The respective involvement of noradrenaline and its deaminated metabolites in waking and paradoxical sleep: A neuropharmacological model

Abstract

To further assess the role of NA and its metabolites in waking, PGO spiking and PS, drugs which selectively inhibit one of the 3 metabolic pathways of NA were administered to chronnically implanted cats which were continuously recorded and periodically observed. The results were the following: (1a) Inhibition of COMT with 100 mg/kg tropolone led to an increase in waking. This drug produced a secondary increase in PGO spiking. (1b) 50 mg/kg tropolone plus 25 mg/kg l-DOPA produced a large increase in waking manifested behaviorally by rage behavior of a hallucinatory nature. Following the period of maximum excitability, PGO spkies invaded the waking record. Spiking was also increased in stages I and II sleep during 24 h post-injection and frequency of spiking in PS and percent of PS were augmented during 24—48 h post-injection. (2) Inhibition of NA reuptake with 5 mg/kg desipramine led to a decrease in waking. This drug was followed by a suppression of spiking and PS. (3a) Inhibition of MAO with 8 mg/kg tranylcypromine, 10 mg/kg pheniprazine and 100 mg/kg pargyline respectively produced strong arousal, mild arousal and sleep. These same inhibitors produced suppression of spiking for 1, 2, and 3 days respectively and of PS for 1, 3, and 4 days respectively. (3b) The inhibitors of MAO in combination with l-DOPA produced very extreme arousal which was characterized by stereotyped hyperactivity and was frequently followed by death. The sleep originally produced by pargyline alone was reversed to a highly intense arousal with DOPA. 2.5 mg/kg pheniprazine and 50 mg/kg pargyline, each in combination with 25 mg/kg l-DOPA produced a long-lasting suppression of PGO spiking and PS. Whereas drug-induced increases in NA levels generally produced an enhancement and increase in duration of waking, this same increase was not associated with an increase in spiking or PS. These phenomena are correlated however with the presumed level of deaminated metabolites of NA, where inhibition of COMT leads to an increase, inhibition of reuptake leads to a decrease, and inhibition of MAO leads to a disappearance of these metabolites, and of PGO spiking and PS. In conclusion it was hypothesized that NA is implicated in the mediation of waking and that its deaminated metabolites are implicated in the generation of PGO spiking and PS.