High doses of amphetamine augment, rather than disrupt, exocytotic dopamine release in the dorsal and ventral striatum of the anesthetized rat

Abstract

High doses of amphetamine (AMPH) are thought to disrupt normal patterns of action potential-dependent dopaminergic neurotransmission by depleting vesicular stores of dopamine (DA) and inducing robust non-exocytotic DA release or efflux via dopamine transporter (DAT) reversal. However, these cardinal AMPH actions have been difficult to establish definitively in vivo. Here, we use fast-scan cyclic voltammetry (FSCV) in the urethane-anesthetized rat to evaluate the effects of 10 and 20 mg/kg AMPH on vesicular DA release and DAT function in dorsal and ventral striata. An equivalent high dose of cocaine (40 mg/kg) was also examined for comparison to psychostimulants acting preferentially by DAT inhibition. Parameters describing exocytotic DA release and neuronal DA uptake were determined from dynamic DA signals evoked by mild electrical stimulation previously established to be reinforcing. High-sensitivity FSCV with nanomolar detection was used to monitor changes in the background voltammetric signal as an index of DA efflux. Both doses of AMPH and cocaine markedly elevated evoked DA levels over the entire 2-h time course in the dorsal and ventral striatum. These increases were mediated by augmented vesicular DA release and diminished DA uptake typically acting concurrently. AMPH, but not cocaine, induced a slow, DA-like rise in some baseline recordings. However, this effect was highly variable in amplitude and duration, modest, and generally not present at all. These data thus describe a mechanistically similar activation of action potential-dependent dopaminergic neurotransmission by AMPH and cocaine in vivo. Moreover, DA efflux appears to be a unique, but secondary, AMPH action.

Figure 1. Effects of AMPH and cocaine on evoked DA dynamics

AMPH and cocaine show time- and dose-dependent effects on the amplitude and dynamics of evoked DA levels in the dorsal (A) and ventral (B) striatum. Application of the stimulus train (60 Hz, 0.4 s) is indicated by the solid line underneath each representative response.

Figure 2. Effects of AMPH and cocaine on evoked [DA]_max

AMPH and cocaine increase [DA]_max in the dorsal (A) and ventral (B) striatum. Data are expressed as a percent of the predrug value (% predrug). Drugs were administered shortly after the evoked response was collected at time 0 min (arrow).

Figure 3. Effects of AMPH and cocaine on neuronal DA uptake

AMPH and cocaine inhibit DA uptake in the dorsal (A) and ventral (B) striatum. Data are expressed as a percent of the predrug value (% predrug). Drugs were administered shortly after the evoked response was collected at time 0 min.

Figure 4. Effects of AMPH and cocaine on exocytotic DA release

AMPH and cocaine augment exocytotic DA release in the dorsal (A) and ventral (B) striatum. Data are expressed as a percent of the predrug value (% predrug). Drugs were administered shortly after the evoked response was collected at time 0 min.

Figure 5. Effects of AMPH on slow changes in the background voltammetric signal

In each panel, the top trace is a continuous recording of background current monitored at the peak oxidation potential for DA across the first 35 minutes of the drug time course. The middle trace is its time-expanded portion demarcated by the solid line underneath the top recording. The INSET to the middle trace is a background subtracted voltammogram collected at the red vertical line. A color plot serially displaying all background subtracted cyclic voltammograms is found at the bottom. The red line also identifies when the individual voltammogram shown in the INSET was collected. The white horizontal line identifies the peak oxidation potential for DA. Panels A, B and C show the effects of 10 mg/kg AMPH in the dorsal striatum. Panel D shows the effects of 40 mg/kg cocaine in the dorsal striatum. Data in all panels were collected in different animals.

Figure 6. Effects of AMPH on fast changes in the background voltammetric signal

In each panel, the top trace is a recording of background current monitored at the peak oxidation potential for DA. The INSET to the middle trace is a background subtracted voltammogram collected at the red vertical line. A color plot serially displaying all background subtracted cyclic voltammograms is found at the bottom. The red line also identifies when the individual voltammogram shown in the INSET was collected. The white horizontal line identifies the peak oxidation potential for DA. Panels A and B show the effects of 20 mg/kg AMPH in the ventral striatum in two individual animals, respectively. The left recording in Panel A is time expanded in the right recording.