Concurrent Autoreceptor-Mediated Control of Dopamine Release and Uptake during Neurotransmission: AnIn VivoVoltammetric Study

Abstract

Receptor-mediated feedback control plays an important role in dopamine (DA) neurotransmission. Recent evidence suggests that release and uptake, key mechanisms determining brain extracellular levels of the neurotransmitter, are governed by presynaptic autoreceptors. The goal of this study was to investigate whether autoreceptors regulate both mechanisms concurrently. Extracellular DA in the caudate-putamen and nucleus accumbens, evoked by electrical stimulation of the medial forebrain bundle, was monitored in the anesthetized rat by real-time voltammetry. Effects of the D2 antagonist haloperidol (0.5 mg/kg, i.p.) on evoked DA levels were measured to evaluate autoreceptor control mechanisms. Two strategies were used to resolve individual contributions of release and uptake to the robust increases in DA signals observed after acute haloperidol challenge in naive animals: pretreatment with 3beta-(p-chlorophenyl)tropan-2beta-carboxylic acid p-isothiocyanatophenylmethyl ester hydrochloride (RTI-76; 100 nmol, i.c.v.), an irreversible inhibitor of the DA transporter, and kinetic analysis of extracellular DA dynamics. RTI-76 effectively removed the uptake component from recorded signals. In RTI-76-pretreated rats, haloperidol induced only modest increases in DA elicited by low frequencies and had little or no effect at high frequencies. These results suggest that D2 antagonism alters uptake at all frequencies but only release at low frequencies. Kinetic analysis similarly demonstrated that haloperidol decreased V(max) for DA uptake and increased DA release at low (10-30 Hz) but not high (40-60 Hz) stimulus frequencies. We conclude that presynaptic DA autoreceptors concurrently downregulate release and upregulate uptake, and that the mechanisms are also independently controlled during neurotransmission.

Testing Computational Models of Dopamine and Noradrenaline Dysfunction in Attention Deficit/Hyperactivity Disorder

“…The improvement in positive Go learning by stimulant medication is consistent with predictions from our BG/DA model, and is similar to patterns we observed in Parkinson's patients on DA medication (Frank et al, 2004), and in healthy participants taking haloperidol, which at single low doses increases phasic DA release Wu et al, 2002). Our model further predicts that by elevating tonic DA levels, stimulant medications may block the effects of DA dips and could therefore even impair NoGo learning (Frank, 2005), as seen with DA medications in several other populations (see Frank and O'Reilly, 2006 and references therein).…”

Sex Differences in Neurochemical Effects of Dopaminergic Drugs in Rat Striatum

“…Haloperidol increases electrically stimulated dopamine signals by blocking presynaptic autoreceptors that inhibit dopamine release and stimulate uptake (Meiergerd et al, 1993;Roth, 1987, 1990;Starke et al, 1989;Cass and Gerhardt, 1994;Wu et al, 2002). These mechanisms play a primary role in the increased basal extracellular dopamine levels that result from D 2 antagonist administration (Imperato and Di Chiara, 1985).…”

“…These responses could be related through autoreceptor control of DAT activity. Stimulation of D 2 autoreceptors increases dopamine uptake (Meiergerd et al, 1993;Cass and Gerhardt, 1994;Wu et al, 2002). D 2 receptor knockout mice have only half the dopamine clearance rate of wild-type mice although DAT expression is identical (Dickinson et al, 1999).…”

Banishing the homunculus: Making working memory work

“…The drugs used (cabergoline and haloperidol) were selective for D2 receptors, which are by far most prevalent in the BG. By acting on presynaptic D2 receptors, cabergoline reduces, while haloperidol enhances, the amount of phasic dopamine that is released during dopaminergic cell bursting (e.g., Wu, Reith, Walker, Kuhn, Caroll, & Garris, 2002). Again, results were consistent with our model: Increases in dopamine during learning caused participants to learn more about the positive outcomes of their decisions (as in medicated Parkinson's patients), whereas decreases in dopamine caused the same participants to learn more about negative outcomes (as in non-medicated patients).…”