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1.
Pharmacol Ther ; 229: 107937, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-34174274

RESUMO

Biased agonism (or "functional selectivity") at G-protein-coupled receptors has attracted rapidly increasing interest as a means to improve discovery of more efficacious and safer pharmacotherapeutics. However, most studies are limited to in vitro tests of cellular signaling and few biased agonists have progressed to in vivo testing. As concerns 5-HT1A receptors, which exert a major control of serotonergic signaling in diverse CNS regions, study of biased agonism has previously been limited by the poor target selectivity and/or partial agonism of classically available ligands. However, a new generation of highly selective, efficacious and druggable agonists has advanced the study of biased agonism at this receptor and created new therapeutic opportunities. These novel agonists show differential properties for G-protein signaling, cellular signaling (particularly pERK), electrophysiological effects, neurotransmitter release, neuroimaging by PET and pharmacoMRI, and behavioral tests of mood, motor activity and side effects. Overall, NLX-101 (a.k.a. F15599) exhibits preferential activation of cortical and brain stem 5-HT1A receptors, whereas NLX-112 (a.k.a. befiradol or F13640) shows prominent activation of 5-HT1A autoreceptors in Raphe nuclei and in regions associated with motor control. Accordingly, NLX-101 is potently active in rodent models of depression and respiratory control, whereas NLX-112 shows promising activity in models of Parkinson's disease across several species - rat, marmoset and macaque. Moreover, NLX-112 has also been labeled with 18F to produce the first agonist PET radiopharmaceutical (known as [18F]-F13640) for investigation of the active state of 5-HT1A receptors in rodent, primate and human. The structure-functional activity relationships of biased agonists have been investigated by receptor modeling and novel compounds have been identified which exhibit increased affinity at 5-HT1A receptors and new profiles of cellular signaling bias, notably for ß-arrestin recruitment versus pERK. Taken together, the data suggest that 5-HT1A receptor biased agonists constitute potentially superior pharmacological agents for treatment of CNS disorders involving serotonergic mechanisms.


Assuntos
Receptor 5-HT1A de Serotonina , Serotonina , Animais , Encéfalo , Humanos , Ratos , Agonistas do Receptor 5-HT1 de Serotonina/farmacologia , Agonistas do Receptor 5-HT1 de Serotonina/uso terapêutico , Agonistas do Receptor de Serotonina/farmacologia
2.
J Atten Disord ; 22(14): 1361-1366, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-23966351

RESUMO

OBJECTIVE: In preclinical studies, lobeline inhibited hyperactivity induced by nicotine and amphetamine, and improved performance and learning in studies utilizing radial-arm maze and spatial-discrimination water maze. This laboratory proof-of-concept study investigated lobeline as a treatment for ADHD symptoms in adults (31.11 ± 7.08 years). METHOD: Using cognitive tasks and self-report measures, the effects of lobeline (0, 7.5, 15, or 30 mg, s.l.) and methylphenidate (0, 15, or 30 mg, p.o.) were assessed in nine volunteers with ADHD. RESULTS: Evidence suggested that lobeline could modestly improve working memory in adults with ADHD, but no significant improvement in attention was observed. Lobeline administration was associated with mild adverse side effects (nausea). CONCLUSION: Further investigation of lobeline on working memory may be warranted.


Assuntos
Transtorno do Deficit de Atenção com Hiperatividade/tratamento farmacológico , Estimulantes do Sistema Nervoso Central/administração & dosagem , Cognição/efeitos dos fármacos , Comportamento Impulsivo/efeitos dos fármacos , Lobelina/administração & dosagem , Memória de Curto Prazo/efeitos dos fármacos , Metilfenidato/administração & dosagem , Agonistas Nicotínicos/administração & dosagem , Adulto , Atenção/efeitos dos fármacos , Atenção/fisiologia , Transtorno do Deficit de Atenção com Hiperatividade/psicologia , Estimulantes do Sistema Nervoso Central/uso terapêutico , Relação Dose-Resposta a Droga , Método Duplo-Cego , Feminino , Humanos , Lobelina/uso terapêutico , Masculino , Metilfenidato/uso terapêutico , Agonistas Nicotínicos/uso terapêutico , Resultado do Tratamento
3.
Psychopharmacology (Berl) ; 216(4): 451-73, 2011 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-21394633

RESUMO

RATIONALE: There is increasing interest in antipsychotics intended to manage positive symptoms via D(2) receptor blockade and improve negative symptoms and cognitive deficits via 5-HT(1A) activation. Such a strategy reduces side-effects such as the extrapyramidal syndrome (EPS), weight gain, and autonomic disturbance liability. OBJECTIVE: This study aims to review pharmacological literature on compounds interacting at both 5-HT(1A) and D(2) receptors (as well as at other receptors), including aripiprazole, perospirone, ziprasidone, bifeprunox, lurasidone and cariprazine, PF-217830, adoprazine, SSR181507, and F15063. METHODS: We examine data on in vitro binding and agonism and in vivo tests related to (1) positive symptoms (e.g., psychostimulant-induced hyperactivity or prepulse inhibition deficit), (2) negative symptoms (e.g., phencyclidine-induced social interaction deficits and cortical dopamine release), and (3) cognitive deficits (e.g., phencyclidine or scopolamine-induced memory deficits). EPS liability is assessed by measuring catalepsy and neuroendocrine impact by determining plasma prolactin, glucose, and corticosterone levels. RESULTS: Compounds possessing "balanced" 5-HT(1A) receptor agonism and D(2) antagonism (or weak partial agonism) and, in some cases, combined with other beneficial properties, such as 5-HT(2A) receptor antagonism, are efficacious in a broad range of rodent pharmacological models yet have a lower propensity to elicit EPS or metabolic dysfunction. CONCLUSIONS: Recent compounds exhibiting combined 5-HT(1A)/D(2) properties may be effective in treating a broader range of symptoms of schizophrenia and be better tolerated than existing antipsychotics. Nevertheless, further investigations are necessary to evaluate recent compounds, notably in view of their differing levels of 5-HT(1A) affinity and efficacy, which can markedly influence activity and side-effect profiles.


Assuntos
Antipsicóticos/farmacologia , Antagonistas dos Receptores de Dopamina D2 , Agonistas do Receptor 5-HT1 de Serotonina/farmacologia , Animais , Antipsicóticos/efeitos adversos , Doenças dos Gânglios da Base/induzido quimicamente , Humanos , Modelos Biológicos , Ligação Proteica , Receptores de Dopamina D2/metabolismo , Esquizofrenia/tratamento farmacológico , Esquizofrenia/fisiopatologia
4.
Int J Neuropsychopharmacol ; 13(10): 1285-98, 2010 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-20059805

RESUMO

F15599 is a novel agonist with high selectivity and efficacy at serotonin 5-HT(1A) receptors (5-HT(1A)Rs). In signal transduction, electrophysiological and neurochemical tests, F15599 preferentially activates post-synaptic 5-HT(1A)Rs in rat frontal cortex. Such a profile may translate to an improved profile of therapeutic activity for mood disorders. The in-vivo effects of F15599 were therefore compared with those of a related compound, F13714, in rat models of antidepressant activity and 5-HT(1A)R activation: forced swimming test (FST), conditioned stress-induced ultrasonic vocalization, 5-HT syndrome, plasma corticosterone and body temperature. Acute administration of F15599 or F13714 reduced immobility in the FST at low doses; these effects were long lasting and the effects of F15599 were maintained after repeated (5 d, p.o.) administration. Both compounds decreased ultrasonic vocalization duration at low doses. In contrast, higher doses of F15599 were required to induce lower lip retraction, elements of the 5-HT behavioural syndrome, hypothermia and to increase plasma corticosterone levels. Notably, there was a greater separation of ED50 between FST and other effects for F15599 than for F13714. Thus, the in-vivo potency of F15599 in models of antidepressant/anti-stress activity is similar to that of F13714, despite the fact that the latter has an in-vitro potency two orders of magnitude greater. In contrast F15599 has a lower propensity than F13714 to induce other serotonergic signs. The distinctive pharmacological profile of F15599 suggests that preferential targeting of post-synaptic 5-HT(1A)Rs constitutes a promising strategy for improved antidepressant therapy.


Assuntos
Aminopiridinas/farmacologia , Antidepressivos/farmacologia , Depressão/tratamento farmacológico , Terapia de Alvo Molecular , Piperidinas/farmacologia , Agonistas do Receptor 5-HT1 de Serotonina/uso terapêutico , Animais , Corticosterona/sangue , Corticosterona/metabolismo , Hipotermia/induzido quimicamente , Masculino , Modelos Animais , Atividade Motora/efeitos dos fármacos , Piperidinas/uso terapêutico , Córtex Pré-Frontal/efeitos dos fármacos , Pirimidinas/uso terapêutico , Ratos , Ratos Sprague-Dawley , Ratos Wistar , Serotonina/farmacologia , Estresse Fisiológico/efeitos dos fármacos , Natação/fisiologia
5.
Behav Brain Res ; 203(2): 288-95, 2009 Nov 05.
Artigo em Inglês | MEDLINE | ID: mdl-19464324

RESUMO

Typical antipsychotics such as haloperidol exert their therapeutic effects via blockade of dopamine (DA) D(2) receptors, leading to extrapyramidal symptoms (EPS) in humans and catalepsy in rodents. In contrast, atypical antipsychotics and new generation D(2)/5-HT(1A) antipsychotics have low cataleptogenic potential. However, there has been no systematic comparative study on the effects of these different classes of antipsychotics in non-human primates, a species displaying a more sophisticated repertoire of behavioural/motor activity than rats. Once weekly, six young adult female non-haloperidol-sensitised cynomolgus monkeys were treated i.m. with a test compound and videotaped to score catalepsy-associated behaviour (CAB: static postures, unusual positions and crouching). Haloperidol, risperidone, olanzapine, nemonapride and remoxipride induced, to different extents, an increase in unusual positions (a response akin to dystonia), some crouching and static postures. In contrast, clozapine, quetiapine, ziprasidone and aripiprazole produced much lower or no unusual positions; clozapine also produced marked increases in static postures and crouching. Among novel D(2)/5-HT(1A) antipsychotics, SLV313 and F15063 augmented the number of unusual positions, albeit at doses 16-63 times higher than those of haloperidol for approximately the same score. SSR181507 and bifeprunox produced moderate static postures, little crouching and negligible unusual positions. These data provide the first comparative analysis in cynomolgus monkeys of EPS liability of conventional, atypical and novel D(2)/5-HT(1A) antipsychotics. They indicate that the latter are less prone than haloperidol to produce CAB, and provide a basis for comparison with rodent catalepsy studies.


Assuntos
Antipsicóticos/efeitos adversos , Catalepsia/induzido quimicamente , Antagonistas de Dopamina/efeitos adversos , Agonistas do Receptor de Serotonina/efeitos adversos , 8-Hidroxi-2-(di-n-propilamino)tetralina/efeitos adversos , Animais , Aripiprazol , Benzamidas/efeitos adversos , Benzodiazepinas/efeitos adversos , Benzoxazóis/efeitos adversos , Clozapina/efeitos adversos , Dibenzotiazepinas/efeitos adversos , Dioxanos/efeitos adversos , Feminino , Haloperidol/efeitos adversos , Macaca fascicularis , Olanzapina , Piperazinas/efeitos adversos , Fumarato de Quetiapina , Quinolonas/efeitos adversos , Remoxiprida/efeitos adversos , Risperidona/efeitos adversos , Tiazóis/efeitos adversos , Tropanos/efeitos adversos , Gravação em Vídeo
6.
Behav Pharmacol ; 18(2): 103-18, 2007 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-17351418

RESUMO

Combining antagonist/partial agonist activity at dopamine D2 and agonist activity at serotonin 5-HT1A receptors is one of the approaches that has recently been chosen to develop new generation antipsychotics, including bifeprunox, SSR181507 and SLV313. There have been, however, few comparative data on their pharmacological profiles. Here, we have directly compared a wide array of these novel dopamine D2/5-HT1A and conventional antipsychotics in rat models predictive of antipsychotic activity. Potency of antipsychotics to antagonize conditioned avoidance, methylphenidate-induced behaviour and D-amphetamine-induced hyperlocomotion correlated with their affinity at dopamine D2 receptors. Potency against ketamine-induced hyperlocomotion was independent of affinity at dopamine D2 or 5-HT1A receptors. Propensity to induce catalepsy, predictive of occurrence of extrapyramidal side effects, was inversely related to affinity at 5-HT1A receptors. As a result, preferential D2/5-HT1A antipsychotics displayed a large separation between doses producing 'antipsychotic-like' vs. cataleptogenic actions. These data support the contention that 5-HT1A receptor activation greatly reduces or prevents the cataleptogenic potential of novel antipsychotics. They also emphasize that interactions at 5-HT1A and D2 receptors, and the nature of effects (antagonism or partial agonism) at the latter has a profound influence on pharmacological activities, and is likely to affect therapeutic profiles.


Assuntos
Antipsicóticos/farmacologia , Comportamento Animal/efeitos dos fármacos , Receptor 5-HT1A de Serotonina/efeitos dos fármacos , Receptores de Dopamina D2/efeitos dos fármacos , Animais , Aprendizagem da Esquiva/efeitos dos fármacos , Catalepsia/induzido quimicamente , Catalepsia/psicologia , Estimulantes do Sistema Nervoso Central/farmacologia , Dextroanfetamina/farmacologia , Relação Dose-Resposta a Droga , Eletrochoque , Antagonistas de Aminoácidos Excitatórios/farmacologia , Injeções Intraperitoneais , Ketamina/farmacologia , Masculino , Metilfenidato/farmacologia , Atividade Motora/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley
7.
Neuropsychopharmacology ; 31(9): 1900-9, 2006 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-16421514

RESUMO

The dopamine D1/D2 agonist apomorphine (0.63 mg/kg) disrupted prepulse inhibition (PPI) of acoustic startle in rats, a model of sensorimotor gating deficits observed in schizophrenia. All current antipsychotics, which antagonize D2 receptors, prevent this apomorphine-induced deficit. A novel class of antipsychotics possesses, in addition to D2 antagonist property, various levels of 5-HT1A agonist activity. Considering that the latter itself produces PPI deficits, it appeared necessary to assess the potential of this novel class of antipsychotics to reverse apomorphine-PPI deficits. Potent D2 antagonists, like haloperidol (0.63-2.5 mg/kg), risperidone (0.63-10 mg/kg), and olanzapine (0.63-40 mg/kg) prevented apomorphine PPI disruption. The atypical antipsychotics, clozapine (40 mg/kg), nemonapride (0.01-2.5 mg/kg), ziprasidone (10 mg/kg), and aripiprazole (0.01 and 10 mg/kg), which all exhibit 5-HT1A agonist properties, reversed PPI deficits at some doses only, whereas the anti-dyskinetic agent sarizotan (0.16-10 mg/kg), an efficacious 5-HT1A agonist, did not. New generation antipsychotics with marked 5-HT1A agonist properties, such as SLV313 and SSR181507 (0.0025-10 mg/kg and 0.16-10 mg/kg, respectively) did not reverse these deficits whereas bifeprunox (0.04-2.5 mg/kg) did. To reveal the contribution of 5-HT1A agonist properties in the lack of effects of SLV313 and SSR181507, we pretreated rats with the 5-HT1A antagonist WAY100635 (0.63 mg/kg). Under these conditions, significant reversal of PPI deficit was observed, indicating that D2 antagonist properties of SLV313 and SSR181507 are now sufficient to overcome the disruptive effects of apomorphine. To summarize, antipsychotics possessing agonist efficacy at 5-HT1A receptors exhibit diverse profiles against apomorphine-induced PPI deficits, depending on the balance between D2 and 5-HT1A activities, suggesting that they may display distinct activity on some aspects of gating deficits in schizophrenic patients.


Assuntos
Antipsicóticos/farmacologia , Apomorfina/antagonistas & inibidores , Apomorfina/farmacologia , Agonistas de Dopamina/farmacologia , Antagonistas de Dopamina/farmacologia , Antagonistas dos Receptores de Dopamina D2 , Agonistas do Receptor 5-HT1 de Serotonina , Agonistas do Receptor de Serotonina/farmacologia , Aminopiridinas/farmacologia , Animais , Dioxanos/farmacologia , Relação Dose-Resposta a Droga , Masculino , Piperazinas/farmacologia , Piperidinas/farmacologia , Piridinas/farmacologia , Ratos , Ratos Sprague-Dawley , Antagonistas da Serotonina/farmacologia , Tropanos/farmacologia
8.
Neuropsychopharmacology ; 31(9): 1869-79, 2006 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-16237379

RESUMO

A new generation of proven or potential antipsychotics, including aripiprazole, bifeprunox, SSR181507 and SLV313, exhibit agonist actions at serotonin 5-HT1A receptors, but little comparative data are available on their pharmacological profiles. Here, we compared in mice the in vivo antipsychotic-like vs cataleptogenic activities of these compounds with those of drugs that exhibit little interaction at 5-HT1A receptors, such as haloperidol, olanzapine and risperidone. All the drugs dose-dependently reduced apomorphine-induced climbing or sniffing and, with the exception of ziprasidone, produced complete suppression of these responses. In the bar catalepsy test, when administered alone, haloperidol, olanzapine and risperidone produced marked catalepsy, whereas, at doses up to 40 mg/kg, aripiprazole, SLV313, SSR181507, and sarizotan produced little or no catalepsy. The latter compounds, therefore, displayed a large separation between doses with 'antipsychotic-like' and those with cataleptogenic actions. When 5-HT1A receptors were blocked by pretreatment with WAY100635 (2.5 mg/kg, s.c.), cataleptogenic properties of SSR181507 and sarizotan were unmasked, and the catalepsy induced by bifeprunox was enhanced. In the case of aripiprazole and SLV313, although WAY100635 produced upward shifts in their dose-response, the magnitude of catalepsy appeared to reach an asymptotic plateau, suggesting that other mechanisms may be involved in their low cataleptogenic liability. The present data confirm that 5-HT1A receptor activation reduces or even completely prevents the cataleptogenic potential of novel antipsychotic agents. Further, they indicate that the balance of affinity and/or efficacy between D2 and 5-HT1A receptors profoundly influences their pharmacological activities, and will likely impact their therapeutic profiles.


Assuntos
Antipsicóticos/farmacologia , Catalepsia/induzido quimicamente , Antagonistas de Dopamina/farmacologia , Antagonistas dos Receptores de Dopamina D2 , Receptor 5-HT1A de Serotonina/efeitos dos fármacos , Agonistas do Receptor de Serotonina/farmacologia , Animais , Apomorfina/farmacologia , Agonistas de Dopamina/farmacologia , Relação Dose-Resposta a Droga , Masculino , Camundongos , Piperazinas/farmacologia , Piridinas/farmacologia , Antagonistas da Serotonina/farmacologia , Comportamento Estereotipado/efeitos dos fármacos
9.
Neuropharmacology ; 49(2): 135-43, 2005 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-15996562

RESUMO

Compounds possessing 5-HT(1A) agonist properties attenuate catalepsy induced by D(2) receptor blockade. Here we examined the role of 5-HT(1A) receptor agonism in the reduced cataleptogenic potential of several novel antipsychotic agents in the crossed leg position (CLP) and the bar catalepsy tests in rats. When administered alone, ziprasidone produced marked catalepsy, whereas aripiprazole, bifeprunox, SLV313, SSR181507 and sarizotan did not. However, when 5-HT(1A) receptors were blocked with the selective antagonist, WAY100635 (0.63 mg/kg, SC), robust cataleptogenic properties of SLV313, bifeprunox and sarizotan were unmasked and the catalepsy induced by ziprasidone was accentuated. In contrast, only modest catalepsy was induced by aripiprazole and SSR181507, even following a higher dose of WAY100635 (2.5 mg/kg). This suggests that these compounds possess other anti-cataleptic properties, such as partial agonism at dopamine D(2) receptors. The capacity to reverse neuroleptic-induced catalepsy was investigated in interaction studies with haloperidol (2.5 mg/kg, SC). Whereas ziprasidone and aripiprazole did not markedly reduce the effects of haloperidol, SLV313 and sarizotan attenuated CLP catalepsy. In contrast, SSR181507 and bifeprunox potently inhibited both CLP and bar catalepsy. Taken together, these data show that 5-HT(1A) receptor activation reduces the cataleptogenic potential of novel antipsychotic agents but indicate marked diversity in the contribution of 5-HT(1A) and/or other mechanisms to the profiles of the drugs.


Assuntos
Antipsicóticos/uso terapêutico , Catalepsia/tratamento farmacológico , Receptor 5-HT1A de Serotonina/fisiologia , Agonistas do Receptor de Serotonina/uso terapêutico , Análise de Variância , Animais , Antiparkinsonianos/uso terapêutico , Comportamento Animal , Catalepsia/induzido quimicamente , Antagonistas de Dopamina , Relação Dose-Resposta a Droga , Interações Medicamentosas , Masculino , Compostos Orgânicos , Piperazinas/farmacologia , Piperazinas/uso terapêutico , Piridinas/farmacologia , Ratos , Ratos Sprague-Dawley , Agonistas do Receptor 5-HT1 de Serotonina , Antagonistas da Serotonina/farmacologia , Agonistas do Receptor de Serotonina/farmacologia
10.
Neuropharmacology ; 49(7): 996-1006, 2005 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-16009387

RESUMO

Considerable interest has arisen in identifying antipsychotic agents with improved efficacy against negative symptoms, such as social withdrawal. In rats, a social interaction deficit can be induced by the NMDA antagonist phencyclidine (PCP). Here, we examined the effects of antipsychotics, reported to exert dual 5-HT(1A)/D(2) actions, on PCP-induced social interaction deficits. Drugs were administered daily for 3 days in combination with either vehicle or PCP (2.5mg/kg, SC) and social interaction was measured on the last day of drug treatment. Pairs of unfamiliar rats receiving the same treatment were placed in a large open field for 10 min and the number of social behaviors were scored. The results indicate that: (1) PCP significantly reduced social interaction by over 50% compared with vehicle-treated controls; (2) haloperidol (0.0025-0.16 mg/kg, SC) and clozapine (0.04-10mg/kg, IP) did not reverse PCP-induced social interaction deficits; (3) the substituted benzamide remoxipride reversed PCP-induced deficits at 0.63 and 2.5mg/kg (4) the 5-HT(1A) agonist 8-OH-DPAT was inactive (at 0.01-0.63 mg/kg, SC); (5) among compounds reported to exert dual 5-HT(1A)/D(2) actions, SSR181507 (at 0.16 mg/kg, SC) and aripiprazole (at 0.04 and 0.16 mg/kg, IP), but not ziprasidone (0.04-2.5mg/kg, IP), SLV313 (0.0025-0.16 mg/kg, SC) or bifeprunox (0.01-0.63 mg/kg, IP), significantly reversed PCP-induced social interaction deficits; and (6) the 5-HT(1A) receptor antagonist WAY100635 blocked the effects of SSR181507 and aripiprazole. These findings indicate that the balance of activity at 5-HT(1A) and D(2) receptors profoundly influences the activity of antipsychotics in this model of social withdrawal, and their potential benefit on at least some of the negative symptoms of schizophrenia.


Assuntos
Antipsicóticos/farmacologia , Antagonistas de Dopamina/farmacologia , Antagonistas dos Receptores de Dopamina D2 , Antagonistas de Aminoácidos Excitatórios/farmacologia , Relações Interpessoais , Fenciclidina/farmacologia , Receptor 5-HT1A de Serotonina/efeitos dos fármacos , Agonistas do Receptor de Serotonina/farmacologia , 8-Hidroxi-2-(di-n-propilamino)tetralina/farmacologia , Animais , Aripiprazol , Clozapina/farmacologia , Dioxanos/farmacologia , Haloperidol/farmacologia , Masculino , Piperazinas/farmacologia , Piridinas/farmacologia , Quinolonas/farmacologia , Ratos , Ratos Sprague-Dawley , Remoxiprida/farmacologia , Antagonistas da Serotonina/farmacologia , Tiazóis/farmacologia , Tropanos/farmacologia
11.
Psychopharmacology (Berl) ; 177(4): 373-80, 2005 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-15448976

RESUMO

RATIONALE: Recent studies suggest that alpha(2) adrenoceptor blockade may improve the antipsychotic-like effects of neuroleptics and attenuate dopamine D(2) receptor antagonist-induced catalepsy. However, several alpha(2) adrenergic antagonists also display serotonin 5-HT(1A) receptor agonist activity, which may contribute to anticataleptic actions. OBJECTIVES: In this study, we examined a series of alpha(2) adrenergic antagonists to determine the role of activity at serotonin 5-HT(1A) receptors in their anticataleptic effects. METHODS: Catalepsy in rats induced by the antipsychotic haloperidol (2.5 mg/kg, SC) was measured using the cross-legged position (CLP) and bar tests. The compounds examined in this study, in decreasing rank order of alpha(2) adrenergic versus 5-HT(1A) receptor selectivity, were atipamezole, methoxy-idazoxan (RX821002), efaroxan, idazoxan, and yohimbine. Antagonism studies were conducted using the selective 5-HT(1A) receptor antagonist N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridinyl) cyclohexanecarboxamide dihydrochloride (WAY100635). RESULTS: Idazoxan, efaroxan, and yohimbine significantly attenuated the cataleptic effects of haloperidol (2.5 mg/kg, SC) in the CLP test and the actions of their highest doses were significantly blocked by pre-treatment with WAY100635 (0.63 mg/kg, SC). In contrast to the other compounds, methoxy-idazoxan was ineffective in the CLP test. Atipamezole exhibited anticataleptic effects in the bar and CLP tests which were not blocked by WAY100635. Similarly, the anticataleptic effects of methoxy-idazoxan and idazoxan in the bar test were not blocked by WAY100635. CONCLUSIONS: Serotonin 5-HT(1A) receptors play a prominent role in anticataleptic effects of certain alpha(2) adrenergic antagonists in the CLP test, whereas alpha(2)-adrenergic mechanisms are likely to be primarily responsible for the anticataleptic effects of these ligands in the bar test.


Assuntos
Antagonistas de Receptores Adrenérgicos alfa 2 , Antagonistas Adrenérgicos alfa/uso terapêutico , Catalepsia/tratamento farmacológico , Postura/fisiologia , Receptor 5-HT1A de Serotonina/fisiologia , Animais , Comportamento Animal/efeitos dos fármacos , Catalepsia/induzido quimicamente , Antagonistas de Dopamina , Relação Dose-Resposta a Droga , Guanosina 5'-O-(3-Tiotrifosfato)/metabolismo , Haloperidol , Masculino , Piperazinas/farmacologia , Piridinas/farmacologia , Ensaio Radioligante , Ratos , Ratos Sprague-Dawley , Receptor 5-HT1A de Serotonina/efeitos dos fármacos , Antagonistas da Serotonina/farmacologia , Agonistas do Receptor de Serotonina/farmacologia
12.
Psychopharmacology (Berl) ; 172(4): 409-14, 2004 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-14668976

RESUMO

RATIONALE: Studies in rats examining the ability of selective dopamine D(2) receptor class antagonists to attenuate the effects of a cocaine challenge have suggested that these agents are less potent in attenuating sensitized as opposed to non-sensitized locomotion. A potential issue with these studies is that the same challenge dose is used in sensitized and control conditions even though that dose may occupy different positions on the respective dose-response curves. OBJECTIVES: To examine whether the ability of dopamine antagonists to attenuate cocaine-induced locomotion differs between sensitized and non-sensitized animals if they are challenged with the same dose of cocaine, and with the lowest dose to maximally increase locomotion, which is lower in sensitized than in non-sensitized animals. METHODS: Mice were treated repeatedly with 20 mg/kg cocaine or saline (for 3 consecutive days) and then challenged (after an 11-day drug-free interval) with different challenge doses of cocaine after pretreatment with a dopamine antagonist or saline. RESULTS: Using the same challenge dose of cocaine in both repeated treatment conditions (i.e. 20 mg/kg), the D(2 )class antagonists eticlopride and raclopride were less potent in attenuating the locomotor effects of cocaine in sensitized than those in non-sensitized animals. In contrast, when the lowest doses to maximally increase locomotion in each of the repeated treatment conditions were used (10 and 40 mg/kg), the D(2 )class antagonists attenuated the locomotor effects of cocaine in sensitized and non-sensitized animals with similar potencies. The ability of the D(1) class antagonist SCH23390 to attenuate the effects of cocaine demonstrated a similar dependency on the challenge dose. CONCLUSIONS: These results show that, under the present conditions, the ability of dopamine antagonists to attenuate cocaine-induced locomotion is similar in sensitized and non-sensitized animals when challenged with pharmacologically equivalent doses of cocaine, but not when challenged with the same dose.


Assuntos
Cocaína/antagonistas & inibidores , Antagonistas dos Receptores de Dopamina D2 , Inibidores da Captação de Dopamina/antagonistas & inibidores , Atividade Motora/efeitos dos fármacos , Animais , Comportamento Animal/efeitos dos fármacos , Benzazepinas/farmacologia , Cocaína/administração & dosagem , Inibidores da Captação de Dopamina/administração & dosagem , Relação Dose-Resposta a Droga , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Racloprida/farmacologia , Salicilamidas/farmacologia
13.
Neuropsychopharmacology ; 26(3): 340-7, 2002 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-11850148

RESUMO

The 5-HT(1A) agonist 8-OH-DPAT has been reported to disrupt prepulse inhibition (PPI) of the acoustic startle reflex after local administration into the raphe nuclei. Because it is likely that 8-OH-DPAT disrupted PPI by activation of somatodendritic inhibitory receptors, and thereby, via a decrease in 5-HT neurotransmission, we tested whether chronic, drug-induced, depletions of 5-HT have similar effects. Rats were drug-treated for three consecutive days and tested in a short PPI paradigm on day 4, and retested 2 h later, after acute saline or drug administration. Repeated treatment with the 5-HT synthesis inhibitor p-chlorophenylalanine methyl ester (PCPA; 160 mg/kg) produced a small, but significant, attenuation of PPI, and a large decrease in extracellular 5-HT levels in the hippocampus, as measured in independent microdialysis experiments. An even larger depletion of 5-HT was obtained by substituting the 3(rd) PCPA administration with the 5-HT releaser d-fenfluramine (10 mg/kg); this combined treatment nearly abolished PPI in the majority of animals. The involvement of 5-HT in the latter effects was confirmed by the finding that low doses of the 5-HT precursor 5-hydroxy-L-tryptophan reinstated PPI during retest. These data, together with recently published studies, provide strong evidence that pharmacologically-induced depletion of 5-HT disrupts PPI.


Assuntos
5-Hidroxitriptofano/farmacologia , Fenclonina/farmacologia , Reflexo de Sobressalto/efeitos dos fármacos , Reflexo de Sobressalto/fisiologia , Antagonistas da Serotonina/farmacologia , Serotonina/metabolismo , Animais , Combinação de Medicamentos , Fenfluramina/farmacologia , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Ácido Hidroxi-Indolacético/metabolismo , Masculino , Ratos , Ratos Sprague-Dawley , Inibidores Seletivos de Recaptação de Serotonina/farmacologia
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