N-tert-butoxycarbonyl-methylenedioxymethamphetamine, an methylenedioxymethamphetamine derivative, exhibits rewarding and reinforcing effects by increasing dopamine levels.

An N-protected methylenedioxymethamphetamine (MDMA), N-tert-butoxycarbonyl-3,4-methylenedioxymethamphetamine (t-BOC-3,4-MDMA), contains tert-butoxycarbonyl and can remain undetected in the illicit drug market. It is a new type of precursor substance that is not a chemical intermediate and can be converted into a controlled substance, MDMA, by deprotection of the N-tert-butoxycarbonyl group. Categorization of this chemical into a precursor or psychotropic substance is an issue because it is an unprecedented precursor that could have misuse potential. Although MDMA causes rewarding and reinforcing effect through dopaminergic transmission, the misuse potential of t-BOC-3,4-MDMA has not yet been characterized. Here, we aim to evaluate the misuse potential of t-BOC-3,4-MDMA. The response to the drug at a dose of 5 mg/kg was determined by a climbing test, and its rewarding and reinforcing properties were assessed through conditioned place preference and self-administration tests. In the conditioned place preference test, intraperitoneal administration of t-BOC-3,4-MDMA (5 mg/kg) significantly altered place preference in mice. In the self-administration models, t-BOC-3,4-MDMA induced drug-taking behavior at the dose of 0.5 mg/kg/infusion (intravenous) during 2 hr sessions under fixed-ratio schedules in mice. In addition, microdialysis experiments verified that t-BOC-3,4-MDMA impacted the dopamine levels of the brain (striatum) of rats. These experimental results indicate that t-BOC-3,4-MDMA has a potential for misuse. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Discriminative stimulus and reinforcing effects of diclazepam in rodents.

Diclazepam, a designer benzodiazepine, is a lesser-known novel anxiolytic substance and a structural analog of diazepam. Although several case studies have reported the adverse effects of diclazepam, their potential impacts remain unknown. Therefore, this study aimed to determine the effects of diclazepam in rodents using drug discrimination, locomotor activity, self-administration (SA), and conditioned place preference (CPP) tests. Sprague-Dawley rats (male, 8 weeks old, weighing 220-450 g, n = 12 per group) and C57BL/6 mice (male, 7 weeks old, weighing 20-25 g, n = 7-8 per group) were administered alprazolam, morphine, and diclazepam. Diclazepam fully elicited alprazolam-appropriate dose-dependent lever responses (>80 %) similar to those of alprazolam. In rats administered 0.5 mg/kg of morphine, a partial substitution (80 %-20 %) was observed. Mice receiving intraperitoneal injections of diclazepam (0.05, 0.2, and 2 mg/kg) showed decreased locomotor activity. In the SA experiment, mice that self-administered intravenous diclazepam (2 µg/kg/infusion) showed significantly higher infusion and active lever responses compared to the vehicle group. No statistically significant rewarding effects of diclazepam at the doses of 0.2 and 2 mg/kg evaluated using the CPP paradigm were found. In conclusion, diclazepam has reinforcing effects and shares the interoceptive effects of alprazolam. Therefore, legal restrictions on the use of diclazepam should be carefully considered.

Rewarding and Reinforcing Effects of 25H-NBOMe in Rodents.

The drug 25H-NBOMe is a new psychoactive substance (NPS). The use of these substances is likely to pose a threat to public health because they elicit effects similar to those of known psychoactive substances with similar chemical structures. However, data regarding the abuse potential of 25H-NBOMe are lacking. Here, we evaluated the abuse liability of 25H-NBOMe in rodents. The rewarding and reinforcing effects were evaluated through conditioned place preference (CPP) and self-administration (SA) tests after administration of 25H-NBOMe. To investigate the effects of 25H-NBOMe on the central nervous system, we determined the changes in dopamine levels by in vivo microdialysis. In the locomotor activity test, 25H-NBOme significantly increased locomotor activity in mice. In the place conditioning test, the 25H-NBOMe (0.1 and 0.5 mg/kg) groups showed a significantly increase in CPP in mice. In the SA test, the 25H-NBOMe (0.01 mg/kg) administered group showed a significant increased number of infusions and active lever presses. In microdialysis, the 25H-NBOMe (10 mg/kg) administered group was significantly increased in rats.

The designer benzodiazepine, flubromazepam, induces reward-enhancing and cardiotoxic effects in rodents.

The use of many benzodiazepines is controlled worldwide due to their high likelihood of abuse and potential adverse effects. Flubromazepam-a designer benzodiazepine-is a long-acting gamma-aminobutyric acid subtype A receptor agonist. There is currently a lack of scientific evidence regarding the potential for flubromazepam dependence or other adverse effects. This study aimed to evaluate the dependence potential, and cardiotoxicity via confirmation of the QT and RR intervals which are the factors on the electrical properties of the heart of flubromazepam in rodents. Using a conditioned place preference test, we discovered that mice treated intraperitoneally with flubromazepam (0.1 mg/kg) exhibited a significant preference for the flubromazepam-paired compartment, suggesting a potential for flubromazepam dependence. In addition, we observed several cardiotoxic effects of flubromazepam; 100-µM flubromazepam reduced cell viability, increased RR intervals but not QT intervals in the electrocardiography measurements, and considerably inhibited potassium channels in a human ether-à-go-go-related gene assay. Collectively, these findings suggest that flubromazepam may have adverse effects on psychological and cardiovascular health, laying the foundation for further efforts to list flubromazepam as a controlled substance at both national and international levels.

Rewarding and reinforcing effects of two dissociative-based new psychoactive substances, deschloroketamine and diphenidine, in mice.

Dissociative-based new psychoactive substances (NPSs) are increasingly available through the Internet, and public health problems related to the recreational use of these substances have been increasing globally. Two such NPSs are deschloroketamine and diphenidine, which are primarily used recreationally as ketamine substitutes. However, there is little scientific evidence to describe the dependence liability of NPSs. This study aimed to evaluate the dependence liability of deschloroketamine and diphenidine via animal behavioral experiments. We evaluated the rewarding and reinforcing effects of these NPSs using the conditioned place preference (CPP) and the self-administration (SA) paradigms in mice. Psychomotor effects and behavioral features of these compounds were assessed by quantifying locomotor activity, stereotypic movements, and dopaminergic neurotransmission. Both deschloroketamine (10 mg/kg) and diphenidine (10-60 mg/kg) produced increased locomotor activation and stereotypy that were similar to the effects of ketamine (10 mg/kg). Both deschloroketamine (10 mg/kg) and diphenidine (10, 20 mg/kg) increased the animals' preference for the drug-paired compartment in the CPP testing. In the SA testing, deschloroketamine (1 mg/kg/infusion) increased the number of active lever presses and the number of infusions received, whereas diphenidine administration (1, 2 mg/kg/infusion) did not alter either of these. Furthermore, both deschloroketamine and diphenidine increased dopamine levels in PC-12 cells. Collectively, the data suggest that deschloroketamine may have both rewarding and reinforcing effects, whereas diphenidine only induced rewarding effect.

The abuse potential of prolintane in rodents: Behavioral pharmacology approaches.

Prolintane (1-Phenyl-2-pyrrolidinylpentane), a synthetic central nervous system (CNS) stimulant, is structurally similar to amphetamine but pharmacologically acts as a dopamine reuptake inhibitor like cocaine. While several case studies reported adverse effects and recreational use of prolintane, the abuse potential of the drug has not been systemically examined yet. In the present study, we evaluated the behavioral effects of prolintane regarding its abuse liability in rodents using locomotor activity, conditioned place preference (CPP), self-administration (SA), and drug discrimination paradigms, as well as in-vivo microdialysis experiment. First, acute prolintane (10 and 20 mg/kg, intraperitoneal injection) increased locomotor activity (distance traveled, cm) in mice but to a lesser degree than methamphetamine (as a positive control). We also found that a single and solitary injection of prolintane (20 mg/kg, IP) significantly increased extracellular dopamine in the striatum. The following result suggests that its stimulatory effects might be associated with the mesolimbic dopaminergic pathway. Further, prolintane produced a significant drug-paired place preference at doses of both 10 and 20 mg/kg. In the SA experiment, the mice that self-administered prolintane intravenously (4 mg/kg/inf) showed a higher infusion and active lever responses but not inactive lever responses. Additionally, cumulative doses of prolintane partially elicited cocaine-appropriate lever responses (38.57% at doses up to 10 mg/kg) in rats. These results implied that prolintane has not only rewarding and reinforcing effects but also interoceptive stimulus properties, which are similar to cocaine at a moderate level. Taken together, this study was the first to show, to our knowledge, that prolintane has a certain level of abuse potential and should be considered carefully as a valuable basis for legal restrictions on use.

Assessment of the abuse potential of methamnetamine in rodents: a behavioral pharmacology study.

RATIONALE: Methamnetamine (MNA; PAL-1046) is a new psychoactive substance that acts as a full biogenic amine transporter (BAT) substrate. BAT substrates promote neurotransmitter release from the nerve terminal and can be abused as stimulants. However, scientific information on the abuse potential of methamnetamine is lacking. OBJECTIVE: We evaluated the abuse liability of methamnetamine. METHODS: The effective dose range of methamnetamine was determined using a climbing behavior test. The rewarding effect and reinforcing effect of the test compound were evaluated in mice by conditioned place preference (CPP) testing and self-administration (SA) testing at the selected doses. Dopamine level changes were analyzed using synaptosomes and in vivo microdialysis to investigate the effects of methamnetamine on the central nervous system. Drug discrimination experiments were used to examine the potential similarity of the interoceptive effects of methamnetamine and cocaine. RESULTS: A significant response was observed in the climbing behavior test with 10 and 40 mg/kg intraperitoneally administered methamnetamine. In the CPP test, mice intraperitoneally administered methamnetamine (10 and 20 mg/kg) showed a significant preference for the drug-paired compartment. In the SA test, mice that intravenously received 1 mg/kg/infusion showed significant active-lever responses. Dopamine was significantly increased in synaptosomes and in in vivo microdialysis tests. Furthermore, methamnetamine showed cross-generalization with cocaine in a dose-dependent manner. CONCLUSIONS: Methamnetamine exhibits interceptive stimulus properties similar to those of cocaine and induces rewarding and reinforcing effects, suggesting its dependence liability potential.

Involvement of the Cuneate Nucleus in the Acupuncture Inhibition of Drug-Seeking Behaviors.

Our previous studies have shown that acupuncture suppresses addictive behaviors induced by drugs of abuse, including cocaine, morphine and ethanol, by modulating GABA neurons in the ventral tegmental area (VTA) and dopamine (DA) release in the nucleus accumbens (NAc). The mechanisms by which the peripheral signals generated by acupoint stimulation are transmitted to brain reward systems are largely unexplored. The present study aims to investigate the role of spinal dorsal column (DC) somatosensory pathways in the acupuncture inhibition of drug addictive behaviors. Thus, we tested whether acupuncture at Shenmen (HT7) points reduces drug-seeking behaviors in rats self-administering morphine or ethanol and whether such effects are inhibited by the disruption of the cuneate nucleus (CN). The stimulation of HT7 suppressed morphine and ethanol self-administration, which were completely abolished by surgical lesioning of the CN. In in vivo extracellular recordings, single-unit activity of the CN was evoked during acupuncture stimulation. The results suggest that acupuncture suppresses morphine- and ethanol-seeking behaviors through the modulation of the CN, second-order neurons of the DC somatosensory pathway.

Acupuncture attenuates alcohol dependence through activation of endorphinergic input to the nucleus accumbens from the arcuate nucleus.

A withdrawal-associated impairment in ß-endorphin neurotransmission in the arcuate nucleus (ARC) of the hypothalamus is associated with alcohol dependence characterized by a chronic relapsing disorder. Although acupuncture activates ß-endorphin neurons in the ARC projecting to the nucleus accumbens (NAc), a role for ARC ß-endorphin neurons in alcohol dependence and acupuncture effects has not been examined. Here, we show that acupuncture at Shenmen (HT7) points attenuates behavioral manifestation of alcohol dependence by activating endorphinergic input to the NAc from the ARC. Acupuncture attenuated ethanol withdrawal tremor, anxiety-like behaviors, and ethanol self-administration in ethanol-dependent rats, which are mimicked by local injection of ß-endorphin into the NAc. Acupuncture also reversed the decreased ß-endorphin levels in the NAc and a reduction of neuronal activity in the ARC during ethanol withdrawal. These results suggest that acupuncture may provide a novel, potential treatment strategy for alcohol use disorder by direct activation of the brain pathway.

Unpleasant Sound Elicits Negative Emotion and Reinstates Drug Seeking.

Although previous studies have suggested an association between unpleasant sounds and the use of drugs, scientific evidence supporting this is lacking. This study investigated in rats (male Sprague-Dawley rats) if aversive sounds modulate dopamine (DA) transmission in the mesolimbic reward system and cocaine reinforcement. For sound stimulation, we used artificial low-frequency ultrasound (ALFUS) in the frequency ranges (22-38 kHz) which produces an aversive response in rats. Rats displayed increased anxiety-like behaviors, 22-kHz ultrasonic vocalizations (USVs), and stress responses with ALFUS. In vivo extracellular recording and immunohistochemistry revealed that ALFUS stimulation activated central amygdalar neurons and amygdalar GABAergic neurons. Amygdalar lesions prevented an increase of 22-kHz USVs by ALFUS. Dopamine levels in NAc decreased during ALFUS stimulation. In rats self-administering cocaine, ALFUS caused reinstatement of cocaine seeking after a period of extinction. Thus, ALFUS stimulation induced negative emotional states in association with a decrease in mesolimbic DA function and reinstatement of cocaine-seeking behaviors, suggesting that exposure to unpleasant sounds enhances negative emotional states and may induce relapse in addicts.

Rewarding effects of 2-desoxypipradrol in mice.

Desoxypipradrol (2-DPMP), a new psychoactive substance (NPS), acts as a norepinephrine-dopamine reuptake inhibitor (NDRI). NDRIs can be addictive due to their action mechanisms similar to cocaine and methamphetamine. However, there is a lack of scientific information regarding the exact dependency of 2-DPMP. Thus, the purpose of this study was to evaluate rewarding and reinforcing effects of 2-DPMP in rodents. The effective dose range of 2-DPMP was determined by climbing behavior test. To evaluate rewarding effects of 2-DPMP, conditioned place preference (CPP) test was performed at selected doses in mice. Self-administration (SA) test was then undertaken at two doses that caused the highest effects in the CPP test. Dopamine level changes were analyzed using synaptosomes in order to investigate effects of 2-DPMP on the central nervous system (CNS). Significant responses were observed in the climbing behavior test at doses of 0.1, 0.5, and 1 mg/kg by intraperitoneal injection (i.p.). In the CPP test, mice i.p. administered 2-DPMP at 1 mg/kg showed a significant preference in drug-paired compartment. In the SA test, mice intravenously given 0.1 mg/kg/infusion showed significantly higher active lever responses. Further, dopamine was increased in a dose-dependent manner. Taken together, these results suggest that 2-DPMP may act on the CNS and induce rewarding and reinforcing effects, indicating its dependence liability.

Spinal pathways involved in somatosensory inhibition of the psychomotor actions of cocaine.

Previous studies have demonstrated that somatosensory stimuli influence dopamine transmission in the mesolimbic reward system and can reduce drug-induced motor behaviors, craving and dependence. Until now, the central links between somatosensory and brain reward systems are not known. Here, we show that the dorsal column (DC) somatosensory pathway contains projections that convey an inhibitory input from the periphery to mesolimbic reward circuits. Stimulation of the ulnar nerve under HT7 acupoint suppressed psychomotor response to cocaine, which was abolished by disruption of the DC pathway, but not the spinothalamic tract (STT). Low-threshold or wide-dynamic range neurons in the cuneate nucleus (CN) were excited by peripheral stimulation. Lesions of dorsal column or lateral habenula (LHb) prevented the inhibitory effects of peripheral stimulation on cocaine-induced neuronal activation in the nucleus accumbens (NAc). LHb neurons projecting to the ventral tegmental area (VTA)/rostromedial tegmental nucleus (RMTg) regions were activated by peripheral stimulation and LHb lesions reversed the inhibitory effects on cocaine locomotion produced by peripheral stimulation. These findings suggest that there exists a pathway in spinal cord that ascends from periphery to mesolimbic reward circuits (spino-mesolimbic pathway) and the activation of somatosensory input transmitted via the DC pathway can inhibit the psychomotor response to cocaine.