Phasic dopamine release evoked by abused substances requires cannabinoid receptor activation

Abstract

Transient surges of dopamine in the nucleus accumbens are associated with drug seeking. Using a voltammetric sensor with high temporal and spatial resolution, we demonstrate differences in the temporal profile of dopamine concentration transients caused by acute doses of nicotine, ethanol, and cocaine in the nucleus accumbens shell of freely moving rats. Despite differential release dynamics, all drug effects are uniformly inhibited by administration of rimonabant, a cannabinoid receptor (CB1) antagonist, suggesting that an increase in endocannabinoid tone facilitates the effects of commonly abused drugs on subsecond dopamine release. These time-resolved chemical measurements provide unique insight into the neurobiological effectiveness of rimonabant in treating addictive disorders.

Figure 1.

Endocannabinoids mediate cocaine-induced increases in subsecond dopamine release. A, Representative traces of dopamine extracellular concentration fluctuations after an injection of cocaine after saline (top), the attenuation of this response by rimonabant after a second cocaine administration (middle) in the same animal and recording location, as well as the effects of saline injection at the same site (bottom). The arrow and dashed line indicate time of drug administration. B, Pooled data of the frequency of dopamine transients (f_DA) in the 4.5 min after the end of each intravenous drug infusion (animals in the control group are shown in white bars). S, Saline; C, first dose of cocaine (3 mg/kg); V/Ri, vehicle (n = 4) or rimonabant (n = 5; 0.3 mg/kg) injection 4.5 min after first dose of cocaine; C2, second dose of cocaine (3 mg/kg) given 30 min after vehicle or rimonabant (Scheffé's test, *p < 0.05 compared with saline; Bonferroni's test, ^∧ p < 0.05 vehicle vs rimonabant-treated animals; Bonferroni's test, ^&p < 0.05 vehicle vs rimonabant-treated animals). C, Amplitude of drug-evoked dopamine transients ([DA]_max). Error bars indicate SEM.

Figure 2.

Cannabinoid receptor blockade attenuates the effects of ethanol of subsecond dopamine release. A, Traces depicting ethanol-induced extracellular dopamine fluctuations after saline injection (top), the attenuation of this response by rimonabant after the second ethanol administration (middle) in the same animal and recording location, and the effects of saline injection at the same site (bottom). The arrow and dashed line indicate time of drug administration. B, Pooled data from ethanol-responsive sites of the frequency of dopamine transients (f_DA) in the 4.5 min after the end of each intravenous drug infusion (animals in the control group are shown in white bars). S, Saline; E, first dose of ethanol (1 g/kg); V/Ri, vehicle (n = 8) or rimonabant (n = 9; 0.3 mg/kg) injection 4.5 min after first dose of ethanol; E2, second dose of ethanol (1 g/kg) given 30 min after vehicle or rimonabant (Scheffé's test, *p < 0.05 compared with saline). C, Amplitude of drug-evoked dopamine transients ([DA]_max). Error bars indicate SEM.

Figure 3.

Nicotine elicits a potent dopamine spillover mediated by CB₁ receptors. A, Dopamine trace showing the effects of nicotine injected after saline on subsecond dopamine release (top) and the dopamine response to nicotine when injected to a different animal in the presence of rimonabant (middle). The bottom panel shows the effects of vehicle injection (recorded from the same site as the trace shown in the top panel). The arrow and dashed line indicate time of drug administration. B, Pooled data of the frequency of dopamine transients (f_DA) in the 4.5 min after the end of each intravenous drug infusion. V/Ri, Vehicle (n = 4) or rimonabant (n = 4; 0.3 mg/kg) injection; nicotine injection (0.3 mg/kg) given 4.5 min after vehicle (V-nic) or rimonabant (Ri-nic). (Student's t test, *p < 0.05 compared with vehicle; ^&p < 0.05, vehicle vs rimonabant-treated animals). C, Amplitude of drug-evoked dopamine transients ([DA]_max). Error bars indicate SEM.