Cocaine self-administration abolishes endocannabinoid-mediated long-term depression of glutamatergic synapses in the ventral tegmental area

Abstract

Drugs of abuse, including cocaine, alter the mechanisms underpinning synaptic plasticity, including long-term potentiation of glutamatergic synapses in the mesolimbic system. These effects are thought to underlie addictive behaviors. In the ventral tegmental area (VTA), glutamatergic synapses also exhibit long-term depression (LTD), a type of plasticity that weakens synaptic strength. This form of synaptic plasticity is induced by low-frequency stimulation and mediated by endocannabinoid (eCB) signaling, which also modulates addictive behaviors. However, it remains unknown whether eCB-LTD in the VTA could be altered by cocaine use. Therefore, the goal of the present study was to examine the impact of cocaine self-administration on eCB-LTD of glutamatergic synapses onto VTA dopaminergic (DA) neurons. To that end, male rats underwent cocaine (0.75 mg/kg/infusion) or saline self-administration under the fixed ratio 1 schedule for 6-9 days. One day after the last self-administration session, the magnitude of eCB-LTD was examined using ex vivo whole-cell recordings of putative VTA DA neurons from naïve rats and rats with saline or cocaine self-administration. The results revealed that cocaine self-administration abolished eCB-LTD. The cocaine-induced blockade of eCB-LTD in the VTA was mediated by an impaired function of presynaptic CB1 receptors. Collectively, these findings indicate that cocaine exposure blunts eCB-mediated synaptic plasticity in midbrain DA neurons. This effect could be one of the cellular mechanisms that mediate, at least in part, addictive behaviors.

Keywords: CB1 receptors; addiction; dopamine; psychostimulant; synaptic plasticity.

Fig. 1.

Cocaine showed a strong reinforcing effect in the self-administration experiment. (A) & (B) Rats self-administered more cocaine (0.75 mg/kg/infusion) than saline (in numbers of infusions) under the fixed ratio 1 reinforcement schedule. (C) & (D) The proportions of active responses (lever presses) were higher in the cocaine than the saline group. The left panels depict data from each session; the right panels present averages across the 6 sessions. Data are expressed as mean ± SEM. ***p < 0.001, saline vs. cocaine.

Fig. 2.

Cocaine self-administration abolished eCB-LTD of glutamatergic synapses onto putative VTA DA neurons. (A) A summary graph of the time course and magnitude of LFS-induced LTD in naïve rats in the absence (●) and presence of AM 251 (3 μm; ○). Note that blockade of CB1Rs abolished the LTD, indicating that the LTD was mediated by eCB signaling. (B) Representative pairs of EPSC traces taken before and during LTD, as indicated by the numbers in graph A (1: in black). (C) A summary graph of the paired-pulse ratios (PPRs) of EPSCs determined before and during LTD. The LTD was associated with a significant increase in PPR, indicating a decrease in glutamate release. (D) A summary graph of the time course and magnitude of the LTD recorded in saline- (●) and cocaine-treated rats (○). Note that cocaine self-administration blocked the LTD. (E) Representative EPSC traces taken at the periods indicated by the numbers in graph D (1: in black). (F) A summary graph of the magnitudes of the LTD recorded in saline and cocaine groups. Data are expressed as mean ± SEM. **: p < 0.01, saline vs. cocaine; ***: p < 0.001, baseline vs. LTD. Scale bars: 50 pA, 10 ms.

Fig. 3.

Cocaine self-administration reduced the function of presynaptic CB1Rs in the VTA. (A) The lower panel is a summary graph of the time course and magnitude of WIN 55,212–2-induced depression of EPSC amplitudes obtained in saline- (●) and cocaine-treated rats (○). The upper panel depicts superimposed EPSC traces taken before and after WIN 55,212–2 (10 μm) application, as indicated by the numbers in the lower panel (1: in black). (B) A summary plot of WIN 55,212–2-induced depression of EPSC amplitudes obtained in saline- and cocaine-treated rats. Note that cocaine self-administration significantly reduced the magnitude of WIN-55,212–2 induced depression of EPSC amplitudes. Data are expressed as mean ± SEM. **: p < 0.01, saline vs. cocaine. Scale bars: 50 pA, 20 ms.