Effects of D‐2 Antagonists on Frequency‐Dependent Stimulated Dopamine Overflow in Nucleus Accumbens and Caudate‐Putamen

Abstract

Stimulated dopamine overflow has been measured with in vivo voltammetry in the caudate-putamen and nucleus accumbens. Overflow was induced by electrical stimulation of the medial forebrain bundle with 120 1-ms, 300-microA, biphasic pulses at frequencies between 10 and 60 Hz. Overflow was measured with a Nafion-coated, carbon-fiber electrode used with fast-scan voltammetry (300 V s-1). Quantification and identification of dopamine concentrations down to 100 nM in vivo is possible with this technique. The overflow curves were fit to a kinetic model that describes the measured response as a function of uptake (characterized by a Vmax and Km) and release (characterized by the concentration of dopamine released per stimulus pulse). Overflow curves in both regions could be described with similar kinetic parameters except for the Vmax, which in the nucleus accumbens was only 60% of that measured in the caudate-putamen. Uptake inhibition by nomifensine (20 mg kg-1) caused an apparent 15-fold change in the value of Km in the nucleus accumbens, similar to results previously reported in the caudate-putamen. In contrast, metoclopramide (10 mg kg-1) and sulpiride (100 mg kg-1) altered the apparent amount of dopamine released per stimulus pulse without a change in the uptake kinetics.

Optogenetic Interrogation of Dopaminergic Modulation of the Multiple Phases of Reward-Seeking Behavior

“…Fibers activated by electrical stimulation (so-called “first stage” fibers) are in fact rostro-caudal glutamatergic fibers targeting the VTA that eventually activate the NAcc projecting dopaminergic neurons (Wise and Bozarth, 1984; Bielajew and Shizgal, 1986; Gallistel, 1986). Electrical stimulations along the MFB are associated with variable dopamine release in the NAcc (Millar et al, 1985; Gratton et al, 1988; May and Wightman, 1989; Fiorino et al, 1993) while reinforcing actions are attenuated by dopamine receptor antagonists and potentiated by drugs that increase the dopaminergic tone (Fouriezos and Wise, 1976; Franklin, 1978; Gallistel and Karras, 1984; Wise, 2004). Although they showed more variable effects than MFB stimulation, electrical stimulations of the VTA also increase dopamine release in the NAcc and are facilitated by drugs enhancing the dopaminergic tone as well (Fibiger et al, 1987; Phillips et al, 1989; Blaha and Phillips, 1990).…”

A rotarod test for evaluation of motor skill learning

“…Nomifensine is known to induce a transient increase in evoked extracellular dopamine (Cragg and Rice, 2004;Robinson and Wightman, 2004). On the other hand, it is well established that stimulation of presynaptic D2 autoreceptors of dopaminergic terminals suppresses dopamine release (May and Wightman, 1989;Schmitz et al, 2002). The transient increase in dopamine release evoked by firing activity of dopaminergic neurons is called phasic or wiring neurotransmission and high-concentration of dopamine is transmitted by D1 receptors (Zoli et al, 1998).…”

Striatal dopamine neurotransmission: Regulation of release and uptake

“…Striatal [DA] o increases with systemic or intra-striatal administration of D2 antagonists, and decreases with intra-striatal infusion of a D2 agonist [250]. In vivo electrochemical studies indicate that basal [DA] o is sufficient for tonic stimulation of D2 autoreceptors, and inhibition of action potential-dependent DA release [251,252]. Mice lacking D2 receptors allowed evaluation of dynamic autoreceptor regulation [223].…”