RESUMO
BACKGROUND: Previous findings have shown that intra-accumbens injection of naltrexone, a non-selective opioid antagonist, blocks the acquisition of rapid tolerance to ethanol in rats. This study investigates the effects of intra-accumbens injection of the selective mu-, delta-, and kappa-opioid antagonists, respectively, naloxonazine, naltrindole, and nor-binaltorphimine, on rapid tolerance to ethanol. METHODS: Male Wistar rats with guide cannulae directed to the shell or the core portions of the nucleus accumbens received a microinjection of naloxonazine (2-4 microg), naltrindole (2-4 microg), nor-binaltorphimine (2.5-5 microg), or vehicle. After 5 min, each group was divided in two groups that received ethanol (2.7 g/kg i.p.) or saline. Rats were then tested for motor coordination on the tilting plane apparatus. Twenty four hours later, all rats received a challenge dose of ethanol (2.7 g/kg i.p.) and were tested on the tilt plane again. RESULTS: Repeated injections of ethanol caused a reduction in motor impairment suggesting the development of tolerance. However, rats injected with 4 microg naloxonazine into either core or shell portions of the nucleus accumbens did not exhibit tolerance when challenged with ethanol on day 2. Rats treated with 5 microg nor-binaltorphimine into accumbens core plus intraperitoneal saline on day 1 showed reduced motor impairment when challenged with ethanol on day 2, suggesting cross-tolerance to ethanol. CONCLUSIONS: Taken together, our results suggests that mu-opioid receptors in both shell and core portions of the nucleus accumbens, and possibly kappa-opioid in the core, participate in the modulation of rapid tolerance to ethanol.
Assuntos
Etanol/farmacologia , Antagonistas de Entorpecentes/farmacologia , Núcleo Accumbens/efeitos dos fármacos , Receptores Opioides kappa/antagonistas & inibidores , Receptores Opioides mu/antagonistas & inibidores , Animais , Tolerância a Medicamentos , Masculino , Microinjeções , Naloxona/análogos & derivados , Naloxona/farmacologia , Naltrexona/análogos & derivados , Naltrexona/farmacologia , Núcleo Accumbens/fisiologia , Ratos , Ratos WistarRESUMO
Several studies have emphasized the role of learning in the development of rapid tolerance and have shown that glutamate-mediated neurotransmission plays an important role in this phenomenon. Since the AMPA/kainate receptor system is directly involved in plasticity mechanisms, the influence of this receptor system on rapid tolerance induced by ethanol was studied using the rotarod. In the first experiment, mice were pretreated with aniracetam, an agonist of AMPA/kainate receptors, 30 min before ethanol (2.75 g/kg; IP) treatment, and tested on the rotarod. After 24 h, the groups were tested on the rotarod under ethanol treatment. Aniracetam facilitated the acquisition of rapid tolerance to ethanol. In the second experiment, mice received DNQX, a competitive antagonist of the AMPA receptor, 30 min before ethanol treatment (3 g/kg) and submitted to the rotarod. This dose of ethanol produced tolerance per se. Groups were tested under ethanol treatment (1.75 g/kg) after 24 h. DNQX blocked rapid tolerance to ethanol. Using a similar protocol, the third experiment showed that DNQX blocked the aniracetam-induced facilitation of rapid tolerance to ethanol. Our results show that aniracetam facilitates whereas DNQX blocks ethanol tolerance, suggesting that the non-NMDA receptors are involved in this phenomenon.
Assuntos
Depressores do Sistema Nervoso Central/farmacologia , Etanol/farmacologia , Antagonistas de Aminoácidos Excitatórios/farmacologia , Nootrópicos/farmacologia , Pirrolidinonas/farmacologia , Quinoxalinas/farmacologia , Animais , Depressores do Sistema Nervoso Central/sangue , Tolerância a Medicamentos , Etanol/sangue , Feminino , Ácido Glutâmico/metabolismo , Camundongos , Equilíbrio Postural/efeitos dos fármacos , Desempenho Psicomotor/efeitos dos fármacos , Receptores de AMPA/antagonistas & inibidores , Receptores de Ácido Caínico/antagonistas & inibidoresRESUMO
OBJECTIVE: The objective of the present study was to investigate the effect of epipregnanolone on the influence of neurosteroids on the development of rapid tolerance to the motor impairing and hypothermic effects of ethanol. METHOD: Experiment 1: on Day 1 groups of mice were pretreated with saline or with epipregnanolone. After 30 min each group was further divided in subgroups that received ethanol or saline. Thirty, 60 and 90 min after the injections the animals were tested on the rota-rod or the body temperature was measured. On Day 2 all groups received ethanol and a similar procedure was followed to evaluate rapid tolerance. Experiment 2 and 3: On Day 1 groups of mice were treated with epipregnanolone and after 15 min each group was divided into three groups in order to receive pregnenolone sulfate, dehydroepiandrosterone sulfate or saline. Thirty minutes later, each group was further divided into two subgroups in order to receive ethanol or saline, respectively, and 30, 60 and 90 min later the animals were tested as in the experiment 1. On Day 2 all groups received ethanol and a similar procedure was followed to evaluate rapid tolerance. RESULTS: Pretreatment with epipregnanolone (0.10-0.30 mg/kg) significantly blocked the development of tolerance to the motor impairing and hypothermic effects induced by ethanol in mice. Considering tolerance to ethanol-induced motor impairment, epipregnanolone (0.15 mg/kg) reversed the stimulatory action of dehydroepiandrosterone sulfate (0.15 mg/kg), but did not affect the actions of pregnenolone sulfate (0.08 mg/kg). Moreover, epipregnanolone prevented the inhibitory action of allotetrahydrodeoxycorticosterone (0.10 mg/kg). In relation to ethanol-induced hypothermia, the results showed that pretreatment with epipregnanolone (0.30 mg/kg) significantly prevented the stimulatory action of dehydroepiandrosterone sulfate and pregnenolone sulfate, as well as the inhibitory action of...
OBJETIVO: O objetivo do presente estudo foi o de investigar o efeito da epipregnanolona sobre a influência de neuroesteróides no desenvolvimento da tolerância rápida aos efeitos de incoordenação motora e hipotermia induzidos pelo etanol. MÉTODO: Experimento 1: no Dia 1, grupos de camundongos foram pré-tratados com salina ou com epipregnanolona. Após 30 min, cada grupo foi subdividido recebendo etanol ou salina. Aos 30, 60 e 90 min após as injeções, os animais foram testados no rota-rod ou a temperatura corporal foi avaliada. No Dia 2, todos os grupos receberam etanol e um procedimento similar foi seguido para avaliar a tolerância rápida. O pré-tratamento com a epipregnanolona (0,10-0,30 mg/kg) bloqueou significantemente o desenvolvimento da tolerância aos efeitos de incoordenação motora e hipotermia induzidos pelo etanol em camundongos. Experimento 2 e 3: no Dia 1, grupos de animais foram tratados com epipregnanolona e, após 15 min, cada grupo foi dividido em três grupos para receber sulfato de pregnanolona, sulfato de dehidroepiandrosterona ou salina. Após 30 min, cada grupo foi dividido em dois subgrupos para receber etanol ou salina, respectivamente, e após 30, 60 e 90 min os animais foram testados como no experimento 1. No Dia 2, todos os grupos receberam etanol e 30 min após foram testados como mencionado no experimento 1. RESULTADOS: Considerando a tolerância ao prejuízo motor induzido pelo etanol, a epipregnanolona (0,15 mg/kg) bloqueou a ação estimulatória do sulfato de dehidroepiandrosterona (0,15 mg/kg), mas não afetou a ação do sulfato de pregnanolona (0,08 mg/kg). Entretanto, a epipregnanolona bloqueou a ação inibitória da alotetrahidrodeoxicorticosterona (0,10 mg/kg). Em relação à hipotermia induzida pelo etanol, os resultados demonstraram que o pré-tratamento com epipregnanolona (0,30 mg/kg) bloqueou significantemente a ação estimulatória do sulfato de dehidroepiandrosterona e do sulfato de pregnanolona, bem como a ação...
Assuntos
Animais , Masculino , Camundongos , Anestésicos/farmacologia , Depressores do Sistema Nervoso Central/farmacologia , Etanol/farmacologia , Hipotermia/induzido quimicamente , Atividade Motora/efeitos dos fármacos , Pregnanolona/farmacologia , Análise de Variância , Temperatura Corporal/efeitos dos fármacos , Desoxicorticosterona/análogos & derivados , Desoxicorticosterona/farmacologia , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Interações Medicamentosas , Tolerância a Medicamentos , Pregnenolona/farmacologiaRESUMO
RATIONALE: Our previous findings have shown rapid cross-tolerance between ethanol and Delta(9)-tetrahydrocannabinol and that intraperitoneal (i.p.) injection of cannabinoid receptor type 1 (CB1R) antagonist SR141716 (SR) does not interfere with tolerance to either of these drugs in mice. OBJECTIVES: This study investigates the effects of SR, alone or in combination with the CB receptor agonist WIN 55,212-2 (WIN), on the development of acute and rapid tolerance to the incoordinating effect of ethanol in rats. MATERIALS AND METHODS: Male Wistar rats received SR, through i.p. (0.5-2.0 mg/kg) or intracerebroventricular (i.c.v.) injections (0.5-4.0 microg), alone or together with WIN (1.0 microg, i.c.v.), in combination with ethanol (2.7 g/kg, i.p.). Another group received WIN (1.0 microg, i.c.v.) in combination with ethanol (2.3 g/kg), and the rats were tested for motor coordination. Rapid tolerance was assessed 24 h later by administering ethanol to all animals and retesting them under the same dose regimen. Acute tolerance was evaluated for 75 min after ethanol (3.0 g/kg, i.p.) in animals treated with SR or WIN (i.c.v.). RESULTS: The reduced motor impairment on day 2 (i.e., rapid tolerance) was blocked by SR (i.p. and i.c.v.). WIN (1.0 microg, i.c.v.) facilitated rapid tolerance and also prevented the blockade of rapid tolerance by SR (1.0 microg, i.c.v.). In the acute tolerance procedure, SR did not affect the motor incoordination induced by ethanol. CONCLUSIONS: The results suggest that the endocannabinoid system may contribute to the development of rapid tolerance to ethanol.
Assuntos
Benzoxazinas/farmacologia , Etanol/farmacologia , Morfolinas/farmacologia , Atividade Motora/efeitos dos fármacos , Naftalenos/farmacologia , Piperidinas/farmacologia , Pirazóis/farmacologia , Analgésicos Opioides/administração & dosagem , Analgésicos Opioides/farmacologia , Animais , Benzoxazinas/administração & dosagem , Depressores do Sistema Nervoso Central/administração & dosagem , Depressores do Sistema Nervoso Central/farmacologia , Relação Dose-Resposta a Droga , Interações Medicamentosas , Tolerância a Medicamentos , Etanol/administração & dosagem , Injeções Intraperitoneais , Injeções Intraventriculares , Masculino , Morfolinas/administração & dosagem , Naftalenos/administração & dosagem , Piperidinas/administração & dosagem , Pirazóis/administração & dosagem , Ratos , Ratos Wistar , Receptor CB1 de Canabinoide/agonistas , Receptor CB1 de Canabinoide/antagonistas & inibidores , Rimonabanto , Fatores de TempoRESUMO
OBJECTIVE: The objective of the present study was to investigate the effect of epipregnanolone on the influence of neurosteroids on the development of rapid tolerance to the motor impairing and hypothermic effects of ethanol. METHOD: Experiment 1: on Day 1 groups of mice were pretreated with saline or with epipregnanolone. After 30 min each group was further divided in subgroups that received ethanol or saline. Thirty, 60 and 90 min after the injections the animals were tested on the rota-rod or the body temperature was measured. On Day 2 all groups received ethanol and a similar procedure was followed to evaluate rapid tolerance. Experiment 2 and 3: On Day 1 groups of mice were treated with epipregnanolone and after 15 min each group was divided into three groups in order to receive pregnenolone sulfate, dehydroepiandrosterone sulfate or saline. Thirty minutes later, each group was further divided into two subgroups in order to receive ethanol or saline, respectively, and 30, 60 and 90 min later the animals were tested as in the experiment 1. On Day 2 all groups received ethanol and a similar procedure was followed to evaluate rapid tolerance. RESULTS: Pretreatment with epipregnanolone (0.10-0.30 mg/kg) significantly blocked the development of tolerance to the motor impairing and hypothermic effects induced by ethanol in mice. Considering tolerance to ethanol-induced motor impairment, epipregnanolone (0.15 mg/kg) reversed the stimulatory action of dehydroepiandrosterone sulfate (0.15 mg/kg), but did not affect the actions of pregnenolone sulfate (0.08 mg/kg). Moreover, epipregnanolone prevented the inhibitory action of allotetrahydrodeoxycorticosterone (0.10 mg/kg). In relation to ethanol-induced hypothermia, the results showed that pretreatment with epipregnanolone (0.30 mg/kg) significantly prevented the stimulatory action of dehydroepiandrosterone sulfate and pregnenolone sulfate, as well as the inhibitory action of allotetrahydrodeoxicorticosterone (0.20 mg/kg), on tolerance to this effect. CONCLUSIONS: The results suggest a differential interaction between neurosteroids that might modulate the development of rapid tolerance to ethanol.
Assuntos
Anestésicos/farmacologia , Depressores do Sistema Nervoso Central/farmacologia , Etanol/farmacologia , Hipotermia/induzido quimicamente , Atividade Motora/efeitos dos fármacos , Pregnanolona/farmacologia , Análise de Variância , Animais , Temperatura Corporal/efeitos dos fármacos , Desoxicorticosterona/análogos & derivados , Desoxicorticosterona/farmacologia , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Interações Medicamentosas , Tolerância a Medicamentos , Masculino , Camundongos , Pregnenolona/farmacologiaRESUMO
Our previous study showed the microinjection of drugs that influence the nitric oxide (NO)-mediated neurotransmission in the hippocampus impacts upon the anxiolytic-like effect of ethanol. In this study, we examined whether NO-dependent pathways of the dorsolateral periaqueductal gray (dlPAG) participate in the anxiolytic effect of ethanol in rats submitted to the elevated plus-maze test. We evaluated the impact on ethanol effects of the nitric oxide synthase (NOS) inhibitor 7-nitroindazole, the soluble guanylate cyclase inhibitor 1H-(1,2,4)-oxodiazolo (4,3-a) quinoxalin-1-one (ODQ), the cyclic guanylate monophosphate (cGMP) analogue 8-bromo-cGMP and the NO donor sodium nitroprusside. The results showed that ODQ and 7-nitroindazole increased the percentage of open arm entries and of time spent on open arms in the elevated plus maze in rats injected with ethanol at 1.0g/kg, a dose that did not produce anxiolysis per se. Conversely, 8-bromo-cGMP and sodium nitroprusside blocked the increased exploration of open arms exhibited by rats treated with a higher dose of ethanol (1.2g/kg). Taken together, the results suggest that the inhibition of NO-dependent pathways of the dlPAG enhances the anxiolytic effect of ethanol, whereas the activation of these pathways results in an opposite effect.
Assuntos
Nível de Alerta/efeitos dos fármacos , Etanol/farmacologia , Medo/efeitos dos fármacos , Aprendizagem em Labirinto/efeitos dos fármacos , Óxido Nítrico/fisiologia , Substância Cinzenta Periaquedutal/efeitos dos fármacos , Animais , Nível de Alerta/fisiologia , Relação Dose-Resposta a Droga , Comportamento Exploratório/efeitos dos fármacos , Medo/fisiologia , Injeções Intraperitoneais , Masculino , Aprendizagem em Labirinto/fisiologia , Vias Neurais/efeitos dos fármacos , Vias Neurais/fisiologia , Orientação/efeitos dos fármacos , Orientação/fisiologia , Substância Cinzenta Periaquedutal/fisiologia , Ratos , Ratos Wistar , Tempo de Reação/efeitos dos fármacos , Tempo de Reação/fisiologiaRESUMO
O objetivo deste artigo é o de revisar e descrever as principais alteracões neurofarmacológicas causadas pela exposicão crônica ao álcool, assim como os fenômenos ocorridos durante o período de abstinência. São apresentados dados referentes às alteracões neuroadaptativas e de tolerância ocorridas nos principais sistemas de monoaminas, aminoácidos neurotransmissores e canais de cálcio, o que está relacionado a uma piora no prognóstico de portadores de comorbidades psiquiátricas com o consumo de álcool. São também descritos alguns estudos relevantes que demonstram o envolvimento de outros mecanismos de acão do álcool no sistema nervoso central, como o envolvimento de opióides, entre outras substâncias. O artigo reafirma a importância, para clínicos e pesquisadores, de um sempre maior entendimento do mecanismo de acão central do álcool, pois dele depende a busca por novas opcões farmacológicas, tanto para a reducão dos danos provocados pelo seu uso crônico, como para o tratamento da síndrome de abstinência a esta substância.
Assuntos
Humanos , Delirium por Abstinência Alcoólica/metabolismo , Alcoolismo/metabolismo , Neurotransmissores/metabolismo , Delirium por Abstinência Alcoólica/fisiopatologia , Intoxicação Alcoólica/metabolismo , Intoxicação Alcoólica/fisiopatologia , Alcoolismo/fisiopatologia , Etanol/metabolismoRESUMO
The objective of this paper is to review and describe the main neuropharmacological changes caused by the chronic use of alcohol and those observed during its withdrawal period. The results show international data referring to the involvement of monoamine systems, neurotransmitters and calcium channels in both neuroadaptation and tolerance to alcohol effects and withdrawal. Relevant studies showing the participation of other systems in those mechanisms, as opioids and other substances, are also shown. The article reinforces the importance, for both physicians and researchers, of an always growing understanding of alcohol central mechanisms of action. This understanding is necessary to new pharmacological options to alcohol harm reduction as well as to alcohol withdrawal treatment.
Assuntos
Delirium por Abstinência Alcoólica/metabolismo , Alcoolismo/metabolismo , Neurotransmissores/metabolismo , Delirium por Abstinência Alcoólica/fisiopatologia , Intoxicação Alcoólica/metabolismo , Intoxicação Alcoólica/fisiopatologia , Alcoolismo/fisiopatologia , Etanol/metabolismo , HumanosRESUMO
RATIONALE: Our previous studies have shown that the inhibition of nitric oxide (NO) synthesis with drugs administered either by systemic or ICV routes blocks the development of tolerance to some of the effects of ethanol. OBJECTIVES: The aim of this study was to further investigate the role of NO-dependent pathways in tolerance to the incoordinating effect of ethanol through ICV administration of drugs that activate or interfere with NO-dependent pathways. METHODS: Male Wistar rats were pretreated with IP ethanol (2.7 g/ kg) or saline before receiving ICV injections of the soluble guanylyl cyclase (sGC) inhibitors methylene blue (30 nmol), 6(phenylamino)-5,8-quinolinedione (LY83583, 10 nmol), 1H-(1,2,4)-oxodiazolo (4,3-a)quinoxalin-1-one (ODQ, 1 nmol), and 4H-8-bromo-1,2,4-oxadiazolo (3,4-d)benz(b)(1,4)oxazin-1-one (NS2028, 10 nmol), or the respective control solutions. The animals were tested on the tilt plane apparatus. Tolerance was assessed 24 h after the first ethanol injection, by administering ethanol to all animals and re-testing them on the tilt plane. The effects of the cyclic guanylate 3',5'-monophosphate (cGMP) analogue, 8-bromo-cGMP (40 nmol or 80 nmol) and of the NO donors S-nitroso-N-acetylpenicillamine (SNAP, 40 or 80 nmol) and sodium nitroprusside (SNP, 40 or 80 nmol) were also studied. RESULTS: All sGC inhibitors significantly blocked rapid tolerance, whereas SNP (40 nmol) and 8-bromo-cGMP (80 nmol) increased the magnitude of ethanol tolerance (ANOVA+Tukey's test). CONCLUSIONS: The present results suggest that activation or inhibition of NO-dependent pathways increases or blocks rapid tolerance, respectively. These results give additional support to the hypothesis that brain NO plays a role in the development of tolerance to ethanol, but it remains to be confirmed if the same basic cellular mechanisms are also applicable to tolerance to other behavioural and/or physiological effects of this drug.
Assuntos
GMP Cíclico/análogos & derivados , Inibidores Enzimáticos/farmacologia , Etanol/farmacologia , Guanilato Ciclase/antagonistas & inibidores , Atividade Motora/efeitos dos fármacos , Óxido Nítrico Sintase/antagonistas & inibidores , Óxido Nítrico/fisiologia , Aminoquinolinas/farmacologia , Animais , GMP Cíclico/farmacologia , Tolerância a Medicamentos/fisiologia , Masculino , Oxidiazóis/farmacologia , Quinoxalinas/farmacologia , Ratos , Ratos WistarRESUMO
Our previous study showed that the neurosteroids pregnenolone sulfate (PS) and epipregnanolone stimulated and blocked, respectively, the demonstration of chronic tolerance to the incoordinating effect of ethanol. The aim of the present study was to investigate the influence of three neurosteroids on the demonstration of tolerance to ethanol-induced hypothermia in mice using the rapid tolerance paradigm. The first experiment defined the doses of ethanol that did or did not induce rapid tolerance to ethanol-induced hypothermia. In the second, the influence of pretreatment of mice with PS (0.08 or 0.15 mg/kg, i.p.) or dehydroepiandrosterone sulfate (DHEAS; 0.15 or 0.20 mg/kg, i.p.) before ethanol (4.0 g/kg, i.p.) on rapid tolerance was studied. The third experiment examined the effect of allotetrahydrodeoxicorticosterone (ALLOT; 0.10 or 0.20 mg/kg, i.p.) before ethanol (4.0 g/kg, i.p.) on rapid tolerance. Results showed that pretreatment with PS or with DHEAS significantly facilitated the demonstration of rapid tolerance, whereas pretreatment with ALLOT interfered with the demonstration of tolerance to the hypothermic effect.