Miller-The ASAM Principles of Addiction Medicine, 7e

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SECTION 1 • Basic Science and Core Concepts

Selective μ agonist drugs, such as morphine, heroin, and most clinically used opioid analgesics, produce analgesia, euphoria, respiratory depression, emesis, and antidiuretic effects. Selec tive κ agonist drugs, such as the experimental compounds eth ylketazocine and bremazocine, produce analgesia, dysphoria, and diuretic effects, but no respiratory depression. There is less known about the direct role of δ receptors. Agonists at μ receptor are more likely to have addiction liability than κ agonists. 70-72 Within the dorsal and ventral striatum, there are areas of overlap between expression of opioid receptors; how ever, their expression patterns tend to differ. μ receptors are expressed in patches, and κ and δ receptors are more diffusely distributed. 73 Almost all that is known about the neurobiology of opi oid reinforcement is derived from animal models. Three approaches have been used to investigate the involvement of various brain regions in opioid reward: (a) intracerebral self administration of opioid agonists, (b) blockade of IV heroin self-administration by intracerebral injections of opioid an tagonists, and (c) disruption of IV heroin self-administration by lesions. Generally, the focus has been on areas associated with the mesolimbic DA system (ventral striatum and VTA), although other regions have also been implicated. Self-administration of drugs directly into various brain regions would seem to be the most straightforward test of their involvement in reinforcement processes; however, the procedures have a number of technical problems that limit their appeal. Issues involving diffusion, osmolarity, and tis sue damage demand thoughtful consideration (see Ref. 74 for review). Nonetheless, several papers have provided evidence that opioid-like compounds are self-administered into dis crete brain regions. The early work focused on the lateral hypothalamus 26,75,76 because this area was intensely studied for its ability to support intracranial electrical self-stimulation. 77 Later, because of interest in the mesolimbic system, interest switched to the ventral striatum and the VTA. The role of the lateral hypothalamus has been challenged, and it is possible that the early results were due to diffusion of drug to other ar eas. 78 The ventral striatum appears to support intracranial self administration of morphine 79 and methionine-enkephalin. 80 These data fit well with the demonstration that intra-NAcc opioids produce a conditioned place preference. 81 Techniques have also been developed to study intracerebral self-injection in mice by using a Y-maze. Selection of one arm of the maze results in a morphine injection, whereas the other arm re sults in a saline injection. Using this method, mice have been shown to self-inject morphine into the lateral septum 82 and the ventral striatum but not the dorsal striatum. 83

useful in screening antipsychotics. We know now that this is true because of the relationship between the importance of DA in stimulating stereotypy and the action of neuroleptic drugs. To re-emphasize, anything can become stereotyped. Behaviors that occur with high frequency have a high like lihood of becoming stereotyped (ie, they occur repetitively and ritualistically) if they occur in the presence of a drug. 51 Lyon and Robbins 52 argue that stereotypy is a process in which there is an increase in frequency in a diminishing number of response categories. The effect is that psychostimulant drugs narrow the behavioral repertoire such that only a few pre dominant behaviors remain. Put another way, the behavioral repertoire becomes focused around the things that occur most frequently. In the case of a person with addiction, the frequent behaviors associated with drug seeking and drug taking be come repetitive and ritualistic. In conclusion, strong evidence from studies using widely different strategies suggests that stimulation of DA receptors in the ventral striatum is associated with drug reinforcement. There is a wealth of evidence from a parallel literature show ing that the mesolimbic DA system is also involved in reward from natural behaviors such as feeding, 53-55 drinking, 56,57 sex ual behaviors, 58,59 and intracranial self-stimulation. 60-62 This enormous amount of literature has resulted in the mesolimbic DA system being called a reward pathway . Whether this term is accurate or biologically meaningful (we think it is not) lies outside the scope of this chapter. However, the immense inter est in the mesolimbic DA pathway demands some discussion of its interconnections. Data from electrophysiological studies show that VTA DA neurons respond to primary reinforcing stimuli (eg, food) and to environmental cues that predict the presentation of re wards. 63,64 Although these neurons receive no direct input from visual, auditory, or somatosensory systems, this information is likely sent via thalamic relays. 65 In fact, the VTA is a part of a widespread collection of neurons that belong to the “isoden dritic core.” 66 This system is a network of neurons stretching from brainstem to telencephalon. The neurons within the net work have similar morphology, send out long projections, and are themselves the target of a great number of contacts from dis tant sources. 67 This network serves an integrative function and responds to changes in the environment that are biologically significant. Although VTA-DA neurons respond differentially than others in the network when exposed to drug cues, they are likely responsive to salience rather than specific rewarding properties of a drug—a topic that is the center of a long debate. Opioids Opioid receptors are expressed throughout the brain, es pecially in limbic and limbic-related structures; they are found in the amygdala, insular cortex, caudate, anterior hy pothalamus, cortex, parietal cortex, putamen, thalamus, and periaqueductal gray. 68 There are three different types of G protein–coupled opioid receptors: μ , κ , and δ , which are acted on by both endogenous and exogenously applied opioids. 69

By far the most sensitive site for intracerebral self- administration of opioids is the VTA. Both μ and δ opioids are self-administered into this region at doses that are not supported in other areas. 28,84-86 The idea that opioids have a significant impact on reinforcement mechanisms through an action in the VTA is supported by a variety of other tech niques. For example, injections of opioid agonists into the VTA also produce a conditioned place preference, 87 facilitate Copyright © 2024 Wolters Kluwer, Inc. Unauthorized reproduction of the content is prohibited.