Pharmacological basis for management of drug dependence.
Neurochemical mechanisms underlying development of drug dependence and withdrawal syndrome remain unclear. Several clinical features of withdrawal syndrome, such as anxiety, are considered to be common among patients with drug dependence induced by different drugs of abuse. In the present study, we investigated whether diazepam-binding inhibitor (DBI), an endogenous anxiogenic neuropeptide, participates in the anxiety associated with drug dependence and its withdrawal symptoms. When we examined brain from mice dependent on alcohol, nicotine, and morphine, we observed that the levels of DBI protein and its mRNA significantly increased. Abrupt cessation of these drugs facilitated further increases in DBI expression. In the cases of nicotine- and morphine-dependent mice, concomitant administration of specific antagonists for nicotinic acetylcholine and m-opioid receptors, respectively, abolished the increased 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 KCl (30 mM)-induced 45Ca2+ influx and enhanced expression of alpha1 subunits for L-type high voltage-gated Ca2+ channels (HVCCs). In addition, the increase in DBI expression was completely blocked by L-type HVCC inhibitors. Therefore, these alterations in DBI expression, mediated via increased influx of Ca2+ through upregulated L-type HVCCs, are closely related to drug dependence and/or its withdrawal syndrome and are considered to be part of a common biochemical process in drug dependence induced by different drugs of abuse.
Katsura
Masashi
M
Department of Pharmacology, Kawasaki Medical School, Kurashiki, Japan.
Ohkuma
Seitaro
S
D000818:Animals; D020746:Calcium Channels, L-Type / Q000378:metabolism; D026261:Diazepam Binding Inhibitor / Q000378:metabolism; D019468:Disease Management; D006801:Humans; D013287:Illicit Drugs / Q000378:metabolism*; D019966:Substance-Related Disorders / Q000378:metabolism*
D020746:Calcium Channels, L-Type; D026261:Diazepam Binding Inhibitor; D013287:Illicit Drugs