Comparative dopamine-cholinergic mechanisms in the olfactory tubercle and the striatum: Effects of metoclopramide

The olfactory tubercle (OT) is a limbic structure containing high dopamine (DA) and acetylcholine (ACh) concentrations. We performed a comparative study of the DA-ACh interactions, the efficacy of autoreceptor control and the effects of metoclopramide in the OT and the nucleus caudate (striatum). Rabbit brain slices from both regions of the same animal were prelabeled with radioactive DA and/or choline and then superfused. Comparable magnitude of DA and ACh release was evoked by electrical stimulation from both regions. DA release was unaltered, whereas ACh release was inversely treated to the stimulation frequency, both in OT and striatum. Apomorphine (APO), a D1-D2 agonist, an LY-171555 (LY), a D2 agonist, inhibited DA and ACh release from OT and striatum with similar EC50 and E(max) (maximal percentage of inhibition). However, the maximal degree of inhibition of ACh release achieved with APO, LY or DA in the OT was only one-half that observed in the striatum. In both regions, the inhibitory effects of DA agonists on DA and ACh release were reduced markedly when the number of electrical pulses and/or the frequency of stimulation were increased. I-Sulpiride, a DA D2 antagonist, increased the evoked release of DA and ACh from OT in direct relationship with the frequency of stimulation. In the OT, increases in synaptic DA achieved by administration of amphetamine or by blockade of the neuronal uptake pump with nomifensine inhibited the evoked release of ACh. Again these drug treatments produced only a 40 to 50% inhibition of ACh release. SKF 38393, a D1 agonist, had no effect per se on DA or ACh release in OT slices from control or from reserpine-treated animals (2 mg/kg s.c. for 3 or 7 days). With the exception of one specific dose combination, coadministration of SKF 38393 and LY produced no additive or synergistic effects on DA or ACh release from OT. APO- and LY-induced inhibition of DA and ACh release were antagonized by I-sulpiride. However, 300 nM SCH 23390, a D1 antagonist, reduced APO inhibition of DA and ACh release without affecting the inhibitory action of LY on DA and ACh release. Metoclopramide, 'a DA antagonist with poor limbic activity', had a similar affinity for OT (pA2: 7.59) and striatal (pA2: 7.59) DA autoreceptors. Its antidopaminergic efficacy on DA receptors modulating ACh release from OT and striatum was also compared. These observations suggest: 1) The efficacy and potency of drugs acting on striatal and limbic DA receptors modulating DA or ACh release is strongly dependent on the level of activity of the neurons. 2) Ventral tegmental and nigrostriatal DA neurons projecting to the OT and striatum, respectively, are under efficient autoreceptor control. The DA autoreceptors are of the D2 subtype. 3) Inhibition of cholinergic function by DA is less efficient in OT than in the striatum. 4) A synergistic interaction may exist between DA D2 and D1 receptors on DA and ACh release from OT. 5) Metoclopramide exerts similar DA receptor antagonistic properties in the OT (limbic) and striatum. Thus, the poor limbic activity of this drug, based on DA antagonistic properties, must be reconsidered.