Effetto nell’auto-somministrazione dell’agonista sintetico del recettore cannabinoide CB1, WIN 55,212-2, nel modello animale di depressione della bulbectomia olfattoria (OBX)

Depression frequently coexists with substances abuse, including heavy or problematic cannabis use. To mimic this comorbidity, we combined the olfactory bulbectomy model of depression with intravenous drug self-administration procedure to verify whether depressive-like rats display higher voluntary intake of the cannabinoid CB1 receptor agonist WIN 55,212-2 (WIN, 12.5 μg/kg/infusion). The olfactory-bulbectomized rat is a well-established model that exhibits a high degree of behavioural and neurochemical similarity to depression. Male Lister Hooded rats were either olfactory-bulbectomized (OBX) or sham-operated (SHAM), and following 21 days they were implanted with intravenous catheters. A 3-week period is necessary for the development of a depressive-like phenotype following OBX surgery, which was verified by means of the motility and sucrose preference test. Indeed, the presence of anhedonia and hypermotility in response to a novel aversive environment are two hallmarks of OBX rats. Only OBX rats displaying a depressive-like phenotype were allowed to self-administer WIN by lever-pressing under a continuous (FR-1) schedule of reinforcement in 2h daily sessions, as previously described (Fattore et al. 2001). Our results show that both OBX and SHAM rats developed stable WIN intake. Yet, rates of responding for WIN was constantly higher in OBX than in SHAM rats starting soon after the first week of training. This finding is in line with previously reported higher intake of methamphetamine (Kucerova et al. 2011) and oral nicotine (Vieyra-Reyes et al. 2008) in OBX than in SHAM animals, which confirms the hypothesis of higher drug intake in depressive-like conditions. Finally, response latency (defined as time elapsed from commencement of the experimental session until the first active lever press) was significantly different between the two groups. More specifically, response latency was shorter in OBX than SHAM rats from day 9 onward, which suggests that after initial exposure to the CB1 receptor agonist the bulbectomized rats may be more motivated than controls to obtain it. Moreover, analysis of temporal patterns of responses revealed quantitative but not qualitative differences between OBX and SHAM rats during self-administration training, since the response rate was typically slow and evenly distributed throughout the 2h test session in both groups. These findings showed that olfactory bulbectomy markedly affects cannabinoid self-administration, likely through a reduction of the cannabinergic rewarding effects to which animals compensate by increasing WIN intake. A number of human and animal studies demonstrated a causal link between altered serotonin 5-HT1B receptor activity and development of neuropsychiatric conditions, including depression and drug addiction Therefore, we evaluated the effect of acute pre-treatment with the serotonin 5-HT1B receptor agonist CGS-12066B (CGS, 2.5-10 mg/kg) on the WIN self-administration. Acute intraperitoneal (IP) pre-treatment with CGS (2.5, 5 and 10 mg/kg) did not significantly modify WIN intake in OBX and SHAM rats. Moreover, since WIN self-administration was shown to be associated to an increased dopamine transmission in the shell of the nucleus accumbens (NAc) (Fadda et al., 2006), we used the in vivo microdialysis technique to test whether OBX and SHAM rats displayed similar increase in dopamine levels within the NAc shell in response to a challenge of WIN at a dose (0.3 mg/kg, IP) that mimics the daily mean amount of drug typically self-administered by trained rats. We found that, contrary to SHAM rats, dopamine levels in the nucleus accumbens of OBX rats did not increase in response to a WIN challenge, suggesting a dopaminergic dysfunction in bulbectomized rats. Altogether our results suggest that WIN is not affected by acute stimulation of 5-HT1B receptors, and that a dopaminergic rather than a 5-HT1B mechanism is likely to underlie enhanced WIN self-administration in OBX rats. To verify whether prolonged stimulation of CB1 receptors could affect the depressive-like phenotype of OBX rats, we also investigated the effect of chronic (2-weeks) treatment with WIN 55,212-2 (0.5 mg/kg, IP) in OBX and SHAM. Although not statistically significant, a trend was found as concerns a potential antidepressive effect of chronic WIN administration in OBX rats. Finally, a [3H]CP-55,940 binding autoradiography study was performed to investigate CB1 receptor-mediated signaling in the brain of olfactory bulbectomized rats. A reduced functionality of CB1 receptors was detected in the caudate-putamen and in the nucleus accumbens core, which confirmed an altered CB1 receptor-mediated limbic signaling in OBX rats. Fattore et al. (2001) Psychopharmacology 156: 410-416. Kucerova et al. (2011) Int J Neuropsychopharmacol. 15:1503-1511. Vieyra-Reyes et al. (2008) Brain Res. Bull. 77: 13-28. Fadda et al. (2006) Neuroreport 17: 1629-1632.