Challenge exposure to whole cigarette smoke condensate upregulates locomotor sensitization by stimulating α4ß2 nicotinic acetylcholine receptors in the nucleus accumbens of rats.

Nicotine, the primary addictive substance in tobacco, produces the psychomotor, rewarding, and reinforcing effects of tobacco dependence by stimulating nicotinic acetylcholine receptors (nAChRs) in the brain. The present study determined that α4ß2 nAChRs regulate locomotor sensitization by altering dopamine concentration in the nucleus accumbens (NAc) after systemic challenge exposure to whole cigarette smoke condensate (WCSC). Rats were administered subcutaneous injection of WCSC (0.2 mg/kg nicotine/day) for 7 consecutive days and then re-exposed to WCSC after 3 days of withdrawal. Challenge exposure to WCSC significantly increased locomotor activity. This increase was decreased by the subcutaneous injection of the α4ß2 nAChR antagonist, DHßE (3 mg/kg), but not by the intraperitoneal injection of the α7 nAChR antagonist, MLA (5 mg/kg). In parallel with a decrease in locomotor activity, blockade of α4ß2 nAChRs with DHßE decreased dopamine concentration in the NAc which was elevated by challenge exposure to WCSC. These findings suggest that challenge WCSC leads to the expression of locomotor sensitization by elevating dopamine concentration via stimulation of α4ß2 nAChRs expressed in neurons of the NAc in rats.

Alpha-pyrrolidinopentiothiophenone (α-PVT) activates the TLR-NF-κB-MAPK signaling pathway and proinflammatory cytokine production and induces behavioral sensitization in mice.

Synthetic cathinones are chemical derivatives of cathinone, a structural analog to amphetamine. It has been shown that synthetic cathinones have abuse potentials similar to psychomotor stimulants such as amphetamine and induce neuroinflammation. Among the novel synthetic cathinones, α-pyrrolidinopentiothiophenone (α-PVT) has been known to produce rewarding and reinforcing effects in rodent models. However, it has not yet been determined whether α-PVT induces neuroinflammation in vivo. In the present study, mice were exposed to repeated saline or α-PVT (20 mg/kg, intraperitoneally) for 7 days to test changes in locomotor activity and neuroinflammation-related factors in the striatum of mice. Repeated administration of α-PVT significantly induced locomotor sensitization. In addition, repeated α-PVT administration significantly increased the number of microglial cells, accompanied by marked increases in TLR1, TLR4, TLR6, and TLR7 mRNA levels in the striatum of mice. Furthermore, acute or repeated α-PVT administration increased the levels of phosphorylated NF-κB, ERK, p38, and JNK MAPK activation and repeated α-PVT, but not acute, increased the levels of TNF-α and IL-6 mRNA in the striatum of mice. Finally, systemic administration of TAK-242 (5 mg/kg, i.p.) or MPLA (50 µg/kg, i.p.), each an inhibitor or activator of TLR4, did not change α-PVT-induced behavioral sensitization in mice. These results suggest that the activation of TLR4 by repeated α-PVT administration may lead to neuroinflammation via TLR-mediated NF-κB and MAPK signaling pathways and the production of TNF-α and IL-6 in the striatum of mice, at least without the regulation of behavioral sensitization.