Serotonin receptor subtypes involved in the elevation of serum corticosterone concentration in rats by direct- and indirect-acting serotonin agonists

The serum corticosterone concentration in rats was increased by injection of quipazine, a relatively nonselective serotonin (5-hydroxytryptamine; 5-HT) agonist, or 8-hydroxy-2-(di-n- propylamino)tetralin (8-OH-DPAT), a serotonin agonist selective for the 5-HT1A subtype of receptor. The quipazine-induced increase in serum corticosterone was antagonized by 17 different serotonin antagonists; of these, MDL 11939, pirenperone, setoperone, mianserin, LY 281067, ketanserin, ritanserin and clozapine have relatively selective affinity for the 5-HT2 subtype of receptor. The 8-OH-DPAT-induced increase in serum corticosterone was not antagonized by metergoline, the most potent antagonist of the quipazine effect, but was antagonized by pindolol or penbutolol, 5-HT1A receptor antagonists. Pindolol did not block the effect of quipazine. The results support earlier evidence that serum corticosterone concentration in rats can be increased by activation of either 5-HT1A or 5-HT2 receptors. Indirect-acting serotonin agonists - fluoxetine, L-5-hydroxytryptophan and p-chloroamphetamine - also increased serum corticosterone concentrations. The increases elicited by those agents, which earlier had been reported not to be blocked by metergoline pretreatment, also were not blocked by pretreatment with pindolol or with the combination of metergoline and pindolol. Thus, an involvement of a specific serotonin receptor subtype in the actions of these indirect agonists has not been established.     

The effects of metergoline and other serotonin receptor antagonists on serum corticosterone in rats.

Metergoline antagonized the elevation of serum corticosterone by quipazine in rats. The ED50 of metergoline was less than 0.1 mg/kg, ip, and the effects of a 3 mg/kg dose persisted for more than 24 h. Metergoline did not antagonize the elevation of serum corticosterone by theophylline or ketamine (i.e. did not prevent corticosterone release nonspecifically) and did not affect the concentration of quipazine in the brain. Since quipazine is a serotonin receptor agonist, the antagonistic effects of metergoline may have been due to competition with quipazine at serotonin receptor sites in the brain. Some other agents capable of blocking serotonin receptors also antagonzied the elevation of serum corticosterone by quipazine. These included LY53857, which gave complete blockade at 3 mg/kg, and cyproheptadine and spiperone, which gave significant but incomplete antagonism at 1 mg/kg. Methysergide at 3 mg/kg did not alter the effect of quipazine. Metergoline did not antagonize the elevation of serum corticosterone by other agents throught to act via serotoninergic mechanisms, namely fluoxetine, fenfluramine, L-5-hydroxytryptophan, N,N-demthyl-5-methoxytryptamine, and 1-(m-trifluoromethylphenyl)piperazine. Thus, the interactions between metergoline and quipazine may have occurred at receptors that are not serotonin receptors or that represent a subset of serotonin receptors not mediating the actions of serotoninergic agents other than quipazine.     

5-HT1c receptor is a prominent serotonin receptor subtype in the central nervous system

Neurons in rat central nervous system (CNS) that express 5-HT1c receptor mRNA have been localized by in situ hybridization histochemistry. The 5-HT1c receptor is expressed in a wide variety of cortical and subcortical neurons including hippocampal pyramidal neurons, neurons within most of the central monoaminergic cell groups, neurons in thalamic sensory relay nuclei, and neurons involved in the central processing and regulation of nociceptive transmission. Therefore, the 5-HT1c receptor is a prominent but poorly characterized central subclass of serotonin (5-HT) receptor. The distribution of the 5-HT1c receptor within the CNS is considerably more widespread than that of the structurally and functionally related 5-HT2 receptor.     

Pathophysiologic control of nuclear triiodothyronine receptor capacity

Mechanisms involved in the reduced T3 receptor capacity found in a variety of pathophysiologic states were investigated by in vitro assessment of T3 receptor-nuclei interaction using tissue prepared from rats. In nuclei from immature animals, nuclear uptake of receptor was reduced, release was accelerated, and these alterations could account for the reduced nuclear receptor capacity. The functions reached the normal adult condition by 30-50 days. Nuclei from animals starved for 72 h showed no change in release of receptor, a 15% decrease in uptake, and 48% decrease in total binding capacity, indicating that the major effect is related to diminished supply of receptor, presumably due to reduced synthesis in the extranuclear compartment. Glucagon administration produced no change in receptor release, 25% decrease in receptor uptake, and nearly equivalent 33% decrease in binding capacity. Alteration in receptor uptake could account largely for changes induced by glucagon. Animals studied 24 h after hepatectomy had a 53% decrease in total binding capacity, but no change in uptake or release, indicating that reduced receptor synthesis is the primary abnormality. Administration of alpha-amanitin caused a 30% diminution in the binding capacity in the nuclei, without change in uptake and release, and cycloheximide caused an 87% decrease in binding capacity, with minimal change in uptake and no change in release. In both instances the alterations are interpretable as diminished synthesis and availability of receptor, rather than alterations in binding receptor to chromatin. The major cause of diminished receptor capacity appears to be reduced cytosolic synthesis of receptor, with reduction in retention by chromatin-associated factors playing a significant role in immature animals, and during glucagon treatment.     

Selective 5-HT1D alpha serotonin receptor gene expression in trigeminal ganglia: implications for antimigraine drug development.

Pharmacological data suggest that the actions of antimigraine drugs such as sumatriptan may be mediated by 5-HT1D-like serotonin receptors on trigeminovascular nerve endings. We sought molecular evidence for the expression of an mRNA species encoding the 5-HT1D receptor subtype in guinea pig and human trigeminal ganglia, using the polymerase chain reaction with oligonucleotides uniquely homologous to the coding sequences of the 5-HT1B/D family (human 5-HT1D alpha and 5-HT1D beta; rat 5-HT1B). A single band of predicted size was observed in samples from guinea pig trigeminal ganglia; sequence analysis revealed the presence of a single message, which was 85% and 71% identical to the human 5-HT1D alpha and 5-HT1D beta receptor DNA sequences, respectively. Similar analyses of postmortem human trigeminal ganglia revealed the presence of 5-HT1D alpha, but not 5-HT1D beta, receptor message. Inasmuch as one recent report found that mRNA encoding only the 5-HT1D beta receptor subtype was expressed by vascular smooth muscle of the central nervous system, the present findings suggest the importance of developing selective 5-HT1D alpha receptor agonists as a strategy to reduce the risk of myocardial infarction and possibly stroke that complicates the acute treatment of migraine headache.     

Selective up-regulation of dopamine D1 receptors in dendritic spines by NMDA receptor activation

Glutamate, by activating N-methyl-d-aspartate (NMDA) receptors, alters the balance between dopamine D1 and D2 receptor signaling, but the mechanism responsible for this effect has not been known. We report here, using immunocytochemistry of primary cultures of rat neostriatal neurons, that activation of NMDA receptors recruits D1 receptors from the interior of the cell to the plasma membrane while having no effect on the distribution of D2 receptors. The D1 receptors were concentrated in spines as shown by colocalization with phalloidin-labeled actin filaments. The effect of NMDA on D1 receptors was abolished by incubation of cells in calcium-free medium and was mimicked by the calcium ionophore ionomycin. Recruitment of D1 receptors from the interior of the cell to the membrane was confirmed by subcellular fractionation. The recruited D1 receptors were functional as demonstrated by an increase in dopamine-sensitive adenylyl cyclase activity in membranes derived from cells that had been pretreated with NMDA. These results provide evidence for regulated recruitment of a G protein-coupled receptor in neurons, provide a cell biological basis for the effect of NMDA on dopamine signaling, and reconcile the conflicting hyperdopaminergic and hypoglutamatergic hypotheses of schizophrenia.     

Increased anxiety of mice lacking the serotonin1A receptor

Brain serotonin (5-HT) has been implicated in a number of physiological processes and pathological conditions. These effects are mediated by at least 14 different 5-HT receptors. We have inactivated the gene encoding the 5-HT_1A receptor in mice and found that receptor-deficient animals have an increased tendency to avoid a novel and fearful environment and to escape a stressful situation, behaviors consistent with an increased anxiety and stress response. Based on the role of the 5-HT_1A receptor in the feedback regulation of the 5-HT system, we hypothesize that an increased serotonergic neurotransmission is responsible for the anxiety-like behavior of receptor-deficient animals. This view is consistent with earlier studies showing that pharmacological activation of the 5-HT system is anxiogenic in animal models and also in humans.     

Selective activation of the M1 muscarinic acetylcholine receptor achieved by allosteric potentiation

The forebrain cholinergic system promotes higher brain function in part by signaling through the M₁ muscarinic acetylcholine receptor (mAChR). During Alzheimer''s disease (AD), these cholinergic neurons degenerate, therefore selectively activating M₁ receptors could improve cognitive function in these patients while avoiding unwanted peripheral responses associated with non-selective muscarinic agonists. We describe here benzyl quinolone carboxylic acid (BQCA), a highly selective allosteric potentiator of the M₁ mAChR. BQCA reduces the concentration of ACh required to activate M₁ up to 129-fold with an inflection point value of 845 nM. No potentiation, agonism, or antagonism activity on other mAChRs is observed up to 100 μM. Furthermore studies in M₁^−/− mice demonstrates that BQCA requires M₁ to promote inositol phosphate turnover in primary neurons and to increase c-fos and arc RNA expression and ERK phosphorylation in the brain. Radioligand-binding assays, molecular modeling, and site-directed mutagenesis experiments indicate that BQCA acts at an allosteric site involving residues Y179 and W400. BQCA reverses scopolamine-induced memory deficits in contextual fear conditioning, increases blood flow to the cerebral cortex, and increases wakefulness while reducing delta sleep. In contrast to M₁ allosteric agonists, which do not improve memory in scopolamine-challenged mice in contextual fear conditioning, BQCA induces β-arrestin recruitment to M₁, suggesting a role for this signal transduction mechanism in the cholinergic modulation of memory. In summary, BQCA exploits an allosteric potentiation mechanism to provide selectivity for the M₁ receptor and represents a promising therapeutic strategy for cognitive disorders.Basal forebrain cholinergic neurons innervate information processing centers in the hippocampus and cortex to promote attention and memory. During AD, these neurons profoundly degenerate, contributing to cognitive impairment (1). While cholinesterase inhibitors demonstrate the therapeutic potential for boosting cholinergic function in AD, they are limited by tolerability and provide modest benefit, thus there remains a tremendous need for improved therapies (2). Selectively targeting the ACh receptors involved in memory, while sparing receptors involved in other physiological processes, could provide additional efficacy, a widely pursued approach that has yet to lead to new medicines.ACh signals by activating ligand-gated ion channels (nicotinic receptors) and metabotropic (muscarinic) G protein-coupled receptors (GPCRs) designated M₁–M₅. Among the mAChRs, M₁ is most abundantly expressed in the hippocampus, cortex, and striatum, and localizes to postsynaptic membranes (3), where it signals via G_q/G₁₁ G-proteins to phospholipase C and through other G-proteins to additional signaling systems (4, 5). M₁ regulates several ion channels including KCNQ inwardly rectifying K⁺ currents, voltage-gated calcium channels, and NMDA receptors (4–9). Thus M₁ could mediate much of the cognitive effects of ACh. Supporting this hypothesis xanomeline, an M₁/M₄ preferring agonist, improved cognition and behavior in AD patients but was not tolerated due to unwanted cholinergic effects (10). Additional studies suggest that M₁ activation could slow AD progression by reducing Aβ42 peptides (11). Thus a drug that activates M₁ could potentially improve cognition while over time slowing the progression of the disease. Unfortunately, conservation of the ACh binding site has precluded the discovery of selective agonists.Many GPCRs, including mAChRs (12), have allosteric binding sites bound by small molecules that activate the receptor in the absence of ligand (allosteric agonist) or enhance the response to native ligand (positive allosteric modulator) (13). As allosteric sites are theoretically under less evolutionary constraint, targeting them affords opportunities for selectivity. This concept was demonstrated by the M₁ allosteric agonist TBPB (14) and a collection of relatively selective positive allosteric modulators (15). Here we describe BQCA [1-(4-methoxybenzyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid], an orally available drug-like molecule that regulates memory and brain function by potentiating M₁.     

Selective ablation of retinoid X receptor alpha in hepatocytes impairs their lifespan and regenerative capacity

Retinoid X receptors (RXRs) are involved in a number of signaling pathways as heterodimeric partners of numerous nuclear receptors. Hepatocytes express high levels of the RXRalpha isotype, as well as several of its putative heterodimeric partners. Germ-line disruption (knockout) of RXRalpha has been shown to be lethal in utero, thus precluding analysis of its function at later life stages. Hepatocyte-specific disruption of RXRalpha during liver organogenesis has recently revealed that the presence of hepatocytes is not mandatory for the mouse, at least under normal mouse facility conditions, even though a number of metabolic events are impaired [Wan, Y.-J., et al. (2000) Mol. Cell. Biol. 20, 4436-4444]. However, it is unknown whether RXRalpha plays a role in the control of hepatocyte proliferation and lifespan. Here, we report a detailed analysis of the liver of mice in which RXRalpha was selectively ablated in adult hepatocytes by using the tamoxifen-inducible chimeric Cre recombinase system. Our results show that the lifespan of adult hepatocytes lacking RXRalpha is shorter than that of their wild-type counterparts, whereas proliferative hepatocytes of regenerating liver exhibit an even shorter lifespan. These lifespan shortenings are accompanied by increased polyploidy and multinuclearity. We conclude that RXRalpha plays important cell-autonomous function(s) in the mechanism(s) involved in the lifespan of hepatocytes and liver regeneration.     

Expression of the serotonin 1b receptor in experimental pulmonary hypertension.

The pathogenesis of pulmonary arterial hypertension (PAH) remains uncertain. Both the serotonin and endothelin (ET) systems are believed to be involved. Recent studies pointed to the importance of the serotonin 2B receptor as a limiting step. The current authors investigated the lung tissue expression of serotonin receptors and of the serotonin transporter (5-HTT) by real-time-quantitative polymerase chain reaction in chronic overcirculation-induced PAH in growing piglets, with and without treatment with the dual ET receptor blocker bosentan. Pulmonary haemodynamic changes were described by pulmonary arterial impedance spectra. Three months after the surgical anastomosis of the left subclavian artery to the pulmonary arterial trunk, there was a shift of the impedance spectra to higher ratios of pressure and flow moduli, with increases in both 0 Hz impedance and characteristic impedance, and these changes were completely prevented by bosentan therapy. There was an increase in the expression of the serotonin 1B receptor. There was no change in the expression of the 5-HTT, and of the serotonin 2B, 1D, and 4 receptors. The overexpression of the serotonin 1B receptor was partially prevented by bosentan therapy. The present authors conclude that this early pulmonary arterial hypertension model is characterised by an endothelin receptor-dependent increased expression of the serotonin 1B receptor.     

Selective serotonin reuptake inhibitors in children and adolescents

This article will review the tolerability, side effects, and effectiveness of selective serotonin reuptake inhibitors (SSRIs) in children and adolescents. We aimed to familiarise the readers with the available data on the pharmacological treatment of childhood psychiatric disorders, especially of depressive disorder and obsessive compulsive disorder. Tricyclic antidepressants (TCAs) have questionable efficacy, definite problems with safety (e.g., cardiotoxicity, lethality in overdose, anticholinergic side effects), and compliance issues. Therefore it is suggested suggest that SSRIs should be the first-line treatment for these disorders in children and adolescents. Studies have shown a significant clinical response to SSRIs and their efficiency has been demonstrated in open and controlled trials. It is often recommended that clinicians should start low and go slow when using SSRIs, and maintain the patient in a symptom-free state for at least six months. The side effects of SSRIs are generally mild, manageable, and seldom require discontinuation of treatment. Children should be monitored closely for infrequent side effects such as gastrointestinal upset, headache, and behavioural activation which may be as severe as mania. There is a great need for controlled trials in childhood psychiatric disorders, especially in anxiety disorders.     

Plasma corticosterone binding capacity in the partially decapitated chick embryo

The C₂₁-steroid binding capacity (i.e., CBG or transcortin) was measured in the normal and partially decapitated (i.e., hypophysectomized) chicken embryo. In normal embryos the transcortin levels increased up to Day 15 of incubation and then sharply decreased until Day 20. The total plasma protein concentration increased until Day 17 and then stabilized. The early partial decapitation of embryos prevented (a) the increase of transcortin level from Days 13 to 15, (b) the decrease in transcortin level from Days 15 to 20, and (c) the increase in total plasma protein after Day 13. The hypophysis-dependent changes in transcortin concentrations are discussed in relation to the effects of partial decapitation on the C₂₁-steroid concentration and the late differentiation of target organs.     

Selective serotonin reuptake inhibitor use by patients with acute coronary syndromes

Background

Selective serotonin reuptake inhibitors are commonly used to treat anxiety, depression, and other conditions that commonly affect patients with coronary artery disease. Selective serotonin reuptake inhibitors inhibit platelet activation and may, therefore, affect outcomes in patients with acute coronary syndromes.

Methods

A retrospective study was performed of 1254 patients with acute coronary syndromes comparing in-hospital bleeding and cardiac event rates in 158 patients who received a selective serotonin reuptake inhibitor and a propensity score-matched group of patients who did not. All patients were treated with a glycoprotein IIb/IIIa inhibitor and almost all also received aspirin, clopidogrel, and heparin.

Results

Patients who received a selective serotonin reuptake inhibitor were significantly more likely to experience any bleeding (37.3% vs 26.6%, OR 1.65, 95% confidence interval (CI), 1.02-2.66, P =.04) and significantly less likely to experience recurrent myocardial ischemia, heart failure, or asymptomatic cardiac enzyme elevation while in the hospital (7.0% vs 13.9%, OR 0.46, 95% CI, 0.22-0.99, P =.04). No differences were observed in death, myocardial infarction during the hospitalization, urgent revascularization, or major bleeding. Bleeding and cardiac events were not affected by antidepressants other than selective serotonin reuptake inhibitors.

Conclusions

Selective serotonin reuptake inhibitor use during a hospitalization for an acute coronary syndrome is associated with reduced rates of recurrent ischemia, heart failure, or cardiac enzyme elevation at the expense of increased bleeding in patients receiving maximal conventional antiplatelet medications and heparin. Clinicians should be aware of this association when treating patients with an acute coronary syndrome.     

Selective silencing of angiotensin receptor subtype 1a (AT1aR) by RNA interference

Angiotensin II exerts its physiological effects by activating multiple subtypes of its receptor such as AT1a-, AT1b-, and AT2-receptors. Because of a high degree of similarity among these G-protein-coupled receptors, it has been difficult to assign diverse physiological actions of angiotensin II through these receptor subtypes. We have developed small interfering RNAs to selectively inhibit the expression of the AT1a receptor (AT1aR) subtype. A dsRNA, AT1 47, was found to be highly selective and efficient in reducing the levels of AT1aR subtype. Transfection of AT1aR-expressing CHO cells with dsRNA AT1 47 resulted in an 80% decrease in the AT1aR expression. In contrast, dsRNA AT1 47 showed no significant effects on both AT1bR and AT2R subtypes. Thus, AT1 47 provides us with a powerful tool to selectively silence this subtype of receptor to investigate its role in cardiovascular physiology.     

Selective blockade of serotonin 5-HT2A receptor increases coronary blood flow via augmented cardiac nitric oxide release through 5-HT1B receptor in hypoperfused canine hearts

Serotonin (5-hydroxytryptamine [5-HT]), which induces vasoconstriction via 5-HT2A receptors in smooth muscle cells and vasodilation through activating nitric oxide (NO) synthase (NOS) via 5-HT1B receptors in endothelial cells, possesses divergent effects on regulating vascular tone. These facts lead us to consider that sarpogrelate, a 5-HT2A receptor blocker, may increase coronary blood flow (CBF) via either attenuation of vasoconstriction through 5-HT2A receptor blockade or augmentation of vasodilation by relative stimulation of NOS through 5-HT1B receptor and we tested this hypothesis in ischemic canine hearts. In open chest dogs, coronary perfusion pressure was reduced so that CBF was decreased to 33% of the baseline and kept constant. Thereafter, sarpogrelate was infused selectively into the left anterior descending artery with and without either an inhibitor of NOS (NG-nitro-L-arginine methyl ester (L-NAME)) or a 5-HT1B receptor antagonist (GR55562). An intracoronary administration of sarpogrelate increased CBF (34.0 +/- 4.0 to 44.5 +/- 4.4 ml/100 g/min, P < 0.05), along with the cardiac NOx release (3.2 +/- 0.6 to 6.8 +/- 1.2 nmol/ml, P < 0.05). The increases in both CBF and NOx by sarpogrelate were completely blunted by the co-administration of either L-NAME or GR55562. Interestingly, sarpogrelate increased the cardiac serotonin release (-4.8 +/- 3.2 vs. 22.1 +/- 1.5 ng/ml, P < 0.05, respectively) in the hypoperfused heart. Immunohistochemical analysis showed that sarpogrelate induced serotonin production in ischemic cardiac myocytes. These results suggest that sarpogrelate increases CBF via augmented cardiac NO production through 5-HT1B receptor activation along with the blockade of 5-HT2A receptors. The increase in cardiac release of serotonin may increase NO production in the ischemic heart.     

Selective filtering of excitatory inputs to nucleus accumbens by dopamine and serotonin

The detailed mechanisms by which dopamine (DA) and serotonin (5-HT) act in the nucleus accumbens (NAc) to influence motivated behaviors in distinct ways remain largely unknown. Here, we examined whether DA and 5-HT selectively modulate excitatory synaptic transmission in NAc medium spiny neurons in an input-specific manner. DA reduced excitatory postsynaptic currents (EPSCs) generated by paraventricular thalamus (PVT) inputs but not by ventral hippocampus (vHip), basolateral amygdala (BLA), or medial prefrontal cortex (mPFC) inputs. In contrast, 5-HT reduced EPSCs generated by inputs from all areas except the mPFC. Release of endogenous DA and 5-HT by methamphetamine (METH) and (±)3,4-methylenedioxymethamphetamine (MDMA), respectively, recapitulated these input-specific synaptic effects. Optogenetic inhibition of PVT inputs enhanced cocaine-conditioned place preference, whereas mPFC input inhibition reduced the enhancement of sociability elicited by MDMA. These findings suggest that the distinct, input-specific filtering of excitatory inputs in the NAc by DA and 5-HT contribute to their discrete behavioral effects.

The nucleus accumbens (NAc), a major node of classic mesolimbic reward circuitry, plays a critical role in a variety of adaptive and pathological motivated behaviors by integrating information carried by inputs from a broad range of brain areas with distinct, yet overlapping functions (1–6). Output from the NAc is provided by medium spiny neurons (MSNs), the activity of which strongly depends on excitatory inputs from these brain areas, most prominently the ventral hippocampus (vHip), periventricular thalamus (PVT), basolateral amygdala (BLA), and medial prefrontal cortex (mPFC) (3, 7–11). The NAc is also a behaviorally important target for two of the brain’s major neuromodulatory systems, dopamine (DA) and serotonin (5-HT) (1, 5, 6, 12–14). DA release in the NAc, whether caused by drugs of abuse or optogenetic stimulation, is powerfully reinforcing and plays a critical role in shaping operant responses (1, 4–6, 15–17). In contrast, unlike DA release, release of 5-HT in the NAc, generated either pharmacologically or optogenetically, is not acutely reinforcing but can powerfully influence sociability (18, 19).The robust differences in the behavioral consequences of DA and 5-HT release in the NAc suggest that these neuromodulators must influence MSN activity in, perhaps profoundly, different ways. Yet little is known about the detailed mechanisms by which these neuromodulators accomplish this task. Because of the importance of excitatory input in controlling MSN activity and the fact that both DA and 5-HT are well established to modulate excitatory synaptic transmission in the NAc (18, 20–23), we hypothesized that an important mechanism by which these neuromodulators might distinctly influence MSN activity is by differentially filtering incoming information from major input structures. Specifically, we hypothesized that DA and 5-HT would depress excitatory synaptic transmission in distinct, input-specific manners. Because of methodological limitations prior to the advent of optogenetics, virtually all previous work examining DA and 5-HT modulation of excitatory transmission in the NAc used bulk electrical stimulation of unknown inputs.Consistent with our hypothesis, exogenously applied DA and 5-HT, as well as release of endogenous DA and 5-HT, depressed excitatory synaptic transmission in distinct, input-specific manners. Input-specific optogenetic inhibition of excitatory inputs to the NAc revealed input-specific effects on conditioned place preference and sociability assays, which are affected by NAc release of DA and 5-HT, respectively. Together, these results provide evidence that the input-specific filtering of excitatory input from distinct brain regions contributes to the behavioral effects of DA and 5-HT release in the NAc and provides a foundation for further work elucidating the neural mechanisms by which modulation of NAc activity influences motivated behaviors.     

Mouse 5HT1B serotonin receptor: cloning, functional expression, and localization in motor control centers.

Serotonin is a neuromodulator that mediates a wide range of effects by interacting with multiple receptors. Using a strategy based on nucleotide sequence homology between genes encoding receptors that interact with guanine nucleotide-binding proteins, we have isolated a mouse gene encoding an additional serotonin receptor. When expressed in cultured cells, it displayed the pharmacological profile and coupling with adenylate cyclase characteristic of the 5HT1B receptor subtype. In NIH 3T3 cells expressing this receptor, serotonin induced a decrease in forskolin-stimulated cAMP levels. This effect was blocked by pertussis toxin, indicating that the 5HT1B receptor interacts with a pertussis toxin-sensitive guanine nucleotide-binding protein. To obtain clues as to the possible function of the 5HT1B receptor, we have analyzed its pattern of expression in the adult mouse brain by in situ hybridization. Our results, together with previous autoradiographic studies, suggest that the 5HT1B receptors are localized presynaptically on the terminals of striatal neurons and Purkinje cells and that they might modulate the release of neurotransmitters such as gamma-aminobutyric acid. The predominant expression of the 5HT1B receptor in the striatum and cerebellum points to an involvement of this receptor in motor control.