Mesolimbicocortical dopamine terminal fields are necessary for normal locomotor and investigatory exploration in rats

Rats explore a novel open field or novel object less after denervation of mesolimbicocortical dopaminergic terminal fields produced by bilateral 6-hydroxydopamine (6-OHDA) microinjections into the anterolateral hypothalamus after pretreatment with desmethylimipramine (DMI). These behavioral deficits were correlated with complete or nearly complete loss of fluorescent dopaminergic (DA) terminals in the nucleus accumbens, olfactory tubercle, dorsal bed nucleus of the stria terminalis, lateral septal nucleus and the deep layers of the frontal and piriform cortices. There were also fewer A10, medial A9, and A8 DA fluorescent cells after the 6-OHDA-DMI injections; this suggests retrograde degeneration of the cells of origin of the mesolimbicocortical DA system. When the DMI pretreatment was omitted, identical bilateral 6-OHDA microinjections also produced severe loss of norepinephrine (NE) fibers in the neocortex, hippocampus, lateral hypothalamus and ventral bed nucleus of the stria terminalis. The addition of this noradrenergic damage did not change the exploratory deficits observed after mesolimbicocortical DA denervation alone. Systemic administration of the DA agonist apomorphine, but not the adrenergic agonist clonidine, to the 6-OHDA-DMI rats repaired the deficits in exploration of a novel open field or novel object. The increased locomotion in a novel open field and investigation of a novel object produced by apomorphine in 6-OHDA-DMI rats were blocked by the DA antagonist, pimozide. This is evidence that apomorphine restored exploratory responses by stimulating dopaminergic receptors. The exploratory responses produced by apomorphine were also blocked by testing rats in a familiar open field or with a familiar novel object. This is evidence that apomorphine facilitates exploratory responding to novel stimuli by 6-OHDA-DMI rats, but that the same dose of apomorphine does not increase activity when 6-OHDA-DMI rats are confronted by familiar stimuli. We conclude: (1) that mesolimbicocortical dopaminergic terminals are necessary for normal exploratory behavior in rats; and (2) that DA released by these terminals may facilitate optimal sensorimotor integration in these terminal fields during spontaneous exploratory behavior.