The noradrenergic cyclic AMP generating system in the limbic forebrain: pharmacological characterization in vitro and possible role of limbic noradrenergic mechanisms in the mode of action of antipsychotics.

The cyclic AMP generating system in slices of the rat limbic forebrain was investigated. In consists of: (u) A noradrenergic system which responds to norepinephrine (NE) and isoproterenol. Though the rise of the nucleotide elicited by isoproterenol is more rapid than that caused by NE, the maximal effect is less than half of that induced by NE; (2) an adenosine-dependent system. The noradrenergic cyclic AMP generating system in the limbic forebrain displays a number of properties of a central NE receptor: it develops supersensitivity to NE and isoproterenol following prolonged deprivation of NE at postsynaptic sites (chronic treatment with reserpine or chemosympathectomy with 6-hydroxydopamine). When noradrenergic terminals are protected from 6-hydroxydopamine by desmethylimipramine, the responses to NE are not enhanced. Responses to NE are blocked by both propranolol and phentolamine, while responses to isoproterenol are blocked by propranolol but not by phentolamine. The adenosine-dependent system does not develop supersensitivity after central chemosympathectomy and is not blocked by either alpha- or beta-antagonists. While not altering the basal level of the nucleotide, clinically effective antipsychotic drugs caused a dose-dependent inhibition of the limbic noradrenergic cyclic AMP response with clozapine and pimozide being particularly potent (IC50 0.06 and 0.08 muM, respectively). Antipsychotic drugs do, however, not affect cyclic AMP responses elicited by adenosine. The results are compatible with the view that the central NE receptor is closely related to or may be an integral part of an adenylate cyclase system and that its blockade in the limbic forebrain by antipsychotic drugs may contribute to their therapeutic action.