No correlation between serotonin and its metabolite 5-HIAA in the cerebrospinal fluid and [(11) C]AZ10419369 binding measured with PET in healthy volunteers.

[(11) C]AZ10419369 is sensitive to pharmacologically enhanced endogenous serotonin levels. Twelve healthy volunteers underwent [(11) C]AZ10419369 PET and lumbar puncture. There were no correlations between [(11) C]AZ10419369 binding and concentrations of serotonin and its metabolite 5-HIAA in cerebrospinal fluid, suggesting that [(11) C]AZ10419369 brain binding does not reflect baseline serotonin levels in cerebrospinal fluid.

Lateral habenula 5-HT1B receptors are involved in regulation of anxiety-like behaviors in parkinsonian rats.

Although the output of the lateral habenula (LHb) controls the activity of midbrain dopaminergic and serotonergic systems, which are implicated in the pathophysiology of anxiety, it is not clear the role of LHb 5-HT1B receptors in regulation of anxiety-like behaviors, particularly in Parkinson's disease-related anxiety. In this study, unilateral 6-hydroxydopamine lesions of the substantia nigra pars compacta in rats induced anxiety-like behaviors, led to decreased normalized δ power and increased normalized θ power in the LHb, and decreased dopamine (DA) level in the prelimbic cortex (PrL) compared with sham rats. Down-regulation of LHb 5-HT1B receptors by RNA interference produced anxiety-like effects, decreased normalized δ power and increased normalized θ power in the LHb in both sham and lesioned rats. Further, intra-LHb injection of 5-HT1B receptor agonist CP93129 induced anxiolytic-like responses, increased normalized δ power and decreased normalized θ power in the LHb, and increased DA and serotonin (5-HT) release in the PrL; conversely, 5-HT1B receptor antagonist SB216641 produced anxiety-like effects, decreased normalized δ power and increased normalized θ power in the LHb, and decreased DA and 5-HT release in the PrL in sham and lesioned rats. Additionally, effects of CP93129 and SB216641 on the behaviors, normalized δ and θ power in the LHb, and DA and 5-HT release in the PrL were decreased in lesioned rats, which were consistent with down-regulation of LHb 5-HT1B receptors after DA depletion. Collectively, these findings suggest that 5-HT1B receptors in the LHb are involved in the regulation of anxiety-like behaviors.

A PET study with [11C]AZ10419369 to determine brain 5-HT1B receptor occupancy of zolmitriptan in healthy male volunteers.

AIM: To investigate the occupancy at brain 5-hydroxytryptamine (5-HT) 1B receptors in human subjects after administration of the antimigraine drug zolmitriptan. METHODS: Positron emission tomography (PET) studies were undertaken using the radioligand [(11)C]AZ10419369 in eight control subjects at baseline and after administration of zolmitriptan orodispersible tablets. The subjects were examined after two consecutive administrations of 10 mg zolmitriptan, approximately 1 week apart. Two of the subjects were subsequently examined after administration of 5 mg zolmitriptan. One week after the last administration of zolmitriptan five of the subjects underwent additional PET measurements without drug pretreatment. RESULTS: After administration of 10 mg zolmitriptan, mean receptor occupancy was 4-5%. No consistent changes in 5-HT1B receptor binding were observed for subjects who received 5 mg zolmitriptan. There was a statistically significant negative relationship between binding potential ( BP ND) and plasma concentration of zolmitriptan and the active metabolite 183C91, respectively. All of the five subjects who were examined 1 week after dosing with zolmitriptan showed higher BP ND post drug administration compared with baseline. CONCLUSION: This is the first demonstration of CNS 5-HT1B receptor occupancy of a triptan. The findings are consistent with the low receptor occupancy previously reported in PET studies with agonists at other G protein coupled receptors.

5-HT1B receptor-AC-PKA signal pathway in the lateral habenula is involved in the regulation of depressive-like behaviors in 6-hydroxydopamine-induced Parkinson's rats.

OBJECTIVE: The aim of the present study was to investigate whether serotonin1B (5-HT1B) receptor-adenylate cyclase (AC)-protein kinase A (PKA) signal pathway in the lateral habenula (LHb) is involved in Parkinson's disease-related depression in sham-lesioned and substantia nigra pars compacta (SNc)-lesioned rats. METHODS: The sucrose preference and forced swim tests were used to measure depressive-like behaviors. In vivo electrophysiology and microdialysis were performed to observe the firing activity of LHb neurons and GABA and glutamate release in the LHb, respectively. Western blotting was used to analyze protein expression of 5-HT1B receptors, AC and phosphorylated PKA at threonine 197 site (p-PKA-Thr197) in the LHb. RESULTS: Unilateral 6-hydroxydopamine lesions of the SNc in rats induced depressive-like behaviors. Intra-LHb injection of 5-HT1B receptor agonist CP93129 produced antidepressant-like effects and the antagonist SB216641 induced depressive-like behaviors in sham-lesioned and SNc-lesioned rats. Further, pretreatment with AC inhibitor SQ22536 and PKA inhibitor KT5720 blocked the behavioral effects of CP93129 in the two groups of rats, respectively. CP93129 decreased the firing rate of LHb neurons and release of GABA and glutamate, but increased the GABA/glutamate ratio, while SB216641 induced the opposite effects. Compared with sham-lesioned rats, effects of CP93129 and SB216641 on the depressive-like behaviors, electrophysiology, and microdialysis were decreased in SNc-lesioned rats, which were associated with decreased expression of 5-HT1B receptors, AC and p-PKA-Thr197 in the LHb. CONCLUSION: 5-HT1B receptor-AC-PKA signal pathway in the LHb is involved in the regulation of depressive-like behaviors, and depletion of DA reduces activity of 5-HT1B receptor-AC-PKA signal pathway.

5-HT1B receptors in the basolateral amygdaloid nucleus regulate anxiety-like behaviors through AC-PKA signal pathway in a rat model of Parkinson's disease.

BACKGROUND: Parkinson's disease (PD) is commonly accompanied with anxiety, multiple studies indicate that the basolateral amygdaloid nucleus (BLA) is closely related to modulation of anxiety and expresses serotonin1B (5-HT1B) receptors, however, effects of BLA 5-HT1B receptors on anxiety-like behaviors are unclear, particularly in PD-related anxiety. METHODS: The open-field and elevated plus maze tests were used to examine anxiety-like behaviors. In vivo electrophysiology and microdialysis were performed to observe the firing activity of BLA neurons and GABA, glutamate, dopamine (DA) and 5-HT release in the BLA, respectively. Western blotting was used to analyze protein expression of 5-HT1B receptors, adenylate cyclase (AC) and phosphorylated protein kinase A at threonine 197 site (p-PKA-Thr197) in the BLA. RESULTS: Intra-BLA injection of 5-HT1B receptor agonist CP93129 produced anxiety-like effects and antagonist SB216641 induced anxiolytic-like responses in sham-operated and 6-hydroxydopamine-lesioned rats. Further, pretreatment with AC inhibitor SQ22536 and PKA inhibitor KT5720 blocked the behavioral effects of CP93129, respectively. Intra-BLA injection of CP93129 increased the firing rate of BLA glutamate neurons and decreased GABA/glutamate ratio and DA and 5-HT levels in the BLA of sham-operated and the lesioned rats, while SB216641 induced the opposite effects. Compared with sham-operated rats, effects of CP93129 and SB216641 on behaviors, electrophysiology and microdialysis were decreased in the lesioned rats, which were associated with decreased expression of 5-HT1B receptors, AC and p-PKA-Thr197 in the BLA. CONCLUSION: These findings suggest that 5-HT1B receptor-AC-PKA signal pathway in the BLA is involved in the regulation of PD-related anxiety.

Serotonin receptors contribute to dopamine depression of lateral inhibition in the nucleus accumbens.

Dopamine modulation of nucleus accumbens (NAc) circuitry is central to theories of reward seeking and reinforcement learning. Despite decades of effort, the acute dopamine actions on the NAc microcircuitry remain puzzling. Here, we dissect out the direct actions of dopamine on lateral inhibition between medium spiny neurons (MSNs) in mouse brain slices and find that they are pathway specific. Dopamine potently depresses GABAergic transmission from presynaptic dopamine D2 receptor-expressing MSNs (D2-MSNs), whereas it potentiates transmission from presynaptic dopamine D1 receptor-expressing MSNs (D1-MSNs) onto other D1-MSNs. To our surprise, presynaptic D2 receptors mediate only half of the depression induced by endogenous and exogenous dopamine. Presynaptic serotonin 5-HT1B receptors are responsible for a significant component of dopamine-induced synaptic depression. This study clarifies the mechanistic understanding of dopamine actions in the NAc by showing pathway-specific modulation of lateral inhibition and involvement of D2 and 5-HT1B receptors in dopamine depression of D2-MSN synapses.

The 5-HT1B receptor - a potential target for antidepressant treatment.

Major depressive disorder (MDD) is the leading cause of disability worldwide. The serotonin hypothesis may be the model of MDD pathophysiology with the most support. The majority of antidepressants enhance synaptic serotonin levels quickly, while it usually takes weeks to discern MDD treatment effect. It has been hypothesized that the time lag between serotonin increase and reduction of MDD symptoms is due to downregulation of inhibitory receptors such as the serotonin 1B receptor (5-HT1BR). The research on 5-HT1BR has previously been hampered by a lack of selective ligands for the receptor. The last extensive review of 5-HT1BR in the pathophysiology of depression was published 2009, and based mainly on findings from animal studies. Since then, selective radioligands for in vivo quantification of brain 5-HT1BR binding with positron emission tomography has been developed, providing new knowledge on the role of 5-HT1BR in MDD and its treatment. The main focus of this review is the role of 5-HT1BR in relation to MDD and its treatment, although studies of 5-HT1BR in obsessive-compulsive disorder, alcohol dependence, and cocaine dependence are also reviewed. The evidence outlined range from animal models of disease, effects of 5-HT1B receptor agonists and antagonists, case-control studies of 5-HT1B receptor binding postmortem and in vivo, with positron emission tomography, to clinical studies of 5-HT1B receptor effects of established treatments for MDD. Low 5-HT1BR binding in limbic regions has been found in MDD patients. When 5-HT1BR ligands are administered to animals, 5-HT1BR agonists most consistently display antidepressant-like properties, though it is not yet clear how 5-HT1BR is best approached for optimal MDD treatment.

Involvement of 5-HT1A/1B receptors in the antinociceptive effect of paracetamol in the rat formalin test.

The mechanism of analgesic action of paracetamol (acetominophen) remains still unknown. However, a relationship between serotonergic system and the effect of paracetamol has been previously demonstrated. The serotonin activity in the brainstem is primarily under the control of 5-HT1A somatodendritic receptors, although some data also suggest the involvement of 5-HT1B receptors. To determine whether the 5-HT1A and 5-HT1B receptors are involved in the antinociceptive effect of paracetamol, we evaluated the effect of paracetamol (0.125-1 g/kg i.p.) followed by different antagonists [WAY 100,635 (0.8 mg/kg s.c.) and SB 216,641 (0.8 mg/kg s.c.)] or agonists [8-OH-DPAT (0.125 mg/kg s.c.) and CP 93,129 (0.125 mg/kg s.c.)] of 5-HT1A and 5-HT1B receptors, respectively, in the rat model of formalin-induced pain. We demonstrated that paracetamol administration showed a dose-dependent antinociceptive effect in the formalin test. WAY 100,635 (5-HT1A antagonist) induced an increase in the antinociceptive effect of paracetamol at 250 mg/kg doses. Conversely, 8-OH-DPAT (5-HT1A agonist) decreased the antinociceptive effect of paracetamol at 500-1000 mg/kg doses. However, SB216641 (5-HT1B antagonist) modified weakly the antinociceptive effect of paracetamol at 250 mg/kg doses and CP 93,129 (5-HT1B agonist) not produce a clear effect in the antinociceptive effect of paracetamol. These results suggest that the antinociceptive effect of paracetamol can be enhanced mainly by compounds having 5-HT1A antagonist properties in the formalin test and maybe by 5-HT1B receptors antagonists.

Cocaine Inhibition of Synaptic Transmission in the Ventral Pallidum Is Pathway-Specific and Mediated by Serotonin.

The ventral pallidum (VP) is part of the basal ganglia circuitry and a target of both direct and indirect pathway projections from the nucleus accumbens. VP is important in cocaine reinforcement, and the firing of VP neurons is modulated in vivo during cocaine self-administration. This modulation of firing is thought to be indirect via cocaine actions on dopamine in the accumbens. Here, we show that cocaine directly inhibits synaptic transmission evoked by selective stimulation of indirect pathway projections to VP neurons. The inhibition is independent of dopamine receptor activation, absent in 5-HT1B knockout mice, and mimicked by a serotonin transporter (SERT) blocker. SERT-expressing neurons in dorsal raphe project to the VP. Optogenetic stimulation of these projections evokes serotonin transients and effectively inhibits GABAergic transmission to VP neurons. This study shows that cocaine increases endogenous serotonin in the VP to suppress synaptic transmission selectively from indirect pathway projections to VP neurons.

S-Ketamine Mediates Its Acute and Sustained Antidepressant-Like Activity through a 5-HT1B Receptor Dependent Mechanism in a Genetic Rat Model of Depression.

Rationale: The mechanisms responsible for the unique antidepressant properties of ketamine have only been partly resolved. Recent preclinical reports implicate the neurotransmitter serotonin [5-hydroxytryptamine (5-HT)] in the antidepressant-like response of ketamine, and modulation of 5-HT1B receptors has been hypothesized to attain an important role. Objectives: To evaluate the role of endogenous stimulation of 5-HT1B heteroreceptors in the antidepressant-like activity of S-ketamine. Method: Flinders sensitive line (FSL) rats, a genetic model of depression, were depleted of endogenous 5-HT by 4-chloro-DL-phenylalanine methyl ester HCl administration (pCPA; 86 mg/kg/day for 3 days). In pCPA-pretreated and control FSL rats, the acute and sustained effects of a single dose of S-ketamine (15 mg/kg) and the selective 5-HT1B receptor agonist CP94253 (1-6 mg/kg) alone and in combination with S-ketamine were studied in the forced swim test (FST), a commonly used assay that detects antidepressant activity. Results: pCPA pretreatment decreased cortical 5-HT levels to ∼6% but did not affect the baseline behavioral phenotype of FSL rats. S-ketamine demonstrated acute and sustained antidepressant-like activity, both of which were abolished by 5-HT depletion. Combining S-ketamine with a sub-effective dose of CP94253 (1 mg/kg) rescued S-ketamine's acute and sustained antidepressant-like effects, when CP94253 was administered 2 h prior to the FST. Co-administration of S-ketamine and CP94253 did not affect the plasma level of either compound, suggesting that the observed behavioral interaction could not be ascribed to a kinetic drug-drug interaction. Conclusion: 5-HT1B receptor activation during testing appears to be critical for S-ketamine's antidepressant-like potentials in this model.

Prophylactic effects of asiaticoside-based standardized extract of Centella asiatica (L.) Urban leaves on experimental migraine: Involvement of 5HT1A/1B receptors.

The present study aimed at evaluation of prophylactic efficacy and possible mechanisms of asiaticoside (AS) based standardized extract of Centella asiatica (L.) Urban leaves (INDCA) in animal models of migraine. The effects of oral and intranasal (i.n.) pretreatment of INDCA (acute and 7-days subacute) were evaluated against nitroglycerine (NTG, 10 mg·kg(-1), i.p.) and bradykinin (BK, 10 µg, intra-arterial) induced hyperalgesia in rats. Tail flick latencies (from 0 to 240 min) post-NTG treatment and the number of vocalizations post-BK treatment were recorded as a measure of hyperalgesia. Separate groups of rats for negative (Normal) and positive (sumatriptan, 42 mg·kg(-1), s.c.) controls were included. The interaction of INDCA with selective 5-HT1A, 5-HT1B, and 5-HT1D receptor antagonists (NAN-190, Isamoltane hemifumarate, and BRL-15572 respectively) against NTG-induced hyperalgesia was also evaluated. Acute and sub-acute pre-treatment of INDCA [10 and 30 mg·kg(-1) (oral) and 100 µg/rat (i.n.) showed significant anti-nociception activity, and reversal of the NTG-induced hyperalgesia and brain 5-HT concentration decline. Oral pre-treatment with INDCA (30 mg·kg(-1), 7 d) showed significant reduction in the number of vocalization. The anti-nociceptive effects of INDCA were blocked by 5-HT1A and 5-HT1B but not 5-HT1D receptor antagonists. In conclusion, INDCA demonstrated promising anti-nociceptive effects in animal models of migraine, probably through 5-HT1A/1B medicated action.

Reduced 5-HT(1B) receptor binding in the dorsal brain stem after cognitive behavioural therapy of major depressive disorder.

Major depression is a significant contributor to the global burden of disease, and its pathophysiology is largely unknown. The serotonin hypothesis is, however, the model with most supporting data, although the details are only worked out to some extent. Recent clinical imaging measurements indeed imply a role in major depressive disorder (MDD) for the inhibitory serotonin autoreceptor 5-hydroxytryptamine1B (5-HT1B). The aim of the current study was to examine 5-HT1B receptor binding in the brain of MDD patients before and after psychotherapy. Ten patients with an ongoing untreated moderate depressive episode were examined with positron emission tomography (PET) and the 5-HT1B receptor selective radioligand [(11)C]AZ10419369, before and after treatment with internet-based cognitive behavioural therapy. All of the patients examined responded to treatment, and 70% were in remission by the time of the second PET measurement. A statistically significant 33% reduction of binding potential (BPND) was found in the dorsal brain stem (DBS) after treatment. No other significant changes in BPND were found. The DBS contains the raphe nuclei, which regulate the serotonin system. This study gives support for the importance of serotonin and the 5-HT1B receptor in the biological response to psychological treatment of MDD.

Dopamine D3 and 5-HT1B receptor dysregulation as a result of psychostimulant intake and forced abstinence: Implications for medications development.

Addiction to psychostimulants, including cocaine and amphetamine, is associated with dysregulation of dopamine and serotonin (5-HT) neurotransmitter systems. Neuroadaptations in these systems vary depending on the stage of the drug taking-abstinence-relapse cycle. Consequently, the effects of potential treatments that target these systems may vary depending on whether they are given during abstinence or relapse. In this review, we discuss evidence that dopamine D3 receptors (D3Rs) and 5-HT1B receptors (5-HT1BRs) are dysregulated in response to both chronic psychostimulant use and subsequent abstinence. We then review findings from preclinical self-administration models which support targeting D3Rs and 5-HT1BRs as potential medications for psychostimulant dependence. Potential side effects of the treatments are discussed and attention is given to studies reporting positive treatment outcomes that depend on: 1) whether testing occurs during self-administration versus abstinence, 2) whether escalation of drug self-administration has occurred, 3) whether the treatments are given repeatedly, and 4) whether social factors influence treatment outcomes. We conclude that D3/D2 agonists may decrease psychostimulant intake; however, side effects of D3/D2R full agonists may limit their therapeutic potential, whereas D3/D2R partial agonists have fewer undesirable side effects. D3-selective antagonists may not reduce psychostimulant intake during relapse, but nonetheless, may decrease motivation for seeking psychostimulants with relatively few side-effects. 5-HT1BR agonists provide a striking example of treatment outcomes that are dependent on the stage of the addiction cycle. Specifically, these agonists initially increase cocaine's reinforcing effects during maintenance of self-administration, but after a period of abstinence they reduce psychostimulant seeking and the resumption of self-administration. In conclusion, we suggest that factors contributing to dysregulation of monoamine systems, including drug history, abstinence, and social context, should be considered when evaluating potential treatments to better model treatment effects in humans. This article is part of a Special Issue entitled 'NIDA 40th Anniversary Issue'.