Alpha₂ - adrenoceptor antagonists : new ways to influence attention and memory

Abstract

In Alzheimer's disease the loss of cholinergic neurons is often thought to be essential but cholinesterase inhibitors have been helpful only for a part of patients. Experimental and clinical evidence supports the importance of noradrenergic neurons in arousal but also in attention and memory. Some of these neurones seem to end in contact with cholinergic neurons. In animal studies, both a2-adrenoceptor agonists and antagonists have been reported to improve some cognitive functions. The reported clinical tests with clonidine have been negative like our experiments with a less sedative a2-agonist, guanfacine, in rats. An injection of atipamezole (ATI), a2-adrenoceptor antagonist (Farmos Group) decreased total motor activity, rearing and grooming in rats in the open-field test. In the Morris water maze, after high doses (>3mg/ kg) of ATI the rats did not swim, after Iow doses they made less errors. In the appetitive spatial memory test, after low doses of ATI, the rats showed slightly less forgetting than the controls. In the passive avoidance test, acute treatment with ATI improved the performance of rats. ATI enhanced the EEG of rats decreasing slow wave spikes like cholinergic drugs do. Autoradiographic localization of ATI binding sites in rat brain slices indicated that those sites are distributed throughout the whole brain and have a similar location to other imidazole containing a2-adrenoceptor antagonists. Several neurotransmitters may be involved in the actions of ATI since it seemed to release noradrenaline and serotonin in brain.