Review Drug Addiction. Part Ii. Neurobiology of Addiction

REVIEW

DRUG ADDICTION. PART II. NEUROBIOLOGY OF ADDICTION

Jerzy Vetulani Institute of Pharmacology, Polish Academy of Sciences, Smêtna 12, PL 31-343 Kraków, Poland

Drug addiction. Part II. Neurobiology of addiction. J. VETULANI. Pol. J. Pharmacol., 2001, 53, 303–317.

The drug addiction may be regarded as the disease of the brain reward system. This system, closely related to the system of emotional arousal, is located predominantly in the limbic structures of the brain. Its existence was proved by demonstration of the “pleasure centers,” that were discovered as location from which electrical self-stimulation is readily evoked. The main neurotransmitter involved in the reward is dopamine, but other monoamines and acetylcholine may also participate. The anatomical core of the reward system are dopaminergic neurons of the ventral tegmentum that project to the nucleus accumbens, amygdala, prefrontal cortex and other forebrain structures. Several of those structures may be specifically involved in the reward produced by different substances, when anticipating the reward. The recent discovery of CART peptides may importantly expand our knowledge about the neurochemistry of reward. Natural rewarding activities and artificial chemical rewarding stimuli act at the same locations, but while natural activities are controlled by feedback mechanisms that activate aversive centers, no such restrictions bind the responses to artificial stimuli. There are several groups of substances that activate the reward system and they may produce addiction, which in humans is a chronic, recurrent disease, characterized by absolute dominance of drug-seeking behavior. The craving induced by substances of addiction inhibits other behaviors. The adaptation of an organism to a chronic intake of drugs involves development of adaptive changes, sensitization or tolerance. It is thought that the gap between sensitization developing for the incentive value of the drug and tolerance to the reward induced by its consumption underlies the vicious circle of events leading to drug dependence. The vulnerability to addiction is dependent not only on the environment, but also on genetic factors.

Key words: addiction, reward, dopamine, CART peptides, addiction vulnerability J. Vetulani

Humanity successfully searched for pleasure- involvement of cognitive system in addiction is, giving substances from the beginning of its history, however, beyond the scope of this review. and in the present days they are still used exten- sively. While the number of widely used substances Arousal system of addiction was reduced, their power and availability still increase. This indicates that the search The brain must be aroused to play its most es- for substances altering the consciousness and im- sential function: to adapt the organism to the envi- proving mood is an important human trait. The ronment in order to secure its life and reproduction. abused substances are generally regarded as harm- The basic arousal system regulates waking and ful both from medical and social point of view, but sleeping. There is a variety of awaking states, and in spite of their use, in most cases they did not im- definition of wakefulness still remains controver- pair the competitiveness of various human tribes, sial. Yet wakefulness is a useful term, though it em- and did not harm the evolutionary success of the braces a number of different states of nervous ac- human species. However, as described earlier [123], tivity, connected with excitation of diverse anato- the recent changes in the use of addictive sub- mical and functional subsystems. stances and the change in the attitude of society to The arousal system comprises three tightly con- this problem resulted in regarding the addiction as nected subsystems: general, directed, and periphe- a serious social plague. Therefore, discovery of ral. The anatomical basis for the subsystem respon- biological basis of the need to use psychoactive sible for general arousal, constituting the basis for substances is of crucial importance. regulation of the central nervous system excitabili- The most dangerous characteristic of psychoac- ty, is the ascending reticular system [115]. The sub- tive substances appears to be their ability to evoke system of directed or goal-oriented arousal is con- addiction. Drug addiction should be considered cerned with motivations and emotions and the a complex disease of the central nervous system, brain structures involved are the hypothalamus and characterized by compulsive, uncontrolled craving the structures of the limbic system, proposed by Pa- for a drug, its seeking and striving to get it at all pez [85]. The further studies extended the number cost, and its use despite obvious, serious health- of structures regarded as constituents of the limbic and life-threatening consequences. For many per- system. The most important anatomical structures sons addiction became a chronic disease, with re- involved in emotions are the prefrontal cortex and lapses occurring even after long abstinence periods. amygdala [25]. The third subsystem links the brain The development of addiction and emergence of with the periphery: this is the system of peripheral craving is connected with direct disturbance of one arousal, which enables the interaction of the central of large functional brain systems, the reward sys- nervous system with peripheral organs both through tem, while indirectly it impairs also remaining sys- the autonomic nervous system and hormonal systems – arousal system, especially its part related to tems via the hypothalamus [97]. This system is ne- emotions, and cognition system. cessary for expression of emotional states. When drug addiction is concerned, the most involved is the system of directed arousal. It provides Functional systems of the brain cortical responses with emotional quality, such as anxiety or curiosity, anger, pleasure, aversion, etc. Behavior of mammals (and presumably lower Existence of the system of directed arousal implies animals) is a resultant of action of three large func- the existence of the mechanism governing a choice tional systems of the brain: arousal, reward and of appropriate goals, which initiates behavioral re- cognition system. These systems are closely interactions necessary to attain these goals and which connected and are necessary for proper functioning signals that the goals have been attained. If these of the organism in the environment. They all are goals are important for subject’s survival or for in- also engaged in the development of drug addiction creasing its reproductive success, such behavioral and drug seeking behavior. The cognitive system is reactions should be reinforced by proper reward. If often the ultimate victim of addiction, as in several they are not beneficial, they should be inhibited in cases of chronic drug addiction cognitive impair- the future by proper punishment. The behavior is ments of various type ensue. The discussion of the thus regulated by the special reward system.

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Reward system dition can modify its preferences: a hungry rat stimulates other regions than a thirsty one. The reward system, which can “praise what is Under normal conditions, the reward system good and punish what is wrong” was discovered at the beginning of the fifties. Earlier experiments on obviously is not stimulated by electric current but the influence of electrical stimulation of different by appropriate neurotransmitters. Stimulation of brain structures on cognitive functions prompted this system depends on the action of catecholami- James Olds and his postgraduate student Peter Mil- nes, particularly dopamine, and of serotonin, while ner to examine the effect of electrical stimulation opioid peptides exert modulatory effects. Addic- on learning. Olds wanted to examine whether sti- tion-forming substances can stimulate release of mulation of the reticular substance could facilitate certain neurotransmitters or mimic their action at learning. Due to technical mistake, probably a ben- the receptor level in the reward system. ding of the stimulation electrode during its inser- The reward system is engaged in all basic types tion, it landed quite far from its destination, in the of behavior: food and water intake, sexual activity, hypothalamus. It appeared that the animal evident- aggression, etc. A decrease in blood glucose level, ly enjoyed passing the current and willingly re- induced by food deprivation, causes hunger, which turned to the experiment. Olds and Milner modified strongly motivates an animal to seek food, since in the experiment in this way that a rat could deliver this state eating strongly stimulates the reward sys- itself the current by pressing a lever located in tem, and becomes pleasurable. Certain ionic chan- the cage [67]. This self-stimulation was particularly ges, induced by lack of drinkable liquids, cause pronounced when electrodes were placed in certain thirst, which in the same way motivates an animal brain regions [83]. At the same time, Delgado et al. to seek water. However, when an animal has con- [26] showed that activation of some brain structures sumed enough food, a satiety center suppresses the in the cat produced vigorous escape responses and reward system connected with feeding, and when appeared to have strongly aversive effects. At pre- thirst is satisfied, stimulating effect of drinking on sent, we know fairy precisely the map of pleasure- the reward system is inhibited. Also sexual drive -affording regions of the brain [82]. The pleasure stimulates the reward system only to certain extent, centers are connected mostly with the ascending so after sexual activity, assuring reproductive suc- dopaminergic and noradrenergic projections in the cess, pleasure disappears. Subtleness of such regu- median forebrain bundle [39] and the terminals in lation is illustrated by Coolidge’s effect, showing the prefrontal cortex [77], the seats of mechanisms that a male not attempting to copulate again with of directed stimulation, and regions responsible for the same female, readily copulates with a new part- general arousal. On the other hand, aversive centers ner, which certainly increases his chance for repro- are located mainly in the periventricular system, ductive success [1]. and are modulated by GABA and serotonin [45]. Aggression is associated with the reward sys- Electrical self-stimulation has been later de- tem as well [6]. It has to give pleasure since it oc- scribed in many vertebrates, beginning from gold- curs in spite of its dangerous consequences, and if fish, across guinea-pigs, dogs, cats to dolphins, it did not bring about such pleasure, aggressive be- monkeys and humans. The places, stimulation of havior, anyhow very helpful in struggle for exis- which produced aversive sensations, have also tence and finding sexual partner, would be uncom- been identified [84]. Humans can report quality of mon. However, excessive, uncontrolled aggression their experiences. Stimulation of the sites evoking is blocked by pain caused by victim’s reaction to pleasure elicited general feeling of bliss, happiness aggression. If an aggressor meets a stronger indi- and unusual well-being. Stimulation of aversive vidual, aggression disappears. Even a very aggres- sites caused a feeling of anxiety, approaching dan- sive dog usually flees after welting. ger, isolation and abandonment. Precisely because the reward system is com- There are numerous bliss centers, and stimula- posed of pleasure and punishment systems, it can tion of different centers appears to generate diffe- function efficiently, and seeking a pleasure does rent feelings. If electrodes are placed simultane- not hinder natural adaptation to the environment. ously in several brain regions and a rat can choose Unfortunately, similarly as most of systems in li- the stimulation site, it changes them frequently, ving organisms, particularly in humans, the reward switching from one to another. Also, animal’s con- system can be a subject to disturbances. Such lack

ISSN 1230-6002 305 J. Vetulani of balance is accompanied by behavioral disturban- the contrary, the lack of expected reward causes re- ces: bulimia or anorexia, psychosexual disturban- duction of dopaminergic signal. It suggests that re- ces or excessive aggressiveness. sponse of mesencephalic dopaminergic neurons is The reward system can be stimulated by certain a sign of learning, encoding anticipated error in the psychotropic substances. It appears that mere seek- expectation of a reward [50]. ing pleasurable drugs, which stimulate reward sys- An alternative theory, called “switch hypothe- tem, is not an aberrant behavior, and even can have sis”, was postulated by Redgrave et al. [98]. This adaptive value. Only when drug addiction occurs it hypothesis assumes that dopaminergic signal de- can be considered the reward system disease. tects unexpected but salient events, including but not limited to a reward. Therefore, dopaminergic Dopamine and reward system system would be significant for associative learning, not necessarily connected with evoked pleasure. In- It is unquestionable at present that dopamine deed, it was shown that dopaminergic system of the plays the key role in motivational behavior and ad- nucleus accumbens was stimulated during learning diction. Dopaminergic theory of reward has been [120]. challenged many times but a general role of dopa- Another hypothesis, fairly similar in general, mine in the reward system was never denied alto- was proposed by Di Chiara [30]. It attributes an im- gether. It has been reviewed in an excellent recent portant role in reward-associated learning pro- article by Kostowski [68]. cesses to mesolimbic dopaminergic transmission, Dopaminergic theory was put forward when the and suggests that drug addiction is a disease of structures which could be electrically self-stimula- dopamine-related associative learning. Di Chiara ted were shown also to be sensitive to dopamine postulates that associative learning and activation [47], and mesencephalic dopaminergic system, be- of dopaminergic neurons evoked by natural re- ginning in the ventral tegmental area and sending warding factors, are different from abnormal asso- its projections to the limbic system structures, espe- ciative learning and dopaminergic activity induced cially to the shell of the nucleus accumbens and by drugs of abuse. According to this hypothesis, prefrontal cortex, was assumed to be the anatomi- dopaminergic activation in the nucleus accumbens cal basis of the reward system [129]. Synaptic do- septi by natural events is subject to habituation. On paminergic transmission in the nucleus accumbens the other hand, addiction-forming drugs produce septi increases as well during natural rewarding ac- effects that are not subject to habituation, which tions, such as feeding, drinking, sexual activity as causes non-adaptive, and even progressively en- after the administration of substances inducing ad- hanced dopamine release after repeated administra- diction [31, 93]. It is believed that chronic admini- tion of addictive drugs. These neurochemical con- stration of such substances evokes long-term adap- sequences of addictive drugs would strengthen as- tive changes in dopaminergic transmission, leading sociation between a salient stimulus and reward, both to disturbance and desensitization of the re- which could be the basis for drug-seeking behavior. ward system to some drug effects [66], and its sen- All these theories confirm the hypothesis devel- sitization to the others [102]. oped by Di Chiara and North as early as in 1992 Till mid nineties, an opinion prevailed that re- [32], suggesting that reward consists of two phases: warding activity was connected with direct stimu- the incentive phase, in which a pleasure is antici- lation of dopamine release by a drug or satisfac- pated, and the consummatory phase, involving ex- tion-affording behavioral stimulus. However, re- perience of a pleasurable stimulus. It appears that cently it has been noticed that dopamine is released dopamine contribution dominates in the first phase. rather in the first phase of the contact with reward. Our common human experience indicates that Schultz [106] observed that although dopamine re- waiting for the expected reward may be equally, if lease increased during pleasurable activities, it was not more, pleasurable than the reward itself (catch- high mainly at the beginning, when pleasurable ex- ing a bunny is not important, what matters is chas- perience was anticipated. Unexpected reward causes ing it). Universal significance of anticipation is strong dopaminergic stimulation, which diminishes confirmed by sexual behavior: most animals, in- upon repetition and learning, until reward presenta- cluding certain invertebrates, engage in prolonged tion does not evoke dopaminergic stimulation. On nuptial rituals before copulation. In all human so-

306 Pol. J. Pharmacol., 2001, 53, 303317 NEUROBIOLOGY OF ADDICTION cieties, pleasure connected with flirting is highly amphetamine-regulated transcripts), and the pepti- appreciated. des encoded by them were designated CART pepti- The fact that reward associated with the antici- des. The presence of CART was demonstrated in pation of pleasure is very high can explain a num- different regions of the rat brain and in endocrine ber of aspects of addiction, particularly craving in- organs, but CART expression increased after psy- duced by cues related with drug use (watching chostimulant treatment only in the striatum. Fol- films showing crack smoking, by cocaine abusers lowing the preparation of appropriate cDNA, CART or inspecting paraphernalia for drug use, e.g. pipe protein was cloned, and the presence of both the collection by a smoker). peptide and its fragments was demonstrated in Dopamine receptors undoubtedly play a crucial the rat neurons by immunohistochemical methods. role in rewarding behaviors, and abnormal seeking CART, CART cDNA and CART proteins have also of the objects that stimulate the reward system. Be- been discovered in humans, and a part of human haviors such as gluttony, hypersexuality, gambling, CART responsible for encoding the propeptide risky behavior or, finally, taking addiction-forming showed 95% homology with rat CART [53]. At drugs, may be a compensation for congenital un- present, CART peptides are believed to reside in derdevelopment of the reward system, which has to certain groups of neurons in the brain. be stimulated stronger to afford the normal level of A rise in CART expression after psychostimu- well-being. Such deduction may be substantiated by lant treatment suggests that they can be associated a large body of evidence, and the most recent and with the reward system and processes implicated in convincing of them has indicated that methylpheni- drug addiction. Location of the neurons containing date evoked feeling of pleasure in those subjects CART peptides, which appear to be secreted by (not drug abusers) whose D2 dopamine receptor neurons, indicates their extensive physiological level in the brain was low, while in those with high functions: they seem to play a role in feeding, level of D2 dopamine receptor, intravenous admini- stress, processing of sensory data, regulation of stration of methylphenidate was aversive [124]. central autonomic functions [70]. Contribution of It should be noted that, possibly, dopamine is CART peptides to rewarding behavior and addic- not the only neurotransmitter engaged in rewarding tions was supported by their distribution in the nu- behavior and addiction, since it was shown that in cleus accumbens, ventral tegmental area and amyg- mutant dopamine-transporter knockout mice, whose dala. As CART peptides were also found in the my- synaptic dopamine level was much higher in com- enteric plexus, they may be classified as brain-gut parison with normal animals, and which exhibited peptides [20]. hyperactive behavior, cocaine still evoked addic- The first physiological role ascribed to CART tion (mice self-administered cocaine) despite that peptides consisted in the inhibition of feeding [69, obviously nonexistent dopamine transporter could 71]. Intracerebroventricular administration of ac- not be further blocked [103]. As cocaine influences tive CART 89-103 peptide fragment was reported also serotonin transporter, this implicates that sero- later not only to inhibit feeding but also to intensify tonergic system also contributes to the development fear reactions in the elevated plus maze test. These and maintenance of addictions. results suggest that CART proteins can be endoge- nous regulators of stress effects on appetite [58]. CART peptides The studies providing a direct proof of a possi- ble role of CART proteins in addiction have been New prospects to approach the problems related conducted recently. They demonstrated that a sin- to the mechanism of drug addiction and even gle administration of CART 55–102 peptide frag- searching the methods for their control, opened ment (that occurs naturally) into the ventral teg- after discovery of specific neuropeptides, termed mental area elevated locomotor activity of rats, CART peptides [70]. while its fourfold administration evoked strong In 1995, Douglass et al. detected a unique place preference, indicating its reinforcing proper- mRNA in the rat striatum, whose expression in- ties. In contrast to the action of exogenous reward- creased five times after the administration of psy- ing stimuli, CART protein-induced locomotor ef- chostimulants, cocaine and amphetamine [35]. fects did not show sensitization or tolerance. They These transcripts were named CART (cocaine- and did not cause sensitization to amphetamine and co-

ISSN 1230-6002 307 J. Vetulani caine, and vice versa, neither cocaine nor ampheta- Craving is the main cause of relapse among mine evoked sensitization to CART proteins. CART drug addicts and its control is a goal of the pre- effect appears to be associated with the stimulation sent-day pharmacotherapy of drug addiction and of the reward system, since their administration will be discussed in the next part of this review. into the substantia nigra did not elicit any changes in locomotor activity [61]. Studies on addiction liability An interesting aspect of CART physiology is the existence of gender differences in CART ex- Addiction liability can be studied in animal mo- pression. Under natural conditions CART mRNA dels since the mechanisms of addiction are univer- expression in the nucleus accumbens septi in males sal, and the results can easily be adopted for hu- is higher than in females, but after several cocaine mans. If any substance evokes addiction in a rat or doses CART expression increases in the amygdala mouse, we can be almost sure that it will be liable of males but not females, while in the nucleus ac- to produce addiction in humans as well. cumbens septi the situation is opposite. These re- Animal studies can employ indirect methods, sults may shed new light on gender differences in the most commonly used being: investigation of addiction and drug abuse [37, 53]. place preference (a rat prefers the place in a cage The important feature of CART peptides and associated with previously experienced pleasure) their analogues is their ability to cross rapidly the and facilitation of electric self-stimulation (activa- blood-brain barrier [59]. It appears that future stu- tion of rewarding centers increases the pleasure of dies will be focused on searching for low molecular self-stimulation of the brain with electric current, weight agonists and antagonists of CART peptides and produces responses even at so weak currents that might find their place in clinical practice as that the control animals do not react to them). These agents of addiction control and treatment of reward methods were described in literature in detail [119, system deficits leading to bulimia or anorexia. 122]. Moreover, the discovery of CART proteins can It seems that addiction liability or the effective- change our views on the mechanism of rewarding ness of agents alleviating craving in drug addicted action of psychostimulants. individuals can be easily examined in humans. As mentioned above, simple watching video tapes which show cocaine taking evokes symptoms of Craving craving in cocaine addicts, and physiological corre- lates of these symptoms are easily measurable [15, Craving, the compulsive desire to seek for and 36]. This model can enable to assess the degree of take a drug, is a complex phenomenon present in addiction and whether the proposed pharmacologi- addicted animals or humans. It can appear after cal treatment increases or decreases cue-induced withdrawal from drug use [38], which leads to a de- drug craving. pression of the activity of dopaminergic system that Direct investigation of addiction liability in- may evoke a feeling of anhedonia [65], or it can de- volves determination if an animal self-administers velop in drug-free addicts in response to a single a substance upon the free choice paradigm. When drug administration (priming effect) [56] or to sig- orally taken substances are tested, an animal chooses nals presaging this possibility (cue-induced crav- between a bottle with a solution of the tested sub- ing) [15, 36]. Activation of dopaminergic system stance and a control liquid (in this way alcohol pre- was observed both following addictive drug ad- ference is tested: an animal has an access to a bottle ministration [117] and presentation of cues associ- with water and the one with alcohol, and the con- ated with drug use to addicted animals [33, 64]. sumed volumes of both liquids are measured and Therefore, craving can be induced equally well by compared). excessive and by insufficient dopaminergic stimu- In other tests, an animal is introduced to an ap- lation. It can be evoked by agonists conveying do- paratus provided with a lever or a switch which paminergic signals and antagonists such as neuro- after activation starts an infusion pump, which de- leptics, despite that the latter block cocaine seeking livers appropriate amount of a solution of the tested behavior [99, 126] and elicit dysphoria [51], thus substance [119]. The substance is most frequently being reluctantly taken by the patients. administered by the intravenous catheter, but a si-

308 Pol. J. Pharmacol., 2001, 53, 303317 NEUROBIOLOGY OF ADDICTION milar device can be used either to opening the ac- we know that their rewarding actions are 100-fold cess to the container with the substance to be taken weaker than those of m-receptor agonists. Agonists orally, or to administer the substance under exa- of k-opioid receptors, which evoke aversive reac- mination into the brain ventricles or structures to tions after peripheral administration, have no ef- elucidate anatomical targets of addictive substance fects whatsoever following administration into the action. ventral tegmental area [78]. Nicotine addiction appears also to be associated Anatomical targets of addictive with the ventral tegmental area. Nicotine receptors substances are reportedly located on dopaminergic neurons in this region [16]. Systemic nicotine administration The reward system comprises a number of brain increases dopaminergic neuron firing [76]. Dopa- structures, and self-stimulation can be initiated after mine antagonists injected into the ventral tegmental activation of many regions [82]. Nevertheless, an area inhibit nicotine self-administration [17–19]. essential role in addiction process has been as- As such effect is not caused by neuroleptics admin- cribed to the mesolimbic dopaminergic system, en- istered into the nucleus accumbens [88], the ventral compassing the ventral tegmental area, where do- tegmental area is believed to trigger nicotine addic- paminergic neurons projecting to the nucleus action. Its neurons form synapses with cholinergic cumbens septi and prefrontal cortex are located. neurons of the laterodorsal tegmental nucleus and The nucleus accumbens, which is a heteroge- pedunculopontine nucleus. nous structure, can be considered a switch between emotional and locomotor systems. The cells of its ventromedial region, called the shell, and believed Addictive drug actions localized to constitute a part of the extended amygdala, project more strongly to the ventral tegmental area, in the nucleus accumbens whereas the cells of the more dorsal and lateral region of the amygdala, the so-called core, projects The nucleus accumbens is the structure, where more strongly to the zona compacta of the substan- the actions of addictive psychostimulants, cocaine tia nigra [132]. The D2 receptors are highly ex- and amphetamine, are localized, as upon peripheral pressed in the shell while D3 receptors are more administration they elevate dopamine level in this abundant in the core [73]. brain region [54, 88, 96]. Studies of various authors Despite the fact that final rewarding effect is have not produced an unequivocal answer whether connected with an elevation of dopamine release in an increase in dopamine release is dependent on the nucleus accumbens [cf. 68], different parts of consumption and remains tonically enhanced over the limbic system seem to be a target of addictive whole self-administration period [128], or the re- drug action. It was demonstrated upon observation lease is triggered by anticipation of each consecu- of animals exhibiting a tendency to drug self-admi- tive injection [46, 62, 63]. It appears that a part of nistration directly into the abovementioned struc- dopaminergic system activation is associated with tures. consummatory phase, while another part depends on awaiting a reward [9, 10, 14, 107]. Addictive drug actions localized It is very interesting that two stimulatory sub- in the ventral tegmental area stances believed to have similar mechanisms of action, amphetamine and cocaine, differ with respect The ventral tegmental area is the place, where to the targets for their addiction-evoking action. rewarding actions of morphine are localized [8, 89]. Rats readily self-administer amphetamine into the Both m- and d-opid receptor agonists exert their re- nucleus accumbens [49, 90], while cocaine self- inforcing effects via this region [3, 28]. m-Opioid -administration is observed only when the drug is receptor agonists block GABA receptors located on given here at high concentrations and for longer dopaminergic neurons and cause disinhibition of periods [43]. Nomifensine, which also blocks do- the latter [57]. Dopaminergic neuron disinhibition pamine uptake and, similarly as amphetamine, does results in the increased dopamine release in the nu- not possess local anesthetic properties, was self- cleus accumbens [29, 75]. Mechanisms of action of -administered into the nucleus accumbens equally d-opioid receptor agonists still remain unclear, but eagerly as amphetamine [11].

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Morphine and met-enkephalin are readily self- receptors on dopaminergic neurons in the ventral -administered into the nucleus accumbens as well tegmental area, which leads to dopamine release [42, 81], and their actions in this structure seem in- [7, 72]. dependent of the effects in the ventral tegmental area. Reinforcing effects of peripheral cocaine and Drug-induced adaptive changes heroin administration are blocked by intra-caudate treatment with pertussis toxin, the substance that Dependence on a drug (and also on other rewarding stimuli) can be defined as a condition in blocks Gi and Go proteins, suggesting the involve- which such changes in psyche have occurred that ment of dopamine D2 receptor [111, 120]. Besides, phencyclidine and NMDA receptor seeking a drug or other rewarding stimulus be- antagonists, MK-801 and CPP, elicit reinforcing ef- comes the main focus of an addict’s life. Undoubt- fect after their administration into the nucleus ac- edly, dependence develops as a result of adaptive cumbens [12]. As mentioned above, it appears that changes evoked by chronic drug use. Exactly these the shell, and not the core, is a target for all com- changes lead to the destruction of addicts’ person- pounds evoking self-stimulation from the nucleus ality. accumbens. Drug-induced adaptive changes can be divided into two basic categories: sensitization and tolerance. Initially, tolerance that accompanies the use of Addictive drug actions in the frontal cortex a majority of addiction-forming substances, and The frontal cortex constitutes also a part of the that consists in progressively weaker drug action, reward system, but in some aspects it differs from including diminishing the rewarding effect, was be- the nucleus accumbens. Thus, rats readily self-ad- lieved to play the primary role in drug addiction. minister cocaine into the medial region of the fron- However, currently it is assumed that sensitization, tal cortex, but, as mentioned above, they do not ex- i.e. enhancement of the response to consecutive hibit this tendency when cocaine is administered drug doses, is equally, if not more important. Sensi- into the nucleus accumbens [44]. Interestingly, am- tization is evoked by many psychostimulants (co- phetamine has no reinforcing properties in the fron- caine, amphetamine, and also nicotine), and the tal cortex [41], whereas it is eagerly self-adminis- way of drug administration is crucial for its devel- tered into the nucleus accumbens. However, there opment [101]. Sensitization could be responsible is no mutual exclusion of these two structures, for priming effect, i.e. drug craving induced in since phencyclidine, MK-801 and CPP have rein- a drug-free addict by a single drug dose. forcing effects both in the prefrontal cortex and nu- Problems connected with tolerance have been cleus accumbens [12]. detailed elsewhere [122]. Tolerance is defined as a need to increase drug doses to experience the Addictive drug actions in the hippocampus same reaction. Tolerance can develop not only in response to addictive substances, since pharmaco- The hippocampal formation has been linked kinetic and metabolic tolerances are important rather with memory processes than addictions, but categories of tolerance as well. One of the causes of opioids, morphine and a-dynorphin are readily self- tolerance is enzymatic induction, due to which -administered by rats into CA3 region of the hippo- a drug is eliminated more rapidly from the organism, campus [110, 116]. and even when its maximum effect remains un- changed, its total effect is weaker, as it acts for Addictive drug actions in the pedunculo- a shorter period of time. Out of addictive sub- pontine nucleus stances capable of evoking enzymatic induction, barbiturates, certain tranquillizers, such as mepro- Contribution of the pedunculopontine nucleus bamate, and nicotine should be mentioned. to addiction-forming processes is corroborated by It is also necessary to mention pharmacokinetic experiments showing the blockade of morphine- sensitization, causing progressively stronger drug and amphetamine-induced place preference by le- action as it continues to be used. It is connected sions to this structure [5]. It also seems that cho- with liver damage and impairment of drug metabo- linergic neurons of this nucleus activate nicotinic lism. Ethanol is the most commonly known sub-

310 Pol. J. Pharmacol., 2001, 53, 303317 NEUROBIOLOGY OF ADDICTION stance which can elicit this phenomenon. Due to animal is tested in the cage in which it was admini- liver damage, an alcoholic metabolizes ethanol less stered the drug or in another place. A number of ex- efficiently and intoxication can be caused by lower periments of Siegel showed that development of alcohol doses, and lasts longer. Pharmacokinetic tolerance to antinociceptive morphine action in rats sensitization has entirely different basis than the or morphine abstinence effects in mice were desensitization mentioned earlier, which is associated pendent on the environment where the drug was with elevated reactivity of dopaminergic system. given and the tests were performed [4, 48, 113]. Functional, i.e. pharmacodynamic tolerance is For instance, rats that received morphine for four another type of tolerance. This tolerance can be days and were tested for antinociceptive response acute or chronic. Three mechanisms are believed in the same cage developed tolerance to antinoci- to be involved: rapid desensitization, linked with ceptive drug effect. However, if fourth drug dose receptor phosphorylation, internalization of the re- was administered in another environment, antinoci- ceptor, and induction of genomic changes leading ceptive morphine action was much stronger [114]. to a decrease in the rate of synthesis of receptor and Furthermore, the fact whether the test is per- in synthesis of defective forms of the receptor. formed under drug influence or not, can be conse- Some addiction-forming substances cause very quential during tolerance development. Carlton and quick development of tolerance. Benzodiazepines, Wolgin [13] examined anorexic effect of ampheta- barbiturates, nicotine and alcohol can be included mine in starving rats, which were allowed only short into this category. It is sometimes connected with access to food during the day. If amphetamine was tachyphylaxis caused by receptor occupancy or de- administered before food availability, tolerance to pletion of neurotransmitter stores, due to drug-in- anorexic action developed over four days. However, duced neurotransmitter release. if amphetamine was given after feeding, the drug Chronic administration of addictive substances administration on fifth day before feeding evoked leads to slow, but much longer-lasting tolerance. full anorexic effect. An array of adaptive changes occur in an organism Similar dependence on the schedule of drug ad- trying to preserve homeostasis. The mechanisms ministration was observed for LSD-induced disrup- involved can be very diverse. As mentioned earlier, tion of operant behavior [79]. they can embrace receptors, their coupling with G The significance of environmental conditions proteins and second messengers-generating en- for development of amphetamine-induced toler- zymes, membrane channels, intracellular calcium ance and sensitization has been discussed by Wol- distribution, and genomic changes. As a result of gin [130]. If environmental factors play such criti- adaptation, and in spite of permanent presence of cal a role in animals, unquestionably they can be a drug attacking its structures, an organism functions even more crucial in humans. almost normally, compensating for drug effects. To assess a degree of tolerance, the tolerance Physical dependence index was introduced. It is defined as a ratio of Dependence was believed to be one of the con- a drug dose acting in an animal with full tolerance sequences of tolerance development. Physical de- to a dose evoking the same response in an animal pendence is characterized by emergence of specific coming into contact with a drug for the first time. behavioral syndrome and symptoms following sud- The tolerance index of LSD and other hallucino- den discontinuation of drug administration in ani- gens, and also some opioids, was estimated at mals and humans who previously had been under 10–100 while the respective value for pentobarbital its chronic influence, or after the treatment of an is 2–3. Tolerance to LSD also develops rapidly addicted individual with an addictive drug antago- [125]. nist. It is undeniably the result of activation of ho- Development of tolerance to a drug is a com- meostatic mechanisms, responsible for tolerance plex phenomenon, and environmental factors play development, which in this situation miss their an important role in this process, which can be ex- aims without inhibition by the drug. perimentally demonstrated not only in humans but It should be noted that symptoms of drug with- also in laboratory rodents. Tolerance development drawal can be observed also in the case of drugs, and degree can depend for example on whether an with no addiction liability, and even those exerting

ISSN 1230-6002 311 J. Vetulani aversive action. For example, abstinence symptoms ported by Leith and Barrett [74], who reported that were reported after chronic neuroleptics admini- electric stimulation of the brain was less effective stration [2, 34]. after withdrawal from chronic amphetamine admi- Tolerance and physical dependence are particu- nistration. It was later confirmed by Wise and Munn larly dangerous aspects of action of some drugs [127], and similar effect was observed following since: ethanol withdrawal [105]. Dackis and Gold [23] 1. When tolerance begins to develop, progres- were the first who postulated that this was an effect sively higher drug doses are required to obtain the of the decreased dopamine level, which was further same therapeutic effect, which accelerates tolerance substantiated by the studies into cocaine [55, 86, development leading to the vicious circle effect. 100, 104], amphetamine [87, 104], opiate [94, 104] 2. Abstinence symptoms are aversive, unpleas- and alcohol [104] action using microdialysis tech- ant for the patient, who starts to seek a drug not for nique. its direct rewarding action but to avoid disagree- This approach differs from that adopted earlier, able abstinence symptoms. which linked dependence with abstinence symp- 3. Long-term use of addiction-forming drugs toms and the whole constellation of accompanying evokes so called chronic tolerance, connected with aversive effects. A decrease in dopaminergic activi- permanent changes in the brain, which lead to drug ty after drug withdrawal is a phenomenon common abuse relapse after detoxification, and constitute for a variety of addictive substances, such as stimu- a personality trait that predisposes an addict to lants, opioids, alcohol, nicotine, evoking diverse, seeking a comforting drug. sometimes negligible symptoms upon withdrawal. The degree of physical dependence is different The mode of drug intake – active or passive – for different addictive substances. Opioids, ethanol, may be critical for the biochemical and behavioral barbiturates and anxiolytics evoke relatively strong consequences. It is a common observation that physical dependence. Cannabinoids cause rapid to- people treated with morphine as an analgesic and lerance development but weak physical dependence. receiving it according to the doctor-controlled sche- Hallucinogens, such as LSD, despite the rapid tole- dule develop morphine-dependence much more rance, elicit no physical dependence. Also, amphet- rarely than persons actively self-administering mor- amine withdrawal does not cause physical absti- phine for recreational purposes. The studies on the nence signs. effect of ethanol in rats demonstrated that the ef- It appears that strong abstinence symptoms are fects of the drug in rats actively working for alco- observed after withdrawal from chronic use of those hol reward were different than those in yoked con- addiction-forming substances which inhibit neu- trols (cf. [68]). ronal activity: opioids do that by increasing potas- Pharmacological history can also influence de- sium ion influx and decreasing calcium ion influx pendence development, which is authenticated by into neurons, while barbiturates and anxiolytics en- the fact that animals previously receiving addictive hance GABAergic transmission, and elevate chlo- substances learn more quickly to self-administer ride ion influx. The abovementioned inhibitory sys- drugs than those which never encountered them tems are interspersed throughout the central nervous earlier [52, 91]. system, thus no wonder that the disturbance of their A growing number of studies have focused on a function causes very complex and diverse absti- role of stress in triggering drug abuse [92, 112]. nence symptoms. It seems that clinically important Stress plays a crucial and complex role in drug kinds of physical dependence are associated with self-administration and self-administration reinsta- brain effort to adapt central inhibitory processes. tement. Relapse and violent craving can be initiated Psychical dependence both in animals and humans by a stressful stimulus, and it can be blocked by CRF administration [108]. Substances which elevate stimulatory neuro- The mechanism of stress-induced craving attack transmitter actions do not cause strong physical de- differs from the mechanism of relapse precipitation pendence, inducing, however, very potent psychi- by priming effect or drug-associated cues, as the cal dependence. former engages noradrenergic system [118]. Dysphoria after drug withdrawal is caused by Recently, molecular biology techniques have depression of the reward system. It was first re- been employed in the studies of drug addiction.

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Addictive drug-induced secondary messenger re- Over the last decade, a number of specific loci sponses [109], self-administration effect on the ex- have been identified, that regulate different aspects pression of early response genes coding for neuro- of drug response: initial sensitivity, tolerance and transmitter receptors [80], and the influence of sensitization development. In mid nineties, 50 loci antisense nucleotides on the action of addictive potentially involved in the regulation of response to substances [40, 60, 95] have been investigated from alcohol, morphine, NO, amphetamine and haloperi- mid nineties. The forecasts presaging a surge in dol were identified using recombinant inbred mice cellular neurobiological studies of drug addiction [21]. Although initially many results were suspec- [24, 109] has proven fully correct. ted to be falsely positive, in the last years, loci responsible for 24 responses to addictive substances, mainly alcohol, cocaine and barbiturates, were es- Addiction and heredity tablished beyond any doubt [22]. Discovery of QTL not necessarily has to con- The hereditary base for drug addiction has been clusively resolve whether indeed a gene responsi- hypothesized long ago, and breeding strains of rats ble for certain trait (e.g. morphine preference) re- preferring or avoiding alcohol (cf. [68]) confirms sides in these loci, since QTL may constitute a re- this notion. However, in humans it was difficult to gulatory sequence, which modifies expression of ascertain whether environmental and family factors other functional genes. If unknown genes are to be were indeed consequential. Especially in alcoholic discovered on the basis of their expression, it is environments, drinking could be regarded as a cul- necessary to review all mRNA transcripts to deter- tural pattern, not connected directly with heredity. mine, which genes are induced or repressed by Only in the last decade, the role of inherited factors a drug. These genes can be cloned, sequenced and has been proven with certainty as a result of inten- identified by comparison with the sequences al- sive examination of twins and families. ready published in databases. Such identification High variability of dopamine D2 receptor in the can be performed by differential display method. human brain is certainly determined genetically. In- This method was applied to identify the abovemen- dividual differences in vulnerability to addiction tioned CART gene encoding new neuropeptide, in- are based, inter alia, on variations in the activity of duced by cocaine and amphetamine [35]. Identifi- dopaminergic neurotransmission, which partly can cation of the genes implicated in drug addiction be attributed to genetic differences. It has been will certainly be facilitated by the technology in- shown that in white population, Taq1A1 and B1 volving automatic preparation of micromatrices markers of restriction length fragment polymor- called DNA chips [27]. phisms (RLFP) of D2 receptor gene are linked with vulnerability to drug addiction, and their incidence REFERENCES is higher in alcoholics and addicts abusing several drugs (polyusers), especially those who prefer co- 1. Ago A.: Sexual motivation – an inquiry into events caine and amphetamine [121]. It can be expected determining the occurrence of sexual behavior. Behav. that dopamine receptor expression is weaker in the Brain Res., 1999, 105, 129–150. subjects bearing the gene with these polymorphism, 2. Amore M., Zazzeri N.: Neuroleptic malignant syn- which, as mentioned above, can be associated with drome after neuroleptic discontinuation. Prog. Neuro- psychopharmacol. Biol. Psychiat., 1995, 19, 1323–1334. higher sensitivity to rewarding drug action [124]. 3. Bals-Kubik R., Ableitner A., Herz A., Shippenberg Individual differences in vulnerability to addic- T.S.: Neuroanatomical sites mediating the motivatio- tion-forming drugs are graded, and the genes re- nal effects of opioids as mapped by the conditioned sponsible for the strength of tendency toward drug place preference paradigm in rats. J. Pharmacol. Exp. addiction are minor genes. Their loci were called Ther., 1993, 264, 489–495. quantitative trait loci (QTL). Therefore, QTL are 4. Baptista M.A., Siegel S., MacQueen G., Young L.T.: such loci in which the genes connected with pheno- Pre-drug cues modulate morphine tolerance, striatal c-Fos, and AP-1 DNA binding. NeuroReport, 1998, 9, typic differences in vulnerability are located. Al- 3387–3390. though individual QTL have slight effect, their 5. Bechara A., Van der Kooy D.: The tegmental pedun- groups can be responsible for genetic determinants culopontine nucleus: a brain-stem output of the limbic of addiction. system critical for the conditioned place preferences

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