Cocaine's effects on the reactivity of the medial prefrontal cortex to ventral tegmental area stimulation: optical imaging study in mice

Abstract

Background and aims: The prefrontal cortex (PFC) is modulated by dopaminergic and glutamatergic neurons that project from the ventral tegmental area (VTA) and disruption of this modulation might facilitate impulsive behaviors during cocaine intoxication. Here, we assessed the effects of acute cocaine (30 mg/kg, i.p.) on the reactivity of the PFC to VTA stimulation.

Methods: Using a genetically encoded calcium indicator (GCaMP6f), we optically imaged the neuronal Ca²⁺ reactance in medial PFC (mPFC) in response to 'tonic-like' (5 Hz) and 'phasic-like' (50 Hz) electrical VTA stimulation. The high temporal and spatial resolutions of our optical system allowed us to capture single Ca²⁺ neuronal transients from individual stimuli with 'tonic-like' stimulation and to visualize single neuronal activation evoked by 'phasic-like' VTA stimulation.

Results: 'Tonic-like' VTA stimulation induced a rapid increase in mean neuronal Ca²⁺ in mPFC followed by a plateau and recovery upon termination of stimulation. After cocaine, the mPFC sensitivity to 'tonic-like' VTA stimulation was attenuated, with a 50.4% reduction (P = 0.03) in the number of Ca²⁺ transients corresponding to single electrical stimuli but the recovery time was lengthened (4.30 ± 0.25 sec to 5.41 ± 0.24 sec, P = 0.03). 'Phasic-like' stimulation evoked a rapid Ca²⁺ fluorescence increase in mPFC with an immediate decay process, and while cocaine did not affect the peak response (7.17 ± 1.07% versus 7.13 ± 0.96%, P = 0.98) it shortened the recovery time to baseline (3.27 ± 0.11 sec versus 2.38 ± 0.23 sec, P = 0.005).

Conclusions: Acute cocaine impairs reactivity of medial prefrontal cortex (mPFC) to ventral tegmental area stimulation, decreasing its sensitivity to 'tonic-like' stimulation and lengthening the recovery time to return to baseline while shortening it for phasic stimulation. These changes in mPFC might contribute to cocaine binging during intoxication.

Keywords: Cocaine; GCaMP6f; deep brain stimulation; medial prefrontal cortex; optical imaging; ventral tegmental area.