D₂ Receptors May Modulate the Function of the Striatal Transporter for Dopamine: Kinetic Evidence from Studies In Vitro and In Vivo

Abstract

Recently it was hypothesized by others that the D2dopamine receptor can regulate the uptake of dopamine. However, the evidence in support of this hypothesis, although compelling, was not based on observations related to direct measures of the kinetic activity of the transporter itself. Here kinetic evidence in support of this hypothesis is shown. The apparent time‐resolved initial velocity of the transport of 1.0 μM dopamine into striatal suspensions, measured using rotating disk electrode voltammetry, was found to increase in the presence of the D2 receptor agonist, quinpirole, at 100 μM. This effect was reversed by sulpiride. In separate studies it was shown that acute and chronic treatments with haloperidol at 0.5 mg/kg, i.p., reduced the reuptake transport of dopamine in vivo following intrastriatal stimulation of its release by K+. Thus, it appears that D2 receptors may influence the functioning of the striatal transporter for dopamine. These results are consistent with a model in which presynaptically released dopamine may feed back onto the function of its transporter to increase the velocity of the clearance of synaptic dopamine following an action potential, suggesting the existence of a mechanism, in addition to release and synthesis modulation, for fine‐tuning dopaminergic chemical signaling.

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).…”

Additive Effects of Genetic Variation in Dopamine Regulating Genes on Working Memory Cortical Activity in Human Brain

“…In the cortex, DATs tend to be found on nonvaricose axon segments of small diameter, which make symmetric synapses (Sesack et al, 1998;Lewis et al, 2001), with a distribution similar to that of some D 2 receptors, a proportion of which are extrasynaptic (Pickel et al, 2002;Negyessy and GoldmanRakic, 2005). Moreover, the functional activity of DAT is regulated by D 2 receptors (Meiergerd et al, 1993;Dickinson et al, 1999;Mortensen and Amara, 2003). Thus, the DAT 10-repeat allele associated with increased expression of the gene may presumably lead to relatively decreased extrasynaptic cortical dopamine levels, which would be associated with reduced D 2 signaling and with increased GABA release, thus secondarily increasing signal-to-noise ratios of pyramidal neurons (Seamans and Yang, 2004).…”

Nicotine Normalizes Increased Prefrontal Cortical Dopamine D1 Receptor Binding and Decreased Working Memory Performance Produced by Repeated Pretreatment with MK-801: A PET Study in Conscious Monkeys

“…There is no evidence that nicotine can act directly on the DAT. However, recent evidence suggests that modulation of several receptors on dopaminergic terminals alters DAT activity (Meiergard et al, 1993;Ichikawa et al, 1995;Yamashita et al, 1995;Izenwasser et al, 1998;Drew et al, 2000;Tsukada et al, 1999aTsukada et al, , b, 2000aTsukada et al, , b, 2001a. In addition, it has been shown that NMDA antagonism increased DAT availability in the monkey striatum as measured by [ 11 C]b-CFT (Tsukada et al, 2000a(Tsukada et al, , 2001a.…”