Simultaneous dopamine and single-unit recordings reveal accumbens GABAergic responses: implications for intracranial self-stimulation

Abstract

Intracranial self-stimulation (ICS) is a motivated behavior that results from contingent activation of the brain reward system. ICS with stimulating electrodes placed in the medial forebrain bundle (MFB) is particularly robust. However, the neurons that course through this pathway use a variety of neurotransmitters including dopamine and GABA. For this reason, the neurotransmitters that are central to this behavior, and the specific roles that they subserve, remain unclear. Here, we used extracellular electrophysiology and cyclic voltammetry at the same electrode in awake rats to simultaneously examine cell firing and dopamine release in the nucleus accumbens (NAc) during ICS and noncontingent stimulation of the MFB. ICS elicited dopamine release in the NAc and produced coincident time-locked changes (predominantly inhibitions) in the activity of a subset of NAc neurons. Similar responses were elicited with noncontingent stimulations. The changes in firing rate induced by noncontingent stimulations were reversed by the GABA(A) receptor antagonist bicuculline. Most time-locked unit activity was unaffected by D1 or D2-like dopamine-receptor antagonists, or by inhibition of evoked dopamine release, although, for a minority of units, the D1 dopamine-receptor antagonist SCH23390 attenuated neural activity. Thus, neurons in the NAc are preferentially inhibited by GABA(A) receptors after MFB stimulation, a mechanism that may also be important in ICS.

Fig. 1.

Responses measured in the NAc during ICS. (A) Dopamine release in the NAc evoked by ICS (24 pulses, 60 Hz, 125 μA) of the MFB using an FR1, TO10″ schedule. The top line indicates the time of each reinforced response. Each lever press caused a stimulation followed by a retraction of the lever for 10 s. The dopamine temporal response, corrected for pH changes, is shown below. The color representation shows all of the voltammetric currents; the white dashed line is at the potential for oxidation of dopamine. The green feature centered on the dashed line is due to the release of dopamine. The blue features are due to a basic pH shift after dopamine release. A cyclic voltammogram obtained at the peak of the last response (asterisk) is shown below the color plot. (B) Representative perievent raster and PEH centered on the ICS lever press (green dashed line). Each tick on the raster plot represents an extracellularly recorded action potential (average waveform shown to the top left). The red line is the evoked dopamine signal averaged from the 63 trials shown. Bin width was 200 ms for both measurements.

Fig. 2.

Responses measured in the NAc during ICS and noncontingent stimulations. (Left) Neural activity ± 8s around the ICS lever press (green dashed line at time 0; 24 pulses, 60 Hz, 125 μA). (Right) Neural activity displayed in the same way obtained during noncontingent stimulations. Data are shown as composite PEHs. Histograms were made by summing data from each unit over individual trials, and sorting according to responses obtained [Top, unaffected (U-type); Middle, inhibited/excited (I/E-type); Bottom, inhibited (I-type)]. The overlaid trace (red) shows the time course of average extracellular dopamine concentration changes measured at the same loci where neurons were recorded after the stimulation. Bin width was 200 ms for all histograms.

Fig. 3.

Inhibitory responses are independent of vesicular dopamine release but modulated by GABA_A receptors. (A) PEH obtained during noncontingent stimulation (green dashed line at time 0; 24 pulses, 60 Hz, 125 μA) with average dopamine response (red line) superimposed. (B) Inhibition of action potential-driven dopamine release with RO (1 mg·kg^-1) decreases background firing rates, but does not eliminate the inhibition of firing caused by the stimulation. (C) Blockade of GABA_A receptors with BIC (200 μg·kg^-1) after RO uncovers a time-locked excitation, whereas background firing is further decreased and dopamine release remains undetectable (Bottom). Bin width was 200 ms, all drugs were delivered intravenously.

Fig. 4.

Composite PEHs showing the effects of dopamine receptor antagonists on inhibitory and excitatory responses time-locked to electrical stimulation of the MFB. Stimulation initiated at time indicated by the green dashed line. (A) Time-locked inhibitions of I-type neurons are unchanged between before (Upper) and after (Lower) administration of SCH23390 (SCH, 40 μg·kg^-1; Left) and raclopride (Raclo, 80 μg·kg^-1, Right). Dopamine release is also unchanged after SCH, but Raclo increases electrically evoked release. (B) The overall response of E-type cells was diminished after SCH treatment, whereas dopamine release was unaltered (Left). Although the time-locked excitation was unchanged by Raclo treatment (Right), dopamine release was again increased (Right). Bin width was 200 ms for all PEHs, all drugs were given intravenously.