Among the numerous definitions for addiction, there lies yet another to define it from a biochemical perspective. Milkman (1983) defines it as " self-induced changes in neurotransmission that result in social problem behaviors." This definition encompasses the psychological, biochemical and social aspects of addictive processes. It is not limited to substance abuse and can be applied to any activity characterized by compulsion, loss of control and continuation of the substance despite harm. This has helped investigators gain a better understanding of the nature of addiction. It has been shown that individuals turn to drugs that elicit a mood or level of arousal consistent with their mode of dealing with stress. Those who deal with stress by confrontation choose drug stimulants. Those who withdrawal from stress choose opiate drugs. Others who deal with stress through activities related to imagery or fantasy turn to hallucinogens. These differences between behavior and drug preference are thought to be biochemically driven.

The basis for biochemical activity is neurotransmission, the mechanism by which signals or impulses are sent from one nerve cell to another. The more rapid the transmission through certain central nervous system (CNS) pathways, the more intense the feeling or state of arousal. Thus, the arousal-type person will seek activities or substances that will increase the rate of neurotransmission in the part of the brain responsible for that mood. Those individuals that indulge in thrill-seeking behavior, such as gambling or skydiving, will choose stimulants such as amphetamines. In contrast, those individuals who seek activities that decrease the rate of neurotransmission, such as meditation, overeating or watching excessive television, will choose depressants such as barbiturates.

Once a change in neurotransmission is brought about, whether from an activity or from a substance, the brain attempts to reestablish the rate of neurotransmission that was present before the activity or substance intake. Once the rate is reestablished, the individual becomes tolerant to the original level of the substance or activity. To achieve the desired state of arousal brought about by a change in the rate of neurotransmission the individual must increase the level of the activity. After this point, there is an altered response of the individual to the drug. Any removal of the activity or drug would then result in withdrawal symptoms. This would compensate for the altered brain chemistry and stress placed on the CNS that was established during the period of abuse.

To understand the relationship between neurotransmission and addiction, one needs to have an understanding of neurotransmission itself. The Central Nervous System (CNS) is composed of the brain and spinal cord. Nerve cells or neurons connect all aspects of the nervous system. The neuron is composed of a body, axon, and dendrites. The Dendrites receive and transmitthe nerve impulse, the body integrates the signal, and the axon propagates it. The body will make the decision as to whether or not to transmit the signal or inhibit the signal from continuing on to the next neuron. The CNS is malleable, rather than hard-wired, and must be able to rapidly adapt to varying signals.

Between nerve cells there are spaces called synaptic junctions. Small molecules known as neurotransmitters are released into the synaptic junction from the pre-synaptic terminal. After they are released, the neurotransmitters can be degraded by enzymes or be integrated into the post-synaptic membrane. Once the neurotransmitters are picked up by the post-synaptic neuron in sufficient quantities, the membrane will depolarize and the signal will be transmitted. Like a lock and key, only certain shapes and sizes of neurotransmitters will fit into the receptors of the post-synaptic neuron. In the post-synaptic terminal, there are receptors that, if bound to by neurotransmitters, will activate adenylate cyclase (figure 4.1). This enzyme converts adenosine triphosphate (ATP) into cyclic adenosine monophosphate (cAMP). cAMP has the effect of increasing membrane sensitivity and subsequent neurotransmission. The direction of the impulse is unipolar, and is always in the same direction.

There are several points at which the transmission of an electrical impulse can be disrupted. Within the pre-synaptic terminal, there are enzymes that will degrade the neurotransmitters before they are released into the synaptic junction. If degraded, these neurotransmitters will never reach the post- synaptic nerve terminal, and the impulse will cease to be transmitted. Degradation can also occur within the synaptic junction itself. Enzymes that remain in the junction can be present in over or under abundance. Hence, transmission can either be enhanced or subdued. Drugs that occupy the receptor but may or may not exhibit the same effect as the neurotransmitter can saturate receptors at the post-synaptic terminal. Lastly, the cAMP pathway can be interrupted which will result in delayed or diminished transmission of the impulse. Each of these points can be altered by exogenous drug administration.

Disruptions of the Neural Networks

Research has demonstrated that changes made to neural networks can result in abnormal and even addictive behavior. For example, in some parts of the CNS, post-synaptic receptors can be occupied by the neurotransmitter dopamine (DA). If the drug Haldol is administered, it will occupy the same receptors and not allow DA to bind. This blocking inhibits the overactive neurotransmission that is associated with schizophrenia and helps to eliminate large mood swings commonly seen amongst schizophrenia patients. Cocaine, on the other hand, prevents the degradation of the neurotransmitter in the synaptic junction. This will result in an overabundance of neurotransmitter in the junction available for binding to the post-synaptic membrane. Overly saturated receptors lead to over-active transmission of the electrical impulse and result in an increased stated of arousal.

Disruptions of the pre-synaptic terminal

Other areas where neurotransmission can be disrupted are located within the pre- synaptic terminal itself. Inside the terminal are monoamine oxidases (MOA), enzymes that degrade neurotransmitters such as dopamine and norepinephrine. In some individuals, there is too much MOA, which results in a lowered level of the neurotransmitter and a subsequent state of depression. Giving these patients MOA inhibitors will transiently resolve the depressive mood.

Disruption of the cAMP system

Disruption of the cAMP system operates in a different fashion and demonstrates the neurochemical mechanism for tolerance. In its homeostatic state, the brain attempts to counter the effects of activities that result in a change of neurotransmission. Thus, an initial increase in cAMP will be countered by a decrease in adenylate cyclase. As adenylate cyclase levels are down regulated, less cAMP is produced, neurotransmission is slowed, and a change in mood results. When this occurs, the desired state of arousal or mood can only be achieved by increased activity or substance ingestion. This phenomenon, known as tolerance, is an important component of addiction and will be discussed later. The cAMP system also achieves a link between biochemistry and withdrawal symptoms. Removal of the activity or drug results in a massive decreased production of cAMP that will lead to symptoms of withdrawal, including anxiety and lethargy.

The neurochemical mechanisms described above are important in the actions of amphetamines and other stimulating activities that increase the rates of neurotransmission and change the behavior of arousal-prone individuals. In contrast, substances or activities that decrease neurotransmission, such as barbiturates or meditation, bring about a release of endorphins or enkephalins. These naturally occurring substances act as the body's own opiates. Opiates or enkephalins attach themselves to the pre-synaptic terminal (figure 4.1) causing a decrease in the release of the neurotransmitter. This decrease in release of the neurotransmitter results in a slowing of neurotransmission that in turn results in the effect desired by satiation-prone individuals. The body counteracts these effects by increasing the level of adenylate cyclase, which will in turn increase the level of camp and the general level of neurotransmission. This will produce an undesirable feeling and the individual will have to increase the dose to achieve the desired effect. In time, the individual will exhibit tolerance and need to increase the satiating activity or substance to achieve the desired effect. Upon removal of the activity or substance, quantities of cAMP and the rate of neurotransmission will increase. This will result in a state of agitation for individuals withdrawing from opiate ingestion or satiation activities.

Although the mechanisms of action for stimulants and opiates are well understood, the effects of hallucinogens are not. There is some data, though, that does support a neurochemical mechanism for the behavior resulting from the use of hallucinogens. There is a very close relationship between the structure of the neurotransmitter seratonin and various hallucinogenic compounds such as LSD, psilocin and DMT. Although not fully understood, it also appears as though tolerance and withdrawal can result from abuse and addiction of these substances. For those exogenous drugs that have structural similarities to endogenous neurotransmitters, some neurochemical mechanism of action is likely to underlie the change in behavior noted with the use of the substance.

The consequences of drug addiction, tolerance and physical dependence, have been studied extensively at the molecular and cellular levels. Tolerance occurs as a result of prolonged exposure to a drug. Physical dependence is a physiologic and biochemical adjustment to the presence of an addicting drug.

There are two kinds of tolerance: metabolic and cellular. Metabolic tolerance reflects an individual's increased ability to metabolize the drug so that the drug concentration in contact with the sites of action is reduced. Cellular tolerance represents decreased sensitivity to a given drug concentration. It is an example of biochemical regulation at the cellular level to maintain homeostasis. Cellular tolerance can be selective, that is, tolerant to only one specific drug, or can manifest cross-tolerance to unrelated drug families. A suggested mechanism for cross-tolerance is receptor desensitization that can be homologous (limited to one receptor) or heterologous (involving several receptors that converge onto a single pathway).

Physical dependence is both a physiologic and a biochemical adaptation to an addicting drug that allows the addicted individual to appear seemingly normal while under a drug concentration that produces the desired effect. By definition, physical dependence is accompanied by some degree of tolerance. The "withdrawal syndrome" is often characterized biologically by effects that are opposite to the acute pharmacological actions of the drug itself. Removal of the drug will unmask an underlying pathophysiology that is noted by odd behavior. Reestablishing an effective drug concentration relieves these abnormalities.

Like tolerance, physical dependence is a consequence, not a precursor, of drug addiction. It can, however, play a role in continuing drug use after the initial use. Even after the first drug dose, a small degree of physical dependence is established. A withdrawal syndrome, no matter how mild, will follow as the initial dose wears off. Once physical dependence is established and the withdrawal syndrome ensues, drug-seeking behavior follows predictably.