Functional alteration in high voltage-gated calcium channels in drug dependence and elucidation of its mechanisms.

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Neuropharmacological mechanisms underlying development of drug dependence and withdrawal syndrome remain unclear at present. Several clinical features of withdrawal syndrome are considered to be common(i.e. anxiety) among patients with drug dependence induced by different drugs of abuse. In the present study, we have investigated functional alterations in diazepam binding inhibitor(DBI), an endogenous anxiogenic neuropeptide, in drug dependence and its withdrawal symptom. The levels of DBI protein and its mRNA significantly increased in the brains from mice dependent on alcohol, nicotine and morphine, and abrupt cessation of these drugs facilitated further increase in DBI expression. Similar patterns of DBI expression were observed in the neurons after sustained exposure to these drugs and its removal from culture medium. Sustained exposure of the neurons to abused drugs significantly increased the KC1(30mM)-induced[^<45>Ca^<2+>]influx and enhanced expression of α1 and α2/δ1 subunits for L-type high voltage-gated Ca^<2+> channels(HVCCs). In addition, the increase in DBI expression by drugs of abuse was completely blocked by L-type HVCC inhibitors. However, the increases in expression of L-type HVCCs after sustained exposures to drugs of abuse were not abolished by inhibitors for protein kinase A,C and CaM kinase II, respectiverly. These data indicate that up-regulation of L-type HVCCs, which causes increase in DBI expression, is considered to be a common biochemical process in drug dependence induced by different drugs of abuse.