Behavioral Mechanisms

Substance use behavior, whether in therapeutic, socially accepted recreational forms or in excessive, socially unacceptable, physically hazardous forms, can be analyzed to determine factors important to the initiation and maintenance of substance abuse. Drug reinforcement is a major factor to be considered in substance-use behavior. Drugs are viewed as reinforcers when they promote and maintain drug-seeking and drug self-administration as a function of the effects the drug produces, which can include the drug’s pharmacologic and nonpharmacologic effects. Two mechanisms of drug reinforcement are hypothesized. In the first hypothesis, the drug produces an inferred mood-elevating or euphorogenic effect and thus acts as a positive reinforcer. In the second, the drug acts as a negative reinforcer by reversing an inferred aversive state, such as a withdrawal syndrome or excessive sleepiness or fatigue. The two processes, positive and negative drug reinforcement, are not necessarily mutually exclusive and can operate concurrently or at the different stages in a drug-abuse cycle (initiation, maintenance, or relapse). These two reinforcement processes lead to the initiation and maintenance of excessive and hazardous drug use.

The state-altering consequences in negative and positive reinforcement can be relevant to the treatment of sleep disorders. The alerting effects of stimulants, for instance, are reinforcing for persons who are sleepy, fatigued, and having difficulty functioning at their desired level. Healthy normal subjects self-administer a stimulant when they are sleepy but not when alert.¹ That self-administration does not imply dependence or abuse. However, in substance abuse, sleepiness may be present as part of a withdrawal syndrome due to abstinence following chronic use of a stimulant. It has been hypothesized that continued substance use, difficulty reducing use, or relapse might reflect self-medication to reverse excessive sleepiness caused by abstinence. For example, in amphetamine or cocaine abuse, excessive sleepiness during initial drug abstinence has been consistently reported, and use of the stimulants reverses the sleepiness. More commonly, in chronic caffeine or nicotine dependence, the 8-hour sleep period is functionally an enforced abstinence. The pharmacokinetics of these drugs and the enforced abstinence of the sleep period can result in enhanced sleepiness in the morning, and, in extreme cases, smoking during the night. Caffeine or nicotine taken immediately when arising reverses the sleepy state, which reinforces use of these stimulants. Clinicians can gauge the severity of a nicotine addiction by asking patients when they have their first morning cigarette.

During a period of chronic drug use, daytime sleepiness can also result from a drug-induced disturbance of nocturnal sleep. All the stimulants reviewed later disrupt nocturnal sleep, and the degree of disruption depends on dose and proximity of their use to the sleep period. Disrupted and fragmented sleep produces daytime sleepiness. Similar to the reinforcement cycle described earlier, a drug-induced sleep disturbance at night could lead to daytime sleepiness, which then enhances the likelihood of self-administration of the stimulant. This is a common vicious circle seen in heavy coffee drinkers.

Daytime sleepiness is not necessarily drug induced. Chronic insufficient sleep in healthy normal persons or disturbed sleep efficiency and circadian dysrhythmia seen in altered work schedules can also cause daytime sleepiness. Night workers and rotating-shift workers have shortened and disturbed sleep when sleeping during the day as well as increased sleepiness when awake at night. Rotating-shift workers and night workers report a disproportionate use of sedating drugs, especially alcohol, to improve sleep and stimulants, especially caffeine, to improve alertness.^2,3 Although healthy normal persons might self-administer a stimulant when experiencing sleepiness, this kind of substance use can increase risks of substance dependence and abuse.

Sedative-hypnotics, tetrahydrocannabinol (THC), and alcohol can become reinforcers and lead to substance dependence or abuse through their capacity to induce sleep in persons with insomnia or to reverse a waking hyperaroused state. In one study, persons who had insomnia but no history of alcoholism or drug abuse and healthy normal subjects were given an opportunity to choose between previously experienced color-coded ethanol and placebo beverages at night before sleep. The insomniac subjects chose ethanol, but healthy normal subjects with a similar level of self-reported social drinking chose placebo.⁴ Interestingly, insomniac subjects showed not only nighttime but also daytime self-administration of benzodiazepine-receptor agonists. However, only insomniac subjects who showed evidence of daytime physiologic hyperarousal self-administered benzodiazepines during the day.⁵ Whether these drug self-administration patterns reflect drug-seeking or therapy-seeking is considered later.

Neurobiological Mechanisms

The positive-reinforcement neurobiology of drug self-administration is generally accepted to involve mesocorticolimbic projections originating in the ventral tegmental area of the rostral reticular activation system and terminating in the nucleus accumbens. Most drugs of abuse interact in some way with this system. This dopamine system is part of a broader dopaminergic system that projects into several forebrain regions and as a whole is considered to have executive and integrative functions.⁶ The dopaminergic neurons of the ventral tegmental area are modulated by a number of other neurotransmitter systems. It is through this modulation that sleep–wake state and level of sleepiness or alertness during wake could have an impact on a drug’s reinforcing properties.

In chronic use, Koob hypothesized that the neurobiological systems involved in acute positive reinforcement adapt by establishing opponent processes.⁶ These opponent processes neutralize the acute reinforcing effects of the drug and during abstinence are left unopposed. Consequently, they produce the abstinence syndrome, an inverse state to the drug state, which becomes a basis of negative reinforcement (reversal of abstinence symptoms). For example, stimulant abstinence produces sleepiness, which in turn leads to self-administration of stimulant drugs. Koob hypothesized that the opponent processes do not necessarily develop through the same neurobiological system that produces positive reinforcement. Other neurobiological systems, and possibly sleep−wake systems, could be one basis of the opponent processes. Consistent with this model are two important sleep–wake findings: One is the REM sleep suppression and REM sleep rebound associated with administration and discontinuation of most of the drugs with an abuse liability. The other, the persisting disturbance of sleep that is found after weeks of abstinence, suggests that some type of neurobiological adaptation to the chronic drug exposure has occurred within sleep–wake systems.

Alcohol and Alcoholism

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