THE ANALEPTIC EFFECT OF METHAMPHETAMINE IN PENTOBARBITAL-NARCOTIZED RATS IS MEDIATED VIA A DOPAMINERGIC-CHOLINERGIC MECHANISM

Methamphetamine (MAP) administered in doses of 0.5 to 5 mg/kg i.p. to rats anesthetized with pentobarbital produced a shortening of the dura tion of loss of righting reflex. This analeptic effect of MAP was bloc ked by atropine but not by atropine methylbromide, indicating the cent ral cholinergic nature of the response. This effect was also blocked b y the D1 and D2 dopamine antagonists SCH 23390 (0.2 mg/kg) and raclopr ide (2 mg/kg), respectively. Pentobarbital decreased sodium-dependent high-affinity choline uptake (HACU) in frontal cortex and hippocampus as measured in synaptosomes from treated rats. MAP given to pentobarbi tal-narcotized rats restored HACU activity to nonanesthetized levels, but this restorative effect of MAP was blocked by SCH 23390 or raclopr ide. These data suggest that in addition to a cholinergic mechanism, t he analeptic effect of MAP involves the dopamine system. alpha-Methyl- p-tyrosine, but not reserpine, pretreatment completely blocked the MAP analeptic response. In reserpinzed rats, MAP produced a markedly enha nced analeptic response. Studies of the effects of repeated administra tion of MAP on its analeptic activity were also undertaken in view of the well known sensitization to the locomotor and stereotypic effects of the amphetamines that occur with repeated intermittent administrati on. Rats pretreated daily with MAP (5 mg/kg) for 5 or 12 days showed n either tolerance nor sensitization to the analeptic effect of subseque nt MAP administrations. H-3-quinuclidinyl benzilate-binding studies al so showed no changes in muscarinic binding characteristics of membrane s prepared from cortex or hippocampus of rats pretreated chronically w ith MAP, These and our earlier studies suggest that the analeptic effe ct of MAP is mediated via a dopaminergic-cholinergic mechanism.