The molecular biology of addictive drugs.
The additive drugs alcohol, morphine, cocaine, and amphetamine are each associated with the development of tolerance and physical dependence. Changes in gene expression occur in cell culture and in vivo with the administration of these centrally-acting drugs. This article reviews those experiments that have studied drug-induced alterations in gene transcription. Ethanol has diverse effects on the amounts of messenger RNA molecules within the central nervous system. Ion channels, neuropeptides, membrane receptors, and immediate early genes represent several regulated mRNAs. The effects are selective, however, as many other specific products are not altered. Evidence for a genetic predisposition to ethanol use reinforces the importance of the genotype. Opioids, cocaine, and amphetamine also affect gene transcription. Messenger RNAs studied have included many of those demonstrated to be altered by alcohol use. Interestingly, use of any of these drugs alters the expression of immediate early genes. These genes may represent an initial step in the pathway that leads to drug addiction. The composite of drug-induced changes in gene expression results in the cellular responses of tolerance and dependence. The characterization of these changes should provide a better understanding of the molecular mechanisms of drug addiction.
Mackler
S A
SA
Department of Pharmacology, University of Pennsylvania School of Medicine, Philadelphia 19104.
Eberwine
J H
JH
D000437:Alcoholism / Q000235:genetics / Q000378:metabolism; D000662:Amphetamines / Q000009:adverse effects* / Q000494:pharmacology; D000818:Animals; D016739:Behavior, Addictive / Q000235:genetics*; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D002478:Cells, Cultured; D003042:Cocaine / Q000009:adverse effects* / Q000494:pharmacology; D000431:Ethanol / Q000009:adverse effects* / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects*; D020022:Genetic Predisposition to Disease; D006801:Humans; D007473:Ion Channels / Q000187:drug effects; D051379:Mice; D009294:Narcotics / Q000009:adverse effects* / Q000494:pharmacology; D009419:Nerve Tissue Proteins / Q000096:biosynthesis / Q000235:genetics; D018377:Neurotransmitter Agents / Q000378:metabolism; D011519:Proto-Oncogenes / Q000187:drug effects; D012313:RNA / Q000096:biosynthesis; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects; D019966:Substance-Related Disorders / Q000235:genetics*
D000662:Amphetamines; D007473:Ion Channels; D009294:Narcotics; D009419:Nerve Tissue Proteins; D018377:Neurotransmitter Agents; D000431:Ethanol; D012313:RNA; D003042:Cocaine