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Simple, rapid and inexpensive rodent models of nicotine physical dependence and withdrawal syndrome have proved useful for preliminary screening of smoking cessation treatments. They have led to an exponential increase of knowledge regarding the underlying neurobiological mechanisms of dependence and withdrawal syndrome. The human nicotine withdrawal syndrome in smoking cessation is variable and multidimensional, involving irritability, anxiety, depression, cognitive and attentional impairments, weight gain, sleep disturbances, and craving for nicotine. Aside from sleep disturbances, analogous phenomena have been seen in rodent models using different measures of withdrawal intensity. It appears likely that different withdrawal phenomena may involve some partially divergent mechanisms. For example, depression-like phenomena may involve alterations in mechanisms such as the mesolimbic dopamine pathway from the ventral tegmental area to the nucleus accumbens. Irritability and anxiety may involve alterations in endogenous opioid systems and other regions, such as the amygdala. This chapter reviews many additional anatomical, neurochemical, and developmental elements that impact nicotine physical dependence.

Caffeine is an excellent model compound for understanding drugs of abuse/dependence (HOLTZMAN 1990). Historically, caffeine use dates back hundreds, possibly thousands, of years (GRAHAM 1984). Caffeine use spread worldwide from its initially constrained geographical origins, despite recurring efforts to restrict or eliminate its use motivated on moral, economic, political, religious or medical grounds (AUSTIN 1979). Currently, caffeine use is almost universal, with more than 80% of adults in North America regularly consuming behaviorally active doses of caffeine (GILBERT 1976; GRAHAM 1978; HUGHES et al. 1993b). The broad generality of caffeine self-administration is reflected in the facts that, worldwide, caffeine consumption occurs in markedly different vehicles (e.g., drinking of coffee, tea, mate, soft drinks; chewing of kola nuts; consumption of cocoa and guarana products) and in widely different, but culturally well-integrated, social contexts (e.g., the coffee break in the United States; tea time in the United Kingdom; kola nut chewing in Nigeria). The dependence-producing nature of caffeine is reflected in the experience of most people who know someone who has expressed a “need” for a cup of coffee or who claimed to be “addicted” to coffee or their morning caffeinated beverage of choice. Consistent with this anecdotal experience, a recent random–digit telephone survey found that about 17% of current caffeine users met the DSM-III-Rpsychiatric criteria for being moderately or severely drug dependent on caffeine (HUGHES et al. 1993b).

The term “addiction” is generally taken to refer to dependent patterns of drug self-administration. Two commonly accepted categories of drug dependence are physical and psychological dependence. Physical dependence refers to a state in which the body has adjusted to the presence of the drug such that when the drug is withdrawn, there are physical symptoms of withdrawal often involving discomfort and pain.1 Psychological dependence, in contrast, is characterized by preoccupation with the drug’s emotional and mental effects, and by persistent craving for these effects.1 These emotional and psychological effects are typically associated with states of positive affect and reflect the rewarding and incentive value of the drug. It is worth noting that psychological dependence may also involve withdrawal reactions to the extent that the drug’s psychological effects induce opposing psychological processes. For example, while a drug’s actions may be associated with euphoric psychological effects, termination of the drug’s actions may be associated with dysphoric effects or depressed mood. Thus, in addition to referring to the incentive value of the drug in question, psychological dependence may also involve negative mood states associated with drug withdrawal.1

Two well-known consequences of frequent and repeated administration of opioids are tolerance and physical dependence. Tolerance is demonstrable by a gradual loss of effectiveness of an agonist after repeated administration, and proportionately higher doses of the compound become necessary to elicit the same response. In the tolerant state, physical dependence also can usually be demonstrated, as evidenced by the need to continue administering the compound to avoid physical discomfort. Its discontinuance results in a constellation of signs and symptoms that are generally opposite to those observed after acute administration and are immediately reversible by readministration of the agonist.

Development of tolerance and dependence limits the therapeutic use of traditional benzodiazepine-(BZ) receptor agonists, such as diazepam (Owen and Tyrer 1983; Woods et al. 1987; Haefely et al. 1990). Recent reports have indicated that partial (low efficacy) BZ-receptor agonists, i. e., compounds which induce smaller fractional responses in their target cells than do full agonists at the same fractional receptor occupancy, may have advantages in this respect, because low-efficacy agonism prevents overstimulation of a receptor population, thereby reducing overdose problems, desensitization responses, and adaptation (Haigh and Feely 1988; Haefely et al. 1990). Indeed, repeated treatment of mice with the partial BZ-receptor agonist, bretazenil (Ro 16–6028), produced no significant tolerance to the anticonvulsant effect, in contrast to the effect of full agonists (Haigh and Feely 1988). Furthermore, again unlike full agonists, physical dependence could not be induced in squirrel monkeys after repeated very high doses of bretazenil as assessed by challenge with the BZ-receptor antagonist, flumazenil (Haefely et al. 1990). Although these data on bretazenil indicate that partial BZ-receptor agonism might have important practical consequences, there are also studies on other partial BZ-receptor agonists reporting less favorable data.

Much progress has been made in the elucidation of opioid receptor heterogeneity during the past 15 years. The existence of three major opioid receptor types (μ, δ, ĸ) (MARTIN et al. 1976; LORD et al. 1977) is now firmly established and there is strong evidence in favor of a fourth receptor type, the c–receptor (SCHULZ et al. 1979). More recently obtained physiological and receptor binding data led to the proposal of various opioid receptor subtypes (μ1, μ2, ĸ1, ĸ2, ĸ3) (reviewed in CLARK et al. 1989). Opioids produce a large variety of well-known central and peripheral effects, including spinal and supraspinal analgesia, tolerance and physical dependence, respiratory depression, euphoria, dysphoria and hallucinations, sedation, appetite suppression and other behavioral effects, control and release of several hormones and neurotransmitters, effects on gastrointestinal motility, hyperthermia/hypothermia, cardiovascular effects, effects on tumor growth, and effects on the immune response. Both for the elucidation of the physiological role(s) of the various receptor classes and for the development of opioid-derived drugs it is of great importance to establish clear-cut correlations between specific opioid receptor types and distinct opioid effects. For this purpose further efforts are needed to develop opioid agonists and antagonists with high selectivity for the various receptor types and subtypes. The fact that morphine displays only limited μ-receptor selectivity is well known and the characterization of the various opioid peptides generated through processing of the three mammalian precursors showed that none of them is very receptor selective (reviewed in HoLLT 1986).

The opioids have played a major role in promoting the understanding of the adaptive processes in the central nervous system. The homeostatic consequences provoked in the organism after chronic opiate administration are the well-known complex syndromes of tolerance and physical dependence. Both phenomena are dynamic and evolve over time. Tolerance to, and physical dependence on, an opioid may develop rapidly or slowly and to varying degrees. The evolution of these processes is exceedingly complex but general as well as specific explanations have been offered.

Acute administration of an opioid agonist produces a well-characterized constellation of effects (which have been reviewed in previous chapters of this book). When the opioid agonist is administered repeatedly, at a proper dose and frequency, two phenomena appear: 1. The intensity of these effects tends to decrease and an increase of the dose is necessary for them to be manifested again. This acquired change in the intensity of effects is called tolerance. 2. Several signs and symptoms appear when agonist concentrations in the organism decrease to a certain extent. This second phenomenon is called withdrawal syndrome. Its presence indicates the existence of physical (or physiological) dependence.

A prominent behavioural effect of all drugs of abuse is their ability to alter both mood and motivational processes. Opioids such as morphine or heroin produce euphoria in humans and compulsive drug-seeking behaviours in several mammalian species. Their repeated administration results in the development of tolerance as well as psychic and/or physical dependence. Although these latter phenomenon may contribute to the addictive process once established, they are not causal factors. Rather, there is now a wealth of evidence indicating that it is the activation of endogenous “reward” pathways in the brain and the positive reinforcing effects produced which underlie the abuse potential of opioids and other psychotropic drugs. In addition, as discussed below, recent studies indicate that opioids may have reinforcing or aversive effects depending on the specific opioidergic system with which they interact in vivo.

Alcohol is a well-known pharmacological agent which affects major psychomotoric and sensory functions via a series of complex physicochemical metabolic processes. The neuropsychopharmacological disturbances in alcoholics may be mediated in large part by alcohol-induced damage to various organ-systems which in turn cause both neurological and psychological disorders (Kalant 1987; Tarter and Edwards 1988).

Chemotherapy of narcotic addiction began in the 1920s with efforts to detoxify patients without suffering or discomfort. Procedures were devised which allowed patients not only to be withdrawn with minimal discomfort but to be restored to apparently good body health after several months of treatment. Many patients who were successfully detoxified and restored to good health, however, not only relapsed to drug use but continued to demonstrate sociopathic behavior following treatment. The major thrust of the treatment of narcotic addiction has since shifted from detoxification to therapies that would facilitate social adjustment and decrease sociopathic behavior. Chemotherapy has come to play a role in achieving these ends.

Traditionally, there has been relatively poor agreement concerning an adequate definition of alcoholism. Although a definition involving excessive drinking that results in injury to an individual’s health, adequate social function, or both would be generally accepted, considerable variation continues to exist in the formulation of more precise definitions with concomitant criteria for differential diagnosis and implications for treatment (WHO Report, 1955; Jellinek, 1960; Keller, 1962; Mendelson and Stein, 1966a; Plaut, 1967; Cahalan, 1970; National Council on Alcoholism, 1972).

The major function of the mammalian nervous system is to process information regarding the external and internal environments and to generate responses to various environmental influences. A further function of the brain is the generation of abstract thought which is not, in an evident way, connected with the body’s immediate environment. These nervous system functions are dependent on the conduction of information along the processes extending from the cell bodies of neurons (i.e., dendrites and axons), and on transmission of information from one neuron to another. The study of ethanol’s effects on the conduction and transmission of information within the brain forms a central theme for generating an understanding of ethanol-induced euphoria, sedation, and the development of tolerance and physical dependence in an individual (neuroadaptive processes).

In 1964, the WHO Expert Committee on Addiction-Producing Drugs recommended substitution of the term “drug dependence” for the terms “drug addiction” and “drug habituation.” The WHO Scientific Group (1964) endorsed this recommendation.

The purposes of this chapter are: (1) to discuss the subjective effects and behavioral correlates, analgesia, and the tolerance and dependence-producing properties of the narcotic analgesics and to relate these changes to their abuse, (2) to review the neurophysiologic and neurochemical literature which bear upon the site and mode of action of narcotic analgesics, and (3) to speculate on the nature of the heroin abuse problem as it relates to the actions of the narcotic analgesics, as well as on areas of research which may lead to the identification of salient psychopathologic processes in the addict.

Although alcohol is one of the earliest drugs used by man to change behavior and to modulate subjective states, less is known about its behavioral pharmacology than about many drugs of more recent origin. This is probably due to a complex interweaving of social attitudes and beliefs about alcohol which have evolved from a common familiarity with drinking and the effects of alcohol intoxication. For many years, the assumption that all is known, coupled with denial that alcoholism is a form of drug addiction, and ambivalence about problem drinking, tended to limit experimental interest in the study of alcohol and behavior (Mello, 1976b, 1978b). Gradually, over the past 15 years, an increasing number of studies have examined the behavioral effects of alcohol in normal social drinkers and in alcohol addicts. The early evidence that alcoholism is a form of addiction (Victor and Adams, 1953; Isbell et al., 1955; Mendelson, 1964) has been consistently reaffirmed (Mello and Mendelson, 1977 for review). As more empirical studies have examined the effects of alcohol during intoxication rather than relying on retrospective self-reports, the limitations of commonly shared expectancies about alcohol’s effects have become increasingly evident. The disparities between anticipated and observed effects of intoxication illustrate how far we now are from a comprehensive understanding of the behavioral pharmacology of alcohol (Mello and Mendelson, 1978 a for review).

Since the 1950s, a number of nonbarbiturate sedatives have been introduced, some categorized as tranquilizers or so-called minor tranquilizers. The first popular minor tranquilizer was meprobamate, which has sedative, hypnotic, and muscle-relaxant effects. At the time of its introduction into medical use, the drug was claimed to be specifically effective for anxiety and convulsive disorders, without having marked general depressant effects. But later it was found that meprobamate is nearly indistinguishable from the barbiturates in its pharmacologic effects. Such drugs as benactyzine, bucli-zine, and hydroxyzine are sometimes classified as anxiolytics, but their use as anxiolytics has become very limited in clinical practice. Therefore, these drugs will not be dealt with here.

Assessment of analgesics is based upon the demonstration of morphine-like subjective effects and physical dependence as demonstrated in substitution tests or direct addiction tests. Similar relative potencies in comparison to morphine for scales measuring subjective effects, miosis, suppression of abstinence and relief of pathological pain are sufficient evidence for classification as a morphine-like agent. Recently the use of the Morphine-Benzedrine Group (MBG) scale has improved the methods for assessing morphine-like subjective effects. Substitution studies conducted at various levels of morphine dependence have demonstrated the ability to assess for levels of morphine-like intrinsic activity. Assessing sedative-hypnotic agents for physical dependence capacity by substitution or direct addiction tests in man is not practical. It appears that from a comparison of secobarbital and pentobarbital, single doses of sedative-hypnotics can be assayed for their ability to facilitate post-rotatory nystagmus and produce scores on scales which measure barbiturate-like subjective effects.

Most studies of drug self-administration have concerned either opiate, depressant, or stimulant drugs (Schuster and Thompson, 1969). Few studies have involved hallucinogenic drug self-administration, primarily because of technical problems (e.g., long duration of action, lack of water solubility) associated with the use of these drugs. The present study investigates the intravenous self-administration of phencyclidine and Δ9-THC, and the self-administration by smoking of a natural cannabis substance (hashish). Phencyclidine is a synthetic anticholinergic drug with hallucinogenic properties (Brawley and Duffield, 1972). Cannabis compounds have been used by man for thousands of years primarily for their behavioral effects and contain Δ9-THC as the principal active ingredient (Mechoulam, 1970). Deneau and Kaymakcalan (1971) have reported intravenous self-administration of THC by monkeys, but only after physical dependence had been established to the drug. No report of phencyclidine self-administration by animals has been found.