Over the last several decades, research on substances of abuse has vastly improved our understanding of human behavior and physiology and the nature of substance abuse and dependence. Basic neurobiological research has enhanced our understanding of the biological and genetic causes of addiction.

These discoveries have helped establish addiction as a biological brain disease that is chronic and relapsing in nature (Leshner, 1997). By mapping the neural pathways of pleasure and pain through the human brain, investigators are beginning to understand how abused psychoactive substances, including stimulants, interact with various cells and chemicals in the brain.

This new information has also improved our understanding of appropriate treatment approaches for different substance use disorders. This chapter describes the effects that cocaine and methamphetamine (MA) use have on the user's brain and behavior, which in turn leads to the stimulant users' unique needs. Knowledge of these effects provides the foundation for stimulant-specific treatment approaches. This knowledge will give treatment providers greater insight into stimulant users and why certain treatment approaches are more effective.

Stimulant Abuse And the Brain

According to National Institute on Drug Abuse Director Alan I. Leshner, Ph.D., the fundamental problem in dealing with any substance of abuse is to understand "the target" (i.e., the user). Therefore, to understand why people take drugs such as cocaine and MA and why some people become addicted, we must first understand what these drugs are doing to their target; that is, how stimulants affect the user.

Discussions of substance abuse and dependence often involve some discussion of the root causes--the societal and risk factors that lead to these conditions. To date, investigators have identified as many as 72 risk factors for substance use and dependence (Leshner, 1998). Among them are poverty, racism, social dysfunction, weak families, poor education, poor upbringing, and substance-abusing peer groups.

These risk factors--as well as other environmental and genetic factors--only influence an individual's initial decision to use substances of abuse. But after initial use, an individual continues to use a substance because she likes its effects: Use modifies mood, perception, and emotional state. All of these effects are modulated through the brain; in order to understand this phenomenon, it is important to understand some basic neuroscience.

For substances of abuse to exert their effects, they must first get to the brain. The four most common routes of administering psychoactive (mood-changing) substances are (1) oral consumption (i.e., swallowing), (2) intranasal consumption (i.e., snorting), (3) inhalation into the lungs (generally by smoking), and (4) intravenously via hypodermic syringe.

A swallowed substance goes to the stomach and on to the intestinal tract. Some substances easily pass through the digestive tract into the bloodstream. Other substances are broken down into their chemical components (i.e., metabolized) in the digestive system, thereby destroying the substance.

Substances that are inhaled into the lungs adhere to the lining of the nasal passages (the nasal mucosa) through which they enter directly into the bloodstream. Inhaled substances are usually first changed into a gaseous form by igniting (e.g., marijuana) or volatilizing by intense heat (e.g., crack cocaine, the ice form of MA). The lungs offer a large surface area through which the gaseous form may quickly pass directly into the bloodstream.

Injected substances obviously enter the bloodstream directly, although at a somewhat regulated rate. In these last three routes of administration, substances enter the bloodstream in their unmetabolized form.

Once a substance enters the bloodstream, it is transported throughout the body to various organs and organ systems, including the brain. Substances that enter the liver may be metabolized there. Substances that enter the kidney may be excreted. If a female substance user is pregnant, and the substance is able to cross the placenta, then the substance will enter the fetus' bloodstream. Nursing babies may ingest some substances from breast milk.

To enter the brain, a substance's molecules must first get through its chemical protection system, which consists mainly of the blood-brain barrier. Tight cell-wall junctions and a layer of cells around the blood vessels keep large or electrically charged molecules from entering the brain. However, small neutral molecules like those of cocaine and MA easily pass through the blood-brain barrier and enter the brain. Once inside the brain, substances of abuse begin to exert their psychoactive effects.

Fundamentals of the Nervous System

The human nervous system is an elaborately wired communication system, and the brain is the control center. The brain processes sensory information from throughout the body, guides muscle movement and locomotion, regulates a multitude of bodily functions, forms thoughts and feelings, modulates perception and moods, and essentially controls all behavior.

The brain is organized into lobes, which are responsible for specialized functions like cognitive and sensory processes and motor coordination. These lobes are made up of far more complex units called circuits, which involve direct connections among the billions of specialized cells that the various substances of abuse may affect.

The fundamental functional unit of the brain's circuits is a specialized cell called a neuron, which conveys information both electrically and chemically. The function of the neuron is to transmit information: It receives signals from other neurons, integrates and interprets these signals, and in turn, transmits signals on to other, adjacent neurons (Charness, 1990).

A typical neuron (see Figure 2-1) consists of a main cell body (which contains the nucleus and all of the cell's genetic information), a large number of offshoots called dendrites (typically 10,000 or more per neuron), and one long fiber known as the axon. At the end of the axon are additional offshoots that form the connections with other neurons.

Within neurons, the signals are carried in the form of electrical impulses. But when signals are sent from one neuron to another, they must cross the gap at the point of connection between the two communicating neurons. This gap is called a synapse. At the synapse, the electrical signal within the neuron is converted to a chemical signal and sent across the synapse to the target (i.e., receiving) neuron. The chemical signal is conveyed via messenger molecules called neurotransmitters that attach to special structures called receptors on the outer surface of the target neuron (Charness, 1990).

The attachment of the neurotransmitters to the receptors consequently triggers an electrical signal within the target neuron. Approximately 50 to 100 different neurotransmitters have been identified in the human body (Snyder, 1986).Figure 2-2 illustrates a typical synaptic connection and depicts the chemical communication mechanism.

Neurotransmitters may have different effects depending on what receptor they activate. Some increase a receiving neuron's responsiveness to an incoming signal--an excitatory effect--whereas others may diminish the responsiveness--an inhibitory effect. The responsiveness of individual neurons affects the functioning of the brain's circuits, as well as how the brain functions as a whole (how it integrates, interprets, and responds to information), which in turn affects the function of the body and the behavior of the individual.

The accurate functioning of all neurotransmitter systems is essential for normal brain activities (National Institute on Alcohol Abuse and Alcoholism [NIAAA], 1994; Hiller-Sturmhfel, 1995).

The Limbic Reward System

The brain circuit that is considered essential to the neurological reinforcement system is called the limbic reward system (also called the dopamine reward system or the brain reward system). This neural circuit spans between the ventral tegmental area (VTA) and the nucleus accumbens(see Figure 2-3). Every substance of abuse--alcohol, cocaine, MA, heroin, marijuana, nicotine--has some effect on the limbic reward system.

Substances of abuse also affect the nucleus accumbens by increasing the release of the neurotransmitter dopamine, which helps to regulate the feelings of pleasure (euphoria and satisfaction). Dopamine also plays an important role in the control of movement, cognition, motivation, and reward (Wise, 1982; Robbins et al., 1989; Di Chiara, 1995).

High levels of free dopamine in the brain generally enhance mood and increase body movement (i.e., motor activity), but too much dopamine may produce nervousness, irritability, aggressiveness, and paranoia that approximates schizophrenia, as well as the hallucinations and bizarre thoughts of schizophrenia. Too little dopamine in certain areas of the brain results in the tremors and paralysis of Parkinson's disease.

Natural activities such as eating, drinking, and sex activate the nucleus accumbens, inducing considerable communication among this structure's neurons. This internal communication leads to the release of dopamine. The released dopamine produces immediate, but ephemeral, feelings of pleasure and elation. As dopamine levels subside, so do the feelings of pleasure. But if the activity is repeated, then dopamine is again released, and more feelings of pleasure and euphoria are produced. The release of dopamine and the resulting pleasurable feelings positively reinforce such activities in both humans and animals and motivate the repetition of these activities.

Dopamine is believed to play an important role in the reinforcement of and motivation for repetitive actions (Di Chiara, 1997; Wise, 1982), and there is an increasing amount of scientific evidence suggesting that the limbic reward system and levels of free dopamine provide the common link in the abuse and addiction of all substances. Dopamine has even been labeled "the master molecule of addiction" (Nash, 1997).

When the nucleus accumbens is functioning normally, communication among its neurons occurs in a consistent and predictable manner. First, an electrical signal within a stimulated neuron reaches its point of connection (i.e., the synapse) with the target neuron.

The electrical signal in the presynaptic neuron triggers the release of dopamine into the synapse. The dopamine travels across the synaptic gap until it reaches the target neuron. It then binds to the postsynaptic neuron's dopamine-specific receptors, which in turn has an excitatory effect that generates an internal electrical signal within this neuron.

However, not all of the released dopamine binds to the target neuron's receptors. Extra dopamine may be chemically deactivated, or it may be quickly reabsorbed by the releasing neuron through a system called the dopamine reuptake transporter(see Figure 2-4).

As soon as the extra dopamine has been deactivated or reabsorbed, the two cells are "reset," with the releasing neuron prepared to send another chemical signal and the target neuron prepared to receive it. Substances of abuse, and especially stimulants, affect the normal functioning of the dopamine neurotransmitter system (Snyder, 1986; Cooper et al., 1991).

Neurological Reinforcement Systems

Psychologists have long recognized the importance of positive and negative reinforcement for learning and sustaining particular behaviors (Koob and LeMoal, 1997). Beginning in the late 1950s, scientists observed in animals that electrically stimulating certain areas of the brain led to changes in mental alertness and behavior.

Rats and other laboratory animals could be taught to self-stimulate pleasure circuits in the brain until exhaustion. If stimulants such as cocaine or amphetamine were administered, for example, sensitivity to pleasurable responses was so enhanced that the animals would choose electrical stimulation of the pleasure centers in their brains over eating or other normally rewarding activities.

The process just described in which a pleasure-inducing action becomes repetitive is called positive reinforcement. Conversely, abrupt discontinuation of the psychoactive substances following chronic use was found to result in discomfort and behaviors consistent with craving. The motivation to use a substance in order to avoid discomfort is called negative reinforcement. Positive reinforcement is believed to be controlled by various neurotransmitter systems, whereas negative reinforcement is believed to be the result of adaptations produced by chronic use within the same neurotransmitter systems.

Experimental evidence from both animal and human studies supports the theory that stimulants and other commonly abused substances imitate, facilitate, or block the neurotransmitters involved in brain reinforcement systems (NIAAA, 1994). In fact, researchers have posited a common neural basis for the powerful rewarding effects of abused substances (for a review, see Restak, 1988).

Natural reinforcers such as food, drink, and sex also activate reinforcement pathways in the brain, and it has been suggested that stimulants and other drugs act as chemical surrogates of the natural reinforcers. A key danger in this relationship, however, is that the pleasure produced by substances of abuse can be more powerfully rewarding than that produced by natural reinforcers (NIAAA, 1996).

Stimulants' Mechanisms of Action

On a short-term basis, stimulants exert their effects by disrupting or modifying the normal communication that occurs among brain neurons and brain circuits. Cocaine and MA have both been shown to specifically disrupt the dopamine neurotransmitter system. This disruption is accomplished by overstimulating the receptors on the postsynaptic neuron, either by increasing the amount of dopamine in the synapse through excessive presynaptic release or by inhibiting dopamine's pattern of reuptake or chemical breakdown (Cooper et al., 1991).

The use of cocaine and MA increases the amount of available dopamine in the brain, which leads to mood elevation (e.g., feelings of elation or euphoria) and increased motor activity. With cocaine, the effects are short-lived; with MA the duration of effect is much longer. As the stimulant level in the brain decreases, the dopamine levels subside to normal, and the pleasurable feelings dwindle away.

A growing body of scientific research based on animal research and brain imaging studies in humans suggests that the chronic use of stimulants affect dopaminergic neurons in limbic reward system structures (e.g., the VTA, nucleus accumbens).

These effects may underlie addiction to stimulants. Although the neurochemical pathways of stimulant addiction are not definitively established, a few researchers have found evidence of changes in the structure and function of brain neurons after chronic stimulant use in humans.

Some researchers propose that the changes may come from dopamine depletion, changes in neurotransmitter receptors or other structures, or changes in other brain messenger pathways that could cause the changes in mood, behavior, and cognitive function associated with chronic stimulant abuse (Self and Nestler, 1995).

Animal studies have demonstrated that high doses of stimulants can have permanent neurotoxic effects by damaging neuron cell-endings (e.g., Selden, 1991). The question of whether stimulants can produce similar effects in humans remains to be answered. Researchers hope that recently developed brain imaging techniques will help provide the answer.

At this time, there is only speculation that such permanent damage may underlie the long-term cognitive impairments seen in some chronic stimulant users. The continuing development and application of new technologies will help expand our knowledge of the neurological effects of stimulants in humans. (The medical aspects of stimulant use disorders are discussed in Chapter 5.)