RESUMO
Milameline (E-1,2,5,6-tetrahydro-1-methyl-3-pyridinecarboxaldehyde, O-methyloxime monohydrochloride, CI-979, PD129409, RU35926) was characterized in vitro and evaluated for effects on central and peripheral cholinergic activity in rats and rhesus monkeys. In muscarinic binding studies, milameline displayed nanomolar affinity with an agonist ligand and micromolar affinity with antagonist ligands, with approximately equal affinities determined at the five subtypes of human muscarinic receptors (hM(1)-hM(5)) with whole cells or membranes from stably transfected Chinese hamster ovary (CHO) cells. On binding, milameline stimulated phosphatidylinositol hydrolysis in hM(1) and hM(3) CHO cells and inhibited forskolin-activated cAMP accumulation in hM(2) and hM(4) CHO cells. Additionally, it decreased K(+)-stimulated release of [(3)H]acetylcholine from rat cortical slices. Responses were not caused by the inhibition of acetylcholinesterase, and there was no significant binding to approximately 30 other neurotransmitter binding sites. In rats, milameline decreased spontaneous and scopolamine-induced swimming activity, improved water-maze performance of animals impaired by basal forebrain lesions, increased cortical blood flow, decreased core body temperature, and increased gastrointestinal motility. Electroencephalogram activity in both rats and monkeys was characterized by a predominance of low-voltage desynchronized activity consistent with an increase in arousal. Milameline also reversed a scopolamine-induced impairment of attention on a continuous-performance task in monkeys. Thus, milameline possesses a pharmacological profile consistent with that of a partial muscarinic agonist, with central cholinergic actions being produced in rats and monkeys at doses slightly lower than those stimulating peripheral cholinergic receptors.
Assuntos
Comportamento Animal/efeitos dos fármacos , Córtex Cerebral/efeitos dos fármacos , Cognição/efeitos dos fármacos , Di-Hidropiridinas/farmacologia , Agonistas Muscarínicos/farmacologia , Oximas/farmacologia , Acetilcolina/metabolismo , Animais , Sítios de Ligação , Células CHO , Inibidores da Colinesterase/farmacologia , Colforsina/metabolismo , Cricetinae , AMP Cíclico , Relação Dose-Resposta a Droga , Eletroencefalografia/efeitos dos fármacos , Humanos , Técnicas In Vitro , Macaca mulatta , Masculino , Neurotransmissores/metabolismo , Fosfatidilinositóis/metabolismo , Potássio/fisiologia , Ratos , Ratos Long-Evans , Receptores Muscarínicos/efeitos dos fármacos , Escopolamina/farmacologia , Fatores de Tempo , TransfecçãoRESUMO
An important experimental challenge in research with squirrel monkeys (Saimiri scureus) is the development of a reliable closed intravenous system for long term drug self-administration studies and the collection of multiple timed blood samples. A surgical procedure using a vascular access port (VAP) system was developed to provide easy access for venous samples or drug infusions. Daily experiments in chaired monkeys were simple and reliable for durations of up to 6 h. The quantitative performance of the VAP system was evaluated by the number of days until port failure for self-administration studies and the number of days during which blood samples could be collected beyond an initial time of 91 days. The mean best performance for VAP system functional time for self-administration studies was 437 +/- 73 and the mean worst performance was 281 +/- 79. The mean best performance for blood withdrawal functional time was 362 +/- 81 and the mean worst performance was 332 +/- 85. The qualitative performance of the VAP system is described including complications that developed during the procedure; corresponding suggestions for corrective actions are discussed. Enhancements to increase port performance are also recommended.
Assuntos
Coleta de Amostras Sanguíneas/métodos , Cateteres de Demora , Transtornos Relacionados ao Uso de Substâncias , Animais , Masculino , Reprodutibilidade dos Testes , Saimiri , AutoadministraçãoRESUMO
Systemic administration of anticholinergic agents impairs cognitive performance in animals and man. The anticholinergic, scopolamine, has profound effects on peripheral and central cholinergic function, making interpretation of its effects on cognitive performance difficult. To circumvent this problem, scopolamine was administered directly to the central nervous system of rhesus monkeys using a subcutaneously implanted infusion pump connected to a cannulae directed toward the right lateral ventricle. Intracerebroventricular (ICV) infusion of scopolamine (0.004, 0.012, 12.5, and 40.0 micrograms/kg/h) produced a dose-dependent decrease in the number of responses on a continuous performance task. Response decrements produced by scopolamine were seen mainly during the last half of the test session and at short stimulus durations. These data suggest that scopolamine produces a deficit in sustained attention or slowing of information processing that is mediated through direct central cholinergic blockade in the rhesus monkey.