Novel Bivalent 5-HT Receptor Antagonists Exhibit High Affinity and Potency in Vitro and Efficacy in Vivo.

The 5-HT receptor (5-HTR) plays an important role in various neuropsychiatric disorders, including substance use disorder and schizophrenia. Homodimerization of this receptor has been suggested, but tools that allow direct assessment of the relevance of the 5-HTR:5-HTR homodimer in these disorders are necessary. We chemically modified the selective 5-HTR antagonist M100907 to synthesize a series of homobivalent ligands connected by ethylene glycol linkers of varying lengths that may be useful tools for probing 5-HTR:5-HTR homodimer function.

Evaluation of the dopamine β-hydroxylase (DβH) inhibitor nepicastat in participants who meet criteria for cocaine use disorder.

In the present study, we tested the hypothesis that the potent and selective dopamine-β-hydroxylase (DβH) inhibitor nepicastat would have minimal effects on cardiovascular and pharmacokinetic parameters associated with cocaine administration and would reduce the positive subjective effects produced by cocaine. We conducted a double-blind, placebo-controlled, inpatient study of oral nepicastat (0, 80 and 160mg) concurrent with intravenous (IV) cocaine (0, 10, 20 and 40mg) in non-treatment seeking participants who metcriteria for cocaine use disorder. Safety analyses revealed that nepicastat was well-tolerated and there were no differences in adverse events observed after nepicastat plus cocaine vs.

Elevated Expression of Serotonin 5-HT(2A) Receptors in the Rat Ventral Tegmental Area Enhances Vulnerability to the Behavioral Effects of Cocaine.

The dopamine mesocorticoaccumbens pathway which originates in the ventral tegmental area (VTA) and projects to the nucleus accumbens and prefrontal cortex is a circuit important in mediating the actions of psychostimulants. The function of this circuit is modulated by the actions of serotonin (5-HT) at 5-HT(2A) receptors (5-HT(2A)R) localized to the VTA. In the present study, we tested the hypothesis that virally mediated overexpression of 5-HT(2A)R in the VTA would increase cocaine-evoked locomotor activity in the absence of alterations in basal locomotor activity.

Peptide inhibitors disrupt the serotonin 5-HT2C receptor interaction with phosphatase and tensin homolog to allosterically modulate cellular signaling and behavior.

Serotonin (5-hydroxytryptamine; 5-HT) signaling through the 5-HT(2C) receptor (5-HT(2C)R) is essential in normal physiology, whereas aberrant 5-HT(2C)R function is thought to contribute to the pathogenesis of multiple neural disorders. The 5-HT(2C)R interacts with specific protein partners, but the impact of such interactions on 5-HT(2C)R function is poorly understood. Here, we report convergent cellular and behavioral data that the interaction between the 5-HT(2C)R and protein phosphatase and tensin homolog (PTEN) serves as a regulatory mechanism to control 5-HT(2C)R-mediated biology but not that of the closely homologous 5-HT(2A)R.

Synergism between a serotonin 5-HT2A receptor (5-HT2AR) antagonist and 5-HT2CR agonist suggests new pharmacotherapeutics for cocaine addiction.

Relapse to cocaine dependence, even after extended abstinence, involves a number of liability factors including impulsivity (predisposition toward rapid, unplanned reactions to stimuli without regard to negative consequences) and cue reactivity (sensitivity to cues associated with cocaine-taking which can promote cocaine-seeking). These factors have been mechanistically linked to serotonin (5-hydroxytryptamine, 5-HT) signaling through the 5-HT(2A) receptor (5-HT(2A)R) and 5-HT(2C)R; either a selective 5-HT(2A)R antagonist or a 5-HT(2C)R agonist suppresses impulsivity and cocaine-seeking in preclinical models. We conducted proof-of-concept analyses to evaluate whether a combination of 5-HT(2A)R antagonist plus 5-HT(2C)R agonist would have synergistic effects over these liability factors for relapse as measured in a 1-choice serial reaction time task and cocaine self-administration/reinstatement assay.

Influence of methamphetamine on genital herpes simplex virus type 2 infection in a mouse model.

Background: Use of the stimulant methamphetamine (METH) is increasingly common, with >35 million users worldwide. There is a known association between stimulant use and an increased incidence of HIV and other sexually transmitted infections (STIs). METH is known to have immune modulatory properties.

5-HT(2C) receptors localize to dopamine and GABA neurons in the rat mesoaccumbens pathway.

The serotonin 5-HT(2C) receptor (5-HT(2C)R) is localized to the limbic-corticostriatal circuit, which plays an integral role in mediating attention, motivation, cognition, and reward processes. The 5-HT(2C)R is linked to modulation of mesoaccumbens dopamine neurotransmission via an activation of γ-aminobutyric acid (GABA) neurons in the ventral tegmental area (VTA). However, we recently demonstrated the expression of the 5-HT(2C)R within dopamine VTA neurons suggesting the possibility of a direct influence of the 5-HT(2C)R upon mesoaccumbens dopamine output.

Selective serotonin 5-HT(2C) receptor activation suppresses the reinforcing efficacy of cocaine and sucrose but differentially affects the incentive-salience value of cocaine- vs. sucrose-associated cues.

Serotonin (5-HT) controls affective and motivational aspects of palatable food and drug reward and the 5-HT(2C) receptor (5-HT(2C)R) has emerged as a key regulator in this regard. We have evaluated the efficacy of a selective 5-HT(2C)R agonist, WAY 163909, in cocaine and sucrose self-administration and reinstatement assays employing parallel experimental designs in free-fed rats. WAY 163909 dose-dependently reduced the reinforcing efficacy of cocaine (ID(50) = 1.

Serotonin (5-hydroxytryptamine) 5-HT(2A) receptor: association with inherent and cocaine-evoked behavioral disinhibition in rats.

Alterations in the balance of functional activity within the serotonin [5-hydroxytryptamine (5-HT)] system are hypothesized to underlie impulse control. Cocaine-dependent subjects consistently show greater impulsivity relative to nondrug using control subjects. Preclinical studies suggest that the 5-HT(2A) receptor (5-HT(2A)R) contributes to the regulation of impulsive behavior and also mediates some of the behavioral effects of cocaine.

Serotonin 5-HT2C receptor protein expression is enriched in synaptosomal and post-synaptic compartments of rat cortex.

The action of serotonin (5-HT) at the 5-HT(2C) receptor (5-HT(2C)R) in cerebral cortex is emerging as a candidate modulator of neural processes that mediate core phenotypic facets of several psychiatric and neurological disorders. However, our understanding of the neurobiology of the cortical 5-HT(2C)R protein complex is currently limited. The goal of the present study was to explore the subcellular localization of the 5-HT(2C)R in synaptosomes and the post-synaptic density, an electron-dense thickening specialized for post-synaptic signaling and neuronal plasticity.

3,4-Methylenedioxymethamphetamine increases susceptibility to genital herpes simplex virus infection in mice.

Abused by >1.2 million Americans, 3,4-methylenedioxymethamphetamine (MDMA) (commonly referred to as ecstasy) is popular in the dance club, rave, and circuit party scenes. MDMA and other similar drugs are reportedly associated with increased incidence of sexually transmitted infectious diseases, such as AIDS and genital herpes, and may have immunological effects.

Prospects for serotonin 5-HT2R pharmacotherapy in psychostimulant abuse.

The serotonin (5-HT) neurotransmitter system provides fundamental modulatory regulation of the limbic-corticostriatal circuitry known to be vital in the development of addiction as well as the aspects of addiction that hinder recovery and contribute to relapse. Thus, components of the 5-HT system may provide novel targets for the development of pharmacological treatments for psychostimulant dependence, which is associated with significant aberrations in dopamine (DA) neurotransmission. Two key modulators of DA signalling within the limbic-corticostriatal circuit are the 5-HT(2A) receptor (5-HT(2A)R) and the 5-HT(2C)R.

Selective ablation of GABA neurons in the ventral tegmental area increases spontaneous locomotor activity.

Gamma-aminobutyric acid (GABA) neurons in the ventral tegmental area (VTA) provide innervation to cortical and subcortical regions of the brain. To solidify the importance of these VTA GABA neurons in behavioral function, we employed the neurotoxin dermorphin-saporin (DS) to selectively lesion VTA GABA neurons prior to assessing spontaneous motor activity. Rats were bilaterally microinfused with DS (1.

Serotonin 5-HT2A and 5-HT2C receptors as potential targets for modulation of psychostimulant use and dependence.

The development of novel pharmacological agents for the treatment of psychostimulant use disorders is an important research imperative. One potential target system that has been largely overlooked is the serotonin (5-HT) neurotransmitter system. Preclinical studies indicate that 5-HT may be important in modulating the reinforcing properties of various drugs of abuse.

Validation of a selective serotonin 5-HT(2C) receptor antibody for utilization in fluorescence immunohistochemistry studies.

Although radioligand binding studies have shown that the serotonin 5-HT(2C) receptor (5-HT(2C)R) is widely expressed throughout the brain, more detailed knowledge of 5-HT(2C)R distribution within different neuronal populations will aid in understanding the mechanisms through which this receptor acts. Double-label immunohistochemical procedures can be utilized to examine the localization of receptors within specific neuronal populations. In order to conduct such studies, however, it was first necessary to examine the utility and specificity of two commercially available anti-5-HT(2C)R antibodies [from Santa Cruz (SC) and BD PharMingen (PH)].

Contribution of serotonin (5-HT) 5-HT2 receptor subtypes to the discriminative stimulus effects of cocaine in rats.

Rationale: The serotonin (5-hydroxytryptamine; 5-HT) 5-HT2 receptor (5-HT2R) family is an important regulator of the behavioral responsiveness to cocaine.

Objective: The present study is an analysis of the role of the 5-HT2R subtypes (5-HT2AR, 5-HT2BR, and 5-HT2CR) in the discriminative stimulus effects of cocaine.

Methods: Male Wistar rats were trained to discriminate cocaine (10 mg/kg) from saline in a two-lever, water-reinforced FR 20 task, and we investigated the ability of the 5-HT2AR antagonist 1(Z)-[2-(dimethylamino)ethoxyimino]-1(2-fluorophenyl)-3-(4-hydroxyphenyl)-2(E)-propene (SR 46349B), the 5-HT2BR antagonist N-(1-methyl-5-indolyl)-N'-(3-methyl-5-isothiazolyl) urea (SB 204741), and the 5-HT2CR antagonist [(+)-cis-4,5,7a,8,9,10,11,11a-octahydro-7H-10-methylindolo(1,7-bC)(2,6)naphthyridine (SDZ SER-082) to substitute for or to modulate the stimulus effects of cocaine.

Contribution of serotonin (5-hydroxytryptamine; 5-HT) 5-HT2 receptor subtypes to the hyperlocomotor effects of cocaine: acute and chronic pharmacological analyses.

The role of serotonin (5-hydroxytryptamine; 5-HT) 5-HT2 receptor subtypes (5-HT2AR, 5-HT2BR, and 5-HT2CR) in acute cocaine-evoked hyperactivity was compared with their contribution to the development and expression of locomotor sensitization upon repeated, intermittent treatment with cocaine (10 mg/kg/day for 5 days) in male Wistar rats. Cocaine-evoked hyperactivity was significantly enhanced by pretreatment with the preferential 5-HT2AR agonist 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) and the 5-HT2CR antagonist SDZ SER-082 [(+)-cis-4,5,7a,8,9,10,11,11a-octahydro-7H-10-methylindolo(1,7-BC)(2,6) naphthyridine fumarate]. The 5-HT2AR antagonist SR 46349B [1(Z)-[2-(dimethylamino)ethoxyimino]-1(2-fluorophenyl)-3-(4-hydroxyphenyl)-2(E)-propene] and the preferential 5-HT2CR agonist MK 212 [6-chloro-2-(1-piperazinyl)pyrazine HCl] (2 mg/kg) significantly attenuated acute cocaine-evoked hyperactivity; however, a lower dose of MK 212 (0.