I. Introduction

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If the entire materia medica at our disposal were limited to the choice and use of only one drug, I am sure that a great many, if not the majority, of us would choose opium (Macht, 1915).

Opium is the dried milky juice of the unripe seed capsule of the poppy, the Papaver somniferum. The word opium is derived from "opos", the Greek word for juice. The first reference to this juice was by Theophrastus (300 B.C.), mentioning it mekonion. The medicinal and nonmedicinal use of opium by the ancient Greeks and Romans is not well documented, but it is generally believed that they were aware of the euphoric and narcotic (from the Greek word for stupor) properties of opium. They probably also knew that it could be applied for pain relief and dysentery. There are suggestions that the opium poppy was cultivated in Persia back to the end of the third millennium B.C. Arabic physicians used opium quite often and Arabic traders brought opium from the eight century A.D. on, first to the East, to India and China, and later to Europe. The Mohammedan prohibition of wine and the banning of tobacco smoking in China may have favored the spread of opium. With the "worldwide" availability of opium, the phenomenon addiction raised its head. An attempt to forbid the import of opium into China by the authorities, led to the so-called "Opium War" between England and China, with the result that opium trade was permitted (Macht, 1915).

Medicinal use of opium was stimulated by the famous physician Paracelsus at the end of the middle ages by the introduction of tincture of opium or laudanum. The name laudanum is probably derived from the Latin "laudandum", which means something to be praised. Several preparations of laudanum were made, all of which contained more or less opium and many other ingredients. Laudanum and other preparations of opium (e.g., extracts of opium and pilulae opii) were widely used for a number of indications. In the beginning of the 19th century, the pharmacist Sertürner isolated an important active principle of opium, the alkaloid morphine (Sertürner, 1806). Morphine was named after the Greek god of dreams, Morpheus. During the nineteenth century many other alkaloids were isolated from opium, some of them with a comparable, but weaker action than morphine and others with a different pharmacological profile. From the mid-nineteenth century on, morphine was parenterally administered as premedication for surgical procedures and for postoperative and chronic pain.

Morphine appeared to be as addictive as opium. This stimulated research to develop nonaddictive opiates, substances with the beneficial therapeutic actions of morphine but lacking its addictive potential. In 1898, heroin was introduced as the ideal nonaddictive substitute for morphine. It lasted quite a long time before it became clear that heroin has a higher addictive potential than morphine. Several claims for nonaddictive opiates followed, but to date, none of these claims have been substantiated. During the 20th century a number of drugs were synthesized with a morphine-like action, but with a structure somewhat different from that of morphine. Examples are meperidine (1939) and methadone (1946). Structure-activity studies with the morphine molecule as starting point resulted in the synthesis of nalorphine, a mixed agonist-antagonist: the drug reverses the typical actions of morphine and it precipitates the abstinence syndrome in opiate addicts, but it also has analgesic properties. Additional research led to the discovery of pure opiate antagonists such as naloxone.

The structural similarities between all substances with an opiate-like action and the discovery of opiate agonists, mixed agonist-antagonists and antagonists, generated the concept of opiate receptors. Goldstein et al. (1971) used radiolabeled levorphanol to discover opiate-binding sites in subcellular fractions of mouse brain. When radioligands with high specific activity became available, stereospecific opiate-binding sites in the central nervous system were demonstrated (Pert and Snyder, 1973; Simon et al., 1973; Terenius, 1973). The finding of opiate-binding sites and the fact that opiate antagonists exerted some intrinsic activity in opiate naive subjects and could diminish nondrug-induced analgesia stimulated thoughts about endogenous compounds with opiate-like action (Lasagna, 1965; Jacob et al., 1974; Akil et al., 1976; Buchsbaum et al., 1977).

In this review, the term opioid will be used for all substances with an opiate-agonistic action. Endogenous and exogenous opioids can be distinguished, depending on whether the substances are normally present in the body or not. The first indication for endogenous opioids came from studies showing that brain extracts contain opioid-like activity (Terenius and Wahlström, 1974; Kosterlitz and Waterfield, 1975). Further investigations led to the isolation and characterization of the enkephalins (from the Greek "in the head"), the first discovered endogenous opioids (Hughes et al. 1975). There appeared to be two pentapeptides, Met- and Leu-enkephalin. The structure of Met-enkephalin was also present as the N-terminal part of the earlier isolated C fragment, part of the fat-mobilizing pituitary hormone -lipotropin (Bradbury et al., 1976). The C fragment, later termed -endorphin (from endogenous morphine), and the enkephalins were shown to induce similar actions as morphine in a number of in vitro and in vivo test procedures. Repeated administration of -endorphin led to tolerance to its analgesic action and to morphine-like withdrawal symptoms upon a challenge with naloxone (Van Ree et al., 1976; Wei and Loh, 1976). Furthermore, -endorphin and the enkephalins were self-administered by laboratory animals, indicating the rewarding properties and addictive potential of these substances (Belluzzi and Stein, 1977; Van Ree et al., 1979; Goeders et al., 1984). Thus, the endogenous opioids may share all its typical opioid-like actions with morphine, both after acute and chronic administration.

After the discovery of another class of endogenous opioids, the dynorphins, (dyn... . from Greek dynamis = power) (Goldstein et al., 1979, 1981), it appeared that most endogenous opioids are generated by enzymatic processing from three precursor molecules, pro-opiomelanocortin (POMC),² proenkephalin (ProEnk), and prodynorphin (ProDyn) (Nakanishi et al., 1979; Kakidani et al., 1982; Noda et al., 1982). Each of these precursors has an unique anatomical distribution throughout the central nervous system (CNS) and in peripheral organs (Akil et al., 1984; Khachaturian et al., 1985). The anterior and neurointermediate lobes of the pituitary gland are major sites of POMC biosynthesis. In the brain, there are two distinct nuclei that contain POMC neurons: the arcuate nucleus of the hypothalamus and the nucleus tractus solitarius. Widespread projections from these neurons are present throughout the brain. From POMC the opioid -endorphin is generated, but also - and -endorphin and several nonopioid peptides, e.g., adrenocorticotropin and - and -melanocyte-stimulating hormones. ProEnk-containing neurons are widely distributed throughout the brain and consist of both local circuits and long projection neurons. ProEnk is the source of Leu- and Met-enkephalin and several extended forms of these pentapeptides. ProDyn-containing cell bodies have a characteristic widespread distribution throughout the CNS. ProDyn-containing neurons have both short and long projection pathways and can generate several opioid peptides, including - and -neoendorphin, dynorphin A, and dynorphin B.

Martin et al. (1976) first postulated the existence of multiple types of opioid receptors. Based on their behavioral and neurophysiological findings in the chronic spinal dog, they distinguished between the µ type (for morphine, which induces analgesia, hypothermia, and meiosis among others), the -type (for ketocyclazocine, which induces depression of flexor reflexes and sedation among others), and -type (for SKF10,047 or N-allylnormetazocine, which induces tachycardia, delirium, and increased respiration among others). Later, a fourth type of opioid receptor, named  (for vas deferens) was identified (Lord et al., 1977). Additional research revealed that the -type receptor is nonopioid in nature, leaving three main type of opioid receptors, µ, , and  (Mannalack et al., 1986). These receptors, belonging to the family of seven transmembrane G protein-coupled receptors, have been cloned using molecular biological techniques (Evans et al., 1992; Kieffer et al., 1992; Reisine and Bell, 1993; Uhl et al., 1994; Knapp et al., 1995). Apart from occurring as separate molecules, brain µ- and -opioid receptors have also been suggested to function as a µ- receptor complex (for review, see Rothman et al., 1993). In slices of rat neostriatum, activation of this complex, which displays an affinity profile for opioid ligands different from nonassociated µ- and -opioid receptors, has been shown to inhibit dopamine (DA) D1-receptor-stimulated adenylate cyclase activity (Schoffelmeer et al., 1992, 1993).

Interestingly, there seems to be some preference for the different endogenous opioid ligands for the different receptors: -endorphin for µ, enkephalins for , and dynorphins for . Subtypes of these receptors have been proposed (µ₁, µ₂; ₁, ₂; 1, 2, 3) (Dhawan et al., 1996) and some evidence is available for some other receptor types [e.g., the  receptor which was labeled as -endorphin specific (Wüster et al., 1979; Narita and Tseng, 1998)]. The International Union of Pharmacology subcommittee on opioid receptors has proposed another terminology to distinguish the opioid receptors: OP1, OP2, and OP3 for the , , and µ receptor, respectively (Dhawan et al., 1996) (Table 1). Another opioid-like receptor has been cloned, termed the ORL-1 opioid receptor (Fukuda et al., 1994; Mollereau et al., 1994; Lachowitz et al., 1995). In addition, some novel endogenous opioids have been isolated, termed orphanin FQ which seems to be an endogenous ligand for ORL-1 and endomorphin-1 and endomorphin-2 which have been proposed to represent a highly specific endogenous ligands for the µ receptor (Meunier et al., 1995, Reinscheid et al., 1995; Zadina et al., 1997). Since the discovery of orphanin FQ/nociceptin released the ORL-1-opioid-like receptor of its orphan status, a novel nomenclature of this receptor and its endogenous ligand has been proposed. By analogy to the known opioid receptors (µ, , and ) the new name for ORL-1 would be o (omicron), after its endogenous ligand (orphanin). Metonymorphin, xenorphin, or endomicron were proposed as possible new names for orphanin FQ/nociceptin (Henderson and McKnight, 1997). It should, however, be noted that, if orphanin FQ/nociceptin were given a new name, then the possible new name for ORL-1 would change as well. We suggest the use of the combination xenorphin/ receptor and consequently XOR and OP4 for the molecular biology and International Union of Pharmacology recommendation nomenclature, respectively (Table 1).

It was generally believed that addicts will initiate their drug-taking habit because of the inherent euphoric action of opioids and will continue their habit to prevent the occurrence of withdrawal symptoms. Therefore, most addiction research was directed at the underlying mechanisms of physical dependence and related withdrawal symptoms. In this framework, drug-taking behavior has been conceptualized in the context of drive reduction (Hull, 1943). There emerged, however, some problems with this concept. The relapse rate in opioid addiction is high, also when the withdrawal symptoms have already disappeared for a long time. Moreover, physical dependence also develops in patients treated with opioids, for example, pain relief, but the percentage of these patients that initiates addictive behavior is quite low. Furthermore, physical dependence hardly develops with some other drugs with high-addictive potential such as cocaine. These observations stimulated research to delineate other factors that could explain the development and maintenance of opioid addiction and drug addiction in general. Among these are the reinforcing properties of drugs, drug-induced craving, and the concept of psychic dependence. During the last decades, several consensus meetings have been organized to provide workable terminology and concepts. However, in the literature of today, the terms addiction, dependence, and drug abuse are still used interchangeably.

Drug abuse may refer to "the use, usually by self-administration, of any drug in a manner that deviates from the approved medical or social patterns within a given culture" (Jaffe, 1990). Drug dependence may be a syndrome manifested by a behavioral pattern in which the use of a given psychoactive drug or class of drugs is given much higher priority than other behaviors that once had higher value. In its extreme form drug dependence is associated with the need for continued drug exposure (compulsive drug use), and it exhibits the characteristic of a chronic relapsing disorder (Edwards et al., 1981). Addiction can be regarded as a severe degree of drug dependence that is an extreme on the continuum of involvement with drug use (Jaffe, 1990). The system of diagnosis for mental disorders published in DSM-IV by the American Psychiatric Association (1994) uses the term substance dependence instead of addiction for the overall behavioral syndrome. Substance dependence is defined as "a cluster of symptoms indicating that the individual continuing use of the substance despite significant substance-related problems". Withdrawal symptoms and tolerance can be present but are not a conditio sine qua non for the diagnosis substance dependence. Substance abuse, a less severe diagnosis, involves a pattern of adverse consequences from repeated use that does not meet criteria for substance dependence (O'Brien, 1996).

The need for continued drug use in drug dependence and addiction is basically of a psychic nature. Psychic dependence has been defined by "a condition in which a drug produces a feeling of satisfaction and a psychic drive that requires periodic or continuous administration of the drug to produce pleasure or to avoid discomforts" (Eddy et al., 1965). Besides development of psychic dependence, physical dependence ["an adaptive state that manifests itself by intense physical disturbances when the administration of the drug is suspended" (Eddy et al., 1965)] can contribute to compulsive drug use but it is not necessary for continued use. Although the nature of psychic and physical dependence is different, both are considered a priori to result from adaptive changes of neural systems in the brain in response to repeated drug use and/or exposure.

With regard to use of drugs, there exists a continuum from no drug use via controlled use to an actual dependence on the drug. The transition from controlled use to dependence may be referred to as initiation of drug dependence. It has been suggested that initially the use of a particular drug is related to its ability to produce effects of well being and euphoria. Environmental variables and/or individual characteristics contribute to whether or not an individual becomes dependent on the drug. At this point a basic emotional feature may have been altered by repeated drug use, which in turn is responsible for the need to experience the effect of the drug again and again. This need is basically of a psychic nature, but it can contain physical elements such as physical dependence. Once a person has become dependent on a drug, discontinuation of drug use is difficult. Even after a prolonged period of abstinence, addicts can relapse into their former habit of drug dependence. A factor that may be important for relapse is craving, a (intense) desire to re-experience the effects of the drug (Rankin et al., 1979; Markou et al., 1993). Drug craving can be conceptualized as the incentive motivation to self-administer a previously consumed drug. This craving may be present during continuous use of the drug and long after abstinence, and may develop on basis of incentive sensitization mechanisms in which associative learning plays a role (Bolles, 1975; Stewart et al., 1984; Robinson and Berridge, 1993). Besides craving, other factors may contribute to relapse, which is the major target for treatment programs of drug addiction.

	II. Reinforcement and Motivation

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Alterations in the organism's environment trigger sensory mechanisms and thus generate information that is conveyed to the CNS. This information and other inputs into the brain are integrated at several levels and can activate or inhibit the brain output systems, including motor systems, thus eliciting behavioral changes. The purpose of these behavioral changes is the adaptation of an organism to changes in environmental conditions, with the ultimate result that survival of the organism or its species is ensured. The extreme of an environmental continuum is that the organism approaches a desirable (pleasant) and avoids a noxious (aversive) environment.

The setpoint of behavioral reactions is determined by genetic factors but its value is being modulated continuously by new experiences and, as a consequence, by acquired behavioral patterns. Behavioral reactions can be acquired through the association of stimuli that are originally neutral to innate reactions. The processes involved are types of associative learning. Forms of nonassociative learning include habituation and sensitization. During habituation, the reflex reaction elicited by a nonnoxious stimulus decreases when the stimulus is presented repeatedly. Sensitization involves an increased reflex reaction to a wide range of stimuli given shortly after the presentation of an intense or noxious stimulus. Through nonassociative learning the organism learns about the properties of one particular stimulus.

Two major classes of associative learning are distinguished: classical and instrumental conditioning. During classical conditioning, a concept which was introduced by Pavlov (1927), the organism learns about the relationship between one stimulus in its environment and another stimulus (the unconditioned and the "neutral" conditioned stimulus). The unconditioned stimulus activates an established reflex and thus elicits an unconditioned reaction (e.g., the presence of food in the mouth results in salivation). Before conditioning the conditioned stimulus does not elicit the unconditioned reaction. After association of the conditioned stimulus and the unconditioned stimulus, the conditioned stimulus evokes a conditioned reaction that resembles the unconditioned one (e.g., when a sound is presented repeatedly, either immediately before or while food is in the mouth, salivation will ultimately follow after the presentation of the sound). Classical conditioning allows the organism to predict the coherence between events in its environment. The conditioned stimulus has become an anticipating signal for the occurrence of the unconditioned stimulus. The conditioned response can prepare the organism to deal with the result of the unconditioned stimulus more efficiently.

Instrumental conditioning, introduced by Thorndike (1913), refers to the process of learning about the relationship between a stimulus and the behavior of the organism. When a certain behavioral act is followed by a favorable change in its environment, the organism tends to repeat this behavior (law of effect). This change in environment can be the occurrence of a pleasant stimulus or the removal of an aversion or noxious stimulus. In instrumental conditioning, in contrast to classical conditioning, the (behavioral) response changes the probability that the unconditioned stimulus will appear, allowing the organism to have more or less control over its environment. Four types of instrumental conditioning can be distinguished: positive reinforcement (presentation of a pleasant stimulus), punishment (presentation of an aversive stimulus), negative punishment (removal of a pleasant stimulus), and negative reinforcement (removal of an aversive stimulus). The frequency of behavioral responses usually increases when positive or negative reinforcement is operative and decreases in the case of punishment, including negative punishment.

Many studies on positive reinforcement in experimental animals use lever manipulation as the behavioral response, and the conditioning in such experiments is also termed operant conditioning. This type of conditioning is often investigated in the so-called "Skinner box" (Skinner, 1938). A typical experiment involves placement of a hungry animal in a box in which a horizontal lever protrudes from a wall. Pressing the lever is followed by presentation of food. The animal learns that this behavioral act is reinforced by food. Thus, when the animal is hungry and is placed in the same box it is likely to press the lever to obtain food. The behavioral act in operant conditioning is termed "operant", and the pleasant stimulus that tends to increase the frequency of the operant is called "positive reinforcer".

Operant conditioning has had a major influence on addiction research and contributed to the concepts in this field. Using the drug self-administration paradigm, it was shown that most if not all abused drugs could serve as positive reinforcer. Another reinforcementrelated property of drugs of abuse is the ability to potentiate the effectiveness of other rewards. The effects of drugs of abuse on the reinforcing effects of intracranial electrical self-stimulation (ICSS) offers a useful model to quantify such property. Besides positive reinforcing effects drugs of abuse have other motivational properties and even may induce a central motivational state. In addition, drugs of abuse are able to confer their positive motivational properties to environmental cues through classical conditioning processes, which in turn, by facilitating successful contact with the drug stimulus, could contribute to drug addiction. The self-administration procedure allows to study certain drug-induced motivational processes, such as craving, using specific methodology like progressive ratio, choice, extinction, conditioned reinforcement, and second-order schedule procedures (Markou et al., 1993). Animal models in which the motivational properties of drugs of abuse can be quantified and in which the drug is investigated, but not self-administered, are, for example, the conditioned place preference and the second-order schedule paradigm. In addition, other properties of the drug such as the discriminative stimulus properties may contribute to the drug use habit. The italicized animal models of drug dependence will be discussed in more detail.

In literature, the concepts of reward and of (positive) reinforcement are often used in describing effects of drugs of abuse. These terms carry different meanings, however, in the sense that reward implies a positive subjective effect of a stimulus, whereas positive reinforcement is strictly a measure of the beneficial effect of a stimulus on acquisition or frequency of a required behavioral response. Thus, whereas reinforcement can be assessed experimentally, reward is a matter of interpreting experimental findings. In translation to drugs of abuse, reward implies the positive subjective effect of the drug and positive reinforcement the facilitating effects of a drug on the learning of a required behavioral response.

In 1940, Spragg (1940) first suggested that drugs could function as positive reinforcers. His suggestion was based on experiments with chimpanzees, which were made physically dependent on morphine by daily treatment with morphine for several months. Then the animals could learn to select one of two boxes concealing a syringe filled with a morphine solution, which would subsequently be administered to the animal by the experimenter. The monkeys opened the box containing the morphine syringe more often than the other box that contained food.

Self-injection by animals was first reported by Headlee et al. (1955), who demonstrated that morphine was injected i.p. by physically dependent rats. In the early 1960s, several investigators developed techniques for i.v. self-administration in rats and monkeys (Weeks, 1962; Thompson and Schuster, 1964). Typically, an animal is surgically prepared with a chronic, indwelling i.v. catheter, which is guided s.c. to the arm, back, or head. Depending on whether primates or rodents are tested, restrainment in the test cages is used. Whereas monkeys are usually restrained by a primate chair or harness and arm arrangement, rats are allowed to move about freely in the test cage. The i.v. catheter is connected with an automatic infusion pump. Intravenous drug injections are made contingent upon a certain behavioral response under specified schedules of reinforcement.

Initial research with the i.v. self-administration method demonstrated that both opioid-dependent and opioid-naive animals would press a lever to receive injections with morphine (Weeks, 1962; Thompson and Schuster, 1964; Deneau et al., 1969). It became clear that besides morphine a wide variety of psychoactive drugs from different pharmacological classes could serve as positive reinforcers in animals. These drugs include psychomotor stimulants, such as amphetamine and cocaine (Pickens and Harris, 1968; Pickens and Thompson, 1968; Van Ree et al., 1978), dissociative anesthetics, such as barbiturates and benzodiazepines (Davis et al., 1968; Pilotto et al., 1984), ethanol (Smith and Davis, 1974), ⁹-tetrahydrocannabinol and the cannabinoid receptor agonist WIN 55,212 (Van Ree et al., 1978; Takahashi and Singer, 1979; Martellotta et al., 1998), phencyclidine (Balster and Woolverton, 1980), and nicotine (Lang et al., 1977; Goldberg and Spealman, 1982). In general, drugs that are self-administered by animals are abused to some extent by humans although there are exceptions. For example, rats will readily self-administer apomorphine (Baxter et al., 1974; Colpaert et al., 1976), whereas humans will not become dependent on this drug because of its nausea-promoting effects. Conversely, drugs that fail to initiate or maintain self-administration behavior in animals have no or little abuse potential in humans. It should, however, be noted that not all drugs are equally powerful as positive reinforcers in animals. For instance, nicotine is self-administered under a narrower unit dose range than opioids and cocaine. Nonetheless, the drug self-administration model can serve as a useful model for the prediction of the abuse potential of drugs in humans (Thompson and Young, 1978; Van Ree et al., 1978; Van Ree, 1979; Collins et al., 1984).

Intravenous self-administration in rats and monkeys is the most frequently used to assess the reinforcing effects of drugs. However, other models using other species (e.g., dogs, cats, mice, or pigeons) or other routes of administration (e.g., intragastric, oral, inhalation, i.c.v., or intracerebral) have been developed (e.g., Smith et al., 1976; Jones and Prada, 1977; Carroll and Meisch, 1978; Van Ree and Niesink, 1978; Van Ree et al., 1979; Kilbey and Ellinwood, 1980; Van Ree and De Wied, 1980; Bozarth and Wise, 1981b; Criswell, 1982; France et al., 1991; Mattox and Carroll, 1996).

Although the positive reinforcing effects of a drug are the most important stimuli in self-administration behavior, other factors may contribute significantly to operant behavior and thus self-administration behavior. These factors include, among others, conditioned or secondary reinforcement and negative reinforcement. Distinctive, neutral environmental stimuli that are repeatedly associated with the primary reinforcing effects of a drug, can acquire (secondary) reinforcing properties through classical conditioning (Davis and Smith, 1976; Beninger, 1983; Stewart et al., 1984). These stimuli are then called conditioned or secondary reinforcers. Although the primary reinforcing effects of the drug mainly determine the initiation of selfadministration behavior, the conditioned or secondary reinforcers maintain this behavior over time, even in the absence of the primary reinforcer. For example, a red light switched on when a monkey presses a lever to obtain a morphine injection subsequently supports lever-pressing when morphine is temporarily not available (Schuster and Woods, 1968). The effects of conditioned reinforcers diminish over time when the drug injection is no longer available. In animals made physically dependent on drugs, an additional factor influencing self-administration behavior is exerted by negative reinforcement, i.e., the animals will continue to self-administer a drug to alleviate or overcome the presumably aversive (negative) state of withdrawal (Solomon, 1980; Koob et al., 1989a).

Intracranial electrical self-stimulation (ICSS) is widely used to explore the involvement of particular brain circuits in reward. Typically, when an animal is equipped with an electrode placed in a "positive" brain area and given the opportunity to perform a behavioral response, e.g., pressing a lever, that is followed by a short-pulse train of electrical current via the electrode, the animal will initiate and maintain responding. Thus, the stimulation serves as an operant reinforcer (Skinner, 1938). The phenomenon of ICSS has been described initially by Olds and Milner (1954), who observed this behavioral pattern in rats equipped with electrodes in the septal area of the brain. ICSS was suggested to be linked to brain circuits implicated in natural incentives such as food and sexual contact (Olds and Milner, 1954; Trowill et al., 1969; Mogenson and Wu, 1982). However, it appeared that a variety of brain structures, related and not related to natural incentives, could support ICSS (Olds et al., 1971; Wise, 1996). Although ICSS resembles other types of reward, it has some unique properties. In most stimulated sites, the rewards are strong and immediately present during stimulation and it lasts not much longer than the stimulus itself. The brain structures in which ICSS can be elicited have been designated as reward or pleasure centers. Whether these various brain structures belong to a single system or to multiple reward circuits operating in parallel is still a matter of debate.

In general, drugs of abuse facilitate ICSS in that the frequency current-response function is shifted leftward in a parallel manner and/or the threshold for eliciting ICSS is decreased. Such findings have been documented for morphine and heroin (Esposito and Kornetsky, 1977; Van Wolfswinkel and Van Ree, 1985b; Hubner and Kornetsky, 1992; Bauco et al., 1993), amphetamines (Gallistel and Karras, 1984; Schaefer and Michael, 1988b), cocaine (Bain and Kornetsky, 1987; Frank et al., 1988; Van Wolfswinkel et al., 1988; Bauco and Wise, 1997), nicotine (Huston-Lyons et al., 1992; Bauco and Wise, 1994; Ivanova and Greenshaw, 1997; Wise et al., 1998), phencyclidine (Kornetsky and Esposito, 1979; Carlezon and Wise, 1993b), and ⁹-tetrahydrocannabinol (Gardner et al., 1988, 1989; Lepore et al., 1996). With respect to ethanol, the data so far are not fully consistent (De Witte and Bada, 1983; Schaefer and Michael, 1987; Bain and Kornetsky, 1989, Moolten and Kornetsky, 1990; Lewis and June, 1994). It seems that facilitation of ICSS is an effect that drugs of abuse have in common, despite the differential pharmacological characteristics of these drugs. Thus, facilitation of ICSS may be relevant for the dependence-creating properties of drugs and worthwhile to analyze in detail to understand the basic mechanisms of drug dependence.

Concerning the neurobiology of ICSS, catecholamines and especially DA have been implicated as important neurotransmitters in the reward circuit (Crow, 1972; German and Bowden, 1974; Wise, 1978). Evidence that DA is involved in ICSS stems from anatomical studies (Corbett and Wise, 1980), lesion experiments (Fibiger et al., 1987), pharmacological manipulations (Zarevics and Setler, 1979; Wise and Rompré, 1989), and neurochemical studies (Nakahara et al., 1992; Fiorino et al., 1993; Di Chiara, 1995). It has been suggested that in particular the mesocorticolimbic DA system is important for ICSS.

Affective (rewarding or punishing) stimuli can evoke approach or avoidance behavior, respectively (Schneirla, 1959). When these stimuli are paired with a neutral environment, these neutral environmental stimuli can gain the capacity of evoking similar approach or avoidance behavior as the affective stimulus (Pavlov, 1927). Affective effects of drugs can thus be assessed by giving the animal the possibility to express attraction or aversion to environments paired with effects of drugs. This principle is the basis of the place-conditioning method. In place-conditioning, individuals are exposed to distinctive neutral environmental cues as conditioning stimulus, after being treated with a drug, the effects of which will then act as an unconditioned stimulus (Hoffman, 1989; Schechter and Calcagnetti, 1993; Bardo et al., 1995). A test apparatus, consisting of (at least) two compartments with distinct visual, olfactory, or tactile cues is used, so that an animal will be able to distinguish between these compartments. In alternating conditioning sessions, the animal is confined to one compartment after being injected with a drug. In a subsequent session, the animal is injected with placebo and placed in the other compartment. This procedure is repeated several times [although significant place-conditioning can be achieved with a single conditioning session (Mucha et al., 1982; Bardo and Neisewander, 1986)] so that the animal learns to associate the cues of one distinct compartment of the test apparatus with the effects of the test drug. On a day after these conditioning sessions, the animal is placed in the test apparatus, without any confinements. The animal will have the opportunity to move freely around the different compartments, and the relative amount of time spent in these compartments is measured. When the animal spends significantly more time in the drug-paired part of the apparatus, it is said to display conditioned place preference. Likewise, a smaller amount of time spent in the drug-paired environment reflects conditioned place aversion.

With respect to conditioned place preference, there are some experimental variables that need to be taken account of. First, the structure of the place-conditioning apparatus may be such that an animal has an initial preference for one or the other compartment. If, for example, an apparatus consisting of a black and a white compartment is used, rats usually have a natural preference for the black (i.e., darker) side of the apparatus. Such preference may be revealed by subjecting the animals to a pretest before conditioning commences. In this case, termed a biased design, the conditioning drug of which a preference is expected is mostly paired with the least preferred compartment of the apparatus. Place-conditioning is then expressed as the amount of time spent in the drug-paired compartment of the test apparatus minus the amount of time spent in that environment during the pretest. A criticism on the biased design is that approach behavior might not be due to positive motivational but to anxiolytic properties of the drug, decreasing the animals' anxiety in a nonpreferred environment. However, the finding that place preference even in an biased design is consistently found with psychostimulant drugs such as amphetamine and cocaine, which do have anxiogenic properties, is hard to reconcile with such reasoning. An alternative experimental design is to pair the conditioning drug with one side of the apparatus in half of the animals and with the other side in the other half of the animals (counterbalanced design). The most elegant approach is to manipulate the different environments in such a way using, for example, different odors that animals no longer prefer one side of the apparatus over the other (unbiased design), and to subsequently condition the animals in a counterbalanced fashion. A second factor is that the effects of a conditioning drug might interfere with exploration of the drug-paired environment. Since environmental novelty can elicit both approach and avoidance behavior, this might influence the expression of conditioned place preference or aversion. To circumvent this, a placeconditioning apparatus consisting of three compartments can be used. Two parts of this apparatus will then be paired with placebo or drug, respectively, whereas the third compartment is completely novel to the animal on the test day. The presence of a novel compartment might then obviate for any influences of exploratory behavior on preference for the placebo- or drug-paired environment, supposedly overruling the relative novelty of one of the two conditioning compartments. Environmental novelty has been shown to elicit conditioned place preference (Bardo et al., 1989) and the capacity of novelty to induce place preference has also been compared with drug-induced place preference. It was shown that rats consistently preferred environments paired with morphine, amphetamine, or apomorphine over novel environments, which were in turn preferred over familiar, saline-paired environments (Parker, 1992).

Place-conditioning studies have been performed with a wide variety of psychoactive drugs as well as with nonpharmacological stimuli. For example, conditioned place preference has consistently been observed using opioids such as morphine, fentanyl, heroin, and -endorphin, psychostimulants, e.g., amphetamine, methylphenidate, cocaine, 3,4-methylenedioxymethamphetamine ("ecstasy"), and nicotine, as well as with benzodiazepines such as diazepam. In addition, nonpharmacological cues such as social and sexual interaction, environmental novelty, and sucrose drinking elicit conditioned place preference. Place aversion has been reported for opioid antagonists such as naloxone, for lithium chloride, and for aggressive attacks, ionizing radiation, and footshock. Mixed results have been reported for apomorphine, caffeine, ethanol, and phencyclidine (for reviews, see Hoffman, 1989; Schechter and Calcagnetti, 1993).

The place-conditioning paradigm has some interesting properties in comparison to other models generally used in addiction research. First, next to positive motivational, also aversive properties of drugs can be assessed. This is also possible with the self-administration method. In that case, the number of self-injections with the drug with aversive effects will be lower than the number of placebo self-injections. To observe these aversive effects, however, relatively high levels of responding for placebo will be required, whereas in the place-conditioning method there is no such restriction. Second, the place-conditioning paradigm is not an operant task, but rather a classical (Pavlovian) conditioning paradigm. During conditioning, the drug will be delivered, irrespective of the behavior of the animal. What is learned is therefore not response conditioning but stimulus conditioning. However, what is measured during testing is not merely the result of classical conditioning because the approach behavior that is measured is not necessarily part of the primary (unconditioned) response of the animal to the drug. Third, the behavior of the animal is measured in the drug-free state. Any drug effects that might interfere with behavioral performance during testing is avoided. However, testing animals in a drug-free state is also a disadvantage. Since conditioning and testing are conducted in two different interoceptive states, state-dependent learning might occur, causing a risk of false negatives. Finally, since significant place-conditioning can be obtained with a small number of conditioning trials, the duration of the experiments is relatively short.

The most serious disadvantage of the place-conditioning technique is that the interpretation of data is difficult. As most if not all substances that are self-administered by humans and laboratory animals also have the property to induce conditioned place preference, it is suggested that their positive affective properties play a significant role in the development of place preference. It is, however, hard to interpret what the animal is exactly expressing with its approach or avoidance behavior. The most likely explanation is that conditioned place preference reflects the desire to experience the effects of the drug. However, since in most cases only time spent in a certain compartment is scored, such a conclusion cannot definitely be drawn.

	III. Self-Administration

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The first studies on i.v. opioid self-administration were performed in the 1960s. Different groups demonstrated that rhesus monkeys and rats would learn to press a lever to receive i.v. infusions with morphine (Weeks, 1962; Thompson and Schuster, 1964; Deneau et al., 1969). These experiments showed that morphine served as a positive reinforcer of self-administration behavior in animals made physically dependent on opioids as well as in animals which were naive to the drug (nondependent). These initial experiments have been replicated and extended by many laboratories over the last decades. Reviewing the studies evaluating the reinforcing properties of opioids in the self-administration paradigm revealed several procedures that could be classified under different headings. In the present overview, we divide them into the "acute" method and the "substitution" method.

In the first method, the acute method, the animal is allowed access to the test drug without previous experience with this drug or any standard drug. Different procedures can be applied. For example, the animal is given initial access to vehicle (usually saline) for a few days to obtain control rates of responding before being offered the test drug. Alternatively, the animal is initially trained to lever-press for a nondrug reinforcer (usually food pellets) on a continuous reinforcement schedule to familiarize the animal with lever-press responding. In a third procedure an animal without any previous experience with the behavioral requirements for the delivery of the drug is offered access to the test drug. During the period of actual access each lever-press results in an infusion. The acute method is useful in assessing whether an animal will initiate self-administration of the test compound, whether responding for the compound will change over time, and to assess dose-response curves of the test compound.

In the substitution method, drug self-administration is first established with a standard compound known to be reinforcing. In short, during daily experimental sessions, animals are trained to respond for an i.v. delivery of a standard compound. This compound is referred to as baseline drug and is known to produce reliable self-administration rates over sessions. In substitution studies evaluating the reinforcing properties of opioids, codeine, a pure opioid agonist, is mostly used as baseline drug, although some studies use cocaine as such. After responding becomes stable, a dose of a test compound or vehicle (usually saline) is substituted for the baseline drug for one or several sessions. If saline is substituted, responding tends to decline to relatively low rates (negative control). On the other hand, when a test compound is substituted, the compound may maintain responding at some level above that of saline. If this occurs, the drug is classified as a positive reinforcer. Using this method dose-response curves of test drugs can be generated and relative reinforcement potencies of several drugs can be determined.

The results of the opioid self-administration studies with these methods have been reviewed (e.g., Johanson and Balster, 1978; Griffiths and Balster, 1979; Woolverton and Schuster, 1983; Collins et al., 1984; Young et al., 1984; Balster and Lukas, 1985; Vaupel et al., 1986; Woods and Winger, 1987). In the next paragraphs, we summarize the early findings and refer to previous reviews for more detailed discussion.

Johanson and Balster (1978) summarized data generated using the substitution method in monkeys to assess the reinforcing properties of several opioid drugs. They reported that, in general, all tested pure opioid agonists are readily self-administered under a variety of experimental protocols. These agonists include the opioid agonists l--acetylmethadol (LAAM), alfentanil, codeine, dihydroetorphine, etonitazine, etorphine, fentanyl, heroin, hydromorphone, levorphanol, methadone, meperidine, morphine, and propoxyphene (Ternes et al., 1985; Bertalmio and Woods, 1989; Beardsley and Harris, 1997). An exception was the opioid agonist tilidine, which acted as a positive reinforcer in one laboratory but not in another laboratory. The mixed opioid agonist-antagonists buprenorphine, butorphanol, -etazocine, nalbuphine, pentazocine, and propiram tested in different laboratories also served as positive reinforcers in the substitution procedure. In contrast, drugs like cyclazocine, ketocyclazocine, levallorphan, nalorphine, naloxone, and naltrexone were not self-administered by monkeys (Slifer and Balster, 1983). Self-administration of opioids appeared to be stereoselective in the sense that the d-isomer dextrorphan was not self-administered, whereas the l-isomer levorphanol was (Winter, 1975). In addition i.v. self-injections have been observed with the enkephalin analog FK-33-824 in monkeys physically dependent on morphine (Mello and Mendelson, 1978).

Comparing the positive reinforcing properties of opioids with their discriminative and antagonistic effects (reversal of behavioral effects of opioid agonists and direct rate-decreasing action), a distinction can be made in three groups, i.e., opioids with morphine-like properties (µ-type opioid), opioids represented by ethylketazocine (-type opioid), and opioid antagonists (Woods et al., 1982; Woolverton and Schuster, 1983; Young et al., 1984; Woods and Winger, 1987). In general, preferential µ-type opioid agonists (such as alfentanil, codeine, etorphine, fentanyl, heroin, levorphanol, meperidine, methadone, and morphine) and the mixed µ-type opioid agonist-antagonists (such as buprenorphine, butorphanol, nalbuphine, pentazocine, profadol, and propiram) that exert morphine-like effects in other systems readily maintain i.v. self-administration in rhesus monkeys. In contrast, the ethylketazocine-like opioid agonists, such as bremazocine, ethylketazocine, ketacyclazocine, ketazocine, and other benzomorphan ligands, in general do not maintain self-administration behavior. Also, the mixed opioid agonist-antagonists, like cyclazocine, nalorphine, and oxilorphan, which share agonistic actions primarily with the ethylketazocine-like opioid agonists, are not self-administered by monkeys. In fact, they act as negative reinforcers in the self-administration procedure. The third group, the opioid antagonists such as naloxone and naltrexone, fails to maintain responding and in higher doses serve as negative reinforcers.

Griffiths and Balster (1979) investigated whether the self-administration paradigm could be useful as a tool in the assessment of the subjective effects of opioids in humans. For that the results of drug self-administration of the above-mentioned opioid drugs by monkeys using the substitution procedure were compared with clinical evaluations of morphine-like signs, symptoms, and subjective effects of a single dose of these opioid drugs in humans (Jasinski, 1977). Of the 33 drugs examined, 4 drugs did not produce similar results in humans and monkeys. Of these four drugs, three (i.e., dextromethorphan, butorphanol, and nalbuphine) were self-administered by monkeys but induced no or equivocal morphine-like effects in humans. One drug, tilidine, produced clear morphine-like subjective effects in humans but did not readily maintain self-administration in monkeys. The opioid antagonists were not self-administered by monkeys nor produced morphine-like effects in humans. The concordance between the human and animal results in this study validates the use of the self-administration paradigm to subjective effects of opioids in humans.

Although the monkey has been the preferred species for testing the abuse potential of new drugs, the increasing costs of this experimental animal led Collins et al. (1984) to develop a rapid screening test for the reinforcing actions of, among others, several opioid drugs in a less expensive animal, the rat. Using the acute self-administration method with drug-naive rats, they showed that the self-administration results with opioid drugs in rats paralleled those obtained with monkeys. Moreover, using drug-naive animals, these results demonstrated that opioid drugs, besides maintaining self-administration behavior, also readily initiate selfadministration behavior. In rats, self-administration has been shown for µ-type opioid agonists 6-acetylmorphine, codeine, dihydroetorphine, dihydromorphine, etonitazene, fentanyl, heroin, meperidine, methadone, morphine, and propoxyphene; the mixed µ-type opioid agonist-antagonists butorphanol, nalbuphine, nalorphine, and pentazocine; and the -type opioids ethylketocyclazocine and ketocyclazocine (e.g., Weeks and Collins, 1964, 1979; Collins and Weeks, 1965; Smith et al., 1976; Van Ree et al., 1978; Collins et al., 1984; Young and Khazan, 1984; Dai et al., 1989; Martin et al., 1997). Furthermore, [D-Ala²]-Met-enkephalin, dynorphin-(1-13), and [D-Ala²]-dynorphin-(1-11) were i.v. self-administred in rats physically dependent on morphine and pretrained to self-inject morphine (Tortella and Moreton, 1980; Khazan et al., 1983). The µ-type antagonists cyclazocine and naloxone were not self-administered (Collins et al., 1984).

In more recent studies another method, the reinstatement model, has been used to assess the effects of opioids on opioid-seeking behavior. Typically, animals are trained to i.v. self-administer opioids. After reliable self-administration, extinction sessions are given during which saline is substituted for the opioid. After termination of responding under extinction conditions, a priming injection with a test drug is given and lever-pressing is assessed. Stewart and coworkers (De Wit and Stewart, 1983; Stewart, 1983) found that priming injections of 50 to 200 µg/kg heroin effectively reinstated heroin-seeking behavior in rats. Priming infusion of pharmacologically related drugs also reinstated responding on the lever associated with heroin infusions. Under these conditions, injections with nalorphine (10 mg/kg) however did not reinstate lever-press behavior and naltrexone (2 mg/kg) suppressed responding below the levels seen after saline injections (Stewart and Wise, 1992). Using this reinstatement procedure, the same research group replicated their findings, in that reexposure to heroin after abstinence reinstated heroin-seeking behavior, whereas an injection of naloxone did not (Shaham and Stewart, 1996; Shaham et al., 1996, 1997). Moreover, they found that brief exposure to footshock stress or corticotropin-releasing hormone reinstated heroin-seeking behavior, thereby mimicking the effect of a noncontingent priming infusion of heroin, although differences may be present with regard to the neurobiology of the various reinstatement stimuli (Shaham and Stewart, 1994, 1995; Shaham et al., 1996, 1997). By contrast, the aversive state of opioid withdrawal, induced by an injection with naltrexone, did not reinstate drug-seeking behavior. Other abused drugs like amphetamine and cocaine are also capable to reinstate drug-seeking behavior in animals, previously trained to self-administer heroin (De Wit and Stewart, 1983; De Vries et al., 1998). It has been argued that the reinstatement model is relevant for assessing opioid-induced relapse.

In general, it seems that both the pure µ-opioid agonists (such as morphine, methadone, codeine, and heroin) and the mixed µ-opioid agonist-antagonists (such as butorphanol, nalbuphine, and buprenorphine) serve as positive reinforcers in the different i.v. self-administration paradigms in monkeys and rats. On the other hand, -opioid agonists (such as ethylketazocine, ketazocine, and benzomorphan ligands) and opioid antagonists (such as levallorphan, naloxone, and naltrexone) do not maintain self-administration behavior or even maintain responses that postpone or terminate their injection (negative reinforcers). In the rat, however, self-administration of (ethyl)ketazocine and nalorphine has been reported.

1. Dose of the Drug. The dose of the drug per injection ("unit dose") is an important and critical factor in drug-taking behavior. A linear function between the log dose of drug delivered per injection and the amount of drug taken (Fig. 1) has been shown to exist for various opioids in different species of animals (Weeks and Collins, 1964, 1979; Smith et al., 1976; Harrigan and Downs, 1978a; Van Ree et al., 1978; Dai et al., 1989). Moreover, studying heroin self-administration, it was demonstrated that the linear relationship between the log unit dose and drug intake is present during initial exposure to heroin and in animals physically dependent on heroin (Van Ree et al., 1978; Dai et al., 1989).

View larger version (11K): [in this window] [in a new window]   Fig. 1.   Self-administration of morphine sulfate in rats. Presented are the mean number of self-infusions (A) and the mean amount of drug intake (B) by either the i.v. () or the intragastric route () versus the unit dose of morphine sulfate per infusion. Data from Smith et al. (1976).

2. Route of Administration. Opioids can be selfadministered via a wide range of routes, i.e., p.o., i.v., i.p., s.c., intragastric, i.c.v., or intracerebral (Smith et al., 1976; Jones and Prada, 1977; Carroll and Meisch, 1978; Van Ree and Niesink, 1978; Van Ree and De Wied, 1980; Bozarth and Wise, 1981b; Goeders et al., 1984; France et al., 1985). Intracerbroventricular and intracerebral administration will be discussed later (see III. Central Sites of Action). One of the difficulties encountered with the oral self-administration procedure is the aversive taste of some opioid drugs. For example, morphine in solution is a weak base with a bitter taste that laboratory animals often do not accept. Nonetheless, several studies have demonstrated reliable oral morphine self-administration in rats (Cappell and LeBlanc, 1971; Leander et al., 1975; Van Ree and Niesink, 1978). Etonitazene, a potent opioid, appeared to have little if any taste and served as a positive reinforcer orally in rats and rhesus monkeys (Wikler et al., 1963; McMillan and Leander, 1976; Meisch and Stark, 1977; Carroll and Meisch, 1978; Heyne, 1996).