Miller-The ASAM Principles of Addiction Medicine, 7e

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SECTION 1 • Basic Science and Core Concepts

cocaine or amphetamine. It has been a considerable challenge, therefore, sorting out what transmitter in which particular area produces toxic effects and adverse reactions on the one hand and pleasurable or positive reinforcing effects on the other. Preclinical Studies of Drug Reinforcement Experiments with nonhuman primates and a variety of other laboratory animals have helped identify the important sites of action for drug reinforcement. It is important to note that, early on, there was considerable skepticism whether anything useful could be learned from laboratory animals regarding hu man drug taking. Given the premise that only humans engage in unhealthy drug use, along with the observation that what distinguishes the human brain from other mammals is the de velopment of the neocortex, the logical conclusion was that this region is responsible for drug addiction. This idea fit well with the idea that drugs were “mind expanding” and that the rea sons why a person might take drugs has to do with their effects on consciousness. Interviews with individuals who use drugs and introspective analysis of drug-taking behavior suggested that some of the reasons that people take drugs is for “pleasure, curiosity, the desire to experiment, the sense of adventure, the search for self-knowledge, the relief of stress and tension, de pression, the feeling of powerlessness, and the lack of belief in the future.” 20 Although these observations are entirely appropri ate for discussion at one level, they also serve to perpetuate the idea that human consciousness and reasoning are the bases for drug reinforcement. The demonstration that nonhuman pri mates and rodents will voluntarily self-administer drugs such as cocaine and heroin has prompted a consideration of concepts other than human consciousness to account for use of drugs, forcing an examination of brain regions other than the cortex. There is an extremely high correlation between the addic tive drugs that are used by humans and drugs that are self administered by other mammalian species such as rat, dog, cat, rabbit, and nonhuman primate. 21,22 These data support the idea that addictive drugs have their reinforcing actions on brain structures that have been relatively conserved through the course of human evolution—that is, limbic and brainstem areas. This being the case, the development of self-administra tion techniques, through intravenous (IV), 23-25 intracranial, 26-28 and inhalation 29 routes, has provided a means to study brain structures responsible for drug reinforcement in animal mod els. Next, as opposed to providing a review of all drug classes, we expand on three specific drug classes commonly explored in reference to addiction. These classes are psychostimulants, opioids, and cannabinoids. Psychostimulants Pharmacological experiments were the first to narrow down the range of possible sites of action for the reinforcing effects of psychostimulant drugs. 30,31 In these studies, rats and monkeys were trained to self-administer cocaine and amphetamine until they showed a stable baseline level of responding ( Fig. 3-5 ). They were then pretreated with a variety of agonists or

bundle that innervates the caudate–putamen. This latter projec tion is known to degenerate in Parkinson disease and is thus associated with motor function. An additional cluster of DA cells in the hypothalamus composes the tuberoinfundibular DA system, which innervates the external layer of the median emi nence. Dahlstroem and Fuxe 19 also described 5-HT cell groups (B1-B9), which lie near the midline of the pons and upper brain stem. Later studies showed clusters of cells also in the caudal LC, area postrema, and interpeduncular nucleus. 14 Generally, the more caudal cell groups innervate the medulla and spinal cord, whereas the more anterior clusters project rostrally ( Fig. 3-4C ). The main point to be taken from an examination of the areas innervated by DA, NA, and 5-HT is that there is hardly a region that is not innervated by at least two of the monoamines. Given that psychostimulants have an effect at the terminal regions of each of these systems, every area of the brain would be expected to be affected to some extent by an injection of Figure 3-4. Schematic diagram illustrating the distribution of the main central neuronal pathways containing noradrenaline (A) , do pamine (B) , and serotonin (C) . The location of cell bodies of origin is indicated by circles with the projections indicated by arrows .

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