5-HT1A Receptor Subtype Research Articles

Pretreatment with either a 5‐HT2C agonist or 5‐HT2A antagonist decreases cocaine self‐administration (848.9)

Cocaine’s abuse related effects have been attributed to its interaction with dopamine systems. However, ligands that target the serotonin 5‐HT2C and 5‐HT2A receptor subtypes have been reported to modulate dopaminergic activity and several of the abuse related effects of cocaine. This suggests that ligands selective for specific serotonin receptor subtypes may be effective anti‐cocaine medications. The present study investigated whether pretreatment with a 5‐HT2C agonist (Lorcaserin) or a 5‐HT2A antagonist (M‐100907) could alter cocaine's reinforcing effects in rhesus monkeys. Two groups of male rhesus monkeys (n=4/group) were trained under a fixed ratio 30 (FR30) schedule to respond for food (1 g banana flavored pellets) and cocaine (0.01 mg/kg/inj). Baseline cocaine (0.003‐0.1 mg/kg/inj) self‐administration followed an inverted‐U shaped function with maximal rate of responding at 0.01 mg/kg/inj. Pretreatment with Lorcaserin (0.56 or 1.0 mg/kg, IM) or M‐100907 (0.32 or 1.0 mg/kg, IM) reduced rate of responding for doses of cocaine at the peak and on the descending limb of the function. Food‐maintained responding was only modestly decreased after pretreatment with either serotonergic compound. These findings suggest that 5‐HT2C agonism and/or 5‐HT2A antagonism may be novel approaches to the treatment of cocaine addiction. Supported by NIDA DA002519 and DA88876.Grant Funding Source: Supported by NIDA DA002519 and DA88876.

Depressed GABA and glutamate synaptic signaling by 5-HT1A receptors in the nucleus tractus solitarii and their role in cardiorespiratory function.

Serotonin (5-HT), and its 5-HT1A receptor (5-HT1AR) subtype, is a powerful modulator of the cardiorespiratory system and its sensory reflexes. The nucleus tractus solitarii (nTS) serves as the first central station for visceral afferent integration and is critical for cardiorespiratory reflex responses. However, the physiological and synaptic role of 5-HT1ARs in the nTS is relatively unknown. In the present study, we examined the distribution and modulation of 5-HT1ARs on cardiorespiratory and synaptic parameters in the nTS. 5-HT1ARs were widely distributed to cell bodies within the nTS but not synaptic terminals. In anesthetized rats, activation of 5-HT1ARs by microinjection of the 5-HT1AR agonist 8-OH-DPAT into the caudal nTS decreased minute phrenic neural activity via a reduction in phrenic amplitude. In brain stem slices, 8-OH-DPAT decreased the amplitude of glutamatergic tractus solitarii-evoked excitatory postsynaptic currents, and reduced overall spontaneous excitatory nTS network activity. These effects persisted in the presence of GABAA receptor blockade and were antagonized by coapplication of 5-HT1AR blocker WAY-100135. 5-HT1AR blockade alone had no effect on tractus solitarii-evoked excitatory postsynaptic currents, but increased excitatory network activity. On the other hand, GABAergic nTS-evoked inhibitory postsynaptic currents did not change by activation of the 5-HT1ARs, but spontaneous inhibitory nTS network activity decreased. Blocking 5-HT1ARs tended to increase nTS-evoked inhibitory postsynaptic currents and inhibitory network activity. Taken together, 5-HT1ARs in the caudal nTS decrease breathing, likely via attenuation of afferent transmission, as well as overall nTS network activity.

Crowding stress inhibits serotonin 1A receptor-mediated increases in corticotropin-releasing factor mRNA expression and adrenocorticotropin hormone secretion in the Gulf toadfish

Stimulation of the serotonin 1A (5-HT1A) receptor subtype by 5-HT has been shown to result in an elevation in plasma corticosteroid levels in both mammals and several species of teleost fish, including the Gulf toadfish (Opsanus beta); however, in the case of teleost fish, it is not clearly known at which level of the hypothalamic-pituitary-interrenal axis the 5-HT1A receptor is stimulated. Additionally, previous investigations have revealed that chronic elevations of plasma cortisol mediate changes in brain 5-HT1Areceptor mRNA and protein levels via the glucocorticoid receptor (GR); thus, we hypothesized that the function of centrally activated 5-HT1A receptors is reduced or abolished as a result of chronically elevated plasma cortisol levels and that this response is GR mediated. Our results are the first to demonstrate that intravenous injection of the 5-HT1A receptor agonist, 8-OH-DPAT, stimulates a significant increase in corticotropin-releasing factor (CRF) precursor mRNA expression in the hypothalamic region and the release of adrenocorticotropic hormone (ACTH) from the pituitary of teleost fish compared to saline-injected controls. We also provide evidence that cortisol, acting via GRs, attenuates the 5-HT1A receptor-mediated secretion of both CRF and ACTH.

Altered expression of 5-HT1A receptors in adult rats induced by neonatal treatment with clomipramine

Chronic administration of clomipramine (CMI) to neonatal rats produces behaviors that resemble a depressive state in adulthood. Dysfunctions in the activity of the central nervous system's serotonergic function are important in understanding the pathophysiology of depression. The serotonin system is implicated in major depression and suicide and is negatively regulated by somatodendritic 5-HT1A autoreceptors. Desensitization of 5-HT1A autoreceptors is implicated in the long latency of some antidepressant treatments. Alterations in 5-HT1A receptor levels are reported in depression and suicide. In this study, we analyzed the effect of neonatal administration of CMI on the activity of 5-HT1A receptors, both pre- and post-synaptically, by administering an agonist of 5-HT1A receptors, 8-OH-DPAT, and then subjecting the rats to the forced swimming test (FST) a common procedure used to detect signs of depression in rats. Also measured were levels of the mRNA expression of 5-HT1A receptors in the dorsal raphe (DR), the hypothalamus and the hippocampus. Wistar rats were injected twice daily with CMI at doses of 15mgkg−1 or saline as vehicle (CON) via s.c. from postnatal day 8 for 14days. At 3–4months of age, one set of rats from each group (CON, CMI) was evaluated for the effect of a selective agonist to the 5-HT1A receptor subtype, 8-OH-DPAT, by testing in the FST. Also determined was the participation of the pre- or post-synaptic 5-HT1A receptor in the antidepressant-like action of 8-OH-DPAT. This involved administering an inhibitor of tryptophan hydroxylase, parachlorophenylalanine (PCPA), and pretreatment with 8-OH-DPAT before the FST test and to evaluate the rectal temperature and locomotor activity. The expression of the mRNA of the 5-HT1A receptors was examined in the dorsal raphe nucleus, the hypothalamus and the hippocampus using the semi-quantitative RT-PCR method. The results from this study corroborate that neonatal treatment with clomipramine induces a pronounced immobility in the FST when animals reach adulthood, manifested by a significant decrease in swimming behavior, though counts of climbing behavior were not modified. This effect was similar in magnitude when 8-OH-DPAT was administered to CON group. Furthermore, the administration of 8-OH-DPAT induces a significant and similar increase in rectal temperature and locomotor activity in both the CON as in the CMI group. Neonatal treatment with CMI resulted in a significant decrease in the expression of the mRNA of the 5-HT1A receptors in the DR (% more than vehicle) in adulthood. In the case of the postsynaptic receptors located in the hypothalamus and hippocampus, neonatal treatment with CMI induced a significant increase in the mRNA expression of the 5-HT1A receptors. These data suggest that neonatal treatment with CMI induces a downregulation of the mRNA of the 5-HT1A autoreceptors in the DR, and an increment in the expression of the postsynaptic 5-HT1A receptors. The results after the administration of PCPA and 8-OH-DPAT on FST, rectal temperature and locomotor activity for both groups suggest that the function of postsynaptic receptors remains unchanged. All together these data show that the depressive behavior observed in adulthood in this animal model may be associated with long-term alterations in the expression of the mRNA of the 5-HT1A receptors.

P.2.d.020 The effectiveness of asenapine in clinical practice: the EXPASEN study

The reverse transcriptase polymerase chain reaction (RT-PCR) technique was used to examine the changes of the expression of 5-hydroxytryptamine (5-HT) receptors in the rat lumbar dorsal root ganglion (DRG) following subcutaneous bee venom (BV) injection into the plantar surface of the unilateral hindpaw. In the DRG ipsilateral to the BV injection, significant increase of mRNA levels of 5-HT1A, 5-HT1B, 5-HT2A and 5-HT3 receptor subtypes were observed at 1 and 4 h after the BV injection, while increase of 5-HT2C, 5-HT4, 5-HT6 and 5-HT7 receptor subtype mRNAs was detected at 4 h only. No such changes were observed in the expressions of 5-HT1D, 5-HT1F and 5-HT5A receptor subtype mRNAs. Upregulation of 5-HT1A, 5-HT1B and 5-HT2A receptor subtype mRNAs was also observed in the contralateral DRG at 4 h. The presence of 5-HT1E, 5-HT2B and 5-HT5B receptor subtype mRNAs was not detected in the rat DRG. The present results suggest that different sets of 5-HT receptor subtypes work at different stages of the inflammatory pain induced by subcutaneous BV injection.

Serotonin Modulates Outward Potassium Currents in Mouse Olfactory Receptor Neurons

Monoaminergic neurotransmitter 5-hydroxytryptamine (5-HT), also known as serotonin, plays important roles in modulating the function of the olfactory system. However, thus far, the knowledge about 5-HT and its receptors in olfactory receptor neurons (ORNs) and their physiological role have not been fully characterized. In the present study, reverse transcription-polymerase chain reaction (RT-PCR) analysis revealed the presence of 5-HT(1A) and 5-HT(1B) receptor subtypes in mouse olfactory epithelium at the mRNA level. With subtype selective antibodies and standard immunohistochemical techniques, both receptor subtypes were found to be positively labeled. To further elucidate the molecular mechanisms of 5-HT act on the peripheral olfactory transduction, the whole-cell patch clamp techniques were used on freshly isolated ORNs. We found that 5-HT decreased the magnitude of outward K(+) current in a dose-dependent manner and these inhibitory effects were markedly attenuated by the 5-HT(1A) receptor blocker WAY-100635 and the 5-HT(1B) receptor antagonist GR55562. These data suggested that 5-HT may play a role in the modulation of peripheral olfactory signals by regulating outward potassium currents, both 5-HT(1A) and 5-HT(1B) receptors were involved in this regulation.

Aggression-reducing effects of F15599, a novel selective 5-HT1A receptor agonist, after microinjection into the ventral orbital prefrontal cortex, but not in infralimbic cortex in male mice

The 5-HT1A receptor subtype has been postulated to modulate aggressive behavior particularly when it is excessive. F15599 is a high affinity and selective 5-HT1A receptor agonist that exhibits biased agonism for postsynaptic receptors that are preferentially coupled to Gαi3 protein subunits, with more potent action in the cortex, and with potential for selectively reducing aggression. The aims of the current study were to investigate the anti-aggressive effects of the novel 5-HT1A receptor agonist, F15599, microinjected into the ventral orbital prefrontal cortex (VO PFC) and into the infralimbic cortex (ILC) of CF-1 male mice that had been previously socially provoked and to confirm the specific action at this receptor by blocking its effects using the 5-HT1A receptor antagonist, WAY100,635. Microinjection of the lower doses of F15599 (0.03 and 0.1μg) into the VO PFC, but not into the ILC, significantly reduced the frequency of attack bites and sideways threats, without affecting other elements of the behavioral repertoire related to aggression such as pursuing and sniffing the intruder and tail rattle. There were also no changes observed in the duration of walking and rearing. Pretreatment with WAY100,635 prevented the anti-aggressive effects of F15599 when microinjected into VO PFC. The present results demonstrated that F15599 is effective in reducing the most intense behavioral elements of aggressive behavior in male mice, when microinjected into the VO PFC, but not into the ILC, without affecting nonaggressive behavior, and confirmed the critical role of this cortical region and specifically the 5-HT1A heteroreceptors in the modulation of escalated aggressive behavior.

Antidepressant activity: contribution of brain microdialysis in knock-out mice to the understanding of BDNF/5-HT transporter/5-HT autoreceptor interactions

Why antidepressants vary in terms of efficacy is currently unclear. Despite the leadership of selective serotonin reuptake inhibitors (SSRIs) in the treatment of depression, the precise neurobiological mechanisms involved in their therapeutic action are poorly understood. A better knowledge of molecular interactions between monoaminergic system, pre- and post-synaptic partners, brain neuronal circuits and regions involved may help to overcome limitations of current treatments and identify new therapeutic targets. Intracerebral in vivo microdialysis (ICM) already provided important information about the brain mechanism of action of antidepressants first in anesthetized rats in the early 1990s, and since then in conscious wild-type or knock-out mice. The principle of ICM is based on the balance between release of neurotransmitters (e.g., monoamines) and reuptake by selective transporters [e.g., serotonin transporter for serotonin 5-hydroxytryptamine (5-HT)]. Complementary to electrophysiology, this technique reflects pre-synaptic monoamines release and intrasynaptic events corresponding to ≈80% of whole brain tissue content. The inhibitory role of serotonergic autoreceptors infers that they limit somatodendritic and nerve terminal 5-HT release. It has been proposed that activation of 5-HT1A and 5-HT1B receptor sub-types limits the antidepressant-like activity of SSRIs. This hypothesis is based partially on results obtained in ICM experiments performed in naïve, non-stressed rodents. The present review will first remind the principle and methodology of ICM performed in mice. The crucial need of developing animal models that display anxiety and depression-like behaviors, neurochemical and brain morphological phenotypes reminiscent of these mood disorders in humans, will be underlined. Recently developed genetic mouse models have been generated to independently manipulate 5-HT1A auto and heteroreceptors and ICM helped to clarify the role of the pre-synaptic component, i.e., by measuring extracellular levels of neurotransmitters in serotonergic nerve terminal regions and raphe nuclei. Finally, we will summarize main advantages of using ICM in mice through recent examples obtained in knock-outs (drug infusion through the ICM probe allows the search of a correlation between changes in extracellular neurotransmitter levels and antidepressant-like activity) or alternatives (infusion of a small-interfering RNA suppressing receptor functions in the mouse brain). We will also focus this review on post-synaptic components such as brain-derived neurotrophic factor in adult hippocampus that plays a crucial role in the neurogenic and anxiolytic/antidepressant-like activity of chronic SSRI treatment. Limitations of ICM will also be considered.

Anticonvulsant Activity and 5-HT1A/5-HT7 Receptors Affinity of Piperazine Derivatives of 3,3-Diphenyl- and 3,3-Dimethyl-succinimides

The series of thirty new 1-[(4-arylpiperazin-1-yl)-alkyl]-3,3-diphenyl- and 3,3-dimethyl-pyrrolidine-2,5-diones was synthesized. The anticonvulsant properties were evaluated in maximal electroshock (MES) and subcutaneous pentylenetetrazole (scPTZ) seizure tests after intraperitoneal injection in mice. The motor impairment was determined in the rotorod test in parallel. Although no anti-seizure properties were found in the scPTZ screen, fourteen compounds showed protection in the MES test at a dose of 100 mg/kg which is known as animal model of human generalized tonicclonic seizures. Taking into consideration the role of 5-HT1A and 5-HT7 receptor subtypes in seizures control as well as the fact that all compounds obtained belong to the class of long-chain arylpiperazines (LCAPs), their 5-HT1A and 5-HT7 serotonin receptor affinities were determined. The most potent 5-HT1A receptor ligands are 2-OCH3 (20, 35), 3-Cl (32) and 3-CF3 (34) derivatives with Ki = 16 nM (20), 33 nM (35), 32 nM (32) and 26 nM (34). Compounds 32 and 35 reveled also high 5-HT7 receptors affinity with the the Ki values 70 nM and 47 nM, respectively. There was no correlation between anticonvulsant properties and 5-HT1A and/or 5-HT7 serotonin receptor affinity. Keywords: Anticonvulsant activity; 5-HT1A/5-HT7 receptor ligands; Arylpiperazines; 3, 3-Disubstituted pyrrolidine-2, 5-diones; In vivo studies; In vitro studies; Succinimides.

Anticonvulsant Activity and 5-HT1A/5-HT7 Receptors Affinity of Piperazine Derivatives of 3,3-Diphenyl- and 3,3-Dimethyl-succinimides

The series of thirty new 1-[(4-arylpiperazin-1-yl)-alkyl]-3,3-diphenyl- and 3,3-dimethyl-pyrrolidine-2,5-diones was synthesized. The anticonvulsant properties were evaluated in maximal electroshock (MES) and subcutaneous pentylenetetrazole (scPTZ) seizure tests after intraperitoneal injection in mice. The motor impairment was determined in the rotorod test in parallel. Although no anti-seizure properties were found in the scPTZ screen, fourteen compounds showed protection in the MES test at a dose of 100 mg/kg which is known as animal model of human generalized tonicclonic seizures. Taking into consideration the role of 5-HT1A and 5-HT7 receptor subtypes in seizures control as well as the fact that all compounds obtained belong to the class of long-chain arylpiperazines (LCAPs), their 5-HT1A and 5-HT7 serotonin receptor affinities were determined. The most potent 5-HT1A receptor ligands are 2-OCH3 (20, 35), 3-Cl (32) and 3-CF3 (34) derivatives with Ki = 16 nM (20), 33 nM (35), 32 nM (32) and 26 nM (34). Compounds 32 and 35 reveled also high 5-HT7 receptors affinity with the the Ki values 70 nM and 47 nM, respectively. There was no correlation between anticonvulsant properties and 5-HT1A and/or 5-HT7 serotonin receptor affinity. Keywords: Anticonvulsant activity; 5-HT1A/5-HT7 receptor ligands; Arylpiperazines; 3, 3-Disubstituted pyrrolidine-2, 5-diones; In vivo studies; In vitro studies; Succinimides.

Quantification of the radio-metabolites of the serotonin-1A receptor radioligand [carbonyl-11C]WAY-100635 in human plasma: An HPLC-assay which enables measurement of two patients in parallel

[Carbonyl-11C]WAY-100635 is a potent and effective antagonist for the 5-HT1A receptor subtype. We aimed to assess the status of [carbonyl-11C]WAY-100635 and its main radio-metabolites, [carbonyl-11C]desmethyl-WAY-100635 and [carbonyl-11C]cyclohexanecarboxylic acid, on the basis of an improved radio-HPLC method. Common methods were characterized by preparative HPLC columns with long runtimes and/or high flow rates. Considering the short half-life of C-11, we developed a more rapid and solvent saving HPLC assay, allowing a fast, efficient and reliable quantification of these major metabolites.

The toadfish serotonin 2A (5-HT2A) receptor: molecular characterization and its potential role in urea excretion

Based on early pharmacological work, the serotonin 2A (5-HT2A) receptor subtype is believed to be involved in the regulation of toadfish pulsatile urea excretion. The goal of the following study was to characterize the toadfish 5-HT2A receptor at a molecular level, to determine the tissues in which this receptor is predominantly expressed and to further investigate the pharmacological specificity of toadfish pulsatile urea excretion by examining the effect of ketanserin, a 5-HT2A receptor antagonist, on resting rates of pulsatile urea excretion. The full-length toadfish 5-HT2A receptor encodes a 496 amino acid sequence and shares 57–80% sequence identity to 5-HT2A receptors of other organisms, with 100% conservation among important ligand-binding residues. Toadfish 5-HT2A receptor mRNA expression was highest in the swim bladder and gonad, followed by the whole brain. All other tissues tested (esophagus, stomach, anterior intestine, posterior intestine, rectum, liver, kidney, heart, muscle and gill) had mRNA expression levels that were significantly less than whole brain. Toadfish 5-HT2A receptor mRNA expression within the brain was highest in the hindbrain, telencephalon and midbrain/diencephalon regions. Treatment with the 5-HT2A receptor antagonist, ketanserin, resulted in a significant decrease in the pulsatile component of spontaneous urea excretion due to a reduction in urea pulse size with no significant change in pulse frequency. These results lend further support for the 5-HT2A receptor in the regulation of pulsatile urea excretion in toadfish.

5-Hydroxytryptamine initiates pulsatile urea excretion from perfused gills of the gulf toadfish (Opsanus beta)

When stressed, toadfish become ureotelic and excrete almost all of their nitrogenous waste in 1–3 daily pulses of urea-N across the gills. Intravascular injections of 5-hydroxytyptamine (5-HT; serotonin) and analogues also elicit marked excretory pulses of urea-N from toadfish in vivo, suggesting that 5-HT release is the proximate trigger for spontaneous pulses. However it is unclear whether 5-HT is acting on the gills directly or elsewhere to cause the effect indirectly. A perfused whole gill preparation which maintained normal pressure relationships and stable vascular resistance was employed to address this question. Bolus injections into the ventral aortic perfusate of either 5-HT (1, 10μmolkg−1) or the specific 5-HT2 receptor agonist α-methyl 5-HT (1, 10μmolkg−1) elicited rapid urea-N pulses from perfused toadfish gills. The effective doses, the post-injection delays (5.5±1.3min, range=2–22), the percent occurrences (57–85%), and the magnitude of the induced urea-N pulses (615.4±131.3μmol-Nkg−1, range 66.0–2634.0), were all similar to those previously reported when these agents were injected in vivo. Bolus injections of 5-HT and α-methyl 5-HT also elicited a biphasic response in ventral aortic pressure, reflecting an initial rapid short-lived vasodilation and a subsequent longer-lasting vasoconstriction. These events were similar to those which have been recorded to occur at a greater frequency during spontaneous urea-N pulsing in vivo. Neither the urea-N pulsing nor the cardiovascular responses to 5-HT were inhibited by the 5-HT2A receptor subtype blocker, ketanserin (pre-injection with 10μmolkg−1 plus 33μmolL−1 in the perfusate). Overall, these results provide strong support for the idea that the proximate stimulus for natural urea pulsing in vivo is 5-HT mobilization, acting directly in the gills.

Serotonergic innervation and serotonin receptor expression of NPY-producing neurons in the rat lateral and basolateral amygdaloid nuclei

Pharmacobehavioral studies in experimental animals, and imaging studies in humans, indicate that serotonergic transmission in the amygdala plays a key role in emotional processing, especially for anxiety-related stimuli. The lateral and basolateral amygdaloid nuclei receive a dense serotonergic innervation in all species studied to date. We investigated interrelations between serotonergic afferents and neuropeptide Y (NPY)-producing neurons, which are a subpopulation of inhibitory interneurons in the rat lateral and basolateral nuclei with particularly strong anxiolytic properties. Dual light microscopic immunolabeling showed numerous appositions of serotonergic afferents on NPY-immunoreactive somata. Using electron microscopy, direct membrane appositions and synaptic contacts between serotonin-containing axon terminals and NPY-immunoreactive cellular profiles were unequivocally established. Double in situ hybridization documented that more than 50 %, and about 30–40 % of NPY mRNA-producing neurons, co-expressed inhibitory 5-HT1A and excitatory 5-HT2C mRNA receptor subtype mRNA, respectively, in both nuclei with no gender differences. Triple in situ hybridization showed that individual NPY mRNA-producing interneurons co-express both 5-HT1A and 5-HT2C mRNAs. Co-expression of NPY and 5-HT3 mRNA was not observed. The results demonstrate that serotonergic afferents provide substantial innervation of NPY-producing neurons in the rat lateral and basolateral amygdaloid nuclei. Studies of serotonin receptor subtype co-expression indicate a differential impact of the serotonergic innervation on this small, but important, population of anxiolytic interneurons, and provide the basis for future studies of the circuitry underlying serotonergic modulation of emotional stimulus processing in the amygdala.

DOI-induced deficits in prepulse inhibition in Wistar rats are reversed by mGlu2/3 receptor stimulation

Prepulse inhibition (PPI) of the acoustic startle response (ASR) provides a measure of sensorimotor gating mechanisms that are impaired in schizophrenia patients. Interactions of the serotonin (5-hydroxytryptamine, 5-HT) and glutamatergic systems, especially via the 5-HT2A receptor subtype, have been implicated in the regulation of PPI. The present study investigated the involvement of interactions between 5-HT2A and metabotropic glutamate (mGlu)2/3 receptors in modulating PPI in Wistar and Lister Hooded rats. Systemic administration of the 5-HT2A/2C receptor agonist DOI ((+/−)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropan hydrochloride; 3mg/kg) reduced PPI and ASR magnitude in Wistar but not in Lister Hooded rats. In Wistar rats, pre-treatment with the mGlu2/3 receptor agonist LY379268 (1mg/kg) attenuated the DOI-induced disruption of PPI as well as the DOI-elicited reductions of ASR magnitude. LY379268 itself did not alter PPI in both strains and only slightly increased ASR magnitudes in Wistar rats. Taken together, these findings support the notion of functionally antagonistic interactions between 5-HT2A and mGlu2/3 which might be involved in regulating sensorimotor gating mechanisms. Additionally, the data suggest that stimulation of mGlu2/3 receptors may be useful to ameliorate sensorimotor gating deficits resulting from an overstimulation of 5-HT2A receptors.

Synthesis, anticonvulsant activity and 5-HT1A/5-HT7 receptors affinity of 1-[(4-arylpiperazin-1-yl)-propyl]-succinimides

BackgroundEpilepsy is the most prevalent neurological disorder, affecting approximately 50 million people worldwide. Even though significant advances have been made in epilepsy research, convulsions in about 30% of epileptics are still inadequately controlled by standard drug therapy. For this reason, constant attempts are made to investigate new chemical agents and mechanisms through which epilepsy can be effectively controlled. Therefore, in the present studies, a series of sixteen new 1-[(4-arylpiperazin-1-yl)-propyl]-3-methyl-3-phenyl- and 3-ethyl-3-methylpyrrolidine-2,5-dione derivatives as potential anticonvulsant agents was synthesized. MethodsAnticonvulsant properties were evaluated in the maximal electroshock (MES), subcutaneous pentylenetetrazole (scPTZ) and psychomotor seizure (6-Hz) tests after intraperitoneal injection in mice. The acute neurological toxicity was determined in the motor impairment rotorod screen. ResultsThe compounds showed activity at a dose of 30mg/kg (4, 8, 16) or 100mg/kg (6, 9, 10, 12, 17, 18) in the MES model in mice. Four or them (8, 10, 16, 17) were also evaluated after po administration in rats. In this series, the most active was 1-{3-[4-(3-chlorophenyl)-piperazin-1-yl]-propyl}-3-methyl-3-phenyl-pyrrolidine-2,5-dione (8) with the ED50 value of 28.2mg/kg, TD50 value of 268.5mg/kg and protective index of 9.52 after po administration in rats. ConclusionsTaking into consideration the role of 5-HT1A and 5-HT7 receptor subtypes in relation to the control of seizures as well as the fact that all compounds obtained belong to the class of long-chain arylpiperazines, their serotonin 5-HT1A and 5-HT7 receptor affinity was determined. The most potent 5-HT1A receptor ligands are 2-OCH3 (11, 19) and 3-Cl (8, 16) derivatives with Ki = 72, 14nM, and 109, 44nM, respectively. With respect to the 5-HT7 receptors, the best Ki values were obtained for derivatives 8 and 11 (Ki = 76nM and 63 nM, respectively).

Neuronal localization of 5-HT2A receptor immunoreactivity in the rat hippocampal region

The 5-HT2A receptor subtype (5-HT2Ar) plays an important role in the modulation of the hippocampal region activity and it has been associated with learning and memory processes. In the present study, the 5-HT2Ar was immunohistochemically localized in the rat hippocampal region, which includes the hippocampal formation and the parahippocampal region. In the hippocampal formation (dentate gyrus, hippocampus proper and subiculum) and entorhinal cortex, the colocalization of the 5-HT2Ar with the inhibitory transmitter γ-aminobutyric acid (GABA) was studied using double immunofluorescence confocal microscopy. The patterns of immunostaining were very different in non-injected and colchicine-injected rats. In untreated rats, the immunoreactivity could be attributed especially to neuropil. Interestingly, in non-injected rats, the 5-HT2Ar immunoreactivity was located in the mossy fibers, suggesting that serotonin acts presynaptically via this receptor subtype directly on glutamate axons. Pretreatment with colchicine increased the number of 5-HT2Ar-immunoreactive somata. Morphological and double immunofluorescence analyses indicated that the 5-HT2Ar was located on both the excitatory and the inhibitory neurons of the rat hippocampal region. The results of the present study suggest that the 5-HT2Ar could participate in the hippocampal neurotransmission by acting on different neuronal populations.

Activation of GABAA or 5HT1A receptors in the raphé pallidus abolish the cardiovascular responses to exogenous stress in conscious rats

Dysfunction in serotonin (5HT) neurotransmission in the brainstem of infants may disrupt protective responses to stress and increase the risk for Sudden Infant Death Syndrome (SIDS). The raphé pallidus (NRP) and other brainstem nuclei are rich in 5HT and are thought to mediate stress responses, including increases in blood pressure (BP) and heart rate (HR). Determining how 5HT neurotransmission in the brainstem mediates responses to stress will help to explain how dysfunction in neurotransmission could increase the risk of SIDS. It was hypothesized that alterations in neurotransmission in the NRP, specifically activation of the 5HT(1A) receptor subtype, would block cardiovascular responses to various types of exogenous stress. Using aseptic techniques, male Sprague-Dawley rats were instrumented with radiotelemetry probes which enabled non-invasive measurement of BP and HR. An indwelling microinjection cannula was also stereotaxically implanted into the NRP for injection of drugs that altered local 5HT neurotransmission. Following a one week recovery period, rats were microinjected with either muscimol (GABA(A) receptor agonist), 8-OH-DPAT (agonist to the inhibitory 5HT(1A) receptor), or a vehicle control (artificial cerebral spinal fluid; ACSF) immediately prior to exposure to one of three stressors: handling, air jet, or restraint. Physical handling and restraint of the animal were designed to elicit a mild and a maximal stress response respectively; while an air jet directed at the rat's face was used to provoke a psychological stress that did not require physical contact. All three stressors elicited similar and significant elevations in HR and BP following ACSF that persisted for at least 15 min with BP and HR elevated by ∼14.0 mmHg and ∼56.3 bpm respectively. The similarity in the stress responses suggest even mild handling of a rat elicits a maximal sympathoexcitatory response. The stress response was abolished following 8-OH-DPAT or muscimol microinjection suggesting the cardiovascular responses to stress are mediated by the NRP and likely involve the 5HT(1A) receptor. Impairment in 5HT(1A) receptor function in the NRP likely impairs the normal cardioprotective responses to stress and may contribute to the etiology of SIDS.

P.1.c.033 Behavioural and biochemical evaluation of the anti-dyskinetic potential of sarizotan, a 5-HT1A agonist, in 6-ODHA lesioned rats

Sprague-Dawley rat pups at 3–4 days prenatally were tested in both the absence and presence of milk following administration of various doses of either the 5-HT1A agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OHDPAT), the 5-HT1B agonist 1-(3-chlorophenyl)piperazine (mCPP), or the 5-HT2 agonist 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI). Administration of 8-OHDPAT decreased mouthing, increased probing and increased behavioral activation. Conversely, the 5-HT2 agonist DOI and the 5-HT1B agonist mCPP increased mouthing and decreased probing. mCPP and DOI differed in their effects on behavioral activation, with mCPP decreasing and DOI increasing this composite behavioral score. mCPP increased grooming, whereas DOI elicited a characteristic unusual positioning of the limbs. Thus it appears that 5-HT1A, 5-HT1B and 5-HT2 receptor subtypes are present in the neonate and elicit differential behavioral responses upon stimulation with selective agonists. Ontogenetic variations in the balance among these receptor subtypes during development may be related to the ontogenetic reversal that has been previously reported in the impact of serotonin manipulations on mouthing and suckling behavior during the neonatal to weanling age period.

Computational Medicinal Chemistry: Part II

Computational Medicinal Chemistry: Part II