Cellular and Molecular Mechanisms of Drug Dependence: An Overview and Update

Article excerpt

Byline: Swapnil. Gupta, Parmananda. Kulhara

Drug dependence is a major cause of morbidity and loss of productivity. Various theories ranging from economic to psychological have been invoked in an attempt to explain this condition. With the advent of research at the cellular and subcellular levels, perspectives on the etiology of drug dependence have also changed. Perhaps the greatest advance has been in the identification of specific receptors for each of the drugs, their target neurotransmitter systems and the intracellular changes produced by them. These receptors also provide potential targets for treatment strategies of drug dependence. This overview attempts to present the mechanisms in the development of dependence and the newer treatment strategies for the major drugs of abuse like alcohol, opioids, cannabis, nicotine and cocaine.

Human addictions are chronically relapsing disorders characterized by compulsive drug use, an inability to limit the intake of drugs and the emergence of a withdrawal syndrome during cessation of drug use. Dependence has been defined as a cluster of behavioral, cognitive and physiological phenomena that develop after repeated substance use. It typically includes a strong desire to take the drug, difficulties in controlling its use, persisting in its use despite harmful consequences, a higher priority given to drug use than to other activities and obligations, increased tolerance and sometimes a physical withdrawal state (International Classification of Diseases (ICD)-10).

Cellular biology is defined as the study of the physiology and biochemistry of intracellular processes. Molecular biology is the branch of biology that seeks to explain all biological processes in terms of genes and genetic changes. With the advent of neuroscience as an indispensable branch of biomedical research, there has been explosive growth in the biological understanding of the process of addiction at the cellular and molecular levels. In this update, we have described recent research findings so as to increase awareness regarding these aspects of drug dependence syndromes.

Neurobiology of Addiction

Drug addiction has been conceptualized as a complex and chronic disease process occurring in the brain, which is modulated by genetic, developmental and environmental factors. The most consistent and reproducible finding in drug addiction is that abused substances activate the mesolimbic dopamine system, which reinforces both pharmacological and natural rewards. The mesolimbic system consists of dopaminergic neurons in the ventral tegmental area (VTA) and their axonal projections to terminal fields in the nucleus accumbens (NAc) and the prefrontal cortex.

Opioids, alcohol, nicotine, cannabinoids and psychostimulants all act on this system to increase synaptic levels of dopamine (DA). All these substances have specific receptors in the brain and the increase in dopamine levels in the mesolimbic system is the final effect that they produce. Receptor-mediated activity is the principal mechanism by which any chemical messenger acts. Chemical messengers are regulatory macromolecules, usually proteins. Receptors have two major functions of recognition and transduction. Correspondingly, each receptor has two domains, i.e., a ligand-binding and an effector domain. The ligand-binding domain has a hydrophilic and a lipophilic region and is usually heteropolymeric. The binding of the ligand causes a change in the quaternary structure of the receptor.

Receptors have various effector mechanisms, which are broadly of four types:

*G protein-coupled receptors (Gs, Gi, Gq and G13) *Receptors with intrinsic ion channels *Enzymatic receptors *Receptors regulating gene expression

One of the most dramatic advances in drug abuse research has been the identification of the target of every major drug of abuse. This advance occurred with the advent of radioligand-binding techniques, the biochemical characterization of drug binding sites and ultimately, with the application of molecular biology to clone and isolate these structures. …