Norepinephrine Protects against Methamphetamine Toxicity through ß2-Adrenergic Receptors Promoting LC3 Compartmentalization.

Norepinephrine (NE) neurons and extracellular NE exert some protective effects against a variety of insults, including methamphetamine (Meth)-induced cell damage. The intimate mechanism of protection remains difficult to be analyzed in vivo. In fact, this may occur directly on target neurons or as the indirect consequence of NE-induced alterations in the activity of trans-synaptic loops. Therefore, to elude neuronal networks, which may contribute to these effects in vivo, the present study investigates whether NE still protects when directly applied to Meth-treated PC12 cells. Meth was selected based on its detrimental effects along various specific brain areas. The study shows that NE directly protects in vitro against Meth-induced cell damage. The present study indicates that such an effect fully depends on the activation of plasma membrane ß2-adrenergic receptors (ARs). Evidence indicates that ß2-ARs activation restores autophagy, which is impaired by Meth administration. This occurs via restoration of the autophagy flux and, as assessed by ultrastructural morphometry, by preventing the dissipation of microtubule-associated protein 1 light chain 3 (LC3) from autophagy vacuoles to the cytosol, which is produced instead during Meth toxicity. These findings may have an impact in a variety of degenerative conditions characterized by NE deficiency along with autophagy impairment.

M100907 and BD 1047 attenuate the acute toxic effects of methamphetamine.

There are no Food and Drug Administration approved pharmacotherapies for methamphetamine (METH) overdose, thus identifying novel drug targets to prevent this devastating adverse event is a public-health imperative. Previous research suggests that serotonin and sigma receptors may contribute to the adverse effects of METH. The present study assessed whether pretreatment with the 5-HT2A receptor antagonist M100907 or the sigma 1 (σ1) receptor antagonist BD 1047 attenuated METH-induced lethality, hyperthermia, convulsions, and seizures. Male, Swiss-Webster mice received intraperitoneal injections of M100907 (1 and 10 mg/kg), BD 1047 (10 mg/kg), or a combination of M100907 (1 mg/kg) and BD 1047 (10 mg/kg) prior to treatment with METH (78 mg/kg). Convulsions and lethality were assessed by observation, core body temperature was assessed by surgically implanted telemetric probes, and seizures were assessed by electroencephalography. M100907 reduced METH-elicited lethality from 67% to 33%, BD1047 reduced METH-elicited lethality from 67% to 50%, and combined administration of both agents eliminated lethality in all mice tested. Similarly, both agents and their combination reduced METH-elicited seizures and convulsions. None of the treatments decreased METH-induced hyperthermia. This research suggests that reducing METH-induced seizures is an important factor in reducing lethality associated with METH overdose. However, future studies should examine whether M100907 and BD 1047 modulate METH-induced hypertension and other adverse effects that may also contribute to METH overdose. Our data support the continued investigation of compounds that target 5-HT2A and σ1 receptors in METH-induced overdose, including their potential to yield emergency reversal agents.

Sigma-1 receptor ligand PD144418 and sigma-2 receptor ligand YUN-252 attenuate the stimulant effects of methamphetamine in mice.

RATIONALE: Previous research indicates that the selective sigma-1 receptor ligand PD144418 and the selective sigma-2 ligands YUN-252 can inhibit cocaine-induced hyperactivity. The effects of these ligands on other stimulants, such as methamphetamine, have not been reported. OBJECTIVES: The present study examined the effects of PD144418 and YUN-252 pretreatment on methamphetamine-induced hyperactivity after acute treatment. METHODS: Mice (n = 8-14/group) were injected with PD144418 (3.16, 10, or 31.6 µmol/kg), YUN-252 (0.316, 3.16, 31.6 µmol/kg), or saline. After 15 min, mice injected with 2.69 µmol/kg methamphetamine or saline vehicle, where distance traveled during a 60-min period was recorded. Additionally, the effect of PD144418 on the initiation and expression of methamphetamine sensitization was determined by treating mice (n = 8-14/group) with PD144418, methamphetamine or saline repeatedly over a 5-day period, and testing said mice with a challenge dose after a 7-day withdrawal period. RESULTS: Results indicate that both PD144418 and YUN-252, in a dose-dependent manner, attenuated hyperactivity induced by an acute methamphetamine injection. Specifically, 10 µmol/kg or 31.6 µmol/kg of PD144418 and 31 µmol/kg of YUN-252 suppressed methamphetamine-induced hyperactivity. In regard to methamphetamine sensitization, while 10 µmol/kg PD144418 prevented the initiation of methamphetamine sensitization, it did not have an effect on the expression. CONCLUSIONS: Overall, the current results suggest an intriguing potential for this novel sigma receptor ligand as a treatment for the addictive properties of methamphetamine. Future analysis of this novel sigma receptor ligand in assays directly measuring reinforcement properties will be critical.

Desensitization of 5-HT-1A Somatodentritic Receptors in Tryptophan Treated and Co-treated Rats Induced by Methylphenidate.

BACKGROUND: Psychostimulants can induce behavioral sensitization by their chronic use. The main target for the action of these drugs is dopamine, neither epinephrine nor serotonin transporters. Serotonin is synthesized by the precursor L-tryptophan. Tryptophan and methylphenidate being 5-HT agonists, both increase the level of serotonin thereby causing desensitization of 5-HT1a receptors. The present study investigated whether behavioral sensitization induced by Methylphenidate is decreased in tryptophan administrated animals. METHODS: The Experiment was divided into 2 phases (1). Behavioral effects of repeated administration of TRP 100 mg/kg and MPD for 14 days in three groups; (i) water (ii) MPD 1.0 mg/kg (iii) TRP. To explore the locomotor effects of treatment, the activity was monitored in a familiar and novel environment. (2) Behavioral consequences of repeatedly administrated MPD (1.0 mg/kg) on pretreated TRP (100 mg/kg) and MPD (1.0 mg/kg) animals following Co-MPD and TRP for 14 days, rats were divided in three groups (i) water, (ii) MPD and (iii) TRP as mentioned in Experiment no 1. After two weeks six subgroups were assigned i.e. (i) water-saline, (ii) water- MPD, (iii) TRP-saline (iv) TRP-MPD (v) MPD-saline and (vi) MPD-MPD+TRP and treated for further 14 days. Locomotor behavior was monitored in familiar environment on the next day and in novel environment on alternate days of each administration. RESULTS: The Results from phase 1 showed increased activity in both (TRP and MPD) treatments. However, the results of phase 2 showed significant decrease in methylphenidate-induced behavioral sensitization by both pretreatment and co-administration with TRP. CONCLUSION: The present study suggests the potential of tryptophan to decrease the risk of behavioral sensitization induced by methylphenidate.

Autophagy plays a pro-survival role against methamphetamine-induced apoptosis in H9C2 cells.

Methamphetamine (METH) is a commonly abused psychostimulant that can induce severe neurotoxicity. Cardiovascular injury caused by METH has recently gained increasing attention; however, the underlying mechanisms remain unclear. As autophagy has been shown to be associated with cell injury, the association between autophagy and METH-mediated cell apoptosis was investigated in the present study. METH treatment significantly increased the expression of two key autophagy proteins, i.e., Beclin-1 and LC3-II, in the cardiomyocyte cell line H9C2. Furthermore, according to western blot and flow cytometry analyses, METH contributed to cell injury and markedly enhanced cleaved-caspase 3 and PARP expression. In addition, the corresponding AKT-mTOR survival pathway axis was appeared deactivated. The autophagic activity was closely associated with METH-mediated cell injury because rapamycin, which is an autophagy inducer, markedly attenuated METH-induced cell injury, while 3-Methyladenine (3-MA), which is an autophagy inhibitor, and bafilomycinA1 (Baf-A1), which is a blocker of autophagosome-lysosome fusion, markedly exacerbated METH-induced cell injury. Notably, defective autophagosome-lysosome fusion might be partially involved in the METH-induced enhancement of LC3-II expression and cell injury. However, the underlying mechanisms require further investigation.

Chemokines and 'bath salts': CXCR4 receptor antagonist reduces rewarding and locomotor-stimulant effects of the designer cathinone MDPV in rats.

BACKGROUND AND PURPOSE: Little is known about how chemokine systems influence the behavioral effects of designer cathinones and psychostimulants. The chemokine CXCL12 and its principal receptor target, CXCR4, are of particular interest because CXCR4 activation enhances mesolimbic dopamine output that facilitates psychostimulant reward, reinforcement, and locomotor activation. Repeated cocaine enhances CXCL12 gene expression in the midbrain and produces conditioned place preference (CPP) that is inhibited by a CXCR4 antagonist. Yet, interactions between chemokines and synthetic cathinones remain elusive. METHODS: We tested the hypothesis that an FDA-approved CXCR4 antagonist (AMD3100) inhibits MDPV-induced reward, locomotor activation and positive affective state in rats using a triad of behavioral assays (CPP, open field, and 50-kHz ultrasonic vocalizations [USVs]). KEY RESULTS: AMD3100 (1, 2.5, 5, 10 mg/kg, ip) significantly reduced MDPV (2 mg/kg, ip)-evoked hyper-locomotion in a dose-related manner. AMD3100 (1, 5, 10 mg/kg) administered during CPP conditioning caused a significant, dose-dependent reduction of MDPV (2 mg/kg x 4 days) place preference. MDPV injection elicited significantly greater 50 kHz USVs in vehicle-pretreated rats but not in AMD3100-pretreated rats. CONCLUSION AND IMPLICATION: A CXCR4 antagonist reduced the rewarding and locomotor-activating effects of MDPV. Our results identify the existence of chemokine/cathinone interactions and suggest the rewarding and stimulant effects of MDPV, similar to cocaine, require an active CXCL12/CXCR4 system.

Actualización en abuso de drogas por vía nasal / Update on drug abuse by nasal route

La vía nasal, ya sea mediante la inhalación o aspiración, se ha convertido en una ruta atractiva para quienes abusan de sustancias, principalmente por la fácil accesibilidad y la rápida absorción sistémica, además de evitar las consecuencias asociadas al uso de drogas intravenosas (enfermedades de transmisión). El objetivo de esta revisión es presentar una actualización de diversas sustancias que son utilizadas por esta vía, enfocándose en aquellas en las que se ha documentado daños en la anatomía nasal.

The nasal route, either by inhalation or aspiration, has become an attractive route for substances abusers, mainly because of its easy accessibility, rapid systemic absorption and also to avoid the consequences associated with intravenous drug use (transmitted diseases). The objective of this review is to present an update of various substances that are used by this route, focusing on those in which damage to the nasal anatomy has been documented.

Vaccine-driven pharmacodynamic dissection and mitigation of fenethylline psychoactivity.

Fenethylline, also known by the trade name Captagon, is a synthetic psychoactive stimulant that has recently been linked to a substance-use disorder and 'pharmacoterrorism' in the Middle East. Although fenethylline shares a common phenethylamine core with other amphetamine-type stimulants, it also incorporates a covalently linked xanthine moiety into its parent structure. These independently active pharmacophores are liberated during metabolism, resulting in the release of a structurally diverse chemical mixture into the central nervous system. Although the psychoactive properties of fenethylline have been reported to differ from those of other synthetic stimulants, the in vivo chemical complexity it manifests upon ingestion has impeded efforts to unambiguously identify the specific species responsible for these effects. Here we develop a 'dissection through vaccination' approach, called DISSECTIV, to mitigate the psychoactive effects of fenethylline and show that its rapid-onset and distinct psychoactive properties are facilitated by functional synergy between theophylline and amphetamine. Our results demonstrate that incremental vaccination against a single chemical species within a multi-component mixture can be used to uncover emergent properties arising from polypharmacological activity. We anticipate that DISSECTIV will be used to expose unidentified active chemical species and resolve pharmacodynamic interactions within other chemically complex systems, such as those found in counterfeit or illegal drug preparations, post-metabolic tissue samples and natural product extracts.

Buspirone attenuates methylphenidate-induced growth inhibition.

Methylphenidate is effective in the treatment of attention deficit hyperactivity disorder (ADHD) in children and adults, but its long term use can cause potential adverse effect on growth rate and variable effects on appetite. Previous studies have shown that long term administration of psychostimulant drugs increases the effectiveness of somatodendritic 5-hydroxytryptamine (5-HT)-1A receptors. Repeated administration of buspirone attenuates the effectiveness of somatodendritic 5-HT1A receptors. The present study was designed to test the hypothesis that co-administration of buspirone may attenuate methylphenidate-induced effects on growth rate and food intake. Growth rate was calculated weekly in terms of change in body weight as percentage of preceding week's body weight and food intake was calculated weekly by subtracting the amount of food left in the hopper from the amount of food placed in the hopper as % in preceding week mg/gm of body weight after long-term administration of methylphenidate, buspirone and their co-administration. Long term oral administration of methylphenidate at a dose of 2.0 mg/kg/day decrease growth rate, but co-administration of buspirone at a dose of 10 mg/kg/day attenuates effect of methylphenidate on growth rate however food intake was significantly greater in all treated groups after 3 weeks of treatment. It is suggested that buspirone may oppose methylphenidate-induced growth inhibition by decreasing the sensitivity of somatodendritic 5-HT1A receptors. These findings may help to extend future therapeutics in ADHD.

Chloramphenicol decreases CB1 receptor expression in the nucleus accumbens and prefrontal cortex and prevents amphetamine-induced conditioned place preference in rats.

Drug dependence seems to involve a learning and memory process. Since learning and memory depend on protein synthesis, drug dependence may depend on protein synthesis, too. Drug-induced reward is a crucial effect for the development of drug-dependence. We used chloramphenicol (CAP, a protein synthesis inhibitor), to evaluate its effects on amphetamine (amph)-seeking behavior, on CB1R expression and on protein synthesis in general, in specific areas of the brain. Two groups of Wistar adult male rats were subjected to amph-induced conditioned place preference (CPP). Rats in group 1 received amph and were kept in the chamber for 30min. Once this period elapsed, they received a subcutaneous injection of saline (veh) and were returned to their home-cage. Rats in group 2 were also treated with amph but received CAP (150mg/kgsc) instead of saline. Once CPP was evaluated rats were sacrificed and the prefrontal cortex (PFC), the nucleus accumbens (NAcc) and the hippocampus (Hipp) were isolated and prepared for CB1R Western blot analysis. A vivarium reared group of rats was added as a non-experimentally manipulated control group. Results indicate that group 1 developed CPP while increasing CB1R expression in the NAcc. Group 2 did not develop CPP, had lower CB1R expression in the PFC and lacked the CB1R increase in the NAcc observed in the amph+veh group. These results support the notion that among the underlying mechanisms for amph-seeking reward is an increase in CB1R, further supporting an interaction between dopamine/endocannabinoids in CPP learning.

Cooling down the bath salts: Carvedilol attenuation of methylone and mephedrone mediated hyperthermia.

The use of the synthetic cathinones ("bath salts"), methylone and mephedrone, has been associated with the development of life-threatening hyperthermia. To date, no direct pharmacological intervention to mitigate the hyperthermia induced by synthetic cathinones has been identified. Here, we investigated the effects of the non-selective α1 and ß adrenergic receptor antagonist carvedilol (5mg/kg ip) on established hyperthermia mediated by methylone and mephedrone (30mg/kg sc) in Sprague-Dawley rats. Methylone and mephedrone induced a hyperthermic response that peaked 60min post treatment. The administration of carvedilol 30min after methylone or mephedrone significantly attenuated these hyperthermic responses. Analysis of the Temperature Area Under the Curve (TAUC) demonstrated carvedilol significantly reduced the TAUC associated with methylone or mephedrone alone. The present study provides the first direct pharmacological intervention for the treatment of synthetic cathinone induced hyperthermia.

Cannabidiol Counteracts Amphetamine-Induced Neuronal and Behavioral Sensitization of the Mesolimbic Dopamine Pathway through a Novel mTOR/p70S6 Kinase Signaling Pathway.

UNLABELLED: Schizophrenia-related psychosis is associated with disturbances in mesolimbic dopamine (DA) transmission, characterized by hyperdopaminergic activity in the mesolimbic pathway. Currently, the only clinically effective treatment for schizophrenia involves the use of antipsychotic medications that block DA receptor transmission. However, these medications produce serious side effects leading to poor compliance and treatment outcomes. Emerging evidence points to the involvement of a specific phytochemical component of marijuana called cannabidiol (CBD), which possesses promising therapeutic properties for the treatment of schizophrenia-related psychoses. However, the neuronal and molecular mechanisms through which CBD may exert these effects are entirely unknown. We used amphetamine (AMPH)-induced sensitization and sensorimotor gating in rats, two preclinical procedures relevant to schizophrenia-related psychopathology, combined with in vivo single-unit neuronal electrophysiology recordings in the ventral tegmental area, and molecular analyses to characterize the actions of CBD directly in the nucleus accumbens shell (NASh), a brain region that is the current target of most effective antipsychotics. We demonstrate that Intra-NASh CBD attenuates AMPH-induced sensitization, both in terms of DAergic neuronal activity measured in the ventral tegmental area and psychotomimetic behavioral analyses. We further report that CBD controls downstream phosphorylation of the mTOR/p70S6 kinase signaling pathways directly within the NASh. Our findings demonstrate a novel mechanism for the putative antipsychotic-like properties of CBD in the mesolimbic circuitry. We identify the molecular signaling pathways through which CBD may functionally reduce schizophrenia-like neuropsychopathology. SIGNIFICANCE STATEMENT: The cannabis-derived phytochemical, cannabidiol (CBD), has been shown to have pharmacotherapeutic efficacy for the treatment of schizophrenia. However, the mechanisms by which CBD may produce antipsychotic effects are entirely unknown. Using preclinical behavioral procedures combined with molecular analyses and in vivo neuronal electrophysiology, our findings identify a functional role for the nucleus accumbens as a critical brain region whereby CBD can produce effects similar to antipsychotic medications by triggering molecular signaling pathways associated with the effects of classic antipsychotic medications. Specifically, we report that CBD can attenuate both behavioral and dopaminergic neuronal correlates of mesolimbic dopaminergic sensitization, via a direct interaction with mTOR/p70S6 kinase signaling within the mesolimbic pathway.

Subjective and Cardiovascular Effects of Intravenous Methamphetamine during Perindopril Maintenance: A Randomized, Double-Blind, Placebo-Controlled Human Laboratory Study.

BACKGROUND: Our pilot study suggested that the angiotensin-converting enzyme inhibitor perindopril might reduce some subjective effects produced by i.v. methamphetamine. We characterized the impact of a wider range of perindopril doses on methamphetamine-induced effects in a larger group of non-treatment-seeking, methamphetamine-using volunteers. METHODS: Before treatment, participants received 30mg methamphetamine. After 5 to 7 days of perindopril treatment (0, 4, 8, or 16mg/d), participants received 15 and 30mg of methamphetamine on alternate days. Before and after treatment, participants rated subjective effects and cardiovascular measures were collected. RESULTS: Prior to treatment with perindopril, there were no significant differences between treatment groups on maximum or peak subjective ratings or on peak cardiovascular effects. Following perindopril treatment, there were significant main effects of treatment on peak subjective ratings of "anxious" and "stimulated"; compared to placebo treatment, treatment with 8mg perindopril significantly reduced peak ratings of both anxious (P=.0009) and stimulated (P=.0070). There were no significant posttreatment differences between groups on peak cardiovascular effects. CONCLUSIONS: Moderate doses of perindopril (8mg) significantly reduced peak subjective ratings of anxious and stimulated as well as attenuated many other subjective effects produced by methamphetamine, likely by inhibiting angiotensin II synthesis. Angiotensin II is known to facilitate the effects of norepinephrine, which contributes to methamphetamine's subjective effects. The lack of a classic dose-response function likely results from either nonspecific effects of perindopril or from between-group differences that were not accounted for in the current study (i.e., genetic variations and/or caffeine use). The current findings suggest that while angiotensin-converting enzyme inhibitors can reduce some effects produced by methamphetamine, more consistent treatment effects might be achieved by targeting components of the renin-angiotensin system that are downstream of angiotensin-converting enzyme.

Rottlerin impairs the formation and maintenance of psychostimulant-supported memory.

RATIONALE AND OBJECTIVE: Since brain proteins such as protein kinase C (PKC), brain-derived neurotrophic factor (BDNF), and mammalian target of rapamycin (mTOR) are involved in the establishment and maintenance of psychostimulant memory, we sought to determine if systemic treatment with rottlerin, a natural compound affecting all these proteins, may modulate stimulant-supported memory. MATERIALS AND METHODS: Stimulant-induced conditioned place preference (CPP) was used in modeling stimulant-supported memory. RESULTS: Three cocaine (10 mg/kg; COC) or three methamphetamine (1 mg/kg; MA) conditioning trials reliably established the drug-induced CPP in male C57BL/6 mice. An intra-peritoneal rottlerin injection (5 mg/kg) at least 24 h prior to the first COC or first MA conditioning trial prevented the establishment of CPP. Following the establishment of the COC- or MA-induced CPP, saline conditioning trial was used to extinguish the CPP. Rottlerin (5 mg/kg, intra-peritoneal (i.p.)) administered 20 h prior to the first saline conditioning trial diminished subsequent drug- and stressor-primed reinstatement of the extinguished CPP. Rottlerin (5 mg/kg, i.p.) produced a fast-onset and long-lasting increase in hippocampal BDNF levels. However, treatment with a BDNF tropomyosin receptor kinase B (TrkB) receptor antagonist, K252a (5 µg/kg), did not affect rottlerin's suppressing effect on COC-induced CPP and treatment with 7,8-dihydroxyflavone (10 mg/kg x 6, 7,8-DHF), a selective TrkB agonist, prior to each conditioning trial did not affect COC-induced CPP. CONCLUSION: These results suggest that systemic rottlerin treatment may impair the formation of COC- and MA-supported memory. Importantly, such a treatment may advance our understanding of the underlying mechanism through which extinction training resulted in the "forgetting" of the COC- and MA-supported memory.

Pseudoginsenoside-F11 inhibits methamphetamine-induced behaviors by regulating dopaminergic and GABAergic neurons in the nucleus accumbens.

RATIONALE: Although dependence to methamphetamine (METH) is associated with serious psychiatric symptoms and is a global health and social problem, no effective therapeutic approaches have been identified. Pseudoginsenoside-F11 (PF11) is an ocotillol-type saponin that is isolated from Panax quinquefolius (American ginseng) and was shown to have neuroprotective effects to promote learning and memory and to antagonize the pharmacological effects of morphine. Furthermore, PF11 also shows protective effects against METH-induced neurotoxicity in mice. However, the effects of PF11 on METH-induced preference and dopamine (DA) release have not been defined. OBJECTIVES: We investigated the effects of PF11 administration on METH-induced hyperlocomotion and conditioned place preference (CPP) in mice. Subsequently, extracellular DA and gamma-aminobutyric acid (GABA) levels were determined in the nucleus accumbens (NAc) of mice after co-administration of PF11 and METH using in vivo microdialysis analyses. Moreover, the effects of PF11 administration on the µ-opioid neuronal responses, DAMGO (µ-opioid receptor agonist; [D-Ala(2), N-MePhe(4), Gly-ol]-enkephalin)-induced hyperlocomotion and accumbal extracellular DA increase were investigated to elucidate how PF11 inhibits METH-induced dependence by dopaminergic neuronal hyperfunction. RESULTS: Co-administration of PF11 and METH for 6 days attenuated METH-induced locomotor sensitization compared with treatment with METH alone. In the CPP test, PF11 administration also inhibited METH-induced place preference. In vivo microdialysis analyses indicated that co-administration of PF11 and METH for 7 days prevented METH-induced extracellular DA increase in the NAc and repeated PF11 administration with or without METH for 7 days increased extracellular GABA levels in the NAc, whereas single administration of PF11 did not. Furthermore, DAMGO-induced hyperlocomotion and accumbal extracellular DA increase were significantly inhibited by acute PF11 administration. CONCLUSIONS: The present data suggest that PF11 inhibits METH-induced hyperlocomotion, preference, and accumbal extracellular DA increase by regulating GABAergic neurons and µ-opioid receptors.

Concentrations of MDPV in rat striatum correlate with the psychostimulant effect.

3,4-methylenedioxypyrovalerone or MDPV is a synthetic cathinone with psychostimulant properties more potent than cocaine. We quantified this drug in the striatum after subcutaneous administration to rats. MDPV reached the brain around 5 min after its administration and peaked at 20-25 min later. The elimination half-life in the striatum (61 min) correlates with the decrease in the psychostimulant effect after 60 min. Around 11% of the administered dose reached the striatum and, considering a homogeneous brain distribution, we determined that around 86% of the plasma MDPV is distributed to the brain. MDPV induced a dose-dependent increase in locomotor activity, rearing behaviour and stereotypies, all prevented by haloperidol. A plot of locomotor activity or stereotypies versus MDPV striatal concentrations over time showed a direct relationship between factors. No free MDPV metabolites were detected in plasma, at any time, but hydrolysis with glucuronidase allowed us to identify mainly three metabolites, one of them for the first time in rat plasma. The present results contribute to evidence that MDPV induces hyperlocomotion mainly through a dopamine-dependent mechanism. Good correlation between behavioural effects and striatal levels of MDPV leads us to conclude that its psychostimulant effect is mainly due to a striatal distribution of the substance. The present research provides useful information on the pharmacokinetics of MDPV, and can help design new experiments with kinetics data as well as provide a better understanding of the effects of MDPV in humans and its potential interactions.

Valproate Inhibits Methamphetamine Induced Hyperactivity via Glycogen Synthase Kinase 3ß Signaling in the Nucleus Accumbens Core.

Valproate (VPA) has recently been shown to influence the behavioral effects of psycho-stimulants. Although glycogen synthase kinase 3ß (GSK3ß) signaling in the nucleus accumbens (NAc) plays a key role in mediating dopamine (DA)-dependent behaviors, there is less direct evidence that how VPA acts on the GSK3ß signaling in the functionally distinct sub-regions of the NAc, the NAc core (NAcC) and the NAc shell (NAcSh), during psycho-stimulant-induced hyperactivity. In the present study, we applied locomotion test after acute methamphetamine (MA) (2 mg/kg) injection to identify the locomotor activity of rats received repeated VPA (300 mg/kg) pretreatment. We next measured phosphor-GSK3ß at serine 9 and total GSK3ß levels in NAcC and NAcSh respectively to determine the relationship between the effect of VPA on MA-induced hyperlocomotor and changes in GSK3ß activity. We further investigated whether microinjection of VPA (300 µg/0.5 µl/side, once daily for 7 consecutive days) into NAcC or NAcSh could affect hyperactivity induced by MA. Our data indicated that repeated VPA treatment attenuated MA-induced hyperlocomotor, and the effect was associated with decreased levels of phosphorylated GSK3ß at Ser 9 in the NAcC. Moreover, repeated bilateral intra-NAcC, but not intra-NAcSh VPA treatment, significantly attenuated MA-induced hyperactivity. Our results suggested that GSK3ß activity in NAcC contributes to the inhibitory effects of VPA on MA-induced hyperactivity.

The disruptive effects of methamphetamine on delayed-matching-to-sample performance reflect proactive interference and are reduced by SCH23390.

Different drugs produce different patterns of impairment on delayed matching-to-sample tasks. For example, (+/-)3,4-methylenedioxymethamphetamine (MDMA) produces an increase in proactive interference. That is, subjects are less accurate when they are required to make a response different to the one they made on the immediately previous trial. The current study assessed whether methamphetamine also produces this particular pattern of disruption in delayed matching-to-sample performance in rats. Methamphetamine primarily reduced accuracy on trials where the correct response differed from the one made on the previous trial. Thus methamphetamine, like MDMA and other stimulant-based drugs of abuse, increased proactive interference. This impairment was reduced by prior administration of the dopamine D1 antagonist SCH23390. These results further extend a general conclusion that a range of stimulant-based drugs may disrupt working memory function indirectly via a tendency to repeat previously made responses and that this disruption is related to D1 receptor activity.

Ginsenoside Re protects methamphetamine-induced mitochondrial burdens and proapoptosis via genetic inhibition of protein kinase C δ in human neuroblastoma dopaminergic SH-SY5Y cell lines.

Recently, we have demonstrated that ginsenoside Re protects methamphetamine (MA)-induced dopaminergic toxicity in mice via genetic inhibition of PKCδ and attenuation of mitochondrial stress. In addition, we have reported that induction of mitochondrial glutathione peroxidase (GPx) is also important for neuroprotection mediated by ginsenoside Re. To extend our knowledge, we examined the effects of ginsenoside Re against MA toxicity in vitro condition using SH-SY5Y neuroblastoma cells. Treatment with ginsenoside Re resulted in significant attenuations against a decrease in the activity of GPx and an increase in the activity of superoxide dismutase (SOD) in the cytosolic and mitochondrial fraction. The changes in glutathione (GSH) paralleled those in GPx in the same experimental condition. Consistently, ginsenoside Re treatment exhibited significant protections against cytosolic and mitochondrial oxidative damage (i.e. lipid peroxidation and protein oxidation), mitochondrial translocation of PKCδ, mitochondrial dysfunction (mitochondrial transmembrane potential and intra-mitochondrial Ca(2+)), apoptotic events [i.e., cytochrome c release from mitochondria, cleavage of caspase-3 and poly(ADP-ribose)polymerase-1, nuclear condensation, terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL)-positive apoptotic cells], and a reduction in the tyrosine hydroxylase (TH) expression and TH activity induced by MA in SH-SY5Y neuroblastoma cells. These protective effects of ginsenoside Re were comparable to those of PKCδ antisense oligonucleotide (ASO). However, ginsenoside Re did not significantly provide additional protective effects mediated by genetic inhibition of PKCδ. Our results suggest that PKCδ is a specific target for ginsenoside Re-mediated protective activity against MA toxicity in SH-SY5Y neuroblastoma cells.

The antipsychotic aripiprazole selectively prevents the stimulant and rewarding effects of morphine in mice.

Aripiprazole is an antipsychotic that acts as a partial agonist at dopamine D2 receptors, with a favorable pharmacological profile. Due to its unique mechanism of action, this compound has potential application as a substitutive therapy for drug addiction. Considering that distinct neural systems subserve the addictive and analgesic actions of opioids, we tested the hypothesis that aripiprazole selectively inhibit the abuse-related, but not the antinociceptive, effects of morphine. The drugs were tested in male Swiss mice for their effects on locomotion, conditioned place preference (CPP) and nociception. Morphine (20mg/kg) increased motor activity, whereas aripiprazole (0.1, 1 and 10mg/kg) did not induce any change. This antipsychotic, however, prevented morphine-induced locomotion. In the conditioning box, aripiprazole did not induce either reward or aversion. Yet, it prevented both the acquisition and the expression of morphine-induced CPP. Finally, none of the doses of this antipsychotic interfere with morphine (5mg/kg)-induced antinociception in the tail-flick test. In conclusion, aripiprazole inhibited the abuse-related effects of morphine at doses that do not interfere with basal locomotion, reward or aversion. Also, it did not alter morphine-induced antinociceptive effects. This antipsychotic should be further investigated as a possible substitutive strategy for treating certain aspects of opioid addiction.