Inhibition of Dopamine Release Via Presynaptic D2 Receptors: Time Course and Functional CharacteristicsIn Vivo

Abstract

Most neurotransmitters inhibit their own release through autoreceptors. However, the physiological functions of these presynaptic inhibitions are still poorly understood, in part because their time course and functional characteristics have not been described in vivo. Dopamine inhibits its own release through D2 autoreceptors. Here, the part played by autoinhibition in the relationship between impulse flow and dopamine release was studied in vivo in real time. Dopamine release was evoked in the striatum of anesthetized mice by electrical stimulation of the medial forebrain bundle and was continuously monitored by amperometry using carbon fiber electrodes. Control experiments performed in mice lacking D2 receptors showed no autoinhibition of dopamine release. In wild-type mice, stimulation at 100 Hz with two to six pulses linearly inhibited further release, whereas single pulses were inefficient. Dopaminergic neurons exhibit two discharge patterns: single spikes forming a tonic activity below 4 Hz and bursts of two to six action potentials at 15 Hz. Stimulation mimicking one burst (four pulses at 15 Hz) promoted extracellular dopamine accumulation and thus inhibited further dopamine release. This autoinhibition was maximal between 150 and 300 msec after stimulation and disappeared within 600 msec. This delayed and prolonged time course is not reflected in extracellular DA availability and thus probably attributable to mechanisms downstream from autoreceptor stimulation. Thus, in physiological conditions, autoinhibition has two important roles. First, it contributes to the attenuation of extracellular dopamine during bursts. Second, autoinhibition elicited by one burst transiently attenuates further dopamine release elicited by tonic activity.

Time window of autoreceptor‐mediated inhibition of limbic and striatal dopamine release

“…It will be interesting to see the extent to which these and other factors participate in vivo. A recent in vivo report using D2 receptor mice finds a similar overall profile of autoinhibition to the present study with a clear onset and offset but slightly shorter peak time (Benoit-Marand et al, 2001b). Considering the methodological differences (in vivo vs. in vitro, D2 knockout mice vs. pharmacological D2 receptor blockade in rats), the findings are encouragingly consonant.…”

Dissociable Control of Impulsivity in Rats by Dopamine D2/3 Receptors in the Core and Shell Subregions of the Nucleus Accumbens

“…The absence of an effect of aripiprazole on impulsivity in this study might suggest that inter-individual differences in impulsivity on the 5-CSRT task are not related to major differences in DA release, consistent with evidence that HI rats do not show higher striatal DA release than non-impulsive rats (Dalley et al, 2007). The lower number of DA D2/3 receptors in the ventral striatum of HI rats would hence not seem to be associated with an impairment in presynaptic function, which would directly affect DA tone (Benoit-Marand et al, 2001), but rather to a change in postsynaptic activity. However, previous research has shown that electrically evoked DA release is increased and decreased in the NAcbS and NAcbC, respectively, in HI compared with LI rats (Diergaarde et al, 2008).…”

Regulation of Akt Signaling by D2and D3Dopamine ReceptorsIn Vivo

“…D 2 receptors exert both presynaptic and postsynaptic functions. In their presynaptic autoreceptor function, mediated by the D 2 S isoform, these receptors are responsible for the regulation of DA synthesis and, consequently, impulse-dependent dopamine release (Baik et al, 1995;Missale et al, 1998;Usiello et al, 2000;Benoit-Marand et al, 2001). Postsynaptic D 2 receptors have been associated with, among other effects, stimulation of locomotion and the development of haloperidol-induced catalepsy (Baik et al, 1995;Usiello et al, 2000).…”

“…Postsynaptic D 2 receptors have been associated with, among other effects, stimulation of locomotion and the development of haloperidol-induced catalepsy (Baik et al, 1995;Usiello et al, 2000). A loss of D 2 autoreceptor function thus should result in an increase of DA synthesis and, consequently, release (Benoit-Marand et al, 2001), which would in turn lead to a reduction in striatal Akt phosphorylation as demonstrated in DAT-KO and amphetamine-treated WT mice (Beaulieu et al, 2004(Beaulieu et al, , 2005. However, the increased basal Akt phosphorylation in D 2 -KO as well as in D 2 L-KO mice, which do not display major changes in D 2 autoreceptor function (Usiello et al, 2000), indicate that the negative regulation of Akt by DA is mostly a postsynaptic phenomena regulated by D 2 receptors.…”