Amphetamine Distorts Stimulation-Dependent Dopamine Overflow: Effects on D2 Autoreceptors, Transporters, and Synaptic Vesicle Stores

Abstract

Amphetamine (AMPH) is known to raise extracellular dopamine (DA) levels by inducing stimulation-independent DA efflux via reverse transport through the DA transporter and by inhibiting DA re-uptake. In contrast, recent studies indicate that AMPH decreases stimulation-dependent vesicular DA release. One candidate mechanism for this effect is the AMPH-mediated redistribution of DA from vesicles to the cytosol. In addition, the inhibition of stimulation-dependent release may occur because of D2 autoreceptor activation by DA that is released via reverse transport. We used the D2 receptor antagonist sulpiride and mice lacking the D2 receptor to address this issue. To evaluate carefully AMPH effects on release and uptake, we recorded stimulated DA overflow in striatal slices by using continuous amperometry and cyclic voltammetry. Recordings were fit by a random walk simulation of DA diffusion, including uptake with Michaelis-Menten kinetics, that provided estimates of DA concentration and uptake parameters. AMPH (10 M) promoted the overflow of synaptically released DA by decreasing the apparent affinity for DA uptake (K m increase from 0.8 to 32 M). The amount of DA released per pulse, however, was decreased by 82%. This release inhibition was prevented partly by superfusion with sulpiride (47% inhibition) and was reduced in D2 mutant mice (23% inhibition). When D2 autoreceptor activation was minimal, the combined effects of AMPH on DA release and uptake resulted in an enhanced overflow of exocytically released DA. Such enhancement of stimulation-dependent DA overflow may occur under conditions of low D2 receptor activity or expression, for example as a result of AMPH sensitization.

Powerful Cocaine-Like Actions of 3,4-Methylenedioxypyrovalerone (MDPV), a Principal Constituent of Psychoactive ‘Bath Salts’ Products

“…Specifically, MDPV and cocaine inhibit dopamine clearance in a manner consistent with the dopamine uptake blockers (John and Jones, 2007), but MPDV is more potent and efficacious (Figure 3c-f). As is typically observed in cyclic voltammetry experiments, uptake inhibition results in a large increase in the magnitude of evoked dopamine signal and a profound broadening of the dopamine decay curve (Schmitz et al, 2001). MDPV causes a much greater increase in the dopamine AUC response when compared with cocaine ( Figure 3e).…”

“…Owing to its high potency at DAT, MDPV may display a slow dissociation from the site (ie, persistent binding), thereby augmenting and extending its pharmacological effects. In fact, previous voltammetric studies have shown that high-affinity dopamine uptake blockers like nomifensine and GBR12909 produce marked inhibition of dopamine clearance that mirrors the effects of MDPV shown here (Bull et al, 1990;Schmitz et al, 2001). It also remains possible that MDPV interacts with nontransporter sites of action, which further enhance its effects on dopamine clearance, and this proposal warrants examination.…”

Glycine Transporter-1 Inhibition Promotes Striatal Axon Sprouting via NMDA Receptors in Dopamine Neurons

“…At the 7 week time point, evoked dopamine release was recorded in coronal brain slices (Schmitz et al, 2001). Striatal brain slices were cut on a vibratome at 250 m thickness.…”

Cyclin-dependent kinase 5 regulates dopaminergic and glutamatergic transmission in the striatum

“…Parasagittal brain slices were prepared as above. Amperometric detection of dopamine release was performed with methods similar to those described (7). Carbon fiber electrodes (WPI, Sarasota, FL; 10-m diameter)…”