Selective blockade of serotonin2C receptor enhances Fos expression specifically in the striatum and the subthalamic nucleus within the basal ganglia

Serotonin_2C (5-HT_2C) receptors are widely expressed in the basal ganglia, a group of brain regions involved in the control of motor behavior. However, it remains unclear whether their tonic influence on neuronal activity is distributed in these regions. We have addressed this question by measuring the product of the proto-oncogene c-Fos in rats after peripheral administration of the non-selective 5-HT antagonist mianserin, the 5-HT_2C/2B antagonist SER-082 or the selective 5-HT_2C antagonist SB 243213. The intraperitoneal administration of 1 mg/kg of SB 243213 or SER-082, but not mianserin, enhanced Fos-immunoreactive cells in the subthalamic nucleus and the striatum, primarily its medial portion. None of these treatments significantly affected Fos expression in the external globus pallidus, the entopeduncular nucleus (the internal globus pallidus in primate) or the substantia nigra pars reticulata. The data suggest that selective blockade of 5-HT_2C receptors is necessary to unmask a tonic regulation of neuronal activity by this receptor in the basal ganglia and that this effect is restricted to the two structures receiving cortical entries, the striatum and the subthalamic nucleus.     

Role of 5-HT2C receptors in the enhancement of c-Fos expression induced by a 5-HT2B/2C inverse agonist and 5-HT2 agonists in the rat basal ganglia

Some non-selective serotonin2C (5-HT_2C) agonists or inverse agonists enhance the product of the proto-oncogene c-Fos within the basal ganglia, a group of brain regions involved in motor behavior and in the ability of these drugs to promote abnormal movements. The role of 5-HT_2C receptors in these effects is unclear. The 5-HT_2C antagonist SB243,213 (1 mg/kg), which enhanced Fos per se in the striatum and the subthalamic nucleus (STN) only, was used to study the implication of 5-HT_2C receptors. The agonists Ro 60-0175 (3 mg/kg) and m-CPP (1 mg/kg) and the inverse agonist SB206,553 (10 mg/kg) enhanced Fos expression in the STN and faintly in the entopeduncular nucleus (EPN, the internal globus pallidus in primate). The effects of these drugs differed mainly in the striatum regarding the magnitude (m-CPP > Ro 60-0175> SB243,213 > SB206,553) or the striatal quadrants (faint to no labeling in lateral striatum) and in the substantia nigra. None of these compounds enhanced Fos expression by themselves in the globus pallidus or in the EPN when combined with SB243,213. Their Fos effect in the STN was reduced significantly by SB243,213 only in the case of m-CPP. In the ventromedial striatum, SB243,213 reduced the effects of m-CPP while SB206,553 reduced the effects of SB243,213. The results show that opposite pharmacological agents alter similarly Fos expression in the EPN or the STN. Although some of the effects of 5-HT agents are related to targets other than 5-HT_2C receptors, the study confirms the existence of multiple 5-HT_2C receptor-dependent controls recruited by these drugs upon basal ganglia activity.     

Stimulation of serotonin2C receptors elicits abnormal oral movements by acting on pathways other than the sensorimotor one in the rat basal ganglia

Serotonin2C (5-HT_2C) receptors act in the basal ganglia, a group of sub-cortical structures involved in motor behavior, where they are thought to modulate oral activity and participate in iatrogenic motor side-effects in Parkinson's disease and Schizophrenia. Whether abnormal movements initiated by 5-HT_2C receptors are directly consequent to dysfunctions of the motor circuit is uncertain. In the present study, we combined behavioral, immunohistochemical and extracellular single-cell recordings approaches in rats to investigate the effect of the 5-HT_2C agonist Ro-60-0175 respectively on orofacial dyskinesia, the expression of the marker of neuronal activity c-Fos in basal ganglia and the electrophysiological activity of substantia nigra pars reticulata (SNr) neuron connected to the orofacial motor cortex (OfMC) or the medial prefrontal cortex (mPFC). The results show that Ro-60-0175 (1 mg/kg) caused bouts of orofacial movements that were suppressed by the 5-HT_2C antagonist SB-243213 (1 mg/kg). Ro-60-0175 (0.3, 1, 3 mg/kg) dose-dependently enhanced Fos expression in the striatum and the nucleus accumbens. At the highest dose, it enhanced Fos expression in the subthalamic nucleus, the SNr and the entopeduncular nucleus but not in the external globus pallidus. However, the effect of Ro-60-0175 was mainly associated with associative/limbic regions of basal ganglia whereas subregions of basal ganglia corresponding to sensorimotor territories were devoid of Fos labeling. Ro-60-0175 (1–3 mg/kg) did not affect the electrophysiological activity of SNr neurons connected to the OfMC nor their excitatory-inhibitory-excitatory responses to the OfMC electrical stimulation. Conversely, Ro-60-0175 (1 mg/kg) enhanced the late excitatory response of SNr neurons evoked by the mPFC electrical stimulation. These results suggest that oral dyskinesia induced by 5-HT_2C agonists are not restricted to aberrant signalling in the orofacial motor circuit and demonstrate discrete modifications in associative territories.     

Subtype specific roles of serotonin receptors in the spine formation of cortical neurons in vitro

Dendritic spines are postsynaptic structures which are formed from filopodia. We examined roles of serotonin (5-HT) receptors in the spine formation. Embryonic rat cortical neurons were cultured for 10 or 14 days and treated by 5-HT receptor agonists for 24 h. At 11 days in vitro, 5-HT_1A agonist increased filopodia density, whereas 5-HT_2A/2C agonist increased the density of puncta and spines. At 15 days in vitro, 5-HT_1A agonist decreased the density of puncta and spines, whereas 5-HT_2A/2C agonist decreased filopodia density with increase of spines. In conclusion, the present study shows 5-HT receptors have subtype-specific effects on the spine formation.     

Elevated 5-HT 2A receptors in postmortem prefrontal cortex in major depression is associated with reduced activity of protein kinase A

Previous human postmortem brain tissue research has implicated abnormalities of 5-HT receptor availability in depression and suicide. Although altered abundance of 5-HT 1A, 5-HT 2A, and 5-HT 2C receptors (5-HT_1A, 5-HT_2A, and 5-HT_2C) has been reported, the causes remain obscure. This study evaluated the availability of these three receptor subtypes in postmortem brain tissue specimens from persons with a history of major depression (MDD) and normal controls and tested the relationships to protein kinases A and C (PKA, PKC). Samples were obtained from postmortem brain tissue (Brodmann area 10) from 20 persons with a history of MDD and 20 matched controls as determined by a retrospective diagnostic evaluation obtained from family members. Levels of 5-HT_1A, 5-HT_2A, and 5-HT_2C receptor were quantitated via Western blot analyses. Basal and stimulated PKA and PKC activity were also determined. The depressed samples showed significantly increased 5-HT_2A receptor abundance relative to controls, but no differences in 5-HT_1A or 5-HT_2C receptors. Basal and cyclic AMP-stimulated PKA activity was also reduced in the depressed sample; PKC activity was not different between groups. 5-HT_2A receptor availability was significantly inversely correlated with PKC activity in controls, but with PKA activity in the depressed sample. Increased 5-HT_2A receptor abundance and decreased PKA activity in the depressed sample are consistent with prior reports. The correlation of 5-HT_2A receptor levels with PKA activity in the depressed group suggests that abnormalities of 5-HT_2A receptor abundance may depend on receptor uncoupling and heterologous regulation by PKA.     

Regional brain serotonin receptor changes in portacaval shunted rats

The pathogenesis of hepatic encephalopathy is unknown, but metabolic perturbations, including hyperammonaemia and increased brain turnover of serotonin (5-HT), have been identified. Possible alterations of 5-HT receptors in the brain have been rudimentarily studied. We therefore investigated the 5-HT_{1 A}, 5-HT_{1 B} and 5-HT_{2 A} receptor density in 18–22 different regions in the brain of portacaval shunted rats by means of radioligand binding with autoradiographical evaluation. The results revealed a decreased 5-HT_{1 A} receptor binding in seven serotonergic projection areas of the brain, and an increase in the nucleus accumbens, hypothalamus and subiculum. No changes in the raphe nuclei were observed. An increased 5-HT_{1 B} receptor binding was seen in five brain regions: basal ganglia, olfactorial regions, hippocampus, mid brain and thalamus. However, decreased binding was seen in three regions of cortical areas and hippocampus. The 5-HT_{2 A} receptor binding site density was essentially unaltered. These findings suggest that perturbations in the central serotonergic neurotransmission may play a functional role in chronic hepatic encephalopathy.     

Polymorphism of Serotonin 5-HT Receptors as the Basis of the Multifunctionality of Serotonin

This review addresses a question at the junction of neurophysiology and neurogenetics – the multiplicity of types and subtypes of serotonin (5-HT) receptors and their roles in the physiological effects of the brain neurotransmitter serotonin. Particular attention is paid to comparison of the behavioral effects of related subtypes of 5-HT receptors – 5-HT₁ (5-HT_1A and 5-HT_1B) and 5-HT₂ (5-HT_2A and 5-HT_2C) receptors – which are involved in the mechanisms regulating behavior and psychopathology. Published data are presented, along with results obtained at the Laboratory for Behavioral Neurogenics, providing evidence that different types of 5-HT receptors can act in different directions as well as similarly, supplementing each other, in the control of physiological functions and behavior. The roles of 5-HT_1A and 5-HT_1B receptors in regulating aggressive behavior, sexual arousal, drinking behavior, and food consumption are discussed. Experimental results demonstrating reciprocal relationships between 5-HT_2A and 5-HT_2C receptors and interactions between 5-HT_1A and 5-HT₃ receptors are presented. These data provide evidence of a complex system for these interactions not only at the receptor level, but also with the involvement of genes controlling the main elements of the serotonin system. Interaction of receptors evidently underlies neuroplasticity and plays a significant role in compensatory processes and in adaptive mechanisms.     

Cardiovascular and respiratory reflexes of the gulf toadfish (Opsanus beta) during acute hypoxia

The acute cardiovascular and respiratory responses of the gulf toadfish, Opsanus beta, to acute hypoxia or exposure to the O₂ chemoreceptor stimulant, sodium cyanide (NaCN) were characterized and the role of serotonin type 2 (5-HT₂) receptors in mediating these responses was investigated. Toadfish responded to hypoxia or NaCN exposure with a decrease in heart rate (fH) and an increase in breathing amplitude (V_AMP) but no change in breathing frequency (fR). The bradycardia appeared to be mediated to some extent by 5-HT₂ receptors, as methysergide, a non-selective 5-HT_1/2 receptor antagonist, and ketanserin, a 5-HT₂ receptor antagonist, attenuated the response. Injection of α-methyl-5-HT, a 5-HT₂ agonist, also resulted in bradycardia that was inhibited by ketanserin, lending further support for 5-HT₂ receptor involvement, possibly 5-HT_2A or 5-HT_2C, in the regulation of fH. External NaCN exposure resulted in a significant decrease in caudal arterial blood pressure (P_CA) that was attenuated by methysergide. In contrast, injection with α-methyl-5-HT resulted in a substantial increase in P_CA that was not affected by ketanserin, suggesting the possible involvement of 5-HT_2B or 5-HT_2C receptors. These data are the first to suggest a unique distribution of 5-HT_2B/2C receptors may be involved in mediating vasoconstriction of the systemic vasculature of toadfish. These data also provide mechanistic support for why pulsatile urea excretion, believed to be regulated by 5-HT via the toadfish 5-HT_2A receptor, is not triggered by hypoxia or external chemoreceptor activation.     

Differential roles of hypothalamic serotonin receptor subtypes in the regulation of prolactin secretion in the turkey hen

In the turkey, exogenous serotonin (5-hydroxytryptamine, 5-HT) increases prolactin (PRL) secretion by acting through the dopaminergic (DAergic) system. In the present study, infusion of the 5-HT_2C receptor agonist, (R)(−)-DOI hydrochloride (DOI), into the third ventricle stimulates PRL secretion, whereas the 5-HT_1A receptor agonist, (+/−)-8-OH-DPAT hydrobromide (DPAT), inhibits PRL secretion. Using the immediate-early gene, c-fos, as an indicator of neuronal activity, in situ hybridization histochemistry showed preferential c-fos co-localization within tyrosine hydroxylase immunoreactive neurons (the rate limiting enzyme in DA synthesis) in the areas of the nucleus preopticus medialis (POM) and the nucleus premammillaris (PMM), in response to DPAT and DOI, respectively. To clarify the involvement of 5-HT_1A and 5-HT_2C receptors in PRL regulation, their mRNA expression was determined on hypothalamic tissue sections from birds in different reproductive stages. A significant difference in 5-HT_1A receptor was observed, with the POM of hypoprolactinemic short day and photorefractory birds showing the highest expression. 5-HT_2C receptors mRNA did not change during the reproductive cycle. The data presented support the notion that DA neurons in the PMM and POM mediate the stimulatory and inhibitory effects of 5-HT, respectively, on PRL secretion and the 5-HTergic system can both stimulate and inhibit PRL secretion.     

Effect of chronic activation of 5-HT3 receptors on 5-HT3, 5-HT1A and 5-HT2A receptors functional activity and expression of key genes of the brain serotonin system

Among serotonin (5-HT) receptors, the 5-HT₃ receptor is the only ligand-gated ion-channel. Little is known about the interaction between the 5-HT₃ receptor and other 5-HT receptors and influence of 5-HT₃ chronic activation on other 5-HT receptors and the expression of key genes of 5-HT system. Chronic activation of 5-HT₃ receptor with intracerebroventricularly administrated selective agonist 1-(3-chlorophenyl)biguanide hydrochloride (m-CPBG) (14 days, 40 nmol, i.c.v.) produced significant desensitization of 5-HT₃ and 5-HT_1A receptors. The hypothermic responses produced by acute administration of selective agonist of 5-HT₃ receptor (m-CPBG, 40 nmol, i.c.v.) or selective agonist of 5-HT_1A receptor (8-hydroxy-2-(di-n-propylamino)tetralin) (8-OH-DPAT, 1 mg/kg, i.p.) was significantly lower in m-CPBG treated mice compared with the mice of control groups. Chronic m-CPBG administration failed to induce any significant change in the 5-HT_2A receptor functional activity and in the expression of the gene encoding 5-HT_2A receptor. Chronic activation of 5-HT₃ receptor produced no considerable effect on the expression on 5-HT₃, 5-HT_1A, and 5-HT transporter (5-HTT) and tryptophan hydroxylase-2 (TPH-2) genes – the key genes of brain 5-HT system, in the midbrain, frontal cortex and hippocampus. In conclusion, chronic activation of ionotropic 5-HT₃ receptor produced significant desensitization of 5-HT₃ and postsynaptic 5-HT_1A receptors but caused no considerable changes in the expression of key genes of the brain 5-HT system.     

Serotonin regulates osteoblast proliferation and function in vitro

The monoamine serotonin (5-hydroxytryptamine, 5-HT), a well-known neurotransmitter, also has important functions outside the central nervous system. The objective of this study was to investigate the role of 5-HT in the proliferation, differentiation, and function of osteoblasts in vitro. We treated rat primary calvarial osteoblasts with various concentrations of 5-HT (1 nM to 10 µM) and assessed the rate of osteoblast proliferation, expression levels of osteoblast-specific proteins and genes, and the ability to form mineralized nodules. Next, we detected which 5-HT receptor subtypes were expressed in rat osteoblasts at different stages of osteoblast differentiation. We found that 5-HT could inhibit osteoblast proliferation, differentiation, and mineralization at low concentrations, but this inhibitory effect was mitigated at relatively high concentrations. Six of the 5-HT receptor subtypes (5-HT_1A, 5-HT_1B, 5-HT_1D, 5-HT_2A, 5-HT_2B, and 5-HT_2C) were found to exist in rat osteoblasts. Of these, 5-HT_2A and 5-HT_1B receptors had the highest expression levels, at both early and late stages of differentiation. Our results indicated that 5-HT can regulate osteoblast proliferation and function in vitro.     

Anticataleptic effects of 5-HT1B 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.     

5-HT1B receptor regulation of serotonin (5-HT) release by endogenous 5-HT in the substantia nigra

Axonal release of serotonin (5-hydroxytryptamine, 5-HT) in the CNS is typically regulated by presynaptic 5-HT autoreceptors. Release of 5-HT in substantia nigra pars reticulata (SNr), a principal output from the basal ganglia, has seemed an interesting exception to this rule. The SNr receives one of the highest densities of 5-HT innervation in mammalian brain and yet negative feedback regulation of axonal 5-HT release by endogenous 5-HT has not been identified here. We explored whether we could identify autoregulation of 5-HT release by 5-HT_1B receptors in rat SNr slices using fast-scan cyclic voltammetry at carbon-fiber microelectrodes to detect 5-HT release evoked by discrete stimuli (50 Hz, 20 pulses) paired over short intervals (1–10 s) within which any autoreceptor control should occur. Evoked 5-HT release exhibited short-term depression after an initial stimulus that recovered by 10 s. Antagonists for 5-HT_1B receptors, isamoltane (1 μM) or SB 224-289 (1 μM), did not modify release during a stimulus train, but rather, they modestly relieved depression of subsequent release evoked after a short delay (≤2 s). Release was not modified by antagonists for GABA (picrotoxin, 100 μM, saclofen, 50 μM) or histamine-H₃ (thioperamide, 10 μM) receptors. These data indicate that 5-HT release can activate a 5-HT_1B-receptor autoinhibition of subsequent release, which is mediated directly via 5-HT axons and not via GABAergic or histaminergic inputs. These data reveal that 5-HT release in SNr is not devoid of autoreceptor regulation by endogenous 5-HT, but rather is under modest control which only weakly limits 5-HT signaling.     

5-HT receptor knockouts: Constitutive,inducible or tissue-specific

Recently, molecular cloning has confirmed and extended our knowledge of the heterogeneity of 5-HT receptors. Besides creating some confusion, molecular techniques have provided new tools to study the function of 5-HT receptors. Recent results gained from targeted disruption of the genes encoding the 5-HT_1B and 5-HT_2C receptors have provided confirmation of pharmacological studies as well as unexpected effects. Such ‘constitutive knockouts’ might undergo compensatory changes during their development that could confound the interpretation of the mutant phenotype. New strategies are currently being developed that may enable receptor expression to be turned on and off at will in specific tissues.     

The serotonergic system in motor and non-motor manifestations of Parkinson’s disease

The understanding of Parkinson’s disease (PD) classically revolves around dopamine depletion within the striatum. However, PD is a multi-systemic disease in which extra-dopaminergic systems are affected. The serotonergic (5-HT) system is one of these and has been extensively studied in PD. Although the 5-HT system uses one transporter (SERT) and 14 receptor sub-types, most of the studies in PD have focussed on SERT and serotonergic type 1A and 2A receptors (5-HT_1A and 5-HT_2A). Post-mortem autoradiographic binding studies and in vivo imaging studies have suggested an involvement of the 5-HT system in PD-related anxiety, depression, psychosis and L-3,4-dihydroxyphenylalanine (L-DOPA)-induced dyskinesia. Pre-clinical and clinical pharmacological studies have shown that SERT blockade might effectively alleviate depression and dyskinesia and, more recently, might exert disease-modifying effects. Enhancing the physiological activity of 5-HT_1A receptors with 5-HT_1A agonists might alleviate anxiety, dyskinesia and tremor, although a deleterious effect on the anti-parkinsonian efficacy of L-DOPA may ultimately limit the use of this class of compounds. Enhanced 5-HT_2A-mediated neurotransmission has been associated with depression, dyskinesia, psychosis and tremor. The current article critically reviews studies assessing the SERT, as well as 5-HT_1A and 5-HT_2A receptors in idiopathic PD and animal models of PD, and discusses unmet challenges to effectively treat manifestations of PD using SERT antagonists, 5-HT_1A agonists and 5-HT_2A antagonists.     

Receptor-genes cross-talk: effect of chronic 5-HT1A agonist 8-hydroxy-2-(di-n-propylamino) tetralin treatment on the expression of key genes in brain serotonin system and on behavior

Dysfunction in brain serotonin (5-HT) system has been implicated in the psychopathology of anxiety, depression, drug addiction, and schizophrenia. The 5-HT_1A receptors play a central role in the control of 5-HTergic neurotransmission. There are some scarce data showing cross-regulation between 5-HT receptors. Here, we investigated whether interaction exists between 5-HT_1A receptor and genes encoding key members in brain 5-HT system. Chronic treatment with selective agonist of 5-HT_1A receptor 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) (1.0 mg/kg i.p., 14 days) produced considerable decrease in hypothermic response to acute administration of 8-OH-DPAT in CBA/Lac mice indicating desensitization of 5-HT_1A receptors. The decrease in 5-HT_1A gene expression as well as decrease in the expression of gene encoding key enzyme in 5-HT synthesis, tryptophan hydroxylase-2 (TPH-2) in the midbrain, and the expression of the gene encoding 5-HT_2A receptor in the frontal cortex was shown. There were no significant changes in 5-HT transporter mRNA level in the midbrain. Despite considerable decrease in the expression of the genes encoding tryptophan hydroxylase-2, 5-HT_1A and 5-HT_2A receptors, chronic 8-OH-DPAT treatment failed to produce significant changes in 5-HT_1A-linked behavior (intermale aggression, open-field behavior, light-dark box, and pinch-induced catalepsy), suggesting compensatory and adaptive effect of genes suppression. The obtained data on the effect of 8-OH-DPAT-induced desensitization of 5-HT_1A receptors on 5-HT_1A, 5-HT_2A and TPH-2 gene expression demonstrated the role of 5-HT_1A receptor as indirect regulator of gene expression. The results provide the first evidence of receptor-key genes interaction in brain 5-HT system and may have profound implications in understanding the functioning of the brain neurotransmitter systems.     

Regulation of gene expression in cultured embryonic mouse mandibular mesenchyme by serotonin antagonists

 During murine embryogenesis, uptake sites for the neurotransmitter serotonin (5-HT) are transiently expressed in craniofacial epithelial structures. Based on malformations produced in cultured mouse embryos exposed to uptake inhibitors or receptor ligands, we have proposed that 5-HT acts as a dose-dependent morphogenetic signal during critical periods of craniofacial development. Several 5-HT receptor subtypes are co-distributed with tenascin and the calcium binding protein S-100β in developing craniofacial mesenchyme. Since these molecules are thought to be important for craniofacial development, their regulation by 5-HT could mediate some of its morphogenetic actions. Mandibular mesenchyme cells, from E12 mouse embryos (plug day=E1), grown in micromass cultures were used as an in vitro model to investigate whether 5-HT regulates expression of these molecules. Immunocytochemistry revealed expression of S-100β, tenascin, cartilage proteoglycan core protein (a component of the cartilage matrix) and a variety of 5-HT receptors in these cultures. To block the actions of 5-HT (from serum in the culture medium), cultures were exposed to one of these selective 5-HT receptor antagonists and effects on expression were investigated using quantitative immunobinding and in situ hybridization assays. These antagonists differentially regulated expression of cartilage core protein, S-100β and tenascin. Antagonism of 5-HT₃ receptors by Zofran or 5-HT_1A receptors by NAN-190 reduced the amount of core protein, whereas antagonism of 5-HT_2A-C receptors by mianserin had no significant effect. All three antagonists stimulated levels of tenascin mRNA and protein. Expression of S-100β mRNA and protein was inhibited by Zofran and stimulated by mianserin, whereas NAN-190 had no significant effect. The differential effects of antagonists suggest that in vivo, 5-HT could: (1) promote expression of cartilage core protein by activation of 5-HT₃ or 5-HT_1A receptors, (2) inhibit production of tenascin by activation of multiple receptors, (3) promote or inhibit synthesis of S-100β by activation of 5-HT₃ or 5-HT₂ receptors, respectively. These actions may be important components of the morphogenetic functions of 5-HT during craniofacial development. Accepted: 12 June 1996     

Serotonin2C receptors and drug addiction: focus on cocaine

This review provides an overview of the role of central serotonin_2C (5-HT_2C) receptors in drug addiction, specifically focusing on their impact on the neurochemical and behavioral effects of cocaine, one of the most worldwide abused drug. First, we described the neurochemical and electrophysiological mechanisms underlying the interaction between 5-HT_2C receptors and the mesocorticolimbic dopaminergic network, in keeping with the key role of this system in drug abuse and dependence. Thereafter, we focused on the role of 5-HT_2C receptors in the effects of cocaine in various preclinical behavioral models used in drug addiction research, such as locomotor hyperactivity, locomotor sensitization, drug discrimination, and self-administration, to end with an overview of the neurochemical mechanisms underlying the interactions between 5-HT_2C receptors, mesocorticolimbic dopamine system, and cocaine. On their whole, the presented data provide compelling preclinical evidence that 5-HT_2C receptor agonists may have efficacy in the treatment of cocaine abuse and dependence, thereby underlying the need for additional clinical studies to ascertain whether preclinical data translate to the human.     

5-HT2 receptors-mediated modulation of voltage-gated K+ channels and neurophysiopathological correlates

The activity of voltage-gated K⁺ channels (Kv) can be dynamically modulated by several events, including neurotransmitter stimulated biochemical cascades mediated by G protein-coupled receptors such as 5-HT₂ receptors (5-HT₂Rs). Activation of 5-HT_2A/CR inhibits the Shaker-like K⁺ channels Kv1.1 and Kv1.2, and this modulation involves the dual coordination of both RPTPα and distinct tyrosine kinases coupled to this receptor; 5-HT₂Rs–mediated modulation of Kv channels controls glutamate release onto prefrontal cortex neurons that might play critical roles in neurophysiological, neurological, and psychiatric conditions. Noticeably, hallucinogens modulate Kv channel activity, acting at 5-HT₂R. Hence, comprehensive knowledge of 5-HT₂R signaling through modulation of distinct K⁺ channels is a pivotal step in the direction that will enable scientists to discover novel 5-HT functions and dysfunctions in the brain and to identify original therapeutic targets.