Dopamine receptor antagonism by the novel antianxiety drug, buspirone.

Buspirone is an anxiolytic drug with a clinical potency similar to that of diazepam, but it lacks affinity for diazepam of y-aminobutyric acid (GABA) binding sites. Because previous reports suggested that buspirone may possess dopamine (DA) agonist activity, buspirone was tested for effects on DA neurotransmission. At presynaptic DA receptors, unlike other DA agonists, buspirone inhibited neither synaptosomal tyrosine hydroxylase activity nor the in vivo y-butyrolactone-induced activation of striatal tyrosine hydroxylase. However, buspirone did inhibit the action of apomorphine, a direct acting DA agonist, in both of these DA autoreceptor test systems with a potency similar to that of chlorpromazine. Striatal DA synthesis and metabolism were markedly increased by buspirone treatment; the maximum effective dose was 3.0 mg/kg, s.c., which caused a 400% increase. Extracellular single cell recordings showed that buspirone, administered intravenously, markedly increased substantia nigra DA neuronal impulse flow and potently reversed inhibition of DA cell impulse flow caused by systemic injection of apomorphine (5 to 10 pg/kg). Inhibition of DA cell impulse flow by iontophoresis of DA was reversed by iontophoretic administration of buspirone, but buspirone did not interfere with the ability of GABA to inhibit DA impulse flow. That buspirone interacts with receptor sites in addition to the DA autoreceptor was indicated by the finding that after DA receptor blockade with haloperidol, buspirone further enhanced DA neuronal impulse flow. Buspirone did not cause catalepsy and did not inhibit apomorphine-induced turning in rats with unilateral 6hydroxydopamine lesions of the substantia nigra, which indicated that the drug has minimal action at the classical postsynaptic DA receptor. These data suggest that (a) buspirone enhances DA neuronal activity, in part, by weakly inhibiting presynaptic DA receptors, and (b) buspirone has minimal effects on postsynaptic DA receptors. Buspirone is a non-benzodiazepine drug which possesses potent anxiolytic activity (Goldberg and Finnerty, 1979). Despite exhibiting clinical potency equal to diazepam for reduction of anxiety, buspirone shows little affinity for or interaction with diazepam or y-aminobutyric acid (GABA) binding in CNS tissue (Stanton et al., 1981). Stanton et al. (1981) also reported that buspirone lacks ’ We thank Mead Johnson Pharmaceutical Division for their generous supply of buspirone hydrochloride, Janet Harkness and Margaret Wintersole for their technical assistance, and Ruth Houser and Laura Boynton for preparing the manuscript. We are grateful for the assistance of Dr. Samuel Speciale with the 6-hydroxydopamine lesions. This research was supported by United States Public Health Service Grants MH-05831, MH-30546, and MH-33513. ‘To whom correspondence should be sent at his current address: Department of Pharmacology, School of Medicine, East Carolina University, Greenville, NC 27834. anticonvulsant and sedative activity. Thus, buspirone represents a novel class of anxiolytic drugs. The only site of pharmacological activity observed by Stanton and coworkers (1981) was in dopamine (DA) receptor binding assays. Buspirone was inactive in all other receptor binding assays (e.g., opiate, 5-hydroxytryptamine (5-HT)l, 5HT2, al, (~2, /3, H1, Hz, etc.). Buspirone displaces a DA agonist (N-n-propyl-norapomorphine) and antagonist (spiperone) from striatal membranes with IC~os of 20 and 290 nM, respectively. Because buspirone does not cause catalepsy, only weakly competes with spiperone binding, and is ineffective as an antipsychotic drug, Stanton et al. (1981) suggested that buspirone has minimal postsynaptic DA receptor blocking properties, but may act as a presynaptic DA autoreceptor agonist because of the higher affinity for the DA agonist binding site. There are presynaptic autoreceptors on the DA cell bodies in the substantia nigra and on DA axon terminals