Seong Shoon Yoon

Menthol, a prevalent additive in tobacco and electronic cigarette products, has been reported to interact with nicotine at both neuropharmacological and behavioral levels. Although menthol alone is not reinforcing, converging evidence suggests that it may modulate the pharmacological and behavioral effects of nicotine through nicotinic acetylcholine receptor (nAChR) mechanisms. Using an inhalation-based rodent model that mimics human exposure to electronic nicotine delivery systems, we examined how menthol aerosol influences nicotine-induced hypothermia, discriminative stimulus effects, and the potential involvement of α4β2* nAChRs in male rats. Plasma nicotine, cotinine, and trans-3′-hydroxycotinine (3′-OH-cotinine) concentrations were also measured to assess pharmacokinetic interactions. Menthol aerosol prolonged and potentiated nicotine-induced hypothermia, and this effect was attenuated by the α4β2* receptor antagonist dihydro-β-erythroidine (DHβE). In drug discrimination (DD) assays, coinhalation of menthol enhanced nicotine-appropriate responding, suggesting facilitation of nicotine’s interoceptive stimulus properties. These effects were also attenuated by DHβE, consistent with involvement of α4β2* nAChR-mediated mechanisms. In addition, the behavioral effects were accompanied by alterations in nicotine pharmacokinetics, including increased levels of nicotine metabolites. Collectively, these findings suggest that menthol modulates nicotine’s pharmacological and behavioral effects, potentially through α4β2* nAChR-dependent mechanisms. By prolonging nicotine’s physiological and interoceptive effects, menthol may increase the salience of nicotine-related cues during inhalation exposure. These interactions could contribute to enhanced abuse liability associated with menthol-containing nicotine products, although further studies are required to establish causal mechanisms. This study provides mechanistic insight into menthol–nicotine interactions and highlights considerations relevant to mentholated e-cigarette products.

Recently, the abuse of synthetic cathinones is increasing among young people. alpha-Pyrrolidinobutiothiophenone (alpha-PBT), a synthetic cathinone, is a designer drug that is freely traded online with no legal restrictions. Moreover, there is currently no scientific basis for legal regulation. Here, we examined the addictive properties of alpha-PBT using a drug discrimination (DD) task. We also investigated the role of alpha-PBT in brain stimulation reward (BSR) using an intracranial self-stimulation (ICSS) paradigm in rats. Initially, the rats were trained to discriminate between cocaine and saline. After the discrimination training criteria were met, we determined the dose-effect curves of cocaine and conducted generalization tests with alpha-PBT and alpha-pyrrolidinopentiothiophenone (alpha-PVT) using a cumulative dosing protocol. In a separate set of studies, we examined the dopaminergic mechanisms underlying the function of alpha-PBT as an interoceptive stimulus (17.8 mg/kg) by intraperitoneally injecting either the dopamine (DA) D1 antagonist SCH23390 (0.06 and 0.12 mg/kg) or the D2 antagonist eticlopride (0.05 and 0.1 mg/kg) 15 min before DD testing. Brain reward function was measured using an ICSS procedure to examine the effects of alpha-PBT on ICSS threshold under the frequency-rate procedure. Our results showed that alpha-PBT functioned as a discriminative cue similar to cocaine in rats. More importantly, SCH23390 abolished the effects of alpha-PBT as an interoceptive stimulus in a dose-dependent manner in rats trained to press a lever to receive cocaine. Similarly, eticlopride dose-dependently attenuated the effect of alpha-PBT used as a discriminative cue. Additionally, cumulative alpha-PBT administration dose-dependently lowered ICSS thresholds compared with those in saline-treated rats. Furthermore, alpha-PBT-induced potentiation of BSR was abolished by pretreatment with both SCH23390 and eticlopride. Taken together, our results suggest that alpha-PBT can function as a cocaine-like discriminative cue via the activation of D1 and D2 receptors. alpha-PBT also appears to influence BSR by reducing the brain reward threshold via changes in D1 and D2 receptors. The present study suggests that alpha-PBT could have addictive properties through DA D1 and D2 receptors and thus poses a threat to humans.

Background and Purpose: α‐Pyrrolidinobutiothiophenone (α‐PBT) is a chemical derivative of cathinone, a structural analogue of amphetamine. Until now, there have been a few previous neurochemical or neurobehavioural studies on the abuse potential of α‐PBT.Experimental Approach: We examined the abuse potential of α‐PBT by measuring psychomotor, rewarding, and reinforcing properties and methamphetamine‐like discriminative stimulus effects in rodents using locomotor activity, conditioned place preference, self‐administration, and drug discrimination studies. To clarify the underlying neuropharmacological mechanisms, we measured dopamine levels and neuronal activation in the dorsal striatum. In addition, we investigated the role of the dopamine D₁ receptor or D₂ receptors in α‐PBT‐induced hyperlocomotor activity, conditioned place preference, and the methamphetamine‐like discriminative stimulus effect of α‐PBT in rodents.Key Results: α‐PBT promoted hyperlocomotor activity in mice. α‐PBT induced drug‐paired place preference in mice and supported self‐administration in rats. In a drug discrimination experiment, α‐PBT fully substituted for the discriminative stimulus effects of methamphetamine in rats. Furthermore, α‐PBT increased dopamine levels and c‐Fos expression in the dorsal striatum of mice, which was associated with these behaviours. Finally, pretreatment with the D₁ receptor antagonist SCH23390 or the D₂ receptors antagonist eticlopride significantly attenuated acute or repeated α‐PBT‐induced hyperlocomotor activity, place preference, and the methamphetamine‐like discriminative stimulus effects in rodents.Conclusions and Implications: These findings suggest that α‐PBT has abuse potential at the highest dose tested via enhanced dopaminergic transmission in the dorsal striatum of rodents. The results provide scientific evidence for the legal restrictions of the recreational use of α‐PBT.

Gu SM, et al. J Vet Sci. 2024 Aug;25:e63. https://doi.org/10.4142/jvs.23325

Rationale Recently, it has been suggested that isoflurane might reduce dopamine release from rat midbrain dopaminergic neurons, the neurobiological substrate implicated in the reinforcing effects of abused drugs and nondrug rewards. However, little is known about effects of isoflurane on neurobehavioral activity associated with chronic exposure to psychoactive substances. Objective The present study was designed to investigate the effects of isoflurane on cocaine-reinforced behavior. Using behavioral paradigm in rats, we evaluated the effects of isoflurane on cocaine self-administration under fixed ratio (FR) and progressive ratio (PR) schedules of reinforcement. We also tested the effects of isoflurane on lever responding by nondrug reinforcers (sucrose and food) in drug-naive rats to control for the nonselective effects of isoflurane on cocaine- and nicotine-taking behavior. To further assess the ability of isoflurane to modulate the motivation for taking a drug, we evaluated the effects of isoflurane on nicotine self-administration. Using different groups of rats, the effects of isoflurane on the locomotor activity induced by a single intraperitoneal injection of cocaine (15 mg/kg) were also examined. Results Isoflurane significantly suppressed the self-administration of cocaine and nicotine without affecting food consumption. Unlike food-reinforced responding, responding for sucrose reinforcement was decreased by isoflurane. Isoflurane reduced breaking points under a PR schedule of reinforcement in a dose-dependent manner, indicating its efficacy in decreasing the incentive value of cocaine. Isoflurane also attenuated acute cocaine-induced hyperlocomotion. Conclusions The results provided evidence that isoflurane decreases cocaine- and nicotine-reinforced responses, while isoflurane effect is not selective for cocaine- and nicotine-maintained responding. These results suggest that isoflurane inhibitions of cocaine- and nicotine-maintenance responses may be related to decreased effects of dopamine, and further investigation will need to elucidate this relationship.

Acupuncture affects the central nervous system via the regulation of neurotransmitter transmission. We previously showed that Shemen (HT7) acupoint stimulation decreased cocaine-induced dopamine release in the nucleus accumbens. Here, we used the intracranial self-stimulation (ICSS) paradigm to evaluate whether HT stimulation regulates the brain reward function of rats. We found that HT stimulation triggered a rightward shift of the frequency–rate curve and elevated the ICSS thresholds. However, HT7 stimulation did not affect the threshold-lowering effects produced by cocaine. These results indicate that HT7 points only effectively regulates the ICSS thresholds of the medial forebrain bundle in drug-naïve rats.

3‐fluoromethamphetamine (3‐FMA), a derivative of methamphetamine (METH), produces behavioral impairment and deficits in dopaminergic transmission in the striatum of mice. The abuse potential of 3‐FMA has not been fully characterized. The aim of this study was to evaluate the effects of 3‐FMA on locomotor activity as well as its rewarding and reinforcing properties in the conditioned place preference (CPP) and self‐administration procedures. Intravenous (i.v.) administration of 3‐FMA (0.5 and 1.0 mg/kg) significantly increased locomotor activity in a dose‐dependent manner in rats. In the CPP procedure, intraperitoneal administration of 3‐FMA (10 and 30 mg/kg) produced a significant alteration in place preference in mice. In the self‐administration paradigms, 3‐FMA showed drug‐taking behavior at the dose of 0.1 mg/kg/infusion (i.v.) during 2 hr sessions under fixed ratio schedules and high breakpoints at the dose of 0.3 and 1.0 mg/kg/infusion (i.v.) during 6 hr sessions under progressive ratio schedule of reinforcement in rats. A priming injection of 3‐FMA (0.4 mg/kg, i.v.), METH (0.2 mg/kg, i.v.), or cocaine (2.0 mg/kg, i.v.) reinstated 3‐FMA‐seeking behavior after an extinction period in 3‐FMA‐trained rats during 2 hr session. Taken together, these findings demonstrate robust psychomotor, rewarding and reinforcing properties of 3‐FMA, which may underlie its potential for compulsive use in humans.

We provide evidence for the effectiveness of acupuncture in an animal model of alcohol dependence.