preproenkephalin and Amphetamine-Related-Disorders

The aim of this study was to determine whether inhibition of the extracellular-regulated kinase signaling pathway decreases acute amphetamine-induced behavioral activity and neuropeptide gene expression in the rat striatum. Western blotting revealed that extracellular-regulated kinase1/2 phosphorylation was highly induced in the rat striatum 15 min after an acute amphetamine (2.5 mg/kg, i.p.) injection without altering the total amount of extracellular-regulated kinase protein. In a separate experiment, the systemic injection of SL327, a selective inhibitor of extracellular regulated kinase kinase that crosses the blood-brain barrier, 1 h prior to amphetamine administration decreased amphetamine-induced vertical and horizontal activity. Quantitative in situ hybridization histochemistry showed that SL327 abolished the high levels of preproenkephalin and preprodynorphin mRNA induced by amphetamine in the striatum with no alteration of their basal levels. In another set of experiments, the hyperlocomotor activity induced by amphetamine was reduced by pretreatment with intra-striatal infusion of U0126. U0126 also blocked the amphetamine-induced increases in phospho-extracellular-regulated kinase and preproenkephalin and preprodynorphin gene expression in the striatum. These data indicate that activation of the extracellular-regulated kinase cascade contributes to the behavioral effects and changes in striatal neuropeptide gene expression induced by acute amphetamine.

Topics: Aminoacetonitrile; Amphetamine; Amphetamine-Related Disorders; Animals; Butadienes; Corpus Striatum; Disease Models, Animal; Dynorphins; Enkephalins; Enzyme Inhibitors; Extracellular Signal-Regulated MAP Kinases; Gene Expression Regulation; Male; MAP Kinase Signaling System; Motor Activity; Neuropeptides; Nitriles; Phosphorylation; Protein Precursors; Rats; Rats, Sprague-Dawley; RNA, Messenger; Up-Regulation

Previous studies have indicated that genetic factors substantially affect development of substance use disorders, including methamphetamine dependence. Prodynorphin (PDYN) is an opioid peptide precursor that yields dynorphins, endogenous kappa opioid-receptor agonists that play important roles in substance abuse. A physiologically active polymorphism of 1-4 repeats of a 68-bp element in the promoter region of the PDYN gene has been identified. We analyzed this polymorphism of the PDYN gene by a case-control association study in 143 patients with methamphetamine dependence and 209 healthy controls in the Japanese population. A 3- or 4-repeat allele in the PDYN gene promoter was found significantly more frequently in patients with methamphetamine dependence than in controls (chi(2)=9.45, p=0.0021). A 3- or 4-repeat allele in the PDYN gene promoter, which was shown to produce significantly higher transcription activity of the PDYN gene than a 1- or 2-repeat allele, is a genetic risk factor for development of methamphetamine dependence (odds ratio: 1.83, 95% CI=1.24-2.68).

Topics: Adult; Amphetamine-Related Disorders; Confidence Intervals; Enkephalins; Female; Gene Frequency; Genetic Predisposition to Disease; Genotype; Humans; Male; Middle Aged; Odds Ratio; Polymorphism, Genetic; Promoter Regions, Genetic; Protein Precursors; Repetitive Sequences, Nucleic Acid; Risk Factors

The present study examined the prodynorphin and kappa opioid receptor mRNA expression levels in the anterior cingulate and dorsolateral prefrontal cortices of subjects diagnosed with schizophrenia, bipolar disorder, or major depression as compared with normal controls without a psychiatric diagnosis. Multivariate analyses failed to reveal any differences in the mRNA expression levels between the four diagnostic groups, though a group trend (non-significant) was evident for the expression of the kappa opioid receptor and prodynorphin mRNAs in the prefrontal cortex. The mRNA expression levels were not associated with lifetime history of antipsychotic treatment or with suicide as a cause of death. The results, however, suggested an influence of certain drugs of abuse on the prodynorphin cortical mRNA expression. Prodynorphin mRNA expression levels were found to be elevated in individuals with a history of marihuana or stimulant use, but not alcohol. Overall, our data do not provide strong evidence for impaired prodynorphin or kappa opioid receptor mRNA levels in the dorsolateral prefrontal or cingulate cortices of schizophrenic, bipolar disorder, or major depressed subjects.

Topics: Adult; Age Factors; Amphetamine-Related Disorders; Bipolar Disorder; Depressive Disorder, Major; Enkephalins; Female; Functional Laterality; Humans; In Situ Hybridization; Male; Marijuana Abuse; Middle Aged; Protein Precursors; Receptors, Opioid, kappa; RNA, Messenger; Schizophrenia; Sex Factors; Suicide