Subject(s)
Antidepressive Agents/therapeutic use , Depressive Disorder/drug therapy , Randomized Controlled Trials as Topic/statistics & numerical data , Age Factors , Aged , Bupropion/therapeutic use , Delayed-Action Preparations , Depressive Disorder/diagnosis , Drug Therapy, Combination , False Negative Reactions , Humans , Paroxetine/therapeutic use , Patient Selection , Psychiatric Status Rating Scales/statistics & numerical data , Recurrence , Research Design/standards , Treatment OutcomeABSTRACT
To assess whether calmodulin (CaM) could have a role in the behavioral sensitization induced by repeated intermittent amphetamine, CaM content was determined in several brain areas from rats repeatedly administered saline or amphetamine. Rats were treated with amphetamine using an escalating dose paradigm and withdrawn for either 4 weeks (withdrawn group) or 30 min (non-withdrawn group). CaM content was measured in cytosol and 100,000 x g membrane fractions from striatum, limbic forebrain, medial prefrontal cortex, hippocampus and cerebellum. In the withdrawn group, CaM was significantly increased in both striatal membranes and cytosol and in the mesolimbic membranes from amphetamine-treated rats. There were no changes in CaM in the medial prefrontal cortex, hippocampus or cerebellum. In the non-withdrawn group, there was no significant change in CaM in striatal or mesolimbic fractions but CaM was significantly decreased in cytosol of the medial prefrontal cortex and hippocampus as compared to saline controls. This decrease could be related to the tolerance that has developed to the amphetamine after the repeated treatments. In the withdrawn group, challenge with a low dose of amphetamine (1 mg/kg) elicited a translocation of CaM from membranes to cytosol in the striatum and limbic forebrain of rats repeatedly treated with amphetamine, but not in saline-treated rats. Our findings that the change in CaM occurs in striatum and limbic forebrain, requires time after treatment to develop and exhibits persistence after withdrawal correlate with known characteristics of behavioral sensitization to amphetamine. These results suggest that CaM could contribute to neurochemical events underlying behavioral sensitization to amphetamine.
Subject(s)
Amphetamine/pharmacology , Brain/metabolism , Calmodulin/metabolism , Animals , Brain/drug effects , Cell Membrane/metabolism , Cerebral Cortex/metabolism , Corpus Striatum/metabolism , Cytosol/metabolism , Dose-Response Relationship, Drug , Female , Hippocampus/metabolism , Limbic System/metabolism , Organ Specificity , Prosencephalon/metabolism , Rats , Rats, Inbred Strains , Reference ValuesABSTRACT
Incubation of tritium-labeled morphine and cold glutathione (GSH) or cold morphine and tritiated GSH with liver microsomal preparations obtained from phenobarbital-treated rats led to the identification by high performance liquid chromatography (HPLC) of a glutathionylmorphine adduct. Liquid secondary ion mass spectral analysis established the molecular weight of the metabolite to be 590 which corresponds to the mass of a mono-GSH-morphine adduct. High resolution (360 and 500 MHz) 1H-NMR experiments have led to the tentative assignment of the structure of this metabolite as 10-alpha-S-glutathionylmorphine. Based on both in vivo and in vitro data, the formation of this product appears to be mediated by cytochrome P-450 and to involve a reactive intermediate that may be responsible for the observed covalent binding of radiolabeled morphine to proteins and, at least in part, for the morphine-induced depletion of GSH in the rat.
