Lack of involvement of dopaminergic and GABA neurones in the inhbitory effect of harmaline on the activity of striatal cholinergic neurones in the rat.

Abstract

Harmaline (10 mg/kg i.p. 45 min) increased acetylcholine (ACh) levels in the rat striatum but did not affect the ACh content of the parietal cortex, the hippocampus or certain limbic nuclei. This change in striatal ACh levels may reflect a decreased utilization of the transmitter. The selective effect of harmaline on striatal cholinergic neurones is probably mediated by interneuronal processes. Various hypotheses were examined: 1. The harmaline-induced increase in striatal ACh levels was not abolished after destruction of the nigrostriatal dopaminergic neurones. Harmaline (10−5 M or 10−4 M) and its metabolites (harmalol, harmine) also failed to modify the activity of the striatal dopamine-sensitive adenylate cyclase. This excludes any involvement of dopaminergic mechanisms in the action of harmaline on striatal cholinergic neurones. 2. The harmaline-induced increase in striatal ACh levels could not be prevented by diazepam (5 mg/kg i.p. 65 min). In contrast the increase in ACh content elicited by picrotoxin (25 mg/kg i.p. 60 min) was abolished by diazepam. Furthermore, the harmaline-and picrotoxin-induced rises in striatal ACh levels were additive. These results suggest that GABA mechanisms are not involved in the effect of harmaline on striatal cholinergic neurones. 3. Parachlorophenylalanine pretreatment (48 and 24 h, 300 mg/kg i.p.) which reduced striatal serotonin (5-HT) levels by 95%, failed to affect ACh levels in the striatum. The inhibitor of 5-HT synthesis did not prevent the harmaline-induced rise in ACh levels. Harmaline (10−5 M or 10−4 M), harmine and harmalol, did not stimulate the 5-HT sensitive adenylate cyclase in the colliculi of newborn rats. It is thus unlikely that harmaline reduces the activity of striatal cholinergic neurones by its effects on 5-HT transmission. Moreover, other monoamine oxidase inhibitors (pargyline and tranylcypromine) were also ineffective on cholinergic neurones.