Neurochemistry of Abused Drugs PDF

Preface

The first reports of neurological disease complicating drug abuse were published almost as soon as purified cocaine and morphine became abundant and cheap in the late 1800s. Today, neurological complaints are among the most common manifestations of drug abuse. At the molecular level, experimental studies have provided some surprising insights into the effects of drug abuse on the brain and plausible explanations for some types of drug toxicity. For example, evidence is emerging that nitric oxide formation plays an important role in cocaine neurotoxicity. Mice sensitized to cocaine administration initially tolerated doses of cocaine that became lethal after less than a week, but pretreatment with agents that inhibit nitric oxide synthetase completely abolished the sensitization process, and all test animals survived. Whether similar changes occur in humans remains to be determined.

All abused drugs, not just cocaine, activate immediate-early gene expression in the striatum, although different drugs induce somewhat different changes. Most activate immediate-early gene expression in several regions of the forebrain, including portions of the extended amygdala, lateral septum, midline/intralaminar thalamic nuclei, and even the cerebral cortex. These changes are especially striking in the case of cocaine. Postmortem studies have shown that, in humans, the numbers of both D1 and D2 dopamine receptors are altered by cocaine use, even with relatively low doses of cocaine. Strong evidence suggests that alterations in dopamine transmitters and receptors play a key role in the process of cocaine addiction and toxicity, but clearly much more is involved.

It has always been a puzzling question that the neurotoxic changes produced by some amphetamines share a strong resemblance with those seen in some degenerative disorders. The answer is no longer quite so puzzling. They share a number of common targets, including the ubiquitin–proteasome system, and both the ubiquitin–proteasome pathway and beta–arrestin are molecular targets of neurotoxicity. This knowledge may very well result in treatments for both.

Even though the mu receptor was first cloned nearly two decades ago, opiate addiction remains a major public health concern. However, the molecular mechanisms of opiate addiction are slowly becoming understood. Many of the changes that occur in neurons exposed to morphine have been known for some time, but not that much is known about the changes in gene expression that underlie these effects. With the advent of microarray analysis and quantitative (real time) PCR, it is now possible to examine the gene expression changes that occur during morphine withdrawal. The possibility of safely and effectively treating addicts (and relieving pain) is a tempting target and will, no doubt, occur in the near future.

The chapters of this book describe the Pandora's box of addictions that now face our society — cocaine, tobacco, methamphetamine, and MDMA. More importantly, they describe what is know at this moment about the neurochemical substrates underlying these disorders. Progress in molecular biology will be stunted until scientists understand the clinical presentations of the diseases they are trying to characterize. Clinicians stand little chance of curing addiction until they understand the underlying neurochemistry. One might say that this volume contains something for everybody.