

Characterization of Behavioral, Signaling and Cytokine Alterations in a Rat Neurodevelopmental Model for Schizophrenia, and Their Reversal by the 5-HT6 Receptor Antagonist SB-399885

et al. 2018

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Post-weaning social isolation of rats produces neuroanatomical, neurochemical and behavioral alterations resembling some core features of schizophrenia. This study examined the ability of the 5-HT6 receptor antagonist SB-399885 to reverse isolation-induced cognitive deficits, then investigated alterations in hippocampal cell proliferation and hippocampal and frontal cortical expression of selected intracellular signaling molecules and cytokines. Male Lister hooded rats (weaned on post-natal days 21–24 and housed individually or in groups of 3–4) received six i.p. injections of vehicle (1% Tween 80, 1 mL/kg) or SB-399885 (5 or 10 mg/kg) over a 2-week period starting 40 days post-weaning, on the days that locomotor activity, novel object discrimination (NOD), pre-pulse inhibition of acoustic startle and acquisition, retention and extinction of a conditioned freezing response (CFR) were assessed. Tissue was collected 24 h after the final injection for immunohistochemistry, reverse-phase protein microarray and western blotting. Isolation rearing impaired NOD and cue-mediated CFR, decreased cell proliferation within the dentate gyrus, and elevated hippocampal TNFα levels and Cdc42 expression. SB-399885 reversed the NOD deficit and partially normalized CFR and cell proliferation. These effects were accompanied by altered expression of several members of the c-Jun N-terminal Kinase (JNK) and p38 MAPK signaling pathways (including TAK1, MKK4 and STAT3). Although JNK and p38 themselves were unaltered at this time point hippocampal TAK1 expression and phosphorylation correlated with visual recognition memory in the NOD task. Continued use of this neurodevelopmental model could further elucidate the neurobiology of schizophrenia and aid assessment of novel therapies for drug-resistant cognitive symptoms.

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“…First studies on this subject indicated that pharmacological blockade of 5-HT 6 receptors reduce formalin-induced nociceptive behavior [21], and that both local peripheral and spinal 5-HT 6 receptors play a pronociceptive role in formalin-induce pain [20]. Then, both peripheral and spinal 5-HT 6 receptors have been shown to play roles in development and maintenance of formalin-induced secondary mechanical allodynia and hyperalgesia [12,14].…”

Section: Discussionmentioning

confidence: 99%

“…5-HT 6 receptors are exclusively localized in painrelated areas, such as periaqueductal gray, spinal cord and dorsal root ganglion [19], indicating that these receptors may play a pivotal role in pain modulation at different levels of central nervous system. 5-HT 6 receptors have been shown to be pronociceptive in formalin-induced pain [20], and 5-HT 6 antagonists have been shown to reduce nociceptive behavior in the same test [21]. Both peripheral and spinal 5-HT 6 receptors have been shown to play role in the development and maintenance of secondary mechanical allodynia and hyperalgesia [12,14].…”

Section: Introductionmentioning

confidence: 99%

Spinal Serotonin and 5HT6 Receptor Levels During Development of Neuropathy and Influence of Blockade of these Receptors on Thermal Hyperalgesia in Diabetic Mice

2019

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Little is known about the role of 5-HT6 receptors in the pathophysiology of neuropathic pain. The aim of this study is firstly, to investigate the influence of spinal and systemic 5-HT6 receptors on thermal hyperalgesia, one of the most significant symptoms of neuropathy occurring in diabetes; and secondly to determine spinal lumbar serotonin and 5-HT6 receptor levels during development of diabetic neuropathy in mice. Diabetes was produced in Balb/c mice with a single injection of streptozocin (150 mg/kg, i.p.). Using the hot plate test, the 5-HT6 antagonist SB-258585 was given systemically (3, 10, 30 mg/kg) and intrathecally (0.01, 0.1, 1 nmol/mouse) to determine its effect on thermal hyperalgesia. Furthermore, on days 7 and 15 of diabetes, development of thermal hyperalgesia was evaluated in relation to changes in spinal serotonin and 5-HT6 receptor levels by using LC/MS/MS and Western blot analyses, respectively. Two-way analysis of variance and unpaired t-tests were used to evaluate data from hot-plate tests and 5-HT levels/ 5-HT6 receptor expression, respectively. Thermal hyperalgesia was observed in neuropathic mice, starting from day 5 after streptozocin administration. On day 15, systemic, but not intrathecal, SB-258585 attenuated thermal hyperalgesia in neuropathic mice. Spinal serotonin levels did not change during development of hyperalgesia after induction of diabetes, whereas spinal 5-HT6 receptor levels were significantly reduced on days 7 and 15. Our findings show that systemic, but not spinal, blockade of 5-HT6 receptors may exert antihyperalgesic effects in neuropathic mice and suggest that systemic 5-HT6 receptors contribute to the pathophysiology of diabetic neuropathy.

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The effects of pharmacological blockade of the 5-HT6 receptor on formalin-evoked nociceptive behaviour, locomotor activity and hypothalamo–pituitary–adrenal axis activity in rats

Cited by 24 publications

References 26 publications

5‐HT₆ receptor agonists and antagonists enhance learning and memory in a conditioned emotion response paradigm by modulation of cholinergic and glutamatergic mechanisms

5‐HT₆ receptor agonists and antagonists enhance learning and memory in a conditioned emotion response paradigm by modulation of cholinergic and glutamatergic mechanisms

Characterization of Behavioral, Signaling and Cytokine Alterations in a Rat Neurodevelopmental Model for Schizophrenia, and Their Reversal by the 5-HT6 Receptor Antagonist SB-399885

Spinal Serotonin and 5HT6 Receptor Levels During Development of Neuropathy and Influence of Blockade of these Receptors on Thermal Hyperalgesia in Diabetic Mice

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The effects of pharmacological blockade of the 5-HT6 receptor on formalin-evoked nociceptive behaviour, locomotor activity and hypothalamo–pituitary–adrenal axis activity in rats

Cited by 24 publications

References 26 publications

5‐HT6 receptor agonists and antagonists enhance learning and memory in a conditioned emotion response paradigm by modulation of cholinergic and glutamatergic mechanisms

5‐HT6 receptor agonists and antagonists enhance learning and memory in a conditioned emotion response paradigm by modulation of cholinergic and glutamatergic mechanisms

Characterization of Behavioral, Signaling and Cytokine Alterations in a Rat Neurodevelopmental Model for Schizophrenia, and Their Reversal by the 5-HT6 Receptor Antagonist SB-399885

Spinal Serotonin and 5HT6 Receptor Levels During Development of Neuropathy and Influence of Blockade of these Receptors on Thermal Hyperalgesia in Diabetic Mice

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5‐HT₆ receptor agonists and antagonists enhance learning and memory in a conditioned emotion response paradigm by modulation of cholinergic and glutamatergic mechanisms

5‐HT₆ receptor agonists and antagonists enhance learning and memory in a conditioned emotion response paradigm by modulation of cholinergic and glutamatergic mechanisms