Sumatriptan reduces severity of status epilepticus induced by lithium-pilocarpine through nitrergic transmission and 5-HT1B/D receptors in rats: A pharmacological-based evidence.

Status epilepticus (SE) is a life-threatening neurologic disorder that can be as both cause and consequence of neuroinflammation. In addition to previous reports on anti-inflammatory property of the anti-migraine medication sumatriptan, we have recently shown its anticonvulsive effects on pentylenetetrazole-induced seizure in mice. In the present study, we investigated further (i) the effects of sumatriptan in the lithium-pilocarpine SE model in rats, and (ii) the possible involvement of nitric oxide (NO), 5-hydroxytryptamin 1B/1D (5-HT1B/1D ) receptor, and inflammatory pathways in such effects of sumatriptan. Status epilepticus was induced by lithium chloride (127 mg/kg, i.p) and pilocarpine (60 mg/kg, i.p.) in Wistar rats. While SE induction increased SE scores and mortality rate, sumatriptan (0.001-1 mg/kg, i.p.) improved it (P < 0.001). Administration of the selective 5-HT1B/1D antagonist GR-127935 (0.01 mg/kg, i.p.) reversed the anticonvulsive effects of sumatriptan (0.01 mg/kg, i.p.). Although both tumor necrosis factor-α (TNF-α) and NO levels were markedly elevated in the rats' brain tissues post-SE induction, pre-treatment with sumatriptan significantly reduced both TNF-α (P < 0.05) and NO (P < 0.001) levels. Combined GR-127935 and sumatriptan treatment inhibited these anti-inflammatory effects of sumatriptan, whereas combined non-specific NOS (L-NAME) or selective neuronal NOS (7-nitroindazole) inhibitors and sumatriptan further reduced NO levels. In conclusion, sumatriptan exerted a protective effect against the clinical manifestations and mortality rate of SE in rats which is possibly through targeting 5-HT1B/1D receptors, neuroinflammation, and nitrergic transmission.

Role of peripheral 5-HT5A receptors in 5-HT-induced cardiac sympatho-inhibition in type 1 diabetic rats.

5-HT inhibits cardiac sympathetic neurotransmission in normoglycaemic rats, via 5-HT1B, 5-HT1D and 5-HT5A receptor activation. Since type 1 diabetes impairs the cardiac sympathetic innervation leading to cardiopathies, this study aimed to investigate whether the serotonergic influence on cardiac noradrenergic control is altered in type 1 diabetic rats. Diabetes was induced in male Wistar rats by streptozotocin (50 mg/kg, i.p.). Four weeks later, the rats were anaesthetized, pithed and prepared for producing tachycardic responses by electrical preganglionic stimulation (C7-T1) of the cardioaccelerator sympathetic outflow or i.v. noradrenaline bolus injections. Immunohistochemistry was performed to study 5-HT1B, 5-HT1D and 5-HT5A receptor expression in the stellate ganglion from normoglycaemic and diabetic rats. In the diabetic group, i) i.v. continuous infusions of 5-HT induced a cardiac sympatho-inhibition that was mimicked by the 5-HT1/5A agonist 5-carboxamidotryptamine (without modifying noradrenaline-induced tachycardia), but not by the agonists indorenate (5-HT1A), CP 93,129 (5-HT1B), PNU 142633 (5-HT1D), or LY344864 (5-HT1F); ii) SB 699551 (5-HT5A antagonist; i.v.) completely reversed 5-CT-induced cardiac sympatho-inhibition; and iii) 5-HT5A receptors were more expressed in the stellate ganglion compared to normoglycaemic rats. These results show the prominent role of the peripheral 5-HT5A receptors prejunctionally inhibiting the cardiac sympathetic drive in type 1 diabetic rats.

5-HT2B, 5-HT7, and DA2 Receptors Mediate the Effects of 5-HT and DA on Agonistic Behavior of the Chinese Mitten Crab (Eriocheir sinensis).

The Chinese mitten crab (Eriocheir sinensis) is a commercially important crab in China and is usually managed at high stocking densities. Agonistic behavior directly impacts crab integrity, survival, and growth and results in economic losses. In the present study, we evaluated the modulatory effects of serotonin (5-HT) and dopamine (DA) though the 5-HT2 and DA2 receptor-cyclic adenosine monophosphate (cAMP)-protein kinase A (PKA) pathway on agonistic behavior. The results showed that injection of either 10-6 mol/crab 5-HT or DA reduced the agonistic behavior of E. sinensis (P < 0.05), as did 10-10 mol/crab DA and 10-8 mol/crab 5-HT and DA (P < 0.05); however, a dose of 10-10 mol/crab 5-HT promoted agonistic behavior. 5-HT significantly increased the mRNA expression level of 5-HT7 receptor and reduced that of the DA2 receptor in the cerebral ganglion (P < 0.05). In contrast to 5-HT, DA significantly decreased 5-HT2B mRNA levels and increased 5-HT7 and DA2 receptor levels in the thoracic ganglia (P < 0.05). In addition, injections of either 5-HT or DA increased the cAMP and PKA levels in hemolymph (P < 0.05). By using in vitro culture of the thoracic ganglia, the current study showed that ketanserin (5-HT2 antagonist) and [R(-)-TNPA] (DA2 agonist) had obvious effects on the expression levels of the two receptors (P < 0.05). In vivo experiments further demonstrated that ketanserin and [R(-)-TNPA] could both significantly reduce the agonistic behavior of the crabs (P < 0.05). Furthermore, both ketanserin and [R(-)-TNPA] promoted the cAMP and PKA levels (P < 0.05). The injection of CPT-cAMP (cAMP analogue) elevated the PKA levels and inhibited agonistic behavior. In summary, this study showed that 5HT-2B and DA2 receptors were involved in the agonistic behavior that 5-HT/DA induced through the cAMP-PKA pathway in E. sinensis.

Serotonin gating of cortical and thalamic glutamate inputs onto principal neurons of the basolateral amygdala.

The basolateral amygdala (BLA) is a key site for crossmodal association of sensory stimuli and an important relay in the neural circuitry of emotion. Indeed, the BLA receives substantial glutamatergic inputs from multiple brain regions including the prefrontal cortex and thalamic nuclei. Modulation of glutamatergic transmission in the BLA regulates stress- and anxiety-related behaviors. Serotonin (5-HT) also plays an important role in regulating stress-related behavior through activation of both pre- and postsynaptic 5-HT receptors. Multiple 5-HT receptors are expressed in the BLA, where 5-HT has been reported to modulate glutamatergic transmission. However, the 5-HT receptor subtype mediating this effect is not yet clear. The aim of this study was to use patch-clamp recordings from BLA neurons in an ex vivo slice preparation to examine 1) the effect of 5-HT on extrinsic sensory inputs, and 2) to determine if any pathway specificity exists in 5-HT regulation of glutamatergic transmission. Two independent input pathways into the BLA were stimulated: the external capsule to mimic cortical input, and the internal capsule to mimic thalamic input. Bath application of 5-HT reversibly reduced the amplitude of evoked excitatory postsynaptic currents (eEPSCs) induced by stimulation of both pathways. The decrease was associated with an increase in the paired-pulse ratio and coefficient of variation of eEPSC amplitude, suggesting 5-HT acts presynaptically. Moreover, the effect of 5-HT in both pathways was mimicked by the selective 5-HT1B receptor agonist CP93129, but not by the 5-HT1A receptor agonist 8-OH DPAT. Similarly the effect of exogenous 5-HT was blocked by the 5-HT1B receptor antagonist GR55562, but not affected by the 5-HT1A receptor antagonist WAY 100635 or the 5-HT2 receptor antagonists pirenperone and MDL 100907. Together these data suggest 5-HT gates cortical and thalamic glutamatergic inputs into the BLA by activating presynaptic 5-HT1B receptors.

The 5-HT1B serotonin receptor regulates methylphenidate-induced gene expression in the striatum: Differential effects on immediate-early genes.

Drug combinations that include a psychostimulant such as methylphenidate (Ritalin) and a selective serotonin reuptake inhibitor such as fluoxetine are indicated in several medical conditions. Co-exposure to these drugs also occurs with "cognitive enhancer" use by individuals treated with selective serotonin reuptake inhibitors. Methylphenidate, a dopamine reuptake inhibitor, by itself produces some addiction-related gene regulation in the striatum. We have demonstrated that co-administration of selective serotonin reuptake inhibitors potentiates these methylphenidate-induced molecular effects, thus producing a more "cocaine-like" profile. There is evidence that the 5-HT1B serotonin receptor subtype mediates some of the cocaine-induced gene regulation. We thus investigated whether the 5-HT1B receptor also modifies methylphenidate-induced gene regulation, by assessing effects of a selective 5-HT1B receptor agonist (CP94253) on immediate-early gene markers ( Zif268, c- Fos, Homer1a) in adolescent male rats. Gene expression was measured by in situ hybridization histochemistry. Our results show that CP94253 (3, 10 mg/kg) produced a dose-dependent potentiation of methylphenidate (5 mg/kg)-induced expression of Zif268 and c- Fos. This potentiation was widespread in the striatum and was maximal in lateral (sensorimotor) sectors, thus mimicking the effects seen after cocaine alone, or co-administration of fluoxetine. However, in contrast to fluoxetine, this 5-HT1B agonist did not influence methylphenidate-induced expression of Homer1a. CP94253 also potentiated methylphenidate-induced locomotor activity. These findings indicate that stimulation of the 5-HT1B receptor can enhance methylphenidate (dopamine)-induced gene regulation. This receptor may thus participate in the potentiation induced by fluoxetine (serotonin) and may serve as a pharmacological target to attenuate methylphenidate + selective serotonin reuptake inhibitor-induced "cocaine-like" effects.

Genetic and Modeling Approaches Reveal Distinct Components of Impulsive Behavior.

Impulsivity is an endophenotype found in many psychiatric disorders including substance use disorders, pathological gambling, and attention deficit hyperactivity disorder. Two behavioral features often considered in impulsive behavior are behavioral inhibition (impulsive action) and delayed gratification (impulsive choice). However, the extent to which these behavioral constructs represent distinct facets of behavior with discrete biological bases is unclear. To test the hypothesis that impulsive action and impulsive choice represent statistically independent behavioral constructs in mice, we collected behavioral measures of impulsivity in a single cohort of mice using well-validated operant behavioral paradigms. Mice with manipulation of serotonin 1B receptor (5-HT1BR) expression were included as a model of disordered impulsivity. A factor analysis was used to characterize correlations between the measures of impulsivity and to identify covariates. Using two approaches, we dissociated impulsive action from impulsive choice. First, the absence of 5-HT1BRs caused increased impulsive action, but not impulsive choice. Second, based on an exploratory factor analysis, a two-factor model described the data well, with measures of impulsive action and choice separating into two independent factors. A multiple-indicator multiple-causes analysis showed that 5-HT1BR expression and sex were significant covariates of impulsivity. Males displayed increased impulsivity in both dimensions, whereas 5-HT1BR expression was a predictor of increased impulsive action only. These data support the conclusion that impulsive action and impulsive choice are distinct behavioral phenotypes with dissociable biological influences that can be modeled in mice. Our work may help inform better classification, diagnosis, and treatment of psychiatric disorders, which present with disordered impulsivity.

Association Study of Gene Polymorphisms in GABA, Serotonin, Dopamine, and Alcohol Metabolism Pathways with Alcohol Dependence in Taiwanese Han Men.

BACKGROUND: The roles of GABA, serotonin, dopamine, and alcohol metabolism pathways in alcohol dependence (AD) are evident from animal models and human studies. Aims of this study were to investigate associations between genes in the 4 pathways and AD. METHODS: Male subjects from 2 independent samples of Taiwanese Han descent, a family sample of 179 trios and a case-control sample of 262 AD cases and 273 normal controls, were included in this study. The Schedules for Clinical Assessment in Neuropsychiatry was used for phenotype assessment of AD. We genotyped 282 single nucleotide polymorphisms (SNPs) located in 61 candidate genes involving alcohol metabolism, serotonin, and GABA systems among the family sample and replicated the top hits in the case-control sample. RESULTS: Fifteen SNPs located in 10 genes showed signals of associations (FBAT test p < 0.05) with AD in the family sample. Three SNPs, rs1229984 in ADH1B, rs671 in ALDH2, and rs2000292 in HTR1B, were significantly replicated in the case-control sample (p = 5.87 × 10(-14) , 5.12 × 10(-14) , and 0.0051, respectively). In the combined meta-analysis, these 3 SNPs and 1 additional SNP, rs698 in ADH1C, showed significant association after correcting for multiple comparisons, and rs1229984 and rs671 showed the strongest association (p < 10(-16) ). Logistic regression conditioning on rs1229984 and rs671 in the case-control sample showed that rs2000292 in HTR1B remained nominally significant. CONCLUSIONS: Genes in alcohol metabolism pathway, especially ADH1B and ALDH2, conferred the major genetic risk for AD in Taiwanese Han population. Some genes in GABA and serotonin pathways showed nominal association with AD.

Repeated administration of the 5-HT1B/1A agonist, RU 24969, facilitates the acquisition of MDMA self-administration: role of 5-HT1A and 5-HT1B receptor mechanisms.

RATIONALE: 3,4 Methylenedioxymethamphetamine (MDMA) preferentially stimulates the release of serotonin (5-HT) that subsequently produces behavioral responses by activation of post-synaptic receptor mechanisms. The 5-HT1A and 5-HT1B receptors are both well localized to regulate dopamine (DA) release, and have been implicated in modulating the reinforcing effects of many drugs of abuse, but a role in acquisition of self-administration has not been determined. OBJECTIVES: This study was designed to determine the effect of pharmacological manipulation of 5-HT1A and 5-HT1B receptor mechanisms on the acquisition of MDMA self-administration. METHODS: The 5-HT1B/1A receptor agonist, RU 24969 (0.0 or 3.0 mg/kg, bid), was administered for 3 days in order to down-regulate both 5-HT1A and 5-HT1B receptors. Following the pretreatment phase, latency to acquisition of MDMA self-administration was measured. RESULTS: Repeated administration of RU 24969 significantly decreased the latency to acquisition and increased the proportion of animals that acquired MDMA self-administration. Dose-effect curves for the 5-HT1A-mediated hyperactivity produced by the 5-HT1A agonist, 8-OH-DPAT, and the 5-HT1B-mediated adipsic response produced by RU 24969 were shifted rightward, suggesting a desensitization of 5-HT1A and 5-HT1B receptor mechanisms. CONCLUSIONS: These data suggest that the initial reinforcing effects of MDMA are modulated by 5-HT1A and/or 5-HT1B receptor mechanisms. The potential impact of these changes on the DAergic response relevant to self-administration and a possible role in conditioned reinforcement pertaining to acquisition of self-administration are discussed.

[The effects of 5-HT1B receptor subtypes on motor behaviors mediated by cerebellar fastigial nucleus].

OBJECTIVE: To investigate the effects of the serotonergic nervous system on motor behaviors mediated by cerebellar fastigial nucleus (FN). METHODS: In this experiment, the main methods are whole-cell patch clamp recording and Rota-rod test. RESULTS: We found that the excitatory synaptic transmission was enhanced in the cerebella FN after blocking 5-hydroxytryptamine,(5-HT)receptor. Microinjection of 5-HT into FNs remarkably promoted motor performances on Rota-rod, which could be reversed by microinjection of 5-HT receptor antagonist SB224289. CONCLUSIONS: These results suggest that the 5-HT can suppress cerebellar FN excitatory synaptic transmission via 5-HT1B receptors, thereby modulate the activity of cerebellar nuclear neurons circuitry, and subsequently influence the cerebellum-mediated ongoing motor balance and coordination.

The Efficacy of Eslicarbazepine Acetate in Models of Trigeminal, Neuropathic, and Visceral Pain: The Involvement of 5-HT1B/1D Serotonergic and CB1/CB2 Cannabinoid Receptors.

BACKGROUND: Many clinical pain states that are difficult to treat share a common feature of sensitization of nociceptive pathways. Drugs that could normalize hyperexcitable neural activity (e.g., antiepileptic drugs) may be useful in relieving these pain states. Eslicarbazepine acetate (ESL) is a novel antiepileptic drug derived from carbamazepine/oxcarbazepine with a more favorable metabolic profile and potentially better tolerability. We examined the efficacy of ESL in models of inflammatory and neuropathic pain and the potential mechanism involved in its action. METHODS: The antinociceptive effects of ESL were assessed in mice models of trigeminal (orofacial formalin test), neuropathic (streptozotocin-induced diabetic neuropathy model), and visceral pain (writhing test). The influence of 5-HT1B/1D serotonin receptor (GR 127935) and CB1 (AM251) and CB2 cannabinoid receptor (AM630) antagonists on the antinociceptive effect of ESL was tested in the model of trigeminal pain. RESULTS: ESL exhibited significant and dose-dependent antinociceptive effects in the second phase of the orofacial formalin test (P ≤ 0.011), in the tail-flick test in diabetic mice (P ≤ 0.013), and in the writhing test (P ≤ 0.003). GR 127935 (P ≤ 0.038) and AM251 and AM630 (P ≤ 0.013 for both antagonists) significantly inhibited the antinociceptive effect of ESL in a dose-related manner. CONCLUSIONS: ESL exhibited efficacy in models of trigeminal, neuropathic, and visceral pain. In the trigeminal pain model, the antinociceptive effect of ESL is, at least in part, mediated by 5-HT1B/1D serotonin and CB1/CB2 cannabinoid receptors. This study indicates that ESL could be useful in the clinical treatment of inflammatory and neuropathic pain.

Effects of acute and sustained administration of vortioxetine on the serotonin system in the hippocampus: electrophysiological studies in the rat brain.

RATIONALE: Vortioxetine is a novel multimodal antidepressant that is a 5-HT1B receptor partial agonist, a 5-HT1A receptor agonist, an inhibitor of the serotonin (5-HT) transporter, and a 5-HT1D, 5-HT3, and 5-HT7 receptor antagonist in vitro. In vivo studies have shown that vortioxetine enhances levels of 5-HT and desensitizes 5-HT1A autoreceptors. OBJECTIVES: The aim of the present study was to investigate the effects of acute and long-term administration of vortioxetine on the terminal 5-HT1B receptor and the tonic activation of 5-HT1A receptor in the rat hippocampus. METHODS: These receptors were assessed following vortioxetine administration acutely or subcutaneously using minipumps for 14 days. These studies were carried out using in vivo electrophysiological recording, microiontophoresis, and stimulation of the ascending 5-HT fibers. RESULTS: Vortioxetine enhanced the inhibitory effect of the stimulation of the 5-HT bundle at a high, but not low frequency and reversed the inhibitory effect of the 5-HT1B receptor agonist CP 94253. These results indicate that this compound acted as a 5-HT1B receptor partial agonist. Vortioxetine inhibited 5-HT reuptake but did not dampen the sensitivity of postsynaptic 5-HT1A receptors on pyramidal neurons. Long-term administration of vortioxetine and escitalopram (both at 5 mg/kg/day) induced an increase of tonic activation of the 5-HT1A receptors in CA3 pyramidal neurons, resulting in an increase in 5-HT transmission. In addition, vortioxetine decreased the function of terminal 5-HT1B autoreceptor following its sustained administration. CONCLUSIONS: Desensitization of 5-HT1B autoreceptor and an increase of tonic activation of 5-HT1A receptors in the hippocampus may contribute to the antidepressant effect of vortioxetine.

Fluoxetine potentiation of methylphenidate-induced gene regulation in striatal output pathways: potential role for 5-HT1B receptor.

Drug combinations that include the psychostimulant methylphenidate plus a selective serotonin reuptake inhibitor (SSRI) such as fluoxetine are increasingly used in children and adolescents. For example, this combination is indicated in the treatment of attention-deficit/hyperactivity disorder and depression comorbidity and other mental disorders. Such co-exposure also occurs in patients on SSRIs who use methylphenidate as a cognitive enhancer. The neurobiological consequences of these drug combinations are poorly understood. Methylphenidate alone can produce gene regulation effects that mimic addiction-related gene regulation by cocaine, consistent with its moderate addiction liability. We have previously shown that combining SSRIs with methylphenidate potentiates methylphenidate-induced gene regulation in the striatum. The present study investigated which striatal output pathways are affected by the methylphenidate + fluoxetine combination, by assessing effects on pathway-specific neuropeptide markers, and which serotonin receptor subtypes may mediate these effects. Our results demonstrate that a 5-day repeated treatment with fluoxetine (5 mg/kg) potentiates methylphenidate (5 mg/kg)-induced expression of both dynorphin (direct pathway marker) and enkephalin (indirect pathway). These changes were accompanied by correlated increases in the expression of the 5-HT1B, but not 5-HT2C, serotonin receptor in the same striatal regions. A further study showed that the 5-HT1B receptor agonist CP94253 (3-10 mg/kg) mimics the fluoxetine potentiation of methylphenidate-induced gene regulation. These findings suggest a role for the 5-HT1B receptor in the fluoxetine effects on striatal gene regulation. Given that 5-HT1B receptors are known to facilitate addiction-related gene regulation and behavior, our results suggest that SSRIs may enhance the addiction liability of methylphenidate by increasing 5-HT1B receptor signaling.

Possible involvement of CA1 5-HT1B/1D and 5-HT2A/2B/2C receptors in harmaline-induced amnesia.

In the present study, effects of the serotonergic system of the dorsal hippocampus (CA1) on harmaline-induced amnesia were examined. A single-trial step-down passive avoidance task was used for the assessment of memory retention in adult male NMRI mice. Pre-training intra-peritoneal (i.p.) administration of harmaline (1mg/kg) induced impairment of memory retention. Moreover, intra-CA1 administration of 5-HT1B/1D receptor agonist, CP94253 (5 ng/mouse), 5-HT1B/1D receptor antagonist, GR127935 (0.05 and 0.5 ng/mouse), 5-HT2A/2B/2C receptor agonist, α-methyl 5-HT (0.5 ng/mouse) and 5-HT2 receptor antagonist, cinancerine (0.5 ng/mouse) impaired memory acquisition, but did not affect locomotor activity and tail flick. Furthermore, pre-training intra-CA1 injection of subthreshold dose of CP94253 (0.05 ng/mouse) or GR127935 (0.005 ng/mouse) reversed impairment of memory acquisition induced by harmaline (1 mg/kg, i.p.). However, pre-training intra-CA1 infusion of subthreshold dose of α-methyl 5-HT (0.005 ng/mouse) or cinancerine (0.005 ng/mouse) with the administration of harmaline (0.5 and 1 mg/kg, i.p.) heighten impairment of memory acquisition. These findings implicate the involvement of CA1 serotonergic mechanism in harmaline-induced impairment of memory acquisition.

Anticataleptic effects of 5-HT(1B) receptors in the globus pallidus.

The globus pallidus occupies an important position in the indirect pathway of the basal ganglia. Being a monoamine neurotransmitter, 5-HT is involved in mediating many physiological functions and pathophysiological processes in several movement disorders. Morphological studies have revealed that the globus pallidus receives serotonergic innervation arising from the raphe nuclei, mainly the dorsal raphe nucleus. A high level of 5-HT and 5-HT(1B) receptors were detected in the globus pallidus. In the present study, bilateral microinjection of 5-HT or 5-HT(1B) receptor agonist, CP-93129, into the globus pallidus significantly alleviated the symptoms of rigidity caused by haloperidol. To further elucidate 5-HT(1B) receptor-induced anticatalepsy, in vivo extracellular recordings were performed to examine the effects of 5-HT(1B) receptor activation on the firing activity of the globus pallidus neurons under the presence of haloperidol. Micro-pressure ejection of 5-HT or CP-93129 increased the spontaneous firing rate of the pallidal neurons. Furthermore, by using immunohistochemistry, positive staining of 5-HT(1B) receptor was observed in the globus pallidus neurons. Taken together, the present findings provide evidence that activation of 5-HT(1B) receptor may exert anticataleptic effects by increasing the activity of pallidal neurons.

Role of 5-HT1B/1D receptors in the reduction of formalin-induced nociception and secondary allodynia/hyperalgesia produced by antimigraine drugs in rats.

AIMS: The present study analyzed the potential antinociceptive effect of the antimigraine drugs sumatriptan, dihydroergotamine or methysergide in rats submitted to the formalin test. Moreover, by using selective antagonists, the role of 5-HT1B/1D serotonergic receptors was investigated in the antinociception induced by these antimigraine drugs. MAIN METHODS: The formalin test was used to assess the nociceptive activity. Overt pain-like behavior (flinching, 1h) and evoked nociception (long-lasting secondary mechanical allodynia and hyperalgesia, 6 days) were determined in the same rat. KEY FINDINGS: Ipsilateral, but not contralateral, pre-treatment (in µg/paw) with sumatriptan (10-300), methysergide (1-30) or dihydroergotamine (1-30) significantly prevented flinching behavior (at 1h) as well as secondary allodynia and hyperalgesia (at day 6) induced by formalin. Interestingly, the antinociceptive (flinching), antiallodynic and antihyperalgesic effects of sumatriptan were completely prevented by peripheral pre-treatment with selective antagonists at the 5-HT1B (SB 224289; 100) or 5-HT1D (BRL 15572; 100) receptors. In contrast, the acute antinociceptive effects of methysergide and dihydroergotamine were partially prevented by SB 224289 and BRL 15572. The antiallodynic and antihyperalgesic effects of both drugs were completely prevented by BRL 15572 and partially prevented by SB 224289. Given alone, SB 224289 or BRL 15572 did not modify per se the long-lasting secondary allodynia and hyperalgesia. SIGNIFICANCE: The above findings suggest that: (i) the antimigraine drugs sumatriptan, methysergide and dihydroergotamine reduce the acute and chronic nociception induced by formalin; and (ii) this antinociceptive effect results from activation of peripheral 5-HT1B/1D serotonergic receptors.

Region-specific regulation of 5-HT1B receptors in the rat brain by chronic venlafaxine treatment.

RATIONALE: Venlafaxine is a non-selective serotonin and noradrenaline reuptake inhibitor antidepressant drug for which clinical studies have suggested a high level efficacy and a possible early action onset compared to the classical antidepressants. Its therapeutic effects might be due, at least in part, to adaptive changes in serotonergic neurotransmission, through the activation of the different 5-HT receptor subtypes. 5-HT(1B) receptors are located in the axon terminals of both serotonergic and non-serotonergic neurons, where they act as inhibitory autoreceptors or heteroreceptors, respectively. However, the information about the involvement of this subtype in the mechanism of action of antidepressants is limited and quite controversial. OBJECTIVES: The aim of this study was to evaluate the effect of venlafaxine (10 mg kg⁻¹ day⁻¹, p.o.) after 21 days of treatment on the density of 5-HT(1B) receptors and their functionality in rat brain. METHODS: Effects of chronic venlafaxine were evaluated at different levels of 5-HT(1B) receptor by using receptor autoradiography, [³5S]GTPγS binding, and the regulation of body temperature induced by selective 5-HT(1B) agonist. RESULTS: Our results show that venlafaxine induced an increase in sensitivity of 5-HT(1B) receptors in hypothalamus both at G-protein level and the control of core temperature without affecting the receptor density. CONCLUSIONS: These results demonstrate that adaptive changes on 5-HT(1B) receptors induced by chronic administration of venlafaxine exhibit regional differences suggesting that the hypothalamus might be an important site of drug action.

A single in vivo cocaine administration impairs 5-HT(1B) receptor-induced long-term depression in the nucleus accumbens.

The nucleus accumbens (NAc) is a crucial forebrain nucleus implicated in reward-based decision-making. While NAc neurons are richly innervated by serotonergic fibers, information on the functional role of serotonin 5-hydroxytryptamine (5-HT) in the NAc is still sparse. Here, we demonstrate that brief application of 5-HT or 5-HT1B receptor agonist CP 93129 induced a long-term depression (LTD) of glutamatergic transmission in NAc neurons. This LTD was presynaptically mediated and inducible by endogenous 5-HT. Remarkably, a single cocaine exposure impaired the induction of LTD by 5-HT or CP 93129. The inhibition was blocked when a selective dopamine D1 receptor antagonist SCH23390 was coadministered with cocaine. Cocaine treatment resulted in increased phosphorylation of presynaptic proteins, rabphilin 3A and synapsin 1, and significantly attenuated CP 93129-induced decrease in rabphilin 3A and synapsin 1 phosphorylation. Application of cAMP-dependent protein kinase inhibitor KT5720 caused a prominent synaptic depression in NAc neurons of mice with a history of cocaine exposure. Our results reveal a novel 5-HT1B receptor-mediated LTD in the NAc and suggest that cocaine exposure may result in elevated phosphorylation of presynaptic proteins involved in regulating glutamate release, which counteracts the presynaptic depressant effects of 5-HT1B receptors and thereby impairs the induction of LTD by 5-HT.

Bidirectional regulation of emotional memory by 5-HT1B receptors involves hippocampal p11.

Cognitive impairments are common in depression and involve dysfunctional serotonin neurotransmission. The 5-HT1B receptor (5-HT(1B)R) regulates serotonin transmission, via presynaptic receptors, but can also affect transmitter release at heterosynaptic sites. This study aimed at investigating the roles of the 5-HT(1B)R, and its adapter protein p11, in emotional memory and object recognition memory processes by the use of p11 knockout (p11KO) mice, a genetic model for aspects of depression-related states. 5-HT(1B)R agonist treatment induced an impairing effect on emotional memory in wild type (WT) mice. In comparison, p11KO mice displayed reduced long-term emotional memory performance. Unexpectedly, 5-HT(1B)R agonist stimulation enhanced memory in p11KO mice, and this atypical switch was reversed after hippocampal adeno-associated virus mediated gene transfer of p11. Notably, 5-HT(1B)R stimulation increased glutamatergic neurotransmission in the hippocampus in p11KO mice, but not in WT mice, as measured by both pre- and postsynaptic criteria. Magnetic resonance spectroscopy demonstrated global hippocampal reductions of inhibitory GABA, which may contribute to the memory enhancement and potentiation of pre- and post-synaptic measures of glutamate transmission by a 5-HT(1B)R agonist in p11KO mice. It is concluded that the level of hippocampal p11 determines the directionality of 5-HT(1B)R action on emotional memory processing and modulates hippocampal functionality. These results emphasize the importance of using relevant disease models when evaluating the role of serotonin neurotransmission in cognitive deficits related to psychiatric disorders.

FOXO1 orchestrates the bone-suppressing function of gut-derived serotonin.

Serotonin is a critical regulator of bone mass, fulfilling different functions depending on its site of synthesis. Brain-derived serotonin promotes osteoblast proliferation, whereas duodenal-derived serotonin suppresses it. To understand the molecular mechanisms of duodenal-derived serotonin action on osteoblasts, we explored its transcriptional mediation in mice. We found that the transcription factor FOXO1 is a crucial determinant of the effects of duodenum-derived serotonin on bone formation We identified two key FOXO1 complexes in osteoblasts, one with the transcription factor cAMP-responsive element-binding protein 1 (CREB) and another with activating transcription factor 4 (ATF4). Under normal levels of circulating serotonin, the proliferative activity of FOXO1 was promoted by a balance between its interaction with CREB and ATF4. However, high circulating serotonin levels prevented the association of FOXO1 with CREB, resulting in suppressed osteoblast proliferation. These observations identify FOXO1 as the molecular node of an intricate transcriptional machinery that confers the signal of duodenal-derived serotonin to inhibit bone formation.

Vasoconstrictor 5-HT receptors in the smooth muscle of the rat middle cerebral artery.

Serotonin (5-HT) can constrict cerebral arteries via activation of 5-HT(1B) and 5-HT(2A) receptors. Our goal was to reveal the importance and relative contribution of the two 5-HT receptor subtypes to the serotonin-induced vasoconstriction in the rat middle cerebral artery. The vasoconstrictor effects of 5-carboxamidotryptamine, sumatriptan and 5-HT were measured without and with pre-treatment with SB 216641 (5-HT(1B) antagonist), or ritanserin, (5-HT(2A) antagonist), in endothelium-denuded arteries, in vitro. All agonists caused vasoconstrictions. The order of potency (EC(50)) of the compounds was: 5-carboxamidotryptamine (14±3 nM)>5-HT (270±30 nM)>sumatriptan (5.8±1.9 µM). The concentration-response curve of 5-carboxamidotryptamine resembled the sum of two sigmoid curves (EC(50) 14±3 nM and 15±7 µM), and SB 216641 and ritanserin antagonized its low and high concentration components, respectively. Vasoconstrictions evoked by 5-HT at low and high concentrations were also fully antagonized by SB 216641 and ritanserin, respectively. Sumatriptan constricted the middle cerebral artery exclusively via 5-HT(1B) receptors. The efficacy of 5-carboxamidotryptamine and sumatriptan was low in comparison to the maximum contractile force elicited by 120 mmol/l KCl, reaching only 18-23% for 5-HT(1B) and 14% for 5-HT(2A) receptor activation. In conclusion, 5-HT produced small vasoconstrictions in the rat middle cerebral artery that were mediated by 5-HT(1B) receptors with high potency and by 5-HT(2A) receptors with low potency. Thus, 5-HT may have a minor physiological role in blood flow regulation via 5-HT(1B) receptor activation while 5-HT(2A) receptors seem to have a pathophysiological role in this vessel.