Methamphetamine decreases calcium-calmodulin dependent protein kinase II activity in discrete rat brain regions.
A Ca(2+)/calmodulin-dependent signaling cascade has been implicated in the regulation of dopaminergic neurotransmission after chronic administration of amphetamine and methamphetamine (METH). We found a decrease in Ca(2+)/calmodulin-dependent protein kinase II (CaM-kinase II) activity in five regions of the rat brain (parietal cortex; frontal cortex; hippocampus; striatum; and nucleus accumbens) after a single injection of METH. Pretreatment with the selective dopamine D1 receptor antagonist SCH 23390 prevented the acute METH-induced decrease in CaM-kinase II activity in the parietal cortex, striatum, nucleus accumbens, and substantia nigra/ventral tegmental area (SN/VTA). Pretreatment with the N-methyl-D-aspartate receptor antagonist MK-801 significantly restored the acute METH-induced decrease in CaM-kinase II activity in the parietal cortex, nucleus accumbens, and SN/VTA. Striatal CaM-kinase II activity was still significantly lower than that of the chronic saline-treated controls after a 1-week, but not a 4-week, abstinence from chronic administration of METH. A METH challenge after a 4-week abstinence period induced a more pronounced decrease in CaM-kinase II activity in rats chronically injected with METH than in rats chronically injected with saline. Western blot analysis revealed that the amount of CaM-kinase II protein was not altered after a single METH injection or after chronic METH injections, compared with saline-treated controls. However, amounts of phosphorylated (Thr(286)) CaM-kinase II in the parietal cortex, striatum and SN/VTA were significantly decreased at 3 h after an acute METH injection compared with saline-treated controls. These results suggest that dephosphorylation of CaM-kinase II may contribute to the decreased enzyme activities induced by acute METH administration, and that chronic treatment with METH leads to an enhanced capacity of METH to decrease CaM-kinase II activity after an extended withdrawal period.
Suemaru
J
J
Department of Neuropsychiatry, Okayama University Medical School, 2-5-1 Shikata-cho, Okayama 700-8558, Japan.
Akiyama
K
K
Tanabe
Y
Y
Kuroda
S
S
D000818:Animals; D001552:Benzazepines / Q000494:pharmacology; D015153:Blotting, Western; D001921:Brain / Q000201:enzymology*; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism*; D000697:Central Nervous System Stimulants / Q000494:pharmacology*; D016291:Dizocilpine Maleate / Q000494:pharmacology; D018492:Dopamine Antagonists / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D008297:Male; D008694:Methamphetamine / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors
D001552:Benzazepines; D000697:Central Nervous System Stimulants; D018492:Dopamine Antagonists; D018691:Excitatory Amino Acid Antagonists; D008694:Methamphetamine; D016291:Dizocilpine Maleate; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases