Subchronic apocynin treatment attenuates methamphetamine-induced dopamine release and hyperactivity in rats.

AIMS: The effects of methamphetamine are linked to stimulation of dopaminergic neurons, which can be accompanied by production of reactive oxygen species (ROS). Apocynin (4-hydroxy-3-methoxy-acetophenone) is a nicotinamide adenine dinucleotide phosphate (NADPH)-oxidase (NOX) inhibitor shown to mitigate oxidative stress in a number of models. The present study aimed at testing whether apocynin suppresses the dopamine-releasing and locomotor-activating properties of methamphetamine. MAIN METHODS: (1) Apocynin (0.01-100µM) was applied to rat striatal slices preloaded with [(3)H]dopamine and its efficacy to evoke [(3)H]overflow and to alter methamphetamine (3µM)-evoked [(3)H]overflow was measured. (2) Groups of rats received apocynin (15 or 50mg/kg/day) or vehicle injection for seven consecutive days, and the efficacy and potency of methamphetamine to evoke [(3)H]overflow were determined. (3) Groups of apocynin-treated rats were administered methamphetamine (0.5 or 1mg/kg) or saline to determine the effect of apocynin on stimulant-induced hyperactivity. KEY FINDINGS: (1) Apocynin applied to striatal slices did not evoke [(3)H]overflow or alter methamphetamine-evoked [(3)H]overflow. (2) However, subchronic apocynin treatment significantly and dose-dependently decreased methamphetamine's potency and efficacy to evoke [(3)H]overflow. (3) Subchronic apocynin treatment also decreased the locomotor activity evoked by methamphetamine. SIGNIFICANCE: Subchronic apocynin treatment diminished methamphetamine induced dopamine-release and its locomotor-activating properties. The pattern of results indicates that apocynin is more effective after repeated, rather than after acute, treatment. The findings also suggest that NOX inhibitors or agents suppressing oxidative stress may constitute a new area for research to understand how methamphetamine produces its deleterious and neurotoxic outcomes in the brain.

Repeated resveratrol treatment attenuates methamphetamine-induced hyperactivity and [3H]dopamine overflow in rodents.

Resveratrol (3,4',5-trihydroxy-trans-stilbene) has been investigated for its potential as a prophylactic against degenerative diseases. It is a sirtulin activator that has recently been shown to regulate dopaminergic systems that contribute to the behavioral effects of methamphetamine and cocaine. The present study examined the impact of resveratrol on stimulant neuropsychopharmacology in rodents. Acute resveratrol treatment (20-40mg/kg) was ineffective to alter methamphetamine (0.5mg/kg)-induced hyperactivity in mice. Rodents received resveratrol once-daily for seven days to determine the effect of repeated polyphenolic treatment. Repeated resveratrol treatment (1-20mg/kg) decreased methamphetamine (0.5mg/kg)-induced hyperactivity in mice. Methamphetamine's (0.1-60µM) efficacy to evoke [(3)H]overflow from rat striatal slices preloaded with [(3)H]dopamine was also attenuated by repeated resveratrol (1mg/kg) treatment. Repeated resveratrol treatment (10-20mg/kg) did not affect cocaine-induced hyperactivity in mice. Overall, these data suggest that resveratrol appears to have metaplastic and prophylactic activity to minimize the effects of methamphetamine to increase locomotor activity and evoke dopamine release. These data encourage future research to further investigate the relationship between polyphenolics and psychostimulant abuse and dependence.

Effects of N-phenylpropyl-N'-substituted piperazine sigma receptor ligands on cocaine-induced hyperactivity in mice.

The present study examined N-phenylpropyl-N'-substituted piperazine sigma receptor ligands on cocaine-induced changes in locomotor activity in mice. Previous reports indicate that N-phenylpropyl-N'-(4-methoxybenzyl)piperazine (Nahas-3h), N-phenylpropyl-N'-(4-methoxyphenethyl)piperazine (YZ-067), and N-phenylpropyl-N'-(3-methoxyphenethyl)piperazine (YZ-185) bind with high affinity (Ki values≈1 nM) to σ1 sigma receptors. YZ-067 and YZ-185 are known to attenuate cocaine-induced convulsions, while Nahas-3h has not been tested in behavioral studies. Nahas-3h significantly attenuated cocaine-induced hyperactivity. YZ-067 decreased the effect of cocaine in a dose-dependent manner. Interestingly, YZ-185 inhibited cocaine's effect at higher doses, but enhanced cocaine's effect at a low dose. The YZ-185 inhibition of cocaine-induced hyperactivity was not surmounted by increasing the cocaine dose. Overall, this study is consistent with previous work showing the ability of certain sigma receptor ligands to affect cocaine-induced hyperactivity. Further, subtle alterations of ligand structure and the specific dosage levels employed influence the behavioral effects observed, with a 3-methoxy substituent apparently conferring the ability of a ligand to enhance cocaine's locomotor stimulatory effects.

The sigma receptor agonist SA4503 both attenuates and enhances the effects of methamphetamine.

BACKGROUND: Methamphetamine's behavioral effects have been attributed to its interaction with monoamine transporters; however, methamphetamine also has affinity for sigma receptors. METHOD: The present study investigated the effect of the sigma receptor agonist SA 4503 and the sigma receptor antagonists BD-1047 and BD-1063 on methamphetamine-evoked [(3)H]dopamine release from preloaded rat striatal slices. The effect of SA 4503 on methamphetamine-induced hyperactivity and on the discriminative stimulus properties of methamphetamine also was determined. RESULTS: SA 4503 attenuated methamphetamine-evoked [(3)H]dopamine release in a concentration-dependent manner. BD-1047 and BD-1063 did not affect release. SA 4503 dose-dependently potentiated and attenuated methamphetamine-induced hyperactivity. SA 4503 pretreatment augmented the stimulus properties of methamphetamine. CONCLUSIONS: Our findings indicate that SA 4503 both enhances and inhibits methamphetamine's effects and that sigma receptors are involved in the neurochemical, locomotor stimulatory and discriminative stimulus properties of methamphetamine.