Mesolimbic dopaminergic decline after cannabinoid withdrawal

Abstract

The mesolimbic dopamine system has recently been implicated in the long-term aversive consequences of withdrawal from major drugs of abuse. In the present study we sought to determine whether mesolimbic dopamine neurons are involved in the neurobiologic mechanisms underlying withdrawal from chronic cannabinoid exposure. Rats were treated chronically with the major psychoactive ingredient of hashish and marijuana, Delta9-tetrahydrocannabinol (Delta9-THC). Administration of the cannabinoid antagonist SR 141716A precipitated an intense behavioral withdrawal syndrome, whereas abrupt Delta9-THC suspension failed to produce overt signs of abstinence. In contrast, both groups showed a reduction in dopamine cells activity as indicated by extracellular single unit recordings from antidromically identified meso-accumbens dopamine neurons. The administration of Delta9-THC to spontaneously withdrawn rats restored neuronal activity. Conversely, SR 141716A produced a further decrease of spontaneous activity in cannabinoid-treated although it was ineffective in control rats. These data indicate that withdrawal from chronic cannabinoid administration is associated with reduced dopaminergic transmission in the limbic system, similar to that observed with other addictive drugs; these changes in neuronal plasticity may play a role in drug craving and relapse into drug addiction.

Figure 1

Mean ± SEM of summed behavioral cannabinoid-withdrawal scores observed for a total of 30-min observation period before electrophysiological experiments. Control (vehicle-treated n = 18). P-W rats (n = 10) treated for 6.5 days with Δ⁹-THC and challenged with the cannabinoid antagonist SR141716A (10 mg/kg i.p.). S-W rats (n = 10) treated for 6.5 days with Δ⁹-THC and challenged with vehicle. Control and S-W groups are not statistically different (Mann–Whitney U test, U: 79–84.5, P > 0.2). Conversely, P-W rats show a marked behavioral withdrawal syndrome whose score is statistically significant (Mann–Whitney U test, U: 69.5, P < 0.001) when compared with the S-W group.

Figure 2

Spontaneous activity of antidromically identified VTA-accumbens DA neurons encountered in a rat belonging to the CTRL (Top) S-W (Middle) and P-W (Bottom) groups, respectively. Each histogram represents the neuronal activity of a single neuron. Note the difference in spontaneous activity in the three groups. Recordings were obtained 24 h after last Δ⁹-THC (S-W) and vehicle administration (CTRL) and 2–3 h after SR 141716A administration (P-W).

Figure 3

Individual firing rates of antidromically identified VTA-accumbens DA neurons recorded from S-W, P-W and Control groups. Each circle represents the mean firing rate of 5-min recording. Note the difference in distribution and the trend in silencing from Control toward cannabinoid withdrawal conditions. Horizontal bars indicate the mean activity as reported in Table 1.

Figure 4

Example of the effect of cumulative doses of the cannabinoid agonist Δ⁹-THC administered i.v. at arrows on an antidromically identified VTA-accumbens DA neuron recorded from a S-W rat. Numbers above arrows indicate dosage expressed in mg/kg. Recording was performed 24 h after last Δ⁹-THC administration.

Figure 5

(A) Effect of the cannabinoid antagonist SR 141716A administered i.v. at arrows on an antidromically identified VTA-accumbens DA neuron recorded from a rat belonging to the S-W group. Recording was performed 24 h after last Δ⁹-THC administration. (B) The figure shows the failure of i.v. SR 141716A, administered at arrows, in altering the spontaneous neuronal activity of an antidromically identified VTA-accumbens DA neuron recorded from a rat belonging to the Control group. Recording was performed 24 h after last vehicle administration. Numbers above arrows indicate dosage expressed in mg/kg.