Miller-The ASAM Principles of Addiction Medicine, 7e

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CHAPTER 3 • The Anatomy of Addiction

Destroying the DA neurons in the VTA also drastically reduced cocaine self-administration. 40 These data were the first to draw attention to the NAcc (more recently referred to as ventral stria tum) as a site for action for psychostimulant reinforcement. 6-OH-DA lesions in other brain regions have had much less dramatic effects. Lesions of the dorsal striatum do not change the rate of cocaine intake, supporting the idea that the ventral striatum has a preferential involvement. 41 Additionally, destruction of DA terminals in the medial PFC or amygdala has only minor effects on the cocaine dose-response curve, which seems to reflect changes in the reinforcing threshold or a change in the anxiogenic effects of cocaine. 42,43 Injections of DA antagonists directly into the brain have also been used to identify the important anatomic sites involved in cocaine action. The evidence consistently shows that the DA receptors in the ventral striatum are an important site of action. Blockade of D 2 receptors produce an apparent decrease in po tency. That is, animals compensate by increasing their hourly drug intake and will “work” less hard for each injection. Injec tions of D 2 antagonists into the dorsal striatum and the medial PFC produce similar effects, albeit less strongly. 44,45 In summary, the data presented are from a wide range of studies using neurotoxins, and specific pharmacological agents are consistent with the idea that the most important site of action for the reinforcing effects of cocaine and amphetamine is at DA terminals in the ventral striatum. It should be empha sized however that, although the ventral striatum is essential for the reinforcing effects of cocaine and amphetamine, other DA projection areas (such as the PFC, amygdala, and dorsal striatum) also contribute to some extent. The site of action for the locomotor-activating effects of psychostimulant drugs seems to largely overlap with the regions responsible for drug reinforcement. Experiments using either lesion or intracerebral injections of DA drugs have shown that stimulation of the DA receptors in the ven tral striatum produces behavioral activating effects (loco motion); stimulation of DA receptors in the dorsal striatum produces stereotypy, 46 which is characterized by repetitive sequences of movements, such as licking and grooming in rodents. 6-OH-DA–induced destruction of DA terminals in the ventral striatum almost completely abolishes the locomo tor stimulant effects of cocaine, while lesions of the dorsal striatum abolish psychostimulant stereotypy. Similarly, direct injections of DA agonists into the ventral striatum produce locomotion, whereas injections into the dorsal striatum pro duce stereotypy. 47-49 The stereotypic response elicited from the dorsal striatum may have relevance to addiction. In rats, stereotyped behavior is often measured on a categorical scale, which includes lick ing, chewing, and gnawing. These high-frequency movements have the appearance of being “hard-wired” responses that are elicited by the drug. It should be emphasized, however, that almost any behavior can become stereotyped. In their influen tial article, Randrup and Munkvad 50 described how the precise forms of stereotyped behavior differ across species and offer the example of a man who repeatedly rebuilt his car engine. They suggested that inhibition of drug-induced stereotypy might be

Pump

Swivel

Computer

antagonists in an effort to identify the specific transmitter systems that modulate reinforcing efficacy. Importantly, it was shown that pretreatment with DA receptor antagonists caused the animals to self-administer cocaine and amphet amine more frequently. 32-34 This is the same result one sees if the concentration of drug is diluted: The animals appear to compensate for the reduction in drug effect by increasing their intake. Note that pretreatment with NA or 5-HT antag onists did not have consistent effects on drug intake. These data prompted Wise 35,36 to champion the idea that stimula tion of DA receptors must be essential for psychostimulant reinforcement. Peripheral injections of DA antagonists narrowed the site of action to DA receptors, but it remained unclear which brain regions mediated this effect. Central manipulations were necessary to identify which brain regions were important. Neurotoxins specific to catecholamine and indolamine neu rons provided a useful tool to examine whether the loss of a particular fiber system would affect drug self-administration. A considerable literature developed around the neurotoxin 6-hydroxydopamine (6-OH-DA) that, depending on the site of injection and other parameters, could be used to completely deplete various brain regions of either DA or NA. Early experi ments showed that removing the noradrenergic innervation of the entire forebrain had almost no effect on cocaine self- administration. In contrast, removal of the DA innervation of the NAcc resulted in a substantial reduction in cocaine’s rein forcing effects. 37-39 In fact, animals will no longer self-administer cocaine if DA levels in the NAcc are reduced by more than 80%. Figure 3-5. In self-administration studies, animals are implanted with permanent indwelling catheters and placed in an experi mental chamber. The catheter is connected to a syringe pump through a fluid swivel that allows free movement throughout the chamber. A computer detects responses on a lever and controls the timing of drug delivery according to the schedule of reinforce ment. For example, on a fixed-ratio one schedule (FR1), every response on the lever results in an infusion of drug.

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