The response of the noNEpinephrine (NE) sensitive cyclic AMP generating system in slices of the rat limbic forebrain after both the acute and chronic administration of the tricyclic antidepressants desipramine (DMI) and iprindole as well as electro-convulsive treatment (ECT) was investigated. Neither the basal level of cyclic AMP nor the hormonal response to NE were altered after administration of a single dose of short term treatment with DMI and iprindole. However, the administration of the antidepressants on a clinically more relevant time basis markedly reduced the sensitivity of the cyclic AMP generating system to NE. This change in sensitivity was not related to the levels of the drugs in brain. The response of cyclic AMP to NE was also reduced by ECT, but the onset of this action was shorter than that observed with the antidepressants. ECT also antagonized the enhanced response of cyclic AMP to NE following destruction of central adrenergic nerve terminals with 6-hydroxydopamine. It thus appears that the therapeutic action of tricyclic antidepressants could be related to postsynaptic adaptive changes in the sensitivity of the noradrenergic adenylate cyclase receptor system rather than to acute presynaptic events.

The noradrenergic cyclic AMP generating system in slices of the limbic forebrain of rats displays characteristics which are compatible with those of a central NE receptor. The cyclic AMP response to a K,,, concentration of NE (concentration of NE which elicits maximal increase in the level of cyclic AMP) is significantly enhanced in slices from reserpinized animals, although the K , value of NE (concentration of NE eliciting half-maximum response) was not significantly changed. Chemosympathectomy with 6-hydroxydopamine (6-OHDA) significantly enhanced the activity of the system to NE and isoproterenol but not to adenosine and reduced the K , value for NE. The changes in the reactivity of the cyclic AMP generating system following 6-OHDA administration appear to be related to a decrease in the availability of NE and not to that of other neurotransmitters as protection by desipramine (DMI) of noradrenergic neurons against the neurotoxic action of 6-OHDA prevented the development of supersensitivity to NE. Conversely, and independent of the actual concentration of NE in brain tissue, a persistent increase in the availability of NE caused by prolonged M A 0 inhibition lead to a marked decrease in the reactivity of the cyclic AMP generating system. The results provide further evidence for a regulatory mechanism in the CNS involving the noradrenergic receptor that adapts its sensitivity to NE in a manner inversely related to the degree of its stimulation by the catecholamine.

The effect of various antipsychotic drugs on the blockade of dopaminergic receptors in striatum and limbic forebrain was examined by establishing dose-response curves for the increase in HVA and for the antagonism of d-amphetamine-induced rotation in rats with unilateral lesions of the substantia nigra. A good quantitative correlation was found between dopaminergic blockade in the striatum as reflected by the ED100 for striatal HVA increase and the ED50 for rotational antagonism and the occurrence of extrapyramidal side effects in man. The ED100 for the increase in HVA in the limbic forebrain showed the same rank order of potency as those in the striatum: Haloperidol greater than primozide greater than chlorpromazine greater than thioridazine greater than clozapine. The results thus demonstrate a very good correlation between the degree of dopaminergic blockade and the increase of extrapyramidal side effects in man, but suggest the possibility of a dissociation between dopaminergic blockade and antipsychotic activity.

No abstract

The present results show that clonidine does not mimic the agonist action of norepinephrine (NE) on the noradrenergic cyclic AMP generating system of the limbic forebrain, but antagonizes the stimulatory effect of NE while not influencing the action of isoprenaline. In self-stimulation behavior, clonidine decreases responding and blocks the facilitation caused by d-amphetamine.

The hydrolysis of ³H-reserpine and the subsequent formation of ³H-trimethoxybenzoic acid (TMBA) were examined. ³H-reserpine disappearance and ³H-TMBA formation were determined by a combination of solvent extraction and thin-layer chromatography. Subcellular fractionation experiments indicated that the greatest amount of hepatic reserpine metabolizing activity was found in the microsomal fraction. This fraction could be stored for up to 14 days at –20 °C without appreciable loss in enzyme activity. Reserpine metabolism was both temperature and pH sensitive with the greatest rate of biotransformation occurring at 37 °C and at a pH of about 7. An NADPH generating system was essential for optimal enzyme activity since metabolism did not occur in the absence of such a system. Both SKF 525-A and carbon monoxide inhibited the metabolism of reserpine. Pretreatment with either phenobarbital or 3-methylcholanthrene did not result in increased hydrolysis activity in either male or female rats. ³ H-reserpine metabolism was reduced by co-incubation with meperidine and possibly with lidocaine and procaine, while succinylcholine had no effect. Species’ differences in reserpine’s metabolism were noted with the mouse and rat showing the greatest hydrolyzing activity followed by the dog, cat and guinea pig.