Estudo farmacológico e de alterações neuroquímicas em córtex pré-frontal e corpo estriado de camundongos após convulsões e morte induzidas por overdose de cocaína

• Autor(a) principal: Macêdo, Danielle Silveira
• Data de Publicação: 2005
• Tipo de documento: Tese
• Idioma: por
• Título da fonte: Repositório Institucional da Universidade Federal do Ceará (UFC)
• Texto Completo: http://www.repositorio.ufc.br/handle/riufc/2707
• topic: Toxicidade Aguda; Corpo Estriado; Córtex Pré-Frontal

Seizures and death are the most important toxic consequences related to cocaine (COC) overdose. In order to determine the main neurotransmitter systems involved with cocaine-induced seizures, male Swiss mice (20-30 g) were pretreated (i.p.) 15, 30 or 60 min before COC 90 mg/kg administration with drugs that interferes with various neurotransmitter systems. The animals were observed (30 min) to determine: latency to first seizure, number of seizures, and number of deaths after cocaine overdose. Gabaergic drugs (diazepam, Phenobarbital and gabapentin) were the best ones, increasing latency to 1st seizure and decreasing cocaine-induced seizures and mortality. The D1 receptor antagonist SCH23390 improved the three parameters observed, while the D2 antagonist pimozide (20 mg/kg) decreased latency. Pirenzepine, a M1 receptor antagonist decreased the number of animals that seized. Fluoxetine, an inhibitor of serotonin reuptake, decreased latency to 1st seizure and survival, and the same happened with mianserin, a 5-HT2 receptor antagonist. Buspirone, a partial agonist of 5HT1A receptor increased animals survival, while ketamine, a NMDA receptor antagonist improved all three parameters evaluated. Lithium decreased the number of animals that seized, while vitamin E decreased the number of animals that seized and also mortality. The opioid antagonist naltrexone, decreased latency and increased cocaine-induced death. It was observed that after cocaine overdose some animals presented only status epilepticus (SE), while others died after seizures. Thus, for neurochemical studies these animals were dissected, striatum (ST) and prefrontal cortex (PFC) removed, and divided in two groups, SE and death. SE decreased (40 %) and increased (125 %) DA levels in ST and PFC, respectively. There was also an increase in DA metabolites, DOPAC and HVA in PFC and ST, respectively. After death, DA levels decreased (38%) in PFC and both metabolites increased in ST. Metabolic rates for this monoamine increased after SE in ST and after death in ST and PFC. The increase in DA metabolism is related to free radicals formation. 5HT increased (123 %) only in PFC after SE, while its metabolite 5HIAA decreased in PFC after SE and death induced by cocaine. The metabolic rate for 5HT decreased after SE in PFC and after death in both areas studied. NA decreased (52 %) in ST and increased (56 %) in PFC during SE, while after death increased in ST and decreased in PFC. Dopaminergic D1-like receptors decreased (46 %) in ST and PFC after SE. This reduction was followed by a decrease and increase, respectively, of the affinity (Kd) receptor-radioactive ligand. An increase (48 % in PFC and 82 % in ST) in D2-like receptors number was observed and followed by an increase in affinity in PFC and decrease in ST. Muscarinic M1 receptors decreased in PFC after cocaine-induced SE and death. AChE activity increased after SE (ST) and after death (ST and PFC). Serotonergic 5HT2 receptors increased (around 46 % and 460 %, respectively to PFC and ST) after SE and death. GABAergic and glutamatergic receptors presentes the same alterations, reduction after SE in both brain areas studied and only in PFC after death. Nitrite/nitrate levels increased in all conditions determined for GABAergic and glutamatergic receptors. MDA levels increased (46 %) only after death in ST. From antioxidant enzymes, catalase had its activity decreased after cocaine overdose in ST and PFC, the same happened with cocaine in low doses (10 and 30 mg/kg), only in ST. Pretreatment with diazepam brought catalase levels to control values. Glutathione increased after death in ST and PFC. Taken together these results showed that cocaine-induced seizures and death are multimediated events and that the brain areas studied, PFC and ST are important to this brain process. Oxidative stress also seems to be involved in this mechanism. These findings may be important for determining the neural mechanisms that mediate acute cocaine toxicity.