Neuropharmacological studies on D145 (1,3-dimethyl-5-aminoadamantan)

The effects of D145 (1,3-dimethyl-5-aminoadamantan) and amantadine on dopaminergic mechanisms in the rat were investigated by use of pharmacological agents known to disrupt dopamine function, by placing electrolytic lesions in the dopamine-containing areas of the extrapyrimidal and mesolimbic systems and by the direct application to dopamine sensitive areas. Stereotypy and circling behaviour were used as behavioural indices of dopaminergic stimulation and apomorphine and d-amphetamine were used as standard dopaminergic agonists. In addition, the possible importance of 5-hydroxytryptamine to the dopamine effects was investigated using electrolytic lesions of the midbrain raphé nuclei. Both D145 and amantadine caused a stereotyped behaviour characterized by periodic sniffing, repetitive limb movements and biting, but the effect of amantadine was far more periodic. In addition D145, but not amantadine, caused marked hyperactivity. These behavioural effects were resistant to pretreatment with alpha-methylparatyrosine but not to combined alpha-methylparatyrosine/reserpine or low doses of haloperidol. Also, the prior administration of D145 or amantadine inhibited the development of the biting components of apomorphine and d-amphetamine stereotypy. Both D145 and amantadine caused circling behaviour in animals with asymmetric lesions of the medial raphé nucleus or unilateral lesions of the substantia nigra but the action of D145 was more intense. Bilateral electrolytic lesions placed in the extrapyrimidal (caudate-putamen, globus pallidus, substantia nigra), mesolimbic (nucleus accumbens septi, tuberculum olfactorium, nucleus interstitialis stria terminalis, nucleus amygdaloideus centralis) nuclei or the neuronal pathways supplying them showed D145 and amantadine to act in both areas although their action on the extrapyrimidal system was most marked. However, of particular note was the significantly greater involvement of the substantia nigra with the D145 effect, and the greater involvement of the D145 effect with mesolimbic function. Lesions placed in the medial and/or dorsal raphé nucleus indicated some involvement of 5-hydroxytryptamine with the actions of both D145 and amantadine. The bilateral intrastriatal application of D145 or amantadine in nialamide pretreated animals failed to induce stereotyped or hyperactive behaviour although contralateral asymmetries, which were abolished by lesions of the substantia nigra, were recorded following the unilateral intrastriatal application of D145 or amantadine in haloperidol pretreated animals.