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Disruptions that decrease neurotransmission
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 () 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.
Hallucinogens
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.
Tolerance and Physical Dependence
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.
Tolerance
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
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.
