Stimulant Effects Of Methamphetamine Research Articles

Differential effects of voluntary exercise and housing density on anxiety-like behavior in C57Bl/6 mice

The interaction of voluntary exercise and housing density on a) anxiety-like behavior and b) the stimulant effects of methamphetamine in C57Bl/6 mice were evaluated. Upon arrival, mice were housed singly or in pairs, and permitted access to home-cage running wheels or not for 4 weeks. Testing for anxiety-like behavior occurred over the next 3 weeks, one test per week [Elevated-Plus Maze (EPM) → Hyponeophagia (HNP) task → Open-Field (OF) task]. The final, OF task involved an 8-hour session in which mice were permitted to explore the chamber (drug free) during Hours 1–3; given an injection (s.c.) of methamphetamine (1.0 mg/kg) after Hour 3; followed by continued behavioral sampling during Hours 4–8. Several tasks (HNP and OF, but not EPM) consistently showed voluntary exercise induced anxiety-like behavior. In addition, two measures (time in center and time resting in the perimeter) in the OF task revealed that exercise mice compared to controls were more responsive to the anxiogenic effects of methamphetamine. Although pair housing was anxiolytic, it did not ameliorate the anxiogenic effects of voluntary exercise. Taken together, these results, when viewed in tandem with previous studies that utilized a less anxious mouse strain (Swiss Webster), may suggest that voluntary exercise is anxiogenic in an anxiety-prone mouse strain such as C57Bl/6 and highlight the importance of considering mouse strain when evaluating the impact of environmental manipulations on anxiety-like behavior in animal models.

Anti‐Methamphetamine Antibody Gene Therapy Ameliorates Methamphetamine‐induced Locomotor Effects in Mice for 8 Months after a Single Treatment

There currently are no FDA‐approved pharmacological treatments to aid in treatment of methamphetamine (METH) substance use disorders. To address this, our laboratory has combined short chain variable fragments (scFvs) derived from antibodies with high binding affinity to METH with adeno‐associated viruses (AAV) to develop a long‐lasting potential therapy. These first generation gene therapies showed expression of the anti‐METH scFvs for at least 212 days but achieved an average serum concentration of less than 70.0 μg/ml in mice. We hypothesized that incorporating a constant region (Fc) derived from an IgG antibody would extend serum half‐life and increase circulating concentrations of the anti‐METH antibody fragment, thus providing greater levels of protection against METH in mice. To test this hypothesis, we cloned an anti‐METH scFv‐Fc encoding DNA sequence into custom expression plasmids and packaged into AAV serotype 8 viral vectors to make AAV‐7F9‐Fc. To test this new gene therapy, BALB/C mice were administered 1×1012 vector copies per mouse of either the AAV‐7F9‐Fc or empty AAV8 vector. Mice were allowed to reach peak AAV‐7F9‐Fc expression (~28 days, as determined by ELISA) before testing in locomotor studies. Locomotor activity was used to measure protection from the stimulant effects of METH. Briefly, after a 30‐minute baseline activity was recorded, mice were administered saline, 0.56, 1.0, 3.0, or 5.56 mg/kg METH sc, and locomotor activity was measured for 90 minutes. METH was administered consecutively with a two‐day washout period in between doses. This regimen was also performed on separate mice 7–8 months after administration of AAV‐7F9‐Fc therapy to test duration of protection. Our results show that by incorporating an IgG Fc moiety into the anti‐METH constructs, the average expression increased by over 30 fold compared to a our first generation scFvs to a peak serum concentration of 5.227.7 μg/ml, and mean of 2,116.1 μg/ml, and persisted over 239 days. The AAV‐7F9‐Fc mice showed significantly less locomotor activity (p < 0.05) than empty AAV8 treated mice at the 1.0 and 3.0 mg/kg METH doses. Furthermore, the AAV‐7F9‐Fc treated mice showed no significant activity differences from baseline at any of the METH doses administered. In a separate, long‐term study, 7–8 months after AAV‐7F9‐Fc treatment, mice showed significantly lower levels of locomotor activity at 0.56 and 1.0 mg/kg sc METH doses than the sham treated group. These data suggest our AAV‐7F9‐Fc can protect against stimulant effects of METH, and that the duration of action is at least 8 months in mice. Overall, these data suggest that 1) the addition of the IgG Fc region into the AAV‐scFv constructs resulted in dramatically higher anti‐METH antibody circulating concentrations than our first generation anti‐METH scFvs and 2) this higher antibody titer was able to provide protection against METH stimulant effects at low to moderate doses for at least 8 months in mice.Support or Funding InformationSupported by NIDA R01 DA036600 & NIGMS T32 GM106999This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Sensitization to the motor stimulant effects of 3,4-methylenedioxypyrovalerone (MDPV) and cross-sensitization to methamphetamine in rats.

In recent years, there has been a dramatic increase in abuse of the synthetic cathinone 3,4-methylenedioxypyrovalerone (MDPV), often in combination with other illicit stimulants. We sought to determine if repeated exposure to MDPV would produce sensitization to the motor stimulant effects of the drug, and whether cross-sensitization would develop with the stimulant effects of methamphetamine (METH). Male Sprague-Dawley rats were administered MDPV (1 or 5 mg/kg) or saline once daily for 5 days at 24 hour intervals, or were administered MDPV (1 mg/kg) or saline once daily for 5 days at 48 hour intervals. For cross-sensitization experiments, rats were administered METH (1 mg/kg) or MDPV (1 or 5 mg/kg) once daily for 5 days at 48 hour intervals, and following a 5 day incubation period, were given an acute challenge injection of either MDPV (0.5 mg/kg) or METH (0.5 mg/kg), respectively. Rats repeatedly administered MDPV (1 mg/kg) every 48 hours, but not every 24 hours, demonstrated increased motor activity when given either a subsequent challenge of MDPV (0.5 mg/kg i.p.) or METH (0.5 mg/kg), indicating the development of behavioral sensitization and cross-sensitization, respectively. Moreover, rats repeatedly administered METH (1 mg/kg) every 48 hours did not exhibit cross-sensitization to the motor stimulating effects of a subsequent challenge with MDPV (0.5 mg/kg). These results suggest that specific patterns of MDPV administration may lead to lasting changes in behavioral responses to subsequent METH exposure.

Discriminative stimulus effects of NMDA, AMPA, and mGluR5 glutamate receptor ligands in methamphetamine-trained rats

Glutamate contributes to the reinforcing and stimulant effects of methamphetamine, yet its potential role in the interoceptive stimulus properties of methamphetamine is unknown. In this study, adult male Sprague-Dawley rats were trained to discriminate methamphetamine [1.0 mg/kg, intraperitoneally] from saline in a standard operant discrimination task. The effects of methamphetamine (0.1-1.0 mg/kg, intraperitoneally); N-methyl-D-aspartate (NMDA) receptor channel blockers, MK-801 (0.03-0.3 mg/kg, intraperitoneally) and ketamine (1.0-10.0 mg/kg, intraperitoneally); polyamine site NMDA receptor antagonist, ifenprodil (1-10 mg/kg); α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate receptor antagonist, 6-cyano-7-nitroquinoxaline-2,3-dione (1-10 mg/kg, intraperitoneally); and metabotropic 5 glutamate receptor antagonist, 6-methyl-2-(phenylethynyl)pyridine (1-10 mg/kg), given alone were determined in substitution tests. The effects of MK-801 (0.03 and 0.1 mg/kg), ketamine (1.0 and 3.0 mg/kg), ifenprodil (5.6 mg/kg), 6-cyano-7-nitroquinoxaline-2,3-dione (5.6 mg/kg), and 6-methyl-2-(phenylethynyl)pyridine (5.6 mg/kg) were also tested in combination with methamphetamine to assess for alterations in the methamphetamine cue. In substitution tests, none of the test drugs generalized to the methamphetamine cue. However, ketamine and ifenprodil produced significant leftward shifts in the methamphetamine dose-response curve. In addition, the potention by MK-801 nearly attained significance. These results suggest that blockade of the NMDA receptor augments the interoceptive stimulus properties of methamphetamine.

Contrasting effects on methamphetamine sensitization of ceruletide, a cholecystokinin-like decapeptide, and haloperidol.

Ceruletide, a cholecystokinin-like decapeptide, and haloperidol show neuroleptic actions through inhibition of dopamine release and blockade of dopamine receptors, respectively. In this study, the effects of both drugs on methamphetamine sensitization were assessed by means of ambulation in mice. The enhancement in ambulation increase caused by five repeated administrations of methamphetamine (2 mg/kg, SC) at 3- to 4-day intervals was dose-dependently reduced when it was administered simultaneously with ceruletide (0.01-0.1 mg/kg, SC) or haloperidol (0.03-0.3 mg/kg, SC). However, only haloperidol could inhibit the induction of methamphetamine sensitization as assessed by challenge with methamphetamine alone. Post-treatment with ceruletide (0.03 mg/kg) 3 h after each methamphetamine accelerated, whereas such post-treatment with ceruletide (0.1 mg/kg) or haloperidol (0.03-0.3 mg/kg) delayed, the induction of methamphetamine sensitization. On the other hand, mice given five pretreatments with ceruletide (0.01-0.1 mg/kg) or haloperidol (0.03-0.3 mg/kg) at 3- to 4-day intervals did not exhibit any significant change in the sensitivity to methamphetamine. The present results suggest that, in contrast to the dose-dependent inhibition of methamphetamine sensitization in the simultaneous administration and post-treatment schedules, although both drugs can antagonize the acute stimulant effect of methamphetamine.

Ice: A New Dosage Form of an Old Drug

Ice, which has been described as the drug of the 1990s, is a pure form of (+)methamphetamine hydrochloride; it is more dangerous because of its purity and because it can be inhaled. Taken by this route, the drug causes an effect similar to that from an intravenous dose, and much more intense than that from ingestion. The detailed mechanism of action differs from that of cocaine, but the overall stimulant effect of methamphetamine is similar. Methamphetamine effects, however, persist for hours, whereas cocaine effects are over in minutes. Ice is, therefore, just another agent for abuse by those seeking psychostimulation and, as with cocaine, compulsive abusers of amphetamines consume the drug repeatedly and continuously. Unlike cocaine, methamphetamine is a synthetic compound and is manufactured in illicit laboratories within the United States.