Sensitized increase of period gene expression in the mouse caudate/putamen caused by repeated injection of methamphetamine.
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Methamphetamine (MAP) causes the sensitization phenomena not only in MAP-induced locomotor activity, dopamine release, and Fos expression, but also in MAP-induced circadian rhythm. Cocaine-induced sensitization is reportedly impaired in Drosophila melanogaster mutant for the Period (Per) gene. Thus, sensitization may be related to induction of the Per gene. A rapid induction of mPer1 and/or mPer2 in the suprachiasmatic nucleus after light exposure is believed to be necessary for light-induced behavioral phase shifting. Although the caudate/putamen (CPu) expresses mPer1 and/or mPer2 mRNA, the function of these genes in this nucleus has not yet been elucidated. Therefore, we examined whether MAP affects the expression of mPer1 and/or mPer2 mRNA in the mouse CPu. Injection of MAP augmented the expression of mPer1 but not mPer2 or mPer3 in the CPu, and this MAP-induced increase in mPer1 expression lasted for 2 h. Also, the MAP-induced increase of mPer1 mRNA was strongly antagonized by pretreatment with a dopamine D1 receptor and N-methyl-D-aspartate (NMDA) receptor antagonist, but not by a D2 receptor antagonist. Interestingly, application of either the D1 or the D2 agonist alone did not cause mPer1 expression. The present results demonstrate that activation of both NMDA and D1 receptors is necessary to produce MAP-induced mPer1 expression in the CPu. Repeated injection of MAP caused a sensitization in not only the locomotor activity but also mPer1 expression in the CPu without affecting the level of mPer2, mPer3, or mTim mRNA. Thus, these results suggest that MAP-induced mPer1 gene expression may be related to the mechanism for MAP-induced sensitization in the mouse. (+info)
The association study of DRD2, ACE and AGT gene polymorphisms and metamphetamine dependence.
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We investigated the association between metamphetamine dependence and TaqI A polymorphism of the dopamine receptor D2 gene (DRD2), I/D polymorphism in angiotensin-converting enzyme (ACE) and M235T polymorphism of the angiotensinogen gene (AGT) in 93 unrelated metamphetamine-dependent subjects and 131 controls. Our results did not prove any association of TaqI A polymorphism of the DRD2 gene, I/D polymorphism of ACE gene, and M235T polymorphism of AGT gene with the metamphetamine dependence in Caucasians of Czech origin. However, a significant difference in allele I frequency between male and female control groups for the I/D ACE polymorphism (p<0.03) was found. (+info)
Dose-related neuroprotective effects of chronic nicotine in 6-hydroxydopamine treated rats, and loss of neuroprotection in alpha4 nicotinic receptor subunit knockout mice.
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The present study examined the effect of a range of doses of chronic nicotine (0.75, 1.5, 3.0 and 30.0 mg kg(-1) day(-1), s.c., 14 days) upon striatal dopaminergic nerve terminal survival following 6-hydroxydopamine (6-OHDA; 10 microg intrastriatal unilaterally) in rats; and the effects of acute nicotine (1 mg kg(-1), s.c.) pretreatment upon striatal neurodegeneration induced by methamphetamine (5 mg kg(-1), i.p., three doses at 2 h intervals) in wild-type and alpha4 nicotinic receptor (nAChR) subunit knockout mice. In both models of Parkinsonian-like damage, loss of striatal dopaminergic nerve terminals was assessed by [(3)H]-mazindol autoradiography. In rats, chronic nicotine infusion delivered by osmotic minipump implanted subcutaneously 7 days prior to intrastriatal 6-OHDA injection produced significant and dose-related protection against 6-OHDA-induced neurodegeneration. Low (0.75 and 1.5 mg kg(-1) day(-1)) but not high (3.0 and 30.0 mg kg(-1) day(-1)) nicotine doses significantly inhibited 6-OHDA-induced degeneration. In wild-type mice, acute nicotine treatment produced significant inhibition of methamphetamine-induced neurodegeneration. In alpha4 nAChR subunit knockout mice, acute nicotine treatment failed to inhibit methamphetamine-induced neurodegeneration. Nicotine is capable of protecting dopaminergic neurons against Parkinsonian-like neurodegeneration in vivo. In rats, this neuroprotective effect is critically dependent upon nicotine dose and is consistent with the activation of nAChRs, as high, desensitizing doses of nicotine fail to be neuroprotective. Further, neuroprotection is absent in alpha4 nAChR subunit knockout mice. The current results therefore suggest that activation of alpha4 subunit containing nAChRs constitutes a major component of the neuroprotective effect of nicotine upon Parkinsonian-like damage in vivo. (+info)
Effect of dizocilpine maleate on discriminative properties of methamphetamine in rats.
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AIM: To study the effect of (+)-10, 11-dihydro-5-methyl-5H-dibenzo [a, d] cyclohepten-5, 10-imine maleate(dizocilpine maleate, MK-801) on the discriminative behavior of methamphetamine (MA). METHODS: Two lever and a fixed-ratio schedule of food presentation reinforcement program were used in discrimination test session. RESULTS: Rats can shape and maintain the discriminative behavior for MA (1 mg/kg, s.c.) and saline (1 mL/kg, s.c.). On pretreatment with dizocilpine maleate (0.1 mg/kg) in MA dependent rats, the correct discrimination percentage of MA was markedly decreased; but pretreatment with dizocilpine maleate (0.025, 0.05 mg/kg) did not block discrimination behavior of MA in antagonistic test. After injection of dizocilpine maleate (0.1 mg/kg) alone in MA dependent rats, six of the seven rats partially or completely responded on the MA associated lever whereas one did not. All of the rats had no substitution after injection of dizocilpine maleate (0.025, 0.05 mg/kg). CONCLUSION: N-methyl-D-aspartate (NMDA) receptor may be involved in psychological dependence of MA. (+info)
The interaction of neuroleptic and muscarinic agents with central dopaminergic systems.
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1. The effect of muscarinic and neuroleptic agents on the turning behaviour induced by methamphetamine and apomorphine in rats with unilateral lesions of the substantia nigra induced by 6-hydroxydopamine has been examined. 2. Turning towards the side of the lesion induced by (+)-methamphetamine (5 mg/kg) was inhibited by alpha-flupenthixol (1 mg/kg) and alpha-clopenthixol (8 mg/kg) but not by high doses of their beta-isomers. 3. Turning was inhibited by chlorpromazine (4 mg/kg) and pimozide (0.2 mg/kg). Thioridazine and clozapine (16 mg/kg) were ineffective. Turning in the same direction produced by scopolamine (10 mg/kg) was also inhibited by alpha-flupenthixol (1 mg/kg) and pimozide (0.25 mg/kg). 4. Turning produced by methamphetamine (5 mg/kg) was inhibited by oxotremorine (0.75 mg/kg) even in the presence of methylatropine (5 mg/kg). 5. Turning away from the side of the lesion induced by apomorphine (0.1 mg/kg) was inhibited by oxotremorine (0.75 mg/kg) but not by thioridazine or clozapine (16 mg/kg). 6. These results are discussed with regard to the mode of action of neuroleptic drugs in producing anti-psychotic effects and drug-induced Parkinsonism. (+info)
It's a rave new world: rave culture and illicit drug use in the young.
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Illicit drug use by young people has changed in the last decade, with the increasing use of "designer" or "club" drugs such as ecstasy. Keeping abreast of current trends in illicit drug use prepares the primary care clinician to recognize the clinical effects of drug use, to manage drug emergencies, and to detect addictive behavior. Today's widely used drugs, their street names, their effects, and how to manage overdoses are reviewed. (+info)
Lobeline attenuates d-methamphetamine self-administration in rats.
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alpha-Lobeline inhibits d-amphetamine-evoked dopamine release from striatal slices in vitro, appearing to reduce the cytosolic pool of dopamine available for reverse transport by the dopamine transporter. Based on this neurochemical mechanism of action, the present study determined if lobeline decreases d-methamphetamine self-administration. Rats were surgically implanted with jugular catheters and were trained to lever press on a fixed ratio 5 schedule for intravenous d-methamphetamine (0.05 mg/kg/infusion). To assess the specificity of the effect of lobeline, another group of rats was trained to lever press on a fixed ratio 5 schedule for sucrose reinforcement. Pretreatment of rats with lobeline (0.3-3.0 mg/kg, 15 min prior to the session) decreased responding for both d-methamphetamine and sucrose reinforcement. Following repeated lobeline (3.0 mg/kg) administration, tolerance developed to the decrease in responding for sucrose; however, the lobeline-induced decrease in responding for d-methamphetamine persisted. Furthermore, the lobeline-induced decrease in responding for d-methamphetamine was not surmounted by increasing the unit dose of d-methamphetamine. These results suggest that lobeline produces a nonspecific rate suppressant effect following acute administration, to which tolerance develops following repeated administration. Importantly, the results also suggest that repeated administration of lobeline specifically decreases responding for d-methamphetamine in a noncompetitive manner. Thus, lobeline may be an effective, novel pharmacotherapy for d-methamphetamine abuse. (+info)
Gender-dependent enhanced adult neurotoxic response to methamphetamine following fetal exposure to the drug.
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Methamphetamine use by females of child-bearing age has become a major public health concern in terms of the long-term risk to the exposed fetus. We examined the possibility of enhanced adult neurotoxic potential of the drug in offspring that had been exposed to methamphetamine in utero during gestational days 7 to 18. While basal levels of monoamines were not affected by prenatal exposure to methamphetamine, we observed an enhanced neurotoxicity in adult male offspring following drug challenge with effects localized primarily to the dopaminergic nigrostriatal projection. This was evidenced by greater methamphetamine-induced reductions of dopaminergic markers in the striatum [dopamine (DA), dihydroxyphenylacetic acid, homovanillic acid (HVA), and 3-methoxytyramine (3-MT)] and ventral brainstem (DA) of prenatal methamphetamine-treated males compared with saline-treated animals. Some effects of prenatal methamphetamine exposure were observed in female offspring, but these were limited to striatal levels of 3-MT and HVA. Differential gender sensitivity to the neurotoxic effect of methamphetamine was shown to be correlated with hyperthermic response. Hyperthermic effects, however, do not account for the increased susceptibility of prenatal methamphetamine-treated males to drug-induced striatal DA neurotoxicity since methamphetamine challenge did not evoke a significantly greater hyperthermic response in these animals compared with prenatal saline-treated males. The findings raise the concern that male methamphetamine abusers may be at risk for an enhanced neurotoxic risk if they were exposed to the drug in utero. (+info)