Miller-The ASAM Principles of Addiction Medicine, 7e

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SECTION 1 • Basic Science and Core Concepts

and striatum. 112 This expression may explain some of the be havioral effects of cannabis (motor, memory, or cognitive im pairment). 113 The CB2 receptor was once thought to be only expressed in peripheral immune cells but has recently been identified in the brain at low levels. 114 Progress in identifying the brain mechanisms associ ated with the reinforcing effects of cannabinoids has been hampered until recently by the lack of a good animal model. Route of administration is a major influence on the reinforcing effects of drugs, and smoking is the preferred route for cannabis use in humans. Smoking, of course, is not an option for studying cannabinoid use in rats, and there have been no reports of successfully training non human primates to smoke cannabis. Instead, attempts have been made to demonstrate IV self-administration of Δ 9-tetrahydrocannabinol (THC), the active ingredi ent in cannabis, and other cannabinoid receptor agonists. Despite a good deal of effort, early studies provided little evidence that rats would self-administer THC , 113 although self-administration of THC and anandamide analogs has been reported in squirrel monkeys. 115,116 More success has been achieved with the synthetic CB1 receptor agonist WIN 55,212-2, which has been shown to be self-administered by mice 117 and rats. 118,119 The neurobiological investigation of cannabinoid self-­ administration is in the early stages although it appears that both opioid and DA mechanisms may interact with cannabi noid reinforcement. 120-122 NEUROANATOMY OF DRUG ADDICTION As discussed above, the acquisition and maintenance of sub stance use disorder involves multiple cortical and subcorti cal brain regions. It also occurs on a continuum where initial exposure may lead to increased and compulsive drug taking. This evolution of drug taking behavior (initial reward-based use leads to habit-based use) is accompanied by a parallel evo lution in neural-network involvement (initial limbic ventral striatal involvement leads to more dorsal striatal governance). This process often occurs despite adverse consequences and at the expense of more socially or biologically important be haviors. Stress and anxiety (both of which are also fueled by the limbic system), in fact precipitate this process and render people who use drugs recreationally particularly vulnerable to risky drug use and substance use disorder. To understand how the behavioral repertoire becomes subverted, it is necessary to consider the structures involved in decision-making and in generating motivated behavior. The research questions that can be addressed by using animal mod els are necessarily different than those that can be asked with human subjects. Animal studies have a number of advantages and are well suited for the investigation of the site of action of drug reinforcement through the use of receptor agonists, an tagonists, and lesion techniques. Animal self-administration studies allow tight control over many variables that could

possibly affect the addiction process including genetics, fre quency of access, dosage, route of administration, and drug history. Understandably, this type of control is unattainable in the investigation of humans with addiction; however, human studies allow for the examination of aspects of addiction that are uniquely human. Addiction is a condition that expresses in the real world and thus encompasses many different fac ets, such as polydrug use, co-occurrence with other disorders, predisposition, drug use history, and environmental context. Thus, the literature on human unhealthy substance use and addiction offers quite different insights. Imaging technology has been a key tool for identifying several subcortical and cortical brain regions important for addiction (see Fig. 3-7 for highlights). The widely used types of functional imaging are positron emission tomography (PET) and functional magnetic resonance imaging (fMRI). These technologies have very different temporal resolutions and lend themselves to assessing distinct aspects of brain function. PET uses a radioisotope that is introduced into the body and binds to specific receptors, transporters, and enzymes. Specific ligands can be visualized, thereby offering insights into drug distribution and changes in receptor mechanism in vivo. fMRI offers much greater temporal and spatial resolution. Changes in the fMRI signal can be assessed on the order of seconds rather than minutes, making it possible to detect metabolic changes associated with transient cognitive demands or crav ing states. Early imaging studies asked the questions, “Where does cocaine act in the brain, and how does it affect brain func tion?” One of the first imaging studies on individuals ad dicted to cocaine was conducted by Volkow et al. 123 in 1988. She found that individuals who chronically use cocaine have decreased relative cerebral blood flow (as measured by PET) in the PFC. Volkow later showed changes in metabolic activ ity (as measured by fluorodeoxyglucose), which depended on the time since the last drug experience. An overall increase in metabolic activity was observed in frontal brain regions dur ing the first week of withdrawal, 124 whereas decreases in meta bolic activity were found after several months. 125 PET has also been used to map the binding sites of cocaine in the human brain. Fowler et al. 126 conducted the first of these studies show ing high cocaine binding in the corpus striatum in nondrug using human subjects. More recent work with PET has shown that striatal do pamine D 2 receptor binding is reduced in those who use co caine, 127 heroin, 128 and methamphetamine 129 and also in DSM IV defined alcohol dependence. 130 This area of work is in good concordance with nonhuman primate PET studies showing decreased D 2 receptor availability in animals that are more susceptible to the reinforcing aspects of cocaine. 131,132

fMRI studies have been used to examine transient drug states, such as drug craving and the “rush” feeling associ ated with drug use. Much of the work in this area has been done by giving cocaine-addicted subjects (because of ethical limitations on giving drug-naive people cocaine) infusions of cocaine and other stimulants while in the fMRI scanner. Copyright © 2024 Wolters Kluwer, Inc. Unauthorized reproduction of the content is prohibited.