RESUMO
Cocaine addiction is a public health issue in many countries, stressing the need for more effective treatments. As all drugs of abuse, cocaine acts on the brain reward system, increasing dopamine (DA) levels. Other neurotransmitters such as acetylcholine (ACh) are involved in the mechanisms underlying the development and the maintenance of cocaine addiction. ACh plays an important role in learning and memory processes and also regulates DA in some specific regions of the central nervous system. The present study investigated the effects of biperiden, a muscarinic cholinergic (mACh) antagonist in two animal models: conditioned place preference (CPP) and behavioral sensitization. Male C57BL/6J mice were used in both studies. The CPP protocol was unbiased and carried out in three phases: habituation, conditioning and testing. For conditioning, cocaine was injected at a dose of 10mg/kg in eight 15 min-sessions. The treatment with biperiden (doses of 0.1, 1 and 10 mg/kg) was made 30 min prior to the testing session. For behavioral sensitization development, cocaine was administered at the dose of 10 mg/kg for 10 days. After sensitization, two challenges were performed: saline and cocaine (5 mg/kg). Biperiden (10 mg/kg) was administered 30 min before the cocaine challenge. At the dose of 10 mg/kg, biperiden blocked the cocaine-CPP expression, suggesting an effect on conditioned memory retrieval. However, the same dose potentiated the expression of behavioral sensitization, suggesting an increase in DA release, probably in the NAc. Biperiden, as other mACh antagonists, may be a promising drug for the pharmacologic treatment of cocaine addiction.
Assuntos
Biperideno/farmacologia , Cocaína/farmacologia , Condicionamento Operante/efeitos dos fármacos , Inibidores da Captação de Dopamina/farmacologia , Antagonistas Muscarínicos/farmacologia , Receptor Muscarínico M1/antagonistas & inibidores , Animais , Aprendizagem por Associação/efeitos dos fármacos , Comportamento Animal/efeitos dos fármacos , Masculino , CamundongosRESUMO
It is well-known that cocaine dependence is a public health issue, and several studies stress the need to look for new and more effective treatments. Although the mesolimbic dopamine (DA) system, which originates in the ventral tegmental area (VTA) and projects to several forebrain structures, is known to be critically involved in the neurobiology of cocaine dependence, acetylcholine (ACh) has also been shown to play an important role in cocaine dependence via its action on this reward system. ACh is also important in the formation of hippocampal memory associated with appetitive behavior. Thus, the aim of this study was to evaluate the effect of biperiden, an ACh antagonist with high affinity for muscarinic M1 type receptors, on the acquisition of cocaine-conditioned place preference (CPP) in mice. The cocaine and biperiden were dissolved in sterile saline and were administered intraperitoneally at a dose of 10mg/kg. The conditioning regime was 8 days long, and the cholinergic antagonist was given immediately at the end of each conditioning session. The test for CPP occurred 24h after the last session. The results showed that animals treated with biperiden spent significantly less time in the cocaine-paired compartment than did the ones treated with saline. This finding represents a reduction in the consolidation of cocaine-induced CPP. One hypothesis that could explain this outcome focuses on the action of cholinergic antagonists on the consolidation of contextual memories. The amnesic effect of M1 antagonists on aversive tasks and on morphine CPP has been demonstrated when administered before the training or the conditioning session. The present study highlights the possibility of impairment in the acquisition of an appetitive memory, even when the cholinergic drug is administered after the conditioning session. This protocol also rejects the possibility of performance disturbance and suggests a possible pharmacological tool in the treatment of cocaine dependence.