Electrophysiological study of the response of ventral tegmental area non-dopaminergic neurons to nicotine after concurrent blockade of orexin receptor-2 and cannabinoid receptors-1.

The ventral tegmental area (VTA) is a key brain region, involved in the dependency on nicotine. Studies have shown that orexin and cannabinoids are likely to play an important role in nicotine dependency. In this study, the effect of orexin receptor-2 (OX2R) and cannabinoid receptor-1 (CB1R) blockade were investigated in response to nicotine in male rats, on the neural activity of VTA. Nicotine was injected subcutaneously and its effect on the firing of VTA non-dopaminergic (ND) neurons was investigated, using in vivo extracellular single unit recording. Nicotine increased the ND neuronal activity of the VTA. AM251 (0.18, 0.9, 1.8 nmol/0.3 µL), as a selective cannabinoid CB1R antagonist, and TCS-OX2-29 (0.5, 1, 5 nmol/0.3 µL), as a selective OX2R antagonist, individually or simultaneously were microinjected into the VTA. The results revealed that blockade of OX2R and CB1R in the VTA could prevent the increased firing rate, caused by nicotine. Concurrent administration of TCS-OX2-29 and AM251 could decrease responsiveness of VTA-ND neurons to nicotine, but it did not show a greater response than their single application. Because the synergistic effect was not observed in the simultaneous blockade of these two receptors, therefore, in order to detect the interactions of these two receptors, further studies are needed in the field of intracellular signaling.