Stimulation Of Locomotor Activity Research Articles

Remodeling p38 signaling in muscle controls locomotor activity via IL-15.

Skeletal muscle has gained recognition as an endocrine organ releasing myokines upon contraction during physical exercise. These myokines exert both local and pleiotropic health benefits, underscoring the crucial role of muscle function in countering obesity and contributing to the overall positive effects of exercise on health. Here, we found that exercise activates muscle p38γ, increasing locomotor activity through the secretion of interleukin-15 (IL-15). IL-15 signals in the motor cortex, stimulating locomotor activity. This activation of muscle p38γ, leading to an increase locomotor activity, plays a crucial role in reducing the risk of diabetes and liver steatosis, unveiling a vital muscle-brain communication pathway with profound clinical implications. The correlation between p38γ activation in human muscle during acute exercise and increased blood IL-15 levels highlights the potential therapeutic relevance of this pathway in treating obesity and metabolic diseases. These findings provide valuable insights into the molecular basis of exercise-induced myokine responses promoting physical activity.

Chiral Resolution of the Enantiomers of the Slow-Onset Dopamine Reuptake Inhibitor CTDP-32476 and Their Activities.

An improved synthesis was developed for CDTP-32476, a potent slow-onset dopamine reuptake blocker that may have utility as a treatment for cocaine abuse. The enantiomers of the compound were separated by fractional crystallization with N-acetylleucine enantiomers. An X-ray crystal structure was obtained of the RR enantiomer paired with N-acetyl-d-leucine. Chiral chromatography showed that the resolved enantiomers were pure with little contamination by the other enantiomer. The enantiomers were tested for their ability to block the reuptake of monoamines at their respective transporters and to stimulate locomotor activity in mice. Both enantiomers potently blocked the reuptake of dopamine and stimulated locomotor activity in mice. The RR enantiomer that corresponds to the active RR enantiomer of methylphenidate was slightly more potent at the dopamine reuptake site. The RR enantiomer also was found to be about twice as selective for the dopamine transporter relative to the norepinephrine transporter, which may have clinical implications. A method for designing slow-onset stimulants is proposed since there is increasing evidence that such activity is an important factor in stimulants that may have limited abuse potential.

Hyperactivity in Mice Induced by Opioid Agonists with Partial Intrinsic Efficacy and Biased Agonism Administered Alone and in Combination with Morphine.

Opioid analgesics such as morphine and fentanyl induce mu-opioid receptor (MOR)-mediated hyperactivity in mice. Herein, we show that morphine, fentanyl, SR-17018, and oliceridine have submaximal intrinsic efficacy in the mouse striatum using 35S-GTPγS binding assays. While all of the agonists act as partial agonists for stimulating G protein coupling in striatum, morphine, fentanyl, and oliceridine are fully efficacious in stimulating locomotor activity; meanwhile, the noncompetitive biased agonists SR-17018 and SR-15099 produce submaximal hyperactivity. Moreover, the combination of SR-17018 and morphine attenuates hyperactivity while antinociceptive efficacy is increased. The combination of oliceridine with morphine increases hyperactivity, which is maintained over time. These findings provide evidence that noncompetitive agonists at MOR can be used to suppress morphine-induced hyperactivity while enhancing antinociceptive efficacy; moreover, they demonstrate that intrinsic efficacy measured at the receptor level is not directly proportional to drug efficacy in the locomotor activity assay.

Neurobehavioral Effects of Fermented Rice Bran Extract in Zebrafish Larvae Model

Rice bran (RB) is a promising food ingredient that can improve biological function. In this study, we investigated the effects of RB, both unfermented (RB30) and fermented (RBF30), with five different microorganisms on the neurobehavioral activity in zebrafish larvae. Analytical methods such as LC–UV and LC–MS were performed for the analysis of RB30 and RBF30 extracts. Interestingly, niacin content, which is known to improve brain functions such as cognition and emotion, was found to be higher in RBF30 than in RB30. Furthermore, niacin content was highly increased in the RBF30-exposed fish, compared to those in the control fish. Therefore, we profiled behavioral patterns and various neurochemistry in zebrafish larvae following supplementation with RBF30 as well as performed calcium imaging on Tg (huC:GAL4-VP16); (UAS:GCaMP7a) zebrafish larvae to determine the correlation of neural activity. RBF30 revealed greater stimulation of locomotor activity without negatively affecting decision-making behavior in zebrafish larvae, as compared to RB30 or niacin. Its behavioral activation is mainly linked with the elevations of neural activity and several neurochemicals such as serotonergic and dopaminergic systems that are implicated in the control of anxiety and stress. Taken together, these results suggest that RBF30 could be a food material that improves the behavioral health by modulating neural activity and brain neurochemistry.

Early detection of cyanide, organophosphate and rodenticide pollution based on locomotor activity of zebrafish larvae.

Cyanide, organophosphate and rodenticides are highly toxic substances widely used in agriculture and industry. These toxicants are neuro- and organotoxic to mammals at low concentrations, thus early detection of these chemicals in the aqueous environment is of utmost importance. Here, we employed the behavioral toxicity test with wildtype zebrafish larvae to determine sublethal concentrations of the above mentioned common environmental pollutants. After optimizing the test with cyanide, nine rodenticides and an organophosphate were successfully tested. The compounds dose-dependently initially (0–60-min exposure) stimulated locomotor activity of larvae but induced toxicity and reduced swimming during 60–120-min exposure. IC50 values calculated based on swimming distance after 2-h exposure, were between 0.1 and 10 mg/L for both first-generation and second-generation anticoagulant rodenticides. Three behavioral characteristics, including total distance travelled, sinuosity and burst count, were quantitatively analyzed and compared by hierarchical clustering of the effects measured by each three parameters. The toxicity results for all three behavioral endpoints were consistent, suggesting that the directly measured parameter of cumulative swimming distance could be used as a promising biomarker for the aquatic contamination. The optimized method herein showed the potential for utilization as part of a monitoring system and an ideal tool for the risk assessment of drinking water in the military and public safety.

Identification of a Novel Neuropeptide S Receptor Antagonist Scaffold Based on the SHA-68 Core.

Activation of the neuropeptide S receptor (NPSR) system has been shown to produce anxiolytic-like actions, arousal, and enhance memory consolidation, whereas blockade of the NPSR has been shown to reduce relapse to substances of abuse and duration of anesthetics. We report here the discovery of a novel core scaffold (+) N-benzyl-3-(2-methylpropyl)-1-oxo-3-phenyl-1H,3H,4H,5H,6H,7H-furo[3,4-c]pyridine-5-carboxamide with potent NPSR antagonist activity in vitro. Pharmacokinetic parameters demonstrate that 14b reaches pharmacologically relevant levels in plasma and the brain following intraperitoneal (i.p.) administration, but is cleared rapidly from plasma. Compound 14b was able to block NPS (0.3 nmol)-stimulated locomotor activity in C57/Bl6 mice at 3 mg/kg (i.p.), indicating potent in vivo activity for the structural class. This suggests that 14b can serve as a useful tool for continued mapping of the pharmacological functions of the NPS receptor system.

Sodium Leak Channel in the Nucleus Accumbens Modulates Ethanol-Induced Acute Stimulant Responses and Locomotor Sensitization in Mice: A Brief Research Report.

Ethanol can induce acute stimulant responses in animals and human beings. Moreover, repeated exposure to ethanol may produce increased sensitivity to its acute locomotor stimulant actions, a process referred to as locomotor sensitization. The molecular mechanism of the development of acute stimulant responses and locomotor sensitization by ethanol is not fully understood. Sodium leak channel (NALCN) is widely expressed in central nervous system and controls the basal excitability of neurons. The present study aims to determine whether NALCN is implicated in the ethanol-induced acute responses and locomotor sensitization in mice. Here, our results showed that ethanol caused acute stimulant responses in DBA/2 mice. Locomotor sensitization was successfully induced following the sensitization procedure. Accordingly, the expression levels of NALCN mRNA and protein in the nucleus accumbens (NAc) were markedly increased in the sensitization mice compared to the control mice. Knockdown the expression levels of NALCN in the NAc alleviated both the ethanol-induced acute responses and locomotor sensitization. Our findings indicate that upregulation of NALCN expression in the NAc contributes to the ethanol-induced acute stimulant responses and locomotor sensitization in DBA/2 mice.

Role of Efficacy as a Determinant of Locomotor Activation Induced by Mu Opioid Receptor Ligands in Male and Female Mice

Background Ligand efficacy is a key determinant of drug effects mediated by receptor targets, and efficacy can be exploited to generate safer therapeutics. As one step in a broader project to examine efficacy requirements for different mu opioid receptors (MOR) effects, this study evaluated locomotor stimulation in mice produced by 8 MOR ligands that vary from low to high efficacy. Additionally, opioid agonist/antagonist mixtures provide a novel strategy to precisely calibrate levels of MOR activation, measure efficacy requirements for different MOR-mediated endpoints, and identify efficacy levels that might optimally balance effectiveness to produce therapeutic effects while minimizing side effects. Accordingly, effects of MOR ligands were compared to effects of fixed-proportion mixtures of the opioid agonist fentanyl and antagonist naltrexone. We hypothesized that MOR ligands would produce an efficacy-dependent increase in locomotor stimulation, and that fentanyl/naltrexone mixtures could be used to compare efficacy requirements for mouse locomotor stimulation relative to other in vivo and in vitro opioid effects. Methods We determined locomotor activity in adult male and female ICR mice after acute treatment with (in order of increasing efficacy) naltrexone, NAQ, nalbuphine, buprenorphine, hydrocodone, morphine, fentanyl, and methadone. Fentanyl/naltrexone mixtures were studied in fixed proportions of 1:1, 3.2:1, 10:1, 32:1, and 100:1. Dose-effect curves for each drug or mixture were determined in separate groups of 12 mice (6 male, 6 female). Treatments were administered subcutaneously 5 min before 100-min sessions, and locomotor activity was quantified as photobeam breaks in chambers with a floor area of 16.8 × 12.7 cm2. Data were analyzed by one- or two-way ANOVA, and the criterion for significance was p<0.05. Additionally, data with the mixtures were used to compare efficacy requirements for locomotor stimulation in this study relative to previously published data for other in vitro and in vivo effects. Results MOR ligands produced an efficacy-dependent increase in maximal locomotor stimulation. Similarly, for the fentanyl/naltrexone mixtures, increasing fentanyl proportions (pFentanyl) also produced graded increases in maximum stimulation (Emax). The curve relating pFentanyl to Emax was used to quantify the effective pFentanyl required to produce 50% of the fentanyl-alone Emax (EP50), and the EP50 (95%CL) served as a metric of the efficacy requirement for any opioid endpoint. In this case, the EP50 for locomotor stimulation in mice was high relative to EP50 values for other in vivo endpoints including fentanyl discrimination in rats and thermal antinociception in mice, rats, and rhesus monkeys, but lower than the EP50 for an in vitro assay of GTPɣS binding in mMOR-CHO cells. Conclusions These results confirm efficacy-dependent stimulation of locomotor activity by MOR ligands in mice. Additionally, these results illustrate the utility of fentanyl/naltrexone mixtures to precisely calibrate net MOR activation, quantify efficacy requirements across different opioid effects, and identify efficacy levels that might be sufficient to produce some drug effects but not others.

Sensitization to amphetamine psychostimulant effect: A key role for ventral tegmental area neurotensin type 2 receptors and MAP kinase pathway.

Neurotensin is an endogenous neuropeptide that acts as a potent modulator of ventral tegmental area (VTA) neurotransmission. The present study was aimed at determining VTA cell population and neurotensin receptor subtype responsible for the initiation of amphetamine-induced psychomotor activity and extracellular signal-regulated kinases (ERK1/2) sensitization. During an induction phase, rats were injected intra-VTA on two occasions, every second day, with [D-Tyr11 ]-neurotensin (D-Tyr-NT), SR142948 (a mix Ntsr1/Ntsr2 receptor subtype antagonist), SR48692 (a Ntsr1 antagonist), D-Tyr-NT+SR142498, D-Tyr-NT+SR48692, or the vehicle. Effects of intra-VTA drugs were evaluated at locomotor activity and ERK1/2 phosphorylation. Five days after the last VTA microinjection, the effect of a systemic injection of amphetamine was tested (sensitization test). Results show that D-Tyr-NT stimulated locomotor activity during the induction phase, an effect that was blocked by SR142948, but not SR48692. Amphetamine also induced significantly higher ambulatory activity in rats preinjected with D-Tyr-NT than in rats preinjected with the vehicle. This sensitization effect was again attenuated by SR142948, but not SR48692, hence suggesting that this effect is mediated by Ntsr2 receptors. To confirm this, we tested a highly selective Ntsr2 peptide-peptoid hybrid ligand, NT150. At the concentration tested, NT150 stimulated locomotor activity and lead to sensitized locomotor activity and a selective neurochemical (pERK1/2) response in tyrosine hydroxylase-positive neurons of the VTA. Both effects were prevented by SR142948. Taken together, these results show that neurotensin, acting on Ntsr2 receptor subtypes, stimulates locomotor activity and initiates neural changes (ERK1/2 phosphorylation) that lead to amphetamine-induced sensitization.

Behavioral effects of four novel synthetic cathinone analogs in rodents.

A new generation of novel cathinone compounds has been developed as stimulant substitutes to avoid drug control laws and detection of use by blood tests. Dipentylone, N-ethylhexedrone, 4-chloroethcathinone (4-CEC), and 4'-methyl-α-pyrrolidinohexiophenone (MPHP) were tested for in vivo psychostimulant-like effects to assess their abuse liability. Locomotor activity was assessed in an open-field assay using Swiss-Webster mice to screen for locomotor stimulant effects and to identify behaviorally-active dose ranges, times of peak effect, and durations of action. Discriminative stimulus effects were assessed in separate groups of Sprague-Dawley rats trained to discriminate cocaine or methamphetamine from vehicle. Dipentylone, N-ethylhexedrone, 4-CEC, and MPHP dose-dependently increased locomotor activity. Dipentylone, N-ethylhexedrone, and MPHP produced maximal stimulant effects similar to cocaine and methamphetamine. 4-CEC was less efficacious, producing peak stimulant effects of about 74% of that of methamphetamine. The compounds were less potent than methamphetamine and approximately equipotent with cocaine. The doses of cocaine, methamphetamine, dipentylone, and 4-CEC that produced peak effects lasted 2 to 3h, the peak dose of N-ethylhexedrone lasted 4h, and the peak dose of MPHP lasted 6h. All four compounds fully substituted for the discriminative stimulus effects of methamphetamine and cocaine, although full substitution by 4-CEC occurred at doses that substantially decreased response rate. Only 4-CEC fully substituted for MDMA. These data provide evidence that the novel cathinone compounds dipentylone, N-ethylhexedrone, 4-CEC, and MPHP demonstrate potential for abuse as psychostimulants, given their ability to stimulate locomotor activity and their substitution for the discriminative stimulus effects of methamphetamine and cocaine.

Neuropharmacological and antidepressant-like effects of ZY-1408: A novel serotonin/norepinephrine reuptake inhibitor and serotonin receptor 2C antagonist

Depression is a common mental illness and leading cause of disability. Most current antidepressants are associated with significant limitations, and in particular, a delayed onset and low rate of efficacy. Consequently, there remains an ongoing need for antidepressants that are either more effective or better tolerated than existing standards. We previously identified ZY-1408 as a drug with a novel chemical structure and potential anti-depressant-like activity. Specifically, ZY-1408 is a novel serotonin 2C (5-HT2C) receptor antagonist and serotonin/norepinephrine (5-HT/NE) reuptake inhibitor. In this study, we further investigated the antidepressant-like efficacy of ZY-1408 using in vitro and in vivo behavioral tests. ZY-1408 showed 5-HT2C receptor antagonist and 5-HT/NE reuptake inhibitor properties in vitro. Meanwhile, ZY-1408 decreased immobility in vivo in a dose-dependent manner in rats (via the forced-swim test) and mice (via the tail-suspension test). The behavioral test results do not appear to result from stimulation of locomotor activity. In chronically stressed rats, repeated ZY-1408 treatment significantly reversed depressive-like behavior, including reduced sucrose preference, decreased locomotor activity, and prolonged time to begin eating. Furthermore, in vivo microdialysis showed that administration of ZY-1408 significantly increased extracellular concentrations of 5-HT and NE in the hippocampus of freely moving rats. Thus, ZY-1408 is a potent and orally active 5-HT2C receptor antagonist and 5-HT/NE reuptake inhibitor with antidepressant-like activity in rodents.

Methiopropamine and its acute behavioral effects in mice: is there a gray zone in new psychoactive substances users?

Methiopropamine is a structural analog of methamphetamine that is categorized as a novel psychoactive substance. It primarily acts as a norepinephrine-dopamine reuptake inhibitor and, secondarily, as a serotonin reuptake inhibitor. In humans, methiopropamine induces stimulation and alertness and increases focus and energy. However, significant side effects are reported, such as tachycardia, anxiety, panic attacks, perspiration, headache, and difficulty in breathing. To date, little data is available regarding its pharmacodynamic effects, thereby we aimed to investigate the acute in vivo effects induced by this drug on sensorimotor responses, body temperature, pain thresholds, motor activity, and cardiovascular and respiratory systems in CD-1 male mice. We selected a range of doses that correspond to the whole range of human reported use, in order to evaluate the threshold of adverse effects presentation. This study demonstrates that methiopropamine acts as a dopaminergic and noradrenergic stimulating drug and that the highest doses (10-30mg/kg) impair the visual placing response, facilitate the acoustic and tactile response, induce hypothermia, increase mechanical and thermal analgesia, stimulate locomotor activity, induce motor stereotypies, and strongly affected cardiovascular and respiratory parameters, increasing heart rate, breath rate, and blood pressure but reducing oxygen saturation. On the contrary, lower doses do not show any of those effects. We hypothesize that there is a range of doses that do enhance performance but do not seem hazardous to users: this gap could induce the perception of safety and increase the abuser population.

Cocaine-induced changes in behaviour and DNA methylation in rats are influenced by inter-individual differences in spontaneous exploratory activity.

Individual differences in behavioural traits influence susceptibility to addictive disorders. Drug addiction involves changes in gene expression, proposed to occur via DNA methylation (DNAm). To investigate DNAm changes in reward-related brain structures (nucleus accumbens (NAc), lateral habenula (LHb)) in response to cocaine exposure in rats differing in spontaneous exploratory activity. Rats were observed in the exploration box and categorised as high- (HE) or low explorers (LE). Rats were administered vehicle or cocaine (12 mg/kg, i.p.) for 7 days, followed by a 14-day withdrawal period and cocaine challenge (7 mg/kg); horizontal locomotor activity was recorded. Brain tissue was dissected after 24 h; we analysed messenger RNA (mRNA) and activity levels of epigenetic DNA modifiers (DNMTs and TETs) as well as mRNA and promoter methylation levels at selected genes previously linked to addictive behaviours. The cocaine challenge dose stimulated locomotor activity in both LE- and HE rats only when administered after a repeated cocaine schedule, suggesting development of behavioural sensitisation. Quantitative polymerase chain reaction analyses demonstrated higher basal expression of Dnmt3a, Tet2 and Tet3 in the LHb of HE- vs. LE rats, and we observed differential effects of cocaine exposure on the expression and activity of epigenetic DNA modifiers in the NAc and LHb of HE- and LE rats. Furthermore, cocaine exposure differentially altered promoter methylation levels of A2AR, Ppp1cc, and Taar7b in the NAc and LHb of HE- and LE rats. DNAm might play a role in the HE- and LE phenotypes as well as mediate behavioural effects of LE- and HE rats in response to drugs of abuse.

Comparative neuropharmacological studies on three pyrrolidine-containing synthetic cathinones

Purpose3,4-Methylenedioxypyrovalerone (3,4-MDPV) is a prevalent member of α-pyrrolidinophenones, a group of new psychoactive substances, known for its strong psychostimulant effect resulting from potent stimulation of dopamine (DA) circuitry in the brain. As 3,4-MDPV and its derivatives are successively being scheduled, each year novel analogs appear on the market. This study aimed at examination and direct comparison of psychostimulant properties of structural isomer of 3,4-MDPV, namely 2,3-MDPV along with a model α-pyrrolidinophenone, pyrovalerone.MethodsOpen field spontaneous locomotor activity of mice was assessed as a measure of psychostimulant potency. To evaluate the in vivo pharmacological properties of the drugs, extracellular levels of DA and serotonin (5-HT) in the mouse striatum were measured using an in vivo microdialysis technique followed by high-performance liquid chromatography with electrochemical detection. Involvement of dopaminergic system in the behavioral effects of the tested α-pyrrolidinophenones was examined by pre-treatment with a selective D1-DA receptor antagonist, SCH 23390, before measurement of locomotor activity in response to the drugs.Results3,4-MDPV, 2,3-MDPV and pyrovalerone produced time- and dose-dependent stimulation of locomotor activity, with 3,4-MDPV being more potent than the other two compounds. Observed locomotor stimulation was mediated by elevated DA-ergic neurotransmission, as all compounds caused a significant increase of extracellular DA levels in the striatum, with 3,4-MDPV being the most potent, and psychostimulant effects were abolished by SCH 23390. Interestingly, the tested pyrovalerones caused in vivo elevation of extracellular 5-HT levels, which contrasted with their in vitro pharmacologic properties.ConclusionsPyrovalerone, 2,3-MDPV and 3,4-MDPV produced psychostimulant effects mediated by stimulation of dopaminergic neurotransmission. Additionally, all tested compounds elevated extracellular levels of 5-HT in vivo.

Effects of monoamine depletion on the ketamine-induced locomotor activity of preweanling, adolescent, and adult rats: Sex and age differences

Ketamine significantly increases the locomotor activity of rodents, however this effect varies according to the sex and age of the animal being tested. To determine the role monoamine systems play in ketamine’s locomotor activating effects: (a) male and female preweanling, adolescent, and adult rats were pretreated with vehicle or the monoamine depleting agent reserpine (1 or 5 mg/kg), and (b) the behavioral actions of ketamine (20 or 40 mg/kg) were then compared to d-amphetamine (2 mg/kg) and cocaine (10 or 15 mg/kg). The ability of reserpine to deplete dorsal striatal dopamine (DA) and serotonin (5-HT) in male and female rats was determined using HPLC. Ketamine caused substantial increases in the locomotion of preweanling rats and older female rats (adolescents and adults), but had only small stimulatory effects on adolescent and adult male rats. When compared to cocaine and d-amphetamine, ketamine was especially sensitive to the locomotor-inhibiting effects of monoamine depletion. Ketamine-induced locomotion is at least partially mediated by monoamine systems, since depleting DA and 5-HT levels by 87–96% significantly attenuated the locomotor activating effects of ketamine in male and female rats from all three age groups. When administered to reserpine-pretreated rats, ketamine produced a different pattern of behavioral effects than either psychostimulant, suggesting that ketamine does not stimulate locomotor activity via actions at the presynaptic terminal. Instead, our results are consistent with the hypothesis that ketamine increases locomotor activity through a down-stream mechanism, possibly involving ascending DA and/or 5-HT projection neurons.

Locomotor activity and discriminative stimulus effects of five novel synthetic cathinone analogs in mice and rats

BackgroundThe development of novel synthetic psychoactive substances continues to accelerate. There are little or no data on the pharmacological mechanisms, behavioral effects, or abuse liability of many of the newer compounds, despite increasing reports of severe adverse effects in recreational users. MethodsThe current study investigated the discriminative stimulus and locomotor stimulant effects of a group of synthetic cathinone analogs: N-ethylpentylone, dimethylone, dibutylone, clephedrone, 3′,4′-tetramethylene-α-pyrrolidinovalerophenone (TH-PVP). Locomotor activity was assessed in an open-field assay using Swiss-Webster mice. Discriminative stimulus effects were assessed in Sprague-Dawley rats trained to discriminate either cocaine, methamphetamine or MDMA from vehicle. ResultsN-Ethylpentylone, dimethylone, dibutylone and clephedrone increased locomotor activity. Maximal effects were similar among the test compounds. Relative potencies were: methamphetamine > N-ethylpentylone > clephedrone > dimethylone > MDMA > cocaine > dibutylone. TH-PVP dose-dependently depressed locomotor activity. N-Ethylpentylone, dimethylone, dibutylone and clephedrone substituted fully for the discriminative stimulus effects of methamphetamine. N-Ethylpentylone, dibutylone and clephedrone fully substituted for cocaine, whereas dimethylone produced a maximum of 67% drug-appropriate responding. Dimethylone, dibutylone and clephedrone fully substituted for MDMA, whereas N-ethylpentylone produced only 50% drug-appropriate responding. TH-PVP produced a maximum of 38% methamphetamine-appropriate responding, 50% cocaine-appropriate responding, and less than 1% MDMA-appropriate responding. ConclusionsThese data provide initial evidence that the novel psychoactive substances N-ethylpentylone, dimethylone, dibutylone, and clephedrone demonstrate potential for abuse as psychostimulants and/or club drugs, given their ability to stimulate locomotor activity and their substitution for the discriminative stimulus effects of methamphetamine, cocaine and/or MDMA. TH-PVP has minimal activity in the assays tested and may have little or no abuse liability.

Reduced Efficacy of d-Amphetamine and 3,4-Methylenedioxymethamphetamine in Inducing Hyperactivity in Mice Lacking the Postsynaptic Scaffolding Protein SHANK1.

Genetic defects in the three SH3 and multiple ankyrin repeat domains (SHANK) genes (SHANK1, SHANK2, and SHANK3) are associated with multiple major neuropsychiatric disorders, including autism spectrum disorder (ASD), schizophrenia (SCZ), and bipolar disorder (BPD). Psychostimulant-induced hyperactivity is a commonly applied paradigm to assess behavioral phenotypes related to BPD and considered to be the gold standard for modeling mania-like elevated drive in mouse models. Therefore, the goal of our present study was to test whether Shank1 plays a role in the behavioral effects of psychostimulants and whether this is associated with genotype-dependent neurochemical alterations. To this aim, male and female null mutant Shank1-/- mice were treated with d-amphetamine (AMPH; 2.5 mg/kg) and 3,4-methylenedioxymethamphetamine (MDMA, commonly known as ecstasy; 20 mg/kg), and psychostimulant-induced hyperactivity was compared to heterozygous Shank1+/- and wildtype Shank1+/+ littermate controls. Results show that Shank1-/- mice display reduced psychostimulant-induced hyperactivity, although psychostimulants robustly stimulated locomotor activity in littermate controls. Shank1 deletion effects emerged throughout development, were particularly prominent in adulthood, and seen in response to both psychostimulants, i.e., AMPH and MDMA. Specifically, while AMPH-induced hyperactivity was reduced but still detectable in Shank1-/- mice, MDMA-induced hyperactivity was robustly blocked and completely absent in Shank1-/- mice. Reduced efficacy of psychostimulants to stimulate hyperactivity in Shank1-/- mice might be associated with alterations in the neurochemical architecture in prefrontal cortex, nucleus accumbens, and hypothalamus. Our observation that psychostimulant-induced hyperactivity is reduced rather than enhanced in Shank1-/- mice clearly speaks against a behavioral phenotype with relevance to BPD. Lack of BPD-like phenotype is consistent with currently available human data linking mutations in SHANK2 and SHANK3 but not SHANK1 to BPD.

Effects of Environmental Variables on the Pharmacological Actions of “Bath Salts” Constituent 3,4‐Methylenedioxypyrovalerone (MDPV) in Mice

Synthetic analogues of cathinone are the active constituents of abused “bath salts” products. 3,4‐methylenedioxypyrovalerone (MDPV) is among the most well‐studied synthetic cathinone given its prevalence in these abused commercial preparations, and it is increasingly used by humans in crowded, hot, and sensory‐rich environments. Given the structural similarity of MDPV to 3,4‐methylenedioxymethamphetamine (MDMA) – the effects of which are dramatically impacted by crowding and ambient temperature — it was of interest to investigate the modulatory effects of similar environmental variables on MDPV‐elicited toxicity and locomotor stimulant effects in mice. Ambient temperature experiments were performed in sound‐attenuating temperature‐controlled enclosures equipped with biotelemetry receivers for recording of horizontal locomotor activity within the home cage. Groups of singly housed mice implanted with radiotelemetry probes were water deprived for 21 hrs, then given a 3‐hr period to orally self‐administer 0.3 mg/ml MDPV or 0.1% quinine solution for 10 consecutive days while the ambient temperature was maintained at 20° or 28°C. Body weight, drug intake, and locomotor activity were measured across successive sessions. Intake of MDPV escalated across successive sessions, such that the dose of self‐administered MDPV was significantly higher on the last 3 days than observed on the first day. In contrast, consumption of quinine did not escalate. There was initially no effect of ambient temperature on quinine or MDPV consumption, but MDPV consumption escalated more rapidly at the 28°C condition. Consumption of MDPV solutions stimulated locomotor activity above levels observed following quinine drinking in both ambient temperature conditions. Body weights remained relatively unchanged. In separate studies, mice were housed singly or in groups of 3 or 6, then administered saline or 0.3, 1.0, 3.0, 10.0, or 17.8 mg/kg MDPV via intraperitoneal injections every 2 hours for a total of 4 injections. Rectal temperatures were obtained before each injection and 2 hours after the 4th injection. Brain regions were collected for neurochemical analysis 10 days after the last MDPV injection. There was no difference in rectal temperature between the crowding conditions prior to MDPV administration, and administration of MDPV did not alter rectal temperature in any housing condition. Body weights decreased as the MDPV dose and crowding condition increased. These experiments suggest that, similar to structurally‐related psychostimulants like MDMA, the pharmacological actions of MDPV are also impacted by environmental variables associated with the settings in which the drug is commonly abused in humans.Support or Funding InformationThese studies supported by DA039195, DA022981 and the UAMS Center for Translational Neuroscience.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Hyperlocomotion induced by inhalation of nicotine and a low dose of Δ9‐Tetrahydrocannabinol in female rats

BackgroundsGrowing availability of e‐cigarette devices permits users to prepare their own cocktail of drugs for inhalation, including polysubstance inhalation. Some individuals use nicotine and (−)‐Δ9‐tetrahydrocannabinol (THC) in combination by smoking tobacco and cannabis together or in sequence; this practice may extend to electronic cigarette users. THC exerts biphasic effects on locomotion in rats, with high doses (e.g., 5 mg kg−1, i.p.) decreasing, and lower doses (e.g., 0.03 mg kg−1, i.p.) increasing, locomotor activity. Nicotine (NIC) also increases locomotor activity in rodents. This study was designed to determine if interactive effects of THC and NIC result from vapor inhalation in rats using a novel e‐cigarette based procedure.MethodsFemale Sprague‐Dawley rats were exposed to vapor produced by the propylene glycol vehicle (PG), NIC (1 mg/mL in PG), THC (12.5 mg/ml in PG) or a combination of NIC with THC for a duration of 15 minutes. Body temperature and locomotor responses were evaluated post‐inhalation using a radiotelemetry system.ResultsLocomotor activity was increased in the rats for the first 60 min after NIC (1 mg/ml) exposure and this effect was blocked by pretreatment with mecamylamine. Activity was also increased 15 min after initiation of THC vapor compared with PG. Female rats did not show any further hyperlocomotion following exposure to the combination of NIC+THC vapor compared with either NIC or THC vapor inhalation, alone. The body temperature was decreased following the THC (12.5 mg/ml) or a combination of THC (12.5 mg/ml) +NIC (1 mg/ml) inhalation with significant effects starting 120 min post‐exposure, while NIC (1 mg/ml) inhalation did not alter the body temperature.DiscussionVapor inhalation of NIC or low dose THC stimulates locomotor activity in female rats. The co‐administration of a lower dose of THC with NIC produced no additive locomotor stimulation in female rats compared to either THC or NIC alone. The observed data provided behavioral evidence to suggest that the effect of nicotine on locomotion might not be modified by the physiological action of cannabinoids.Support or Funding InformationFunding support provided by USPHS grants AA007456, DA035482 and DA041967This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Chemical synthesis of 7α-hydroxypregnenolone, a neuroactive steroid that stimulates locomotor activity

7α-Hydroxypregnenolone is an endogenous neuroactive steroid that stimulates locomotor activity. A synthesis of 7α-hydroxypregnenolone from pregnenolone, which takes advantage of an orthogonal protecting group strategy, is described. In detail, the C7-position was oxidized with CrO3 and 3,5-dimethylpyrazole to yield a 7-keto steroid intermediate. The resulting 7-ketone was stereoselectively reduced to the 7α-hydroxy group with lithium tri-sec-butylborohydride. In contrast, reduction of the same 7-ketone intermediate with NaBH4 resulted in primarily the 7β-hydroxy epimer. Furthermore, in an alternative route to the target compound, the 7α-hydroxy group was successfully incorporated by direct C–H allylic benzoyloxylation of pregnenolone-3-acetate with CuBr and tert-butyl peroxybenzoate followed by saponification. The disclosed syntheses to 7-oxygenated steroids are amenable to potentially obtain other biologically active sterols and steroids.