Drug Dependence

Drug dependence is a condition in which an individual feels compelled to repeatedly administer a psychoactive drug. When this is done to avoid physical discomfort or withdrawal, it is known as physical dependence; when it has a psychological aspect (the need for stimulation or pleasure, or to escape reality), then it is known as psychological dependence. Repeated drug use is a learned behavior that is reinforced, both by the pleasurable effects of the drug and by the negative effects of drug abstinence (withdrawal). These effects are the basis of drug craving in drug-dependent individuals. Psychological dependence is caused by the positive reinforcement of drug use that results from the activation of neurons located in the nucleus accumbens. Physical dependence is a state in which continued drug use is required to prevent an unpleasant withdrawal syndrome. Hence, physical dependence leads to negative reinforcement of drug use. Both psychological and physical dependence appear to result from neuronal adaptation to the presence of the drug, albeit in different areas of the brain.

Psychological Dependence

The craving for alcohol, barbiturates, caffeine, cocaine, opioids, and tobacco is remarkably similar, despite the varied behavioral and physiologic effects that these drugs produce. This similarity supports the hypothesis that psychological dependence is mediated by a common neuronal pathway that leads to behavioral reinforcement of drug use. Psychoactive drugs that evoke behavioral reinforcement of their use appear to sensitize dopaminergic neurons that project from the ventral tegmental area to the nucleus accumbens. Other psychoactive drugs that are used for their mind-altering effects, including lysergic acid diethylamide (LSD), have a much smaller effect on the dopamine pathway and cause little reinforcement, resulting in less compulsive use of LSD and other such agents.

Much evidence indicates that dopamine mediates drug reinforcement by binding to dopamine D₁ receptors in the nucleus accumbens. This signal transduction pathway activates adenylyl cyclase, increasing cyclic adenosine monophosphate (cAMP) levels and activating cAMP-dependent kinases. The kinases, in turn, activate other proteins in the signal transduction pathway, including transcription factors. In the accumbens, the transcription factor, cAMP-response element binding protein, increases the synthesis of G proteins, cAMP-dependent protein kinases, and other cell transduction molecules that amplify responses to dopamine. Dopamine release onto accumbens neurons also increases the expression of glutamate receptors, which strengthens synaptic pathways for dopamine neurotransmission in a manner much like the molecular mechanisms of learning discovered in the hippocampus. These mechanisms lead to sensitization to dopamine, which underlies the behavioral reinforcement of drug use.

The peak of dopamine release in the nucleus accumbens occurs at the time of the drug’s peak effect on the central nervous system (CNS). The degree of short-term reinforcement of drug use is linked to the rate of increase of dopamine levels in the nucleus accumbens. This relationship appears to account for the propensity of some drugs to produce drug dependence. It also appears to explain the difference in reinforcement effects produced by different routes of administration of a particular drug. For example, the oral administration of an opioid or cocaine causes less reinforcement and psychological dependence than does the intravenous administration or inhalation of an equivalent dose of the same drug. The differences in effect are determined by the rate at which the drug is distributed to the brain and the rate at which dopamine levels in the nucleus accumbens are increased. Figure 25-1 illustrates the neuroanatomy and mechanisms of reinforcement for drugs of abuse.

Drug Addiction

Drug addiction usually refers to an extreme pattern of drug abuse in which an individual is continuously preoccupied with drug procurement and use and thus neglects other responsibilities and personal relationships. Addiction is usually associated with a high level of drug dependence. The term addict has a pejorative connotation, however, and the modern treatment of substance abuse as a disease state calls for use of the term drug-dependent individuals or patients. Such patients are said to have a substance abuse disorder, as outlined in the Diagnostic and Statistical Manual of Mental Disorders, used by psychiatrists.

Classification of Drugs of Abuse

The psychoactive drugs that are used by some individuals for nonmedicinal purposes can be classified as CNS depressants, CNS stimulants, and miscellaneous agents, with the latter group including marijuana, hallucinogens, and phencyclidine (PCP). In many cases, individuals with a substance-abuse disorder are using legal or illegal substances as self-medication for comorbid disorders such as anxiety or depression. After describing the pharmacologic effects of these drugs and any clinical use that they may have, this chapter discusses the treatment of substance abuse. Tables 25-1, 25-2, and 25-3 provide information about the manifestations and treatment of drug intoxication and withdrawal.

Pharmacokinetics

Ethanol has sufficient lipid solubility to enable rapid and almost complete absorption from the gut. It is more rapidly absorbed from the duodenum than from the stomach, and food slows its absorption by slowing the rate of gastric emptying. Ethanol is widely distributed throughout the body and has a volume of distribution that is roughly equivalent to the total body water, or about 38 L/70 kg of body weight.

As shown in Figure 25-2, ethanol is primarily oxidized by alcohol dehydrogenase to form acetaldehyde and is then oxidized by acetaldehyde dehydrogenase to form acetate. The acetate derived from ethanol enters the citric acid cycle for further oxidation to carbon dioxide and water. The oxidation of ethanol uses significant quantities of nicotinamide adenine dinucleotide (NAD), and the depletion of NAD is responsible for some of the metabolic effects of ethanol that are described later. Ethanol at higher or chronic doses also undergoes oxidation by cytochrome P450 enzymes, namely the CYP2E1 isozyme. Unlike alcohol dehydrogenase metabolism, CYP2E1 metabolism is induced by long-term alcohol use, contributing to alcohol tolerance in heavy drinkers.

About 2% of ethanol is excreted unchanged by the kidneys and lungs. The concentration of ethanol in alveolar air is about 0.05% of that in the blood, and this relationship is used to estimate the blood alcohol concentration (BAC) in exhaled air when the breathalyzer test is administered. Because ethanol can markedly impair the psychomotor skills required to safely drive a vehicle, nearly all nations prohibit the operation of motor vehicles while under the influence of alcohol. As of July 2004, the legal limit of blood alcohol is a BAC less than 0.08% (80 mg/dL) in all states and federal territories of the United States.

The capacity of alcohol dehydrogenase to metabolize ethanol is limited because the enzyme is saturated at relatively low ethanol concentrations. Hence, ethanol metabolism exhibits zero-order kinetics, except when serum concentrations of ethanol are very low. For this reason, the BAC is largely determined by the rate of ethanol ingestion. An adult weighing 70 kg usually metabolizes only about 10 mL of absolute ethanol per hour, which is roughly equivalent to the amount of ethanol contained in one alcoholic drink. A BAC of 0.08% to 0.10% in most cases is reached after consuming two to four standard drinks in an hour. A standard drink is a 12-ounce serving of beer, a 5-ounce glass of wine, or 1.5-ounces (shot) of 80 proof distilled spirits.