Miller-The ASAM Principles of Addiction Medicine, 7e

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CHAPTER 3 • The Anatomy of Addiction

drive, motivation). Some of these executive functions include the ability to differentiate conflicting thoughts, evaluate future consequences of current activities, planning goal-directed ac tivities, and behavioral inhibition. The prefrontal cortex (PFC) is thought to be the “hub” of executive function in the brain, and contains dense projections to the striatal areas listed previously. While modern human functional brain imaging studies often parcellate the frontal cortex into 15 or more subregions (eg, Automated Anatomi cal Labeling atlas), broadly there are three widely established functional parcellations: (a) the orbitofrontal and the ventro medial areas (often considered complements to the limbic system 14 ; (b) the dorsolateral PFC (often considered a key hub in the executive control system) 15 ; and (c) the cingulate cortex (involved in error monitoring, salience detection, and modu lating the intensity of a stimulus-response). 16 NEUROANATOMY OF DRUG REINFORCEMENT “Site of action” is a concept that defines the access point for a drug to produce a specific response. If that response is defined behaviorally (eg, anorexic, convulsant, antidepressant effect), then the site of action may refer to the receptors (primary mo lecular component) or the brain regions responsible for that particular behavioral response. It is one thing to describe all possible sites where a drug can affect the brain; it is a more difficult matter to narrow down the possibilities to a particular binding site in a circumscribed region. Research into the site of action for the reinforcing effects of psychostimulant drugs, such as cocaine and amphetamine, offers a good example of how this investigative process occurs. In vitro experiments have shown that cocaine binds to dopa mine, noradrenaline, and serotonin (DA, NA, and 5-HT) trans porters and blocks the reuptake of these neurotransmitters 17 ; amphetamine acts additionally as a releasing agent. Both of these actions result in an increased concentration of monoamine neu rotransmitters in the synapse. Therefore, psychostimulant drugs act as indirect agonists everywhere these transmitters are found. An examination of the anatomic projections of the cat echolamine systems shows that they have extensive and diffuse projections throughout the neural axis. The cell bodies of these transmitter systems are loosely organized in an anteroposte rior fashion. Based on their histochemical mapping studies, Dahlstroem and Fuxe 18 proposed a nomenclature wherein cell clusters were numbered from posterior to anterior and given a letter prefix according to whether they were dopaminergic/ noradrenergic (A) or serotoninergic (B). Fig. 3-4A shows the distribution of NA fibers. The locus coeruleus (LC) (A6) is lo cated in the dorsal brain stem and sends ascending projections to terminal regions of the cortex, hippocampus, and cerebellum. More caudal and ventral NA cells groups (A1-A5) innervate the hypothalamus and brain stem. Dopaminergic innervations are more circumscribed ( Fig. 3-4B ). DA cell groups within the ventral tegmental area (VTA) and substantia nigra (A8, A9, and A10) project in a topographic manner to the striatum. The more medial group (A10) sends projections to the ventral striatum, whereas the more lateral groups form a nigrostriatal

As one may expect, the topographical organization of these striatal connections is more complex in primates than rodents. Haber et al. 13 have elegantly described the topography of striato nigrostriatal circuitry, including reciprocal synaptic connections between the striatum and substantia nigra pars compacta/reticu late. This complex intrastriatal connectivity provides an iterative and redundant network for integration of various cortical inputs with thalamic outputs ( Fig. 3-3 ). This circuitry has been described as a series of ascending spiraling connections between adjacent striatal regions via the ventral midbrain (substantia nigra). In this manner the accumbens shell influences the accumbens core, the core influences the central striatum, and the central striatum in fluences the dorsolateral striatum. Executive Function and the Prefrontal Cortex Executive function refers to multiple aspects of cognitive con trol (eg, decision making, future thinking, choice) which of ten provide a counterbalance to limbic activity (eg, arousal, Figure 3-3. Striatonigrostriatal connections form a series of as cending spiraling loops. Projections from the NAcc shell termi nate in both the VTA and ventromedial SNc. The VTA sends recip rocal projections back to the shell and neurons from the medial SN project forward to the NAcc core. The projections continue to go back and forth between the striatum and substantia nigra, spi raling upward, so that the shell influences the core, the core influ ences the central striatum, and so on. These striatonigrostriatal connections continue to occur even past the anterior commissure ( top right schematic ). These posterior portions of the caudate and putamen have reciprocal connections with the dorsal portions of the SN. VTA, ventral tegmental area; SNc, substantia nigra pars compacta; SNr, substantia nigra pars reticulate. (Adapted from Haber SN, Fudge JL, McFarland NR. Striatonigrostriatal path ways in primates form an ascending spiral from the shell to the dorsolateral striatum. J Neurosci . 2000;20:2369-2382.)

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