ALTERATIONS OF CALMODULIN AND ITS MESSENGER-RNA IN RAT-BRAIN AFTER ACUTE AND CHRONIC ADMINISTRATION OF METHAMPHETAMINE

The effect of acute and chronic administration of methamphetamine (MET H) on the levels of calmodulin (CaM) and its mRNAs has been investigat ed in rat brain using antisense oligonucleotides to three distinct rat CaM genes (CaM I, CaM II, CaM III). CaM I mRNA was reduced in the str iatum and nucleus accumbens within 2 h of acute administration of 4 mg /kg METH, but returned to the control level by 6 h. The CaM content in both the cytosolic and membrane fractions of the striatum was reduced 0.5, 2, and 6 h after acute administration of METH. In the chronic ex periments, rats were treated with either 4 mg/kg METH or saline once d aily for 14 days. This was followed by a withdrawal period of 28 days, and thereafter, the animals were challenged with either METH (4 mg/kg , i.p.) or saline. All the animals were decapitated 6 h after this inj ection. There were four treatment groups: METH-METH (MM); METH-saline (MS); saline-METH (SM); and saline-saline (SS). There was a significan t decrease in the mRNA for CaM I and CaM II in the striatum, and CaM I I and CaM III in the nucleus accumbens in the MS group and the MS and MM groups, respectively, when compared to the SS group. The CaM conten t in the striatal membrane fraction decreased in both the SM and MS gr oups but not in the MM group. In contrast, the CaM content in the memb rane fraction of the mesolimbic area showed a significant increase in the MM group. The CaM content in the cytosolic fraction of these brain areas decreased in both the SM and MM groups. The total CaM decreased significantly in the SM and MM groups of the striatum, but increased significantly in the MM group of the mesolimbic area. The mRNA for CaM I and CaM III decreased significantly in the MM group, and in the SM and MM groups, in the substantia nigra pars compacta (SNC) and ventral tegmental area (VTA), respectively. The CaM content in both the cytos olic and membrane fractions and total CaM content of the SN/VTA decrea sed significantly in the SM, MS and MM group as compared with the SS g roup. In the medial prefrontal cortex and hippocampus the significant increase of CaM content in the membrane fraction of the MM group was a lso found, but neither the CaM content in the cytosol fraction nor tot al CaM content changed. These results suggest that chronic METH admini stration leads to a translocation of CaM from the cytosolic to membran e fractions; these may underlie METH-induced behavioral sensitization. (C) 1997 Elsevier Science B.V.