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The effects of dopaminergic stimulants on the cyclic GMP content in the medial forebrain and the cerebellum were studied in mice pretreated with dopaminergic antagonists, cholinolytics and agents enhancing GABAergic transmission. Low doses of butyrophenones (haloperidol and spiroperidol) inhibited the rise in cyclic GMP levels and the stereotyped behaviour induced by amphetamine, but were without effect on the same biochemical and behavioural changes elicited by apomorphine. Higher doses effectively blocked the rise in cyclic GMP levels and the stereotyped behaviour elicited by both drugs. These findings suggest that low doses of the dopaminergic antagonists may predominantly act by interfering with the release of dopamine from presynaptic stores, while high doses may act by blockade of the postsynaptic dopaminergic receptor. The rise in cerebellar cyclic GMP levels elicited by dopaminergic stimulants appears not to involve cholinergic transmission, since atropine did not block the effects of the dopaminergic stimulants. Enhancement of GABAergic transmission by diazepam or aminooxyacetic acid antagonized the rise in cerebellar cyclic GMP content induced by the dopaminergic stimulants, but was without effect on the cyclic GMP content in the medial forebrain. Cyclic AMP levels were not affected by any of the drugs in both parts of the brain.

The correlations between the relaxing effect of papaverine derivatives, inhibition of low Km-phosphodiesterase (cAMP-PDE = EC 3.1.4.17) activity and cyclic 3',5'-AMP (cAMP) levels in isolated rabbit ileum were investigated. There was a strong correlation between the relaxing effect, inhibition of PDE activity and cAMP content for eupaverine, ethylpapaverine and papaverine. Eupaverine was the most effective relaxing agent (I50 = 7.5 muM) and the most potent inhibitor of PDE activity (Ki = 0.6 muM), followed by ethylpapaverine (I50 = 10 muM;Ki 0.8 muM) and papaverine (I50 = 20 muM;Ki = 2 muM). In contrast, there was a strong relaxing effect (I50 = 6 muM) but only slight inhibition of PDE activity (Ki = 350 muM) by tetrahydropapaveroline (THP). The adenylate cyclase stimulating effect of THP which was shown by others is most likely the reason for comparatively higher cAMP levels, which were found to be elevated about seven times over basal levels of 0.35 nmoles/g wet weight, and effective relaxation. Relaxation could be induced by exogenously added cAMP (I50 = 45 muM) and dibutyryl-cAMP (I50 = 450 muM). Our results support the assumption that smooth muscle relaxation in rabbit ileum is mediated by cAMP. Some of these observations have been published in abstract form (Schulz and Berndt, 1972).

In mice, Arecoline in vivo dose-dependently increased the cGMP concentrations of the cerebellum and the "cereberum" (= parts of cortex, hippocampus, hypothalamus, thalamus, striatum and midbrain) without influencing thecAMP levels. The cholinesterase inhibitors paraoxon and physostigmine caused an elevation only in "cerebrum", whereas the cGMP content of the cerebellum even decreased. Pretreatment with atropine prevented the rise in cGMP levels as well as the symptoms of cholinergic stimulation elicited by arecoline or paraoxon. Diazepam reduced cGMP levels below control values and blocked the effect of arecoline, while typical symptoms due to arecoline, e.g., tremor and salivation remained unaffected. The tripeptide prolyl-leucyl-glycinamide (MIF) had no effect on either cGMP values or the peripheral signs of cholinergic stimulation elicited by arecoline. The results show that elevation of cGMP in the central nervous system caused by cholinomimetic agents can be prevented not only by cholinolytics, blocking muscarinic receptors but also by influencing other mechanisms to be discussed.