Piotr Popik MD PhD

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Alcohol and other drugs of abuse produce dependence, a chronic and relapsing disorder that is an enormously destructive public health problem. In the United States, mortality that can be attributed to these disorders is greater than mortality attributable to all other factors combined (1). Currently, there are a limited number of available medications to treat alcohol, opioid, and nicotine dependence, and no medication to treat cocaine, other stimulants, or cannabis dependence. Success rate of available treatments is relatively low, only 30-50% of patients remain abstinent at 1 yr after completion of the most successful treatment programs (2,3). Despite recent advances in the understanding of the neurobiolog-ical basis for these disorders and the development of new psychotherapeutic approaches, there is a lack of viable pharmacological treatments. At the same time, societal and political pressures continue for the development of effective and inexpensive treatments.

Substances that are abused by humans, including opiates, psychostimulants, marijuana, alcohol, and sedatives, differ in chemical structures and acute pharmacological effects. However, the pathological, compulsive pattern of their intake share many common features. This suggests that a limited number of neural pathways may mediate the "addictive" qualities of drugs of abuse. If there is a common neural substrate that is central to the development and the maintenance of drugs of abuse dependence, it might be a target for pharmacological treatments. It has previously been suggested (4-6) that N-methyl-d-aspartate (NMDA) receptors constitute the target component of this pathway. Preclinical research suggests that antagonists of this receptor modulate pathophysiological processes common to the development, maintenance, and expression of drugs of abuse dependence and have a potential to be developed as pharma-cotherapeutics. Preliminary results from clinical trials are encouraging further clinical development.


Animals and people associate internal drive states with the knowledge about the external environment in which these states were experienced. The use of such associations provide means for a better quality of life. This is because learning that some environmental stimuli may be predictive of the occurrence of primary reinforcers (unconditioned stimuli, UCS) enhance chances of survival. For example, the knowledge that certain stimuli (conditioned stimuli, CS) are signaling the availability of food, sexual partner, or another potent reinforcer, such as a drug of abuse, increases its availability, and thus enhances the (subjective) well-being of an individual (7).

The laboratory model to test the development and expression of such associations is the conditioned place preference (CPP) test (8,9). It allows investigating associations of biologically relevant

From: Contemporary Clinical Neuroscience: Glutamate and Addiction Edited by: Barbara H. Herman et al. © Humana Press Inc., Totowa, NJ

stimuli (internal drive states produced by primary reinforcers) with previously neutral contextual cues; such associations develop following contingent pairings. In its simplest form, the CPP apparatus is made of two or more distinctive environments (compartments) that differ in visual, olfactory, and tactile cues. During conditioning, a drug effect is consistently paired with one chamber, whereas the other chamber is paired with the effect of the vehicle. After several pairings, the testing phase is carried out, during which the animal (now drug-free and having a free choice) demonstrates a preference to a drug-paired environment. This is measured by the time that the animal spends in drug-associated chamber. All of the numerous variants of this procedure are based on the assumption that an animal learns to approach stimuli paired with rewarding properties of the drug and that, through repetitive pairing, an initially neutral environment gains incentive salience. These procedures are related to operant second-order schedule studies, which have shown that exteroceptive stimuli can exert powerful control over drug-seeking and drug-taking (10). CPP is now among the most commonly used methods for the assessment of rewarding effects of pharmacological and nonpharmaco-logical reinforcers (11) (see refs. 12 and 13 for a review). This paradigm represents an indirect measure of drug reinforcement (as opposed to, e.g., the drug self-administration procedure). There are a number of advantages of the CPP technique over those techniques based on other measures of drug reward, like drug self-administration procedure. These include extreme sensitivity to the low doses of drugs of abuse [e.g., 0.08 mg/kg of morphine (11)] and the ability to produce CPP response after a single drug-environment pairing (11,14). The single pairing is important in light of human research indicating that the effect of the initial drug experience may be the best predictor of later drug abuse (15) and in light of animal data demonstrating the development of tolerance (16) accompanying administration of several doses of an opiate that could be a confounding factor in studying drug reward. Moreover, in CPP studies, both the rewarding as well as aversive properties of drugs may be measured at the same time. In this paradigm, the testing is conducted under drug-free conditions (eliminating, e.g., motor effects of drugs that may obscure the measurement of its reinforcing effects in other tests). In addition, most often, drugs are given parenterally, which is impossible in self-administration studies. The CPP paradigm allows administration of known and planned drug doses (which is difficult in paradigms where animals are themselves administering the drugs and, therefore, the dose depends on the animal's rate of responding). Finally, it is possible to study nonpharmacolog-ical rewards as well; these include the rewarding properties of food and that of social and sexual interactions.

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