Addiction and Drug Dependence
- Actions of Caffeine in the Brain with Special Reference to Factors That Contribute to Its Widespread Use

V. Addiction and Drug Dependence

A. Definitions

Drug dependence may be used to denote "a state of affairs when administration of the drug is sought compulsively, leading to disrupted behavior if necessary to secure its supply. Use continues despite the adverse psychological or physical effects of the drug" (Rang et al., 1995

Drug (or substance) abuse "are general terms, meaning the use of illicit substances" (Rang et al., 1995), whereas the term drug addiction is older and focused on physical dependence. In popular usage, addiction is a term indiscriminately used to describe all sorts of habits from relatively harmless ones to openly dangerous ones. A stricter usage emphasizes that addiction refers to compulsive drug use (O'Brien, 1995). Up until the late 1960s separate definitions for "addictions" and "habits" as proposed by the World Health Organization (1957) were used in the scientific and medical world. Drug-addiction as a state of periodic or chronic intoxication was then characterized by four criteria: 1) An overpowering desire or compulsive need to obtain the substance by any means. 2) A tendency to increase the dose progressively. 3) A psychic and generally a physical dependence on the effects. 4) Detrimental effects on the individual and the society. This concept of addiction would fit the opiates and alcoholism but not necessarily cocaine, which does not create any clear physiological withdrawal.

Drug-habit consisting of the repeated (not intoxicating) consumption of a substance was also characterized by four criteria which contrast with those of addiction: 1) A strong but not compulsive desire to take the substance for the sense of improved well being. 2) A moderate or no tendency to increase the dose. 3) A psychic dependence but no physiological abstinence syndromes. 4) Detrimental effects, if any, primarily on the individual but not on the society. This latter set of criteria was considered at that time to fit coffee-drinking

As pointed out by O'Brien (1995), "abuse and addiction are behavioral syndromes that exist along a continuum from minimal use, to abuse, to addictive use". The modern diagnostic manuals of the World Health Organization (WHO, 1992) and the American Psychiatric Association (APA, 1992, 1994) no longer use the terms addiction or habit. These terms have been given up for their "lack of precision" and their "discriminating connotation". The more recent manuals instead formulated a set of criteria for "substance dependence". This construct differs in very important aspects from the older concepts. It combines the old criteria of habit and addiction into a single list, and it does not rely on quantitative (often value-based) aspects of the criteria, but rather on qualitative "Yes or No" statements. Furthermore, it requires only that three (nonspecified) of the six (WHO, 1992) or seven (APA, 1987, 1994) criteria be fulfilled for the diagnosis "dependence". The old definitions of addiction and habit required the fulfillment of all four respective criteria.

The seven criteria of dependence as proposed by the APA (1987) in DSM-III are: 1) Tolerance (not specified for severity). 2) Substance-specific withdrawal syndrome (psychic or physiological, not specified for severity). 3) Substance is taken in greater amounts or over longer periods than intended. 4) Persistent desire or unsuccessful attempts to cut down or control use. 5) A great deal of activity and time spent in order to obtain the substance or recover from its effects. 6) Important social, occupational, or recreational activities given up or reduced because of substance use. 7) Use despite knowledge of persistent or recurrent physical or psychological problems likely to be caused or exacerbated by the substance. Although a new revised version appeared as DSM-IV (APA, 1992), the older DSM-III version is still in use and served as the basis for most of the recent discussions and controversies about substance use.

The six criteria as proposed by the WHO (1992) in ICD-10 differ only modestly from those of the APA, mainly by a different sequence, slightly different formulations, and the combination of the two DSM criteria 5 and 6 into a single item.

Accordingly, all nonmedical and more or less regular use of any psychoactive substance can be considered as "dependence", which is seen further by DSM-IV as a "substance related disorder". The only possibility to differentiate between substances that remains is, therefore, to locate them within a continuum of the number of criteria that are met and to specify the severity and frequency of occurrence. DSM-IV does not consider caffeine as a substance of dependence on the basis of such evaluations, but this is, as noted above, contentious. Furthermore, it lists intoxication and anxiety disorders as possible substance disorders.

Central to all the above attempts to define drug dependence is the concept of drug reinforcement. This has been defined as "a form of behavioral plasticity in which behavioral changes occur in response to some exposure to a reinforcing drug. Drugs are classified as reinforcers if the probability of a drug-seeking response is increased when the response is temporarily paired with drug exposure" (Self and Nestler, 1995). The drug somehow utilizes the brain's intrinsic motivational systems that are involved in maintaining various behaviors necessary for the survival of the individual or species.

"Chronic exposure to reinforcing drugs can lead to addiction, which is also characterized by an increase in drug-seeking behavior" (Self and Nestler, 1995). Thus a sustained increase in drug-seeking behavior (i.e., craving) is a core feature of clinical drug addiction. Importantly, addicted subjects usually exhibit a sustained increase in drug-seeking even when the drug has been withdrawn. Sometimes, the withdrawal is associated with negative affective states (i.e., dysphoria) and the drug can relieve these symptoms. Indeed, drug dependence can be defined as the need to sustain drug intake to eliminate the risk of withdrawal symptoms. Both craving and withdrawal effects are related to a process of habituation to the drug. The sometimes severe withdrawal symptoms are generally possible to limit and the physical dependence is not the reason why many subjects revert to drug use after being drug-free for long periods (O'Brien, 1995; Rang et al., 1995).

Koob (1996) has recently discussed the transition that occurs from a controlled drug use to the lack of control that is characteristic of drug dependence. A priori one can outline four types of reinforcement: positive reinforcement, negative reinforcement, conditioned positive reinforcement, and conditioned negative reinforcement (Wikler, 1973). Because a positive reinforcement is clearly of fundamental importance in establishing a drug-taking behavior, it has been hypothesized to be the key process (Wise, 1988). However, others have emphasized withdrawal as the driving force of addiction, and argued that the defining characteristic of drug dependence is the establishment of a negative affective state (see Koob, 1996). Such a state may on the one hand have a basis in the neurobiological setup of the individual---genetic and environmental factors both playing a role---and on the other in changes brought about by the long-term drug use itself. Furthermore, other cues---internal as well as external---may become associated by processes known as classical conditioning to both the positive and the negative affective states related to the presence or absence of the drug (Wikler, 1973). These theories thus invoke a critically important role of the basic neuronal circuitry that is involved in motivation and also postulate that drugs can induce important adaptive changes in these mechanisms.

B. On the Neuronal and Molecular Basis of Drug Reinforcement and Addiction

In pioneering studies, Olds and Milner (1954

Over the past several years our knowledge about the neuronal and molecular substrates underlying reinforcement and drug dependence has increased substantially. The molecular mechanisms were recently reviewed (see Self and Nestler, 1995) and the critical role of the mesolimbic dopamine system emphasized (Wise and Bozarth, 1987; Di Chiara, 1995; Koob, 1996). The mesolimbic dopamine system consists of the dopaminergic neurons that originate in the VTA and terminate in the nucleus accumbens. Two drugs, cocaine and amphetamine, target this system directly. Cocaine is known to exert its primary effect by blocking the sodium-dependent dopamine reuptake transporter (Kilty et al., 1991; Shimada et al., 1991). Amphetamine acts both by inhibiting the transporters and by releasing dopamine from intracellular stores. In animals with a targeted disruption of the dopamine transporter, amphetamine does not increase dopamine levels (Giros et al., 1996). This may be due in part to the fact that amphetamine needs to be transported via this system to exert its actions. It is known that rats will self-administer amphetamine and dopamine directly into the nucleus accumbens. By contrast, cocaine is not readily self-administered into the accumbens, but lesions of the dopamine neurons or drugs that attenuate dopamine actions will substantially reduce the reinforcing properties of cocaine (see Self and Nestler, 1995). Opiates also interact with the mesolimbic dopamine system. They are self-administered not only when given systemically, but also when injected into the VTA, where they act by disinhibiting the dopaminergic neurons (Johnson and North, 1992).

Drugs that enhance dopaminergic transmission tend to enhance an animal's response to brain self-stimulation, for example by reducing the reward threshold, whereas dopamine receptor antagonists have the opposite effect (see Wise, 1996). Reward thresholds are also decreased by cocaine, heroin and morphine, nicotine, phencyclidine, cannabis, and possibly ethanol (see Wise, 1996). Many of the same drugs, including ethanol (Rossetti et al., 1992) and cannabinoids also increase dopamine levels in the nucleus accumbens.

Phencyclidine (PCP) is also self-administered in humans, monkeys, and rodents (see Carlezon and Wise, 1996). In rodents, self-administration is erratic when the drug is given systemically but reliable when it is injected into the nucleus accumbens (Carlezon and Wise, 1996). The effect of PCP was shared by other inhibitors of NMDA receptors including MK-801, and was not influenced by DA receptor antagonists. The latter finding indicates that it is not the DA neuron per se that is important to induce self-administration but rather the activity of the neurons activated by both DA and NMDA receptors.

The nucleus accumbens is functionally and morphologically divided into a core and a shell part. The medioventral (shell) part is related to the limbic "extended amygdala" assumed to play a role in emotional and motivational functions, whereas the laterodorsal (core) part is viewed as a part of the striatopallidal complex and to be concerned with motor functions (see Heimer et al., 1985). The extended amygdala receives input from basolateral amygdala, frontal cortex, and hippocampus and sends efferents to the medial part of the ventral pallidum as well as the lateral hypothalamus.

Interestingly, i.v. administration of recognized drugs of abuse such as cocaine, morphine, and amphetamine, and even nicotine, increases the extracellular levels of DA specifically in the shell part of the accumbens (Pontieri et al., 1995). Nicotine has the same ability to increase DA specifically in the shell as compared to the core part of the nucleus accumbens (Pontieri et al., 1996). This is also manifested as a selective increase in glucose utilization in the shell part of the nucleus accumbens. Quite recently, cannabinoids were shown to have a similar effect (Tanda et al., 1997). There is also evidence that direct injection of drugs into the shell part of nucleus accumbens is much more efficacious in inducing drug-related behavior than is an injection into the core part of nucleus accumbens (see Ikemoto et al., 1997).

The regulation of the mesolimbic DA system was recently reviewed (White, 1996). The midbrain DA neurons with cell bodies in VTA respond with an increase in firing or even with burst activity to novel, unexpected events (Schultz, 1992). In particular, primary rewards such as food and water, when presented in an unexpected manner, are among the most effective stimuli for VTA DA neurons (Mirenowicz and Schultz, 1994). Furthermore, it is possible to condition the activation of these neurons by traditional methods (Schultz, 1992). Thus there is excellent evidence that the VTA DA neurons are deeply involved in reward-driven learning of the type that seems a priori to be involved in drug addiction.

In nonhuman primates, Schultz and coworkers (1997) have identified dopaminergic neurons whose fluctuating output appears to signal changes or errors in predictions concerning future salient and rewarding events. The neurons were suggested to provide information about appetitive stimuli, but not about aversive stimuli, which might mean that the absence of an expected reward is interpreted as "punishment" (Schultz et al., 1997). Moreover, the information would include a value component that if, and only if, combined with specific information about the nature of the specific stimulus, would provide an excellent basis for decisions. Indeed, in the basal ganglia, there are tonically active neurons that develop a response to conditioning that is spatially distributed, temporally coordinated, predictive of reward, and dependent on DA (Graybiel et al., 1994). Furthermore, in some of the output structures from the basal ganglia, the morphological distinguishing criteria of such integration have been detected (Bevan et al., 1997).

The VTA DA neurons receive a major excitatory input from prefrontal cortex, but also excitatory inputs from amygdala, and possibly the entopeduncular nucleus and the pedunculopontine region (see White, 1996). Many, but perhaps not all, of these inputs use an excitatory amino acid as the major transmitter, and NMDA receptors have been particularly implicated in producing the bursting type of activity (Johnson et al., 1992; Gonon and Sundström, 1996). Several lines of evidence indicate the presence of a major GABAergic inhibitory input from the nucleus accumbens (see White, 1996). There is also evidence for control by nicotinic receptors (Calabresi et al., 1989), but the localization of these receptors is unclear. There is some as yet incomplete evidence for control of VTA neuronal activity by 5-HT and noradrenaline. Finally, adenosine A1 receptors are present in VTA and regulate the firing of the dopaminergic neurons and thereby the release of DA in the nucleus accumbens (Ballarin et al., 1995). Thus, several neuronal pathways and transmitter and modulator systems act in concert to modulate the activity of the critically important DA neurons in the VTA, but their relative roles under in vivo conditions and how they interact is still incompletely known (White, 1996). Although it seems clear that habit-forming drugs do not all activate the reward systems in the brain in the same way, it is nonetheless established that several of the more addictive substances synergize with endogenous rewarding mechanisms involving the medial forebrain bundle, and that they directly or indirectly elevate DA levels in the nucleus accumbens (Wise, 1996).

Given that many drugs of abuse interact with the VTA DA neurons (Koob, 1992; Self and Nestler, 1995) it is obviously interesting to examine if such drugs produce lasting effects on these neurons. At least for some drugs such adaptive changes have been shown to occur. For example, amphetamine was shown to decrease the sensitivity of the DA D2 receptors on VTA neurons (Seutin et al., 1991). The subsensitivity probably does not involve any significant decrease in the number of D2 receptors (Peris et al., 1990), but it may involve a decreased ability of the receptors to couple to the relevant G-proteins (Nestler et al., 1990). The decreased sensitivity of soma-dendritic D2 receptors in VTA may provide a partial explanation for the long-term increases in drug-induced release of DA in the nucleus accumbens (see Self and Nestler, 1995). However, additional mechanisms are probably involved, including changes in the glutamatergic transmission. Thus, NMDA receptor antagonists prevent the development of drug-induced sensitization of dopaminergic transmission (Karler et al., 1989; Wolf et al., 1994). It should also be pointed out that the two mechanisms, i.e., a desensitization of D2 receptors and a sensitization to glutamatergic input, may be closely linked at the cellular level. Thus, the role of DA may be predominantly to regulate the efficiency of the glutamatergic neurotransmission (Gonon and Sundström, 1996).

The release of DA in the nucleus accumbens depends not only on the overall rate of firing of the VTA DA neurons, but it is also critically dependent on the firing pattern. The levels of DA are much higher when the neurons fire in a burst mode, probably because under those circumstances the inactivation mechanisms cannot keep up with the release (Chergui et al., 1994, 1997). Burst stimulation of the medial forebrain bundle leads to changes in the expression of NGFI-A (zif/268) mRNA in the nucleus accumbens. Specifically, this is seen in the GABAergic medium-sized spiny neurons that also express Substance P mRNA (Chergui et al., 1997). These neurons are known to express most of the D1 receptors in the nucleus accumbens, and indeed the change in the expression of the IEGs following burst stimulation of the medial forebrain bundle is inhibited by dopamine D1 receptor antagonists (Chergui et al., 1996, 1997). These data thus indicate that burst firing of VTA DA neurons causes an increase in the free extracellular DA level in the nucleus accumbens and that this, in turn, leads to an activation of DA D1 receptors that is manifested in an altered gene expression.

It is known that different individuals are differently susceptible to drug dependence. Among the many factors that might predispose an individual to drug dependence, animal experiments have identified stress as one (see Piazza and Le Moal, 1998). As discussed, several types of stressors can facilitate acquisition, maintenance, and reinstatement of self-administration of drugs such as heroin and cocaine (Piazza and Le Moal, 1998). The mechanism may be related to an effect of glucocorticoids on drug-induced release of DA.

Much of the above discussion centers on the idea that alterations in the DA neurons themselves or in the levels of the transmitter is the important factor. However, it is obvious that the effect of an alteration in the amount of DA at a relevant target neuron might be mimicked by a stimulus that enhances the actions of a normal level of DA. Such plastic changes may be brought about via multiple mechanisms as exemplified in other well-studied cases of plasticity of central synapses. As will be obvious from the discussion in Section III, there is good evidence that caffeine could do just this by interacting with receptors that coexist with DA receptors.

Dopamine acts on two classes of receptors: D1-like (D1 and D5) and D2-like (D2, D3, D4), which differ in their G-protein coupling and distribution in the brain (see Jaber et al., 1996). Both these classes of receptors may be involved in the motivational symptoms of drug addiction (see Self and Nestler, 1995). It has been shown that D1 receptor agonists delay the initiation of cocaine self-administration, whereas D2 agonists have no such effect (Self, 1992). However, in other studies, the relative potency of agonists was suggested to reflect an importance of D3 receptors (Caine and Koob, 1993). The dopamine D4 receptor may also play a role because motor behavior responses to cocaine, ethanol, and methamphetamine are enhanced in mice lacking this receptor (Rubinstein et al., 1997). Furthermore, D1 agonists decrease reinstatement of cocaine-seeking behavior, whereas D2 agonists enhance it (Self et al., 1996). Moreover, in mice with a targeted disruption of the dopamine D2 receptor, opiates did not have a rewarding effect (Maldonado et al., 1997), even though the rewarding effect of food was maintained. Any attempt to associate a given behavior, short- or long-term, to a single dopamine receptor subtype is complicated by the fact that D1-like and D2-like receptors functionally interact in a highly complex manner. Although either a D1-like or a D2-like agonist may under some circumstances have rewarding properties per se, a combination of the two produces much larger effects (see Ikemoto et al., 1997).

Dopamine D1 receptors appear to be important for the motor effects of cocaine (Xu et al., 1994). These receptors are also important in the phenomenon of sensitization (see Self and Nestler, 1995; Hyman, 1996). A single dose of a drug that activates dopamine receptors can sensitize an animal for months to the locomotor effect of amphetamine or cocaine and this is blocked by D1 antagonists and correlated with an increased responsiveness of D1 receptors in the nucleus accumbens (Henry and White, 1995). D1 receptors are known to interact with NMDA receptors to phosphorylate CREB and this leads to an increased expression of several IEGs that act as transcription factors (see Konradi et al., 1994; Hyman, 1996). These molecular events have been hypothesized to lead to behavioral sensitization. In particular, changes in dynorphin might provide a mechanism for producing dysphoria when the drug is discontinued (see Hyman, 1996). Part of the sensitization to both cocaine and morphine may be exerted at the level of the dopaminergic cell bodies in the VTA (Bonci and Williams, 1996). Whereas activation of dopamine D1 receptors normally augments the GABAB receptor-mediated inhibitory postsynaptic potentials, D1 receptor stimulation given after chronic cocaine or morphine inhibits these responses. Interestingly, the mechanism appears to involve release of adenosine that acts on adenosine A1 receptors (Bonci and Williams, 1996).

According to the model of Schultz et al. (1997) signaling via the dopaminergic neurons would provide a type of general value-related information that only provides a basis for decisions about specific actions if combined with specific information about different types of stimuli. Therefore, a very general activation or inactivation of parts of this dopaminergic signaling machinery would theoretically generate information that is too unspecific to be of use in decision-making by rats or humans. If, however, the adaptive processes require not only the activation of dopamine receptors, but also activation of a glutamatergic input, as postulated above, we could have a mechanism that would allow for a synthesis of nonspecific motivational input and specific information about drug-related cues---exactly as postulated by the psychological theories of drug dependence.

For obvious reasons there is much less information about the neuronal substrates for drug dependence in humans. In a recent study using functional magnetic resonance imaging, the brain regions activated by cocaine in humans were studied (Breiter et al., 1997). In agreement with the extensive literature on rodents and subhuman primates, cocaine (0.6 mg/kg) caused a clearcut increase in the signal in nucleus accumbens/subcallosal cortex (Breiter et al., 1997). These changes could be correlated to the craving, but not to the "rush". The latter, which by definition occurred very rapidly, correlated better with changes in activity in caudate-putamen, thalamus, posterior hippocampus, insula, cingulate, and parahippocampal gyri. The widespread sustained changes after cocaine could indicate that the sustained behavior changes, including craving, reflect a change in the overall pattern of brain activity rather than a focused alteration in one or more specific regions or brain nuclei (Breiter et al., 1997).

; see Wise, 1996) showed that electrical stimulation of certain brain areas can induce a learned place preference and that stimulation of these brain areas was rewarding in the sense that it could act as an operant reinforcer (see Wise, 1996). It was soon realized that this could best be explained if the electrical stimulation of these brain areas activated brain circuitry relevant to the pursuit of natural incentives (Olds and Milner, 1954; Olds, 1956). It is now clear that many brain areas, from the olfactory bulb and frontal cortex in the rostral part of the brain all the way to the nucleus tractus solitarii in the caudal brain can serve as substrates for such rewarding stimulation (see Wise, 1996). Drugs with habit-forming properties act through these same incentive-forming brain circuits (Wise and Bozarth, 1987; Koob, 1992, 1996).).

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