RESUMO
Post-traumatic stress disorder (PTSD) is a debilitating psychiatric syndrome that occurs in individuals exposed to extremely threatening or traumatic events. In both animals and humans, dopamine (DA) function appears to be dysregulated in brain areas involved in the conditioned fear response(s) that underlie PTSD. In this study, we determined the effect of the selective DA D3 receptor antagonists YQA14A (6.25, 12.5 and 25 mg/kg i.p.) and SB-277011A (6 mg/kg i.p.) on tone-induced fear (assessed by measuring freeze time) in a modified version of the single-prolonged stress (SPS) model of PTSD in adult male Sprague-Dawley rats. Rats pretreated with vehicle and then subjected to restraint stress, forced swim and random foot shock (SPS) in the presence of a distinctive tone, displayed a significantly increased tone-induced contextual freeze time and fecal pellet mass following re-exposure to the tone. Rats pretreated with a single i.p. injection of 6.25 or 12.5 mg/kg of YQA14 or 6 mg/kg of SB-277011A showed significantly attenuated contextual freeze time in the presence of the tone when tested 14 days after exposure to SPS. Overall, our results indicate that selectively antagonizing DA D3 receptors significantly decreases freezing time caused by an environment previously associated with stress. If our findings can be extrapolated to humans with PTSD, they suggest that DA D3 receptors may play a role in the pathophysiology of PTSD, and may have therapeutic utility for the clinical management of PTSD.
Assuntos
Benzoxazóis/farmacologia , Nitrilas/farmacologia , Piperazinas/farmacologia , Psicotrópicos/farmacologia , Receptores de Dopamina D3/antagonistas & inibidores , Transtornos de Estresse Pós-Traumáticos/tratamento farmacológico , Tetra-Hidroisoquinolinas/farmacologia , Animais , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Fezes , Reação de Congelamento Cataléptica/efeitos dos fármacos , Reação de Congelamento Cataléptica/fisiologia , Masculino , Atividade Motora/efeitos dos fármacos , Atividade Motora/fisiologia , Distribuição Aleatória , Ratos Sprague-Dawley , Receptores de Dopamina D3/metabolismo , Transtornos de Estresse Pós-Traumáticos/metabolismo , Estresse Psicológico/tratamento farmacológico , Estresse Psicológico/metabolismoRESUMO
We determined the effect of the selective dopamine D3 receptor antagonist SB-277011A on reactivation of conditioned place preference (CPP) to cocaine elicited by priming injections of cocaine or exposure to food deprivation stress (21 h) in male Sprague-Dawley rats. Animals paired with the cocaine-associated chamber displayed a robust and consistent CPP response. This CPP was extinguished after repeated pairings of the conditioned stimuli (cocaine-paired chamber contextual cues) in the absence of the unconditioned stimulus (cocaine). Twenty-four hours later, the administration of 5 mg kg(-1) i.p. of cocaine (immediately before the test) or exposure to 21 h of food deprivation reactivated the expression of the cocaine-induced CPP. In contrast, administration of 1 ml kg(-1) i.p. of vehicle did not reactivate the CPP response. Administration of the selective dopamine D3 receptor antagonist SB-277011A (3-24 mg kg(-1) i.p.) 30 min before cocaine administration on the test day produced a significant attenuation of CPP reactivation. Reactivation of the CPP response produced by food deprivation was also significantly attenuated by SB-277011A (6 or 12 mg kg(-1) i.p.) given 30 min before the test session. SB-277011A (12 or 24 mg kg(-1) i.p.) did not itself produce reactivation of the CPP response. Overall, these results suggest that the reactivation of the incentive value of drug-associated cues by cocaine or food deprivation is attenuated by selective antagonism of D3 receptors.
Assuntos
Cocaína/farmacologia , Condicionamento Psicológico/efeitos dos fármacos , Antagonistas de Dopamina/farmacologia , Inibidores da Captação de Dopamina/farmacologia , Nitrilas/farmacologia , Comportamento Espacial/efeitos dos fármacos , Tetra-Hidroisoquinolinas/farmacologia , Animais , Condicionamento Psicológico/fisiologia , Extinção Psicológica/efeitos dos fármacos , Extinção Psicológica/fisiologia , Privação de Alimentos/fisiologia , Masculino , Distribuição Aleatória , Ratos Sprague-Dawley , Receptores de Dopamina D3/antagonistas & inibidores , Receptores de Dopamina D3/metabolismo , Comportamento Espacial/fisiologiaRESUMO
The authors show that the dopamine D3 antagonist SB-277011-A consistently and persistently decrease binge-like EtOH consumption at 30 mg/kg and it decreases binge-like consumption on days 3, 7, 9, and 11-13 at 15 mg/kg. These findings suggest that the brain's D3 receptor may also be involved in not only ethanol reward but binge drinking as well.
Assuntos
Dissuasores de Álcool/farmacologia , Consumo Excessivo de Bebidas Alcoólicas/tratamento farmacológico , Nitrilas/farmacologia , Receptores de Dopamina D3/antagonistas & inibidores , Tetra-Hidroisoquinolinas/farmacologia , Animais , Consumo Excessivo de Bebidas Alcoólicas/metabolismo , Depressores do Sistema Nervoso Central/administração & dosagem , Antagonistas de Dopamina/farmacologia , Ingestão de Líquidos/efeitos dos fármacos , Água Potável/administração & dosagem , Etanol/administração & dosagem , Camundongos Endogâmicos C57BL , Distribuição Aleatória , Receptores de Dopamina D3/metabolismoRESUMO
We examined the effect of acute administration of the selective D3 receptor antagonist SB-277011A on morphine-triggered reactivation of cocaine-induced conditioned place preference (CPP) in adult male Sprague-Dawley rats. Repeated pairing of animals with 15 mg/kg i.p. of cocaine HCl or vehicle to cue-specific CPP chambers produced a significant CPP response compared to animals paired only with vehicle in both chambers. Expression of the CPP response to cocaine was then extinguished by repeatedly giving the animals vehicle injections in the cocaine-paired chambers. The magnitude of the CPP response after extinction was not significantly different from that of animals paired only with vehicle. Expression of the extinguished CPP response was reactivated by acute administration of 5 mg/kg i.p. of morphine but not by vehicle. Acute administration of 6 or 12 mg/kg i.p. (but not 3 mg/kg) of SB-277011A significantly attenuated morphine-triggered reactivation of the cocaine-induced CPP. SB-277011A itself (12 mg/kg i.p.) did not reactivate the extinguished CPP response. Overall, SB-277011A decreases the incentive motivational actions of morphine. The present findings suggest that central D3 dopamine receptors are involved in relapse to cocaine-seeking behavior, that a final common neural mechanism exists to mediate the incentive motivational effects of psychostimulants and opiates, and that selective dopamine D3 receptor antagonists constitute promising compounds for treating addiction.
Assuntos
Cocaína/farmacologia , Condicionamento Clássico/efeitos dos fármacos , Antagonistas de Dopamina/farmacologia , Morfina/farmacologia , Nitrilas/farmacologia , Receptores de Dopamina D3/antagonistas & inibidores , Tetra-Hidroisoquinolinas/farmacologia , Animais , Sinais (Psicologia) , Comportamento de Procura de Droga , Masculino , Motivação/efeitos dos fármacos , Ratos , Ratos Sprague-DawleyRESUMO
We examined the effect of SB-277011A, a selective D(3) receptor antagonist, on the conditioned place aversion (CPA) response associated with naloxone-induced withdrawal from acute morphine administration in male Sprague-Dawley rats. Morphine (5.6 mg/kg i.p.) was given, followed 4 hrs later by naloxone (0.3 mg/kg i.p.) and prior to placing the animals in one specific chamber of the test apparatus. All animals were subjected to 2 of these trials. A significant CPA occurred in animals that received an i.p. injection of vehicle 30 minutes prior to the measurement of chamber preference. The pretreatment of animals (30 minutes prior to testing) with 3 mg/kg i.p. of SB-277011A did not significantly alter the CPA compared to animals treated with vehicle (1 ml/kg i.p. of deionized distilled water). In contrast, the acute pretreatment of animals with 6, 12 or 24 mg/kg i.p. of SB-277011A significantly decreased the CPA compared to vehicle-treated animals. In fact, the 12 and 24 mg/kg doses of SB-277011A significantly increased the time spent in the chamber where animals were paired with morphine and naloxone. These results suggest that the selective antagonism of D(3) receptors attenuates the CPA produced by a model of naloxone-induced withdrawal from acute morphine dependence.
Assuntos
Condicionamento Operante/efeitos dos fármacos , Antagonistas de Dopamina/farmacologia , Nitrilas/farmacologia , Receptores de Dopamina D3/antagonistas & inibidores , Síndrome de Abstinência a Substâncias/tratamento farmacológico , Tetra-Hidroisoquinolinas/farmacologia , Animais , Aprendizagem da Esquiva/efeitos dos fármacos , Masculino , Morfina/farmacologia , Naloxona/farmacologia , Antagonistas de Entorpecentes/farmacologia , Entorpecentes/farmacologia , Ratos , Ratos Sprague-Dawley , Receptores de Dopamina D3/metabolismoRESUMO
The mesolimbic dopamine (DA) pathway plays an integral role in the reinforcing properties of many drugs of abuse, including alcohol (ethanol/EtOH). It has been reported that selective and acute blockade of the DA D3 receptor by SB-277011A will attenuate EtOH preference, intake, and lick responses in EtOH preferring rats. However, alcohol consumption that leads to abuse is often marked by binge drinking-which is characterized as bringing ones blood EtOH levels to ≥80 mg/dL within 2 hours of the initial drink. It is unclear if brain mechanisms implicated in EtOH reward are equally implicated in EtOH binge consumption and abuse. Therefore, in this study, we examined the effect of the preferential D3 receptor antagonist S33138 on ethanol (6% v/v) and water consumption in male C57BL/6J mice using a restricted-access binge-drinking model. Ethanol drinking was not significantly altered by the intraperitoneal (i.p.) administration of 0.16 mg/kg of S33138. In contrast, the i.p. administration of 0.64 or 2.5 mg/kg i.p. of S33138 produced a significant decrease in ethanol consumption on days 1 and 7 and days 7-14 compared to vehicle treated animals. However, the mean water consumption was significantly decreased by (1) 0.16 and 0.64 mg/kg i.p. of S33138 on Day 1 and (2) 2.5 mg/kg i.p. of S33138 at Days 1, 7, and 7-14. Our studies indicate that a low dose of S33138 significantly decreases binge drinking, and that it does not significantly alter the consumption of water. In addition, S33138 alone is not appetitive.
Assuntos
Acetanilidas/farmacologia , Benzopiranos/farmacologia , Consumo Excessivo de Bebidas Alcoólicas/tratamento farmacológico , Receptores de Dopamina D3/antagonistas & inibidores , Acetanilidas/uso terapêutico , Animais , Benzopiranos/uso terapêutico , Consumo Excessivo de Bebidas Alcoólicas/fisiopatologia , Ingestão de Líquidos , Etanol/toxicidade , Masculino , Camundongos , Camundongos Endogâmicos C57BLAssuntos
Cocaína/administração & dosagem , Condicionamento Operante/efeitos dos fármacos , Sinais (Psicologia) , Antagonistas de Dopamina/farmacologia , Inibidores da Captação de Dopamina/administração & dosagem , Nitrilas/farmacologia , Tetra-Hidroisoquinolinas/farmacologia , Análise de Variância , Animais , Meio Ambiente , Masculino , Ratos , Ratos Sprague-Dawley , AutoadministraçãoRESUMO
Recent reports have suggested an involvement of the brain cannabinoid system in the morphine-reward pathway. To address this question we evaluated whether CB1 receptor knockout mice would show a conditioned place preference to morphine. CB1 receptor knockout mice developed a strong place preference to 4 and 8 mg/kg morphine, similar to that in wild-type Swiss-Webster mice. This data thus does not support a contribution of the brain cannabinoid system to morphine reward.
Assuntos
Comportamento de Escolha/efeitos dos fármacos , Comportamento de Escolha/fisiologia , Condicionamento Psicológico , Morfina/farmacologia , Entorpecentes/farmacologia , Receptores de Droga/fisiologia , Animais , Camundongos , Camundongos Knockout/genética , Receptores de Canabinoides , Receptores de Droga/genéticaRESUMO
Exposure to heavy ions during a Mars mission might damage the brain, thus compromising mission success and the quality of life of returning astronauts. Several workers have suggested that the dopamine system is particularly sensitive to heavy ion radiation, but direct evidence for this notion is lacking. We examined measures of brain dopamine viability at times up to 15 months after acute exposure of rats to (56)Fe (1.2-2.4 Gy). No effects were seen in brain sections stained for tyrosine hydroxylase, the classical marker for dopamine cells and nerve terminals. Locomotion stimulated by cocaine, which directly activates the dopamine system, was reduced at 6 months but not at 12 months. Furthermore, in a visually cued lever-pressing test, reaction times, which are prolonged by dopamine system damage, were identical in irradiated and control animals. However, learning times were increased by irradiation. Our data suggest that the midbrain dopamine system is not especially sensitive to damage by (56)Fe particles at doses much higher than would be associated with travel to and from Mars.