Miller-The ASAM Principles of Addiction Medicine, 7e

41

CHAPTER 3 • The Anatomy of Addiction

Martin et al. 103 examined regional differences in the ventral striatum by using beta-FNA. This drug is an irreversible an tagonist at the μ -opioid receptor producing what amounts to a reversible lesion. Beta-FNA blocks the receptor rendering it unavailable for many days, until new receptor populations can be synthesized. Beta-FNA was found to produce site-specific effects, attenuating heroin self-administration when injected into the caudal but not rostral NAcc. The hypothesis that the mesolimbic DA systems mediate the reinforcing effects of opioids has been proposed. Certainly, it is clear that psychostimulants and opioids have independent sites of action at the receptor level. DA antagonists potently affect cocaine but not heroin self-administration; conversely, opioid antagonists potently affect heroin but not cocaine self administration. 104,105 However, it has been shown that opioids indirectly affect DA cell firing through inhibition of GABA in terneurons in the VTA. 106 This disinhibition can result in en hanced DA release in the NAcc. 107 Heroin self-administration increases DA in the ventral striatum, and this has been argued to be the mechanisms of action for heroin reinforcement. 108 Curiously, DA cell bodies in the VTA seem to be more im portant for heroin self-administration than the DA innervation of the ventral striatum. Bozarth and Wise 109 showed that 6-OH DA lesions of the VTA impair the acquisition of IV heroin self-administration. By contrast, 6-OH-DA–induced depletion within of the NAcc has very little effect on heroin self-admin istration in spite of the fact that 6-OH-DA such lesions dra matically reduce or abolish cocaine self-administration. 110,111 It appears that some, but not all, of the reinforcing effects of opioids are mediated through an action on DA mechanisms. Cannabinoids The characterization of cannabinoid receptors in the brain has been an important first step in identifying the site of ac tion for the reinforcing effects of cannabis. Two cannabinoid receptors (CB1 and CB2) have been identified to date. Both are G protein–coupled receptors and function to inhibit ad enylate cyclase. They are acted on by endogenous cannabi noids and exogenous activators such as cannabis. Figure 3-6 represents CB1 expression in the rat brain. As in humans, the CB1 receptor is highly expressed in the brain and found in the basal ganglia, hippocampus, cerebellum, cerebral cortex,

brain stimulation reward, 88,89 and reinstate extinguished lever responding that was trained under IV heroin reward. 90 It should be noted that there are a few reports of reinforc ing effects produced by intracerebral injections of opioids into the hippocampus 91 and periaqueductal gray. The doses used in these studies are relatively high, and it remains unclear wheth er these are important but less sensitive sites or whether diffu sion of the drug to other areas accounts for those observation. When self-administering IV heroin, animals respond to a decrease in the unit injection dose by taking injections more frequently. A similar phenomenon can be observed when ani mals are treated with a systemic injection of naloxone (a μ an tagonist), suggesting that animals compensate for a reduced drug effect by increasing their drug intake. 92 Several laborato ries have used this compensatory response to evaluate the ef fects of opioid antagonists injected into various brain regions. Increases in IV heroin self-administration have been shown after injections of low doses of opioid antagonists into the NAcc, 93-95 periaqueductal gray, 94 stria terminalis, 96 and lateral hypothalamus, but not the PFC. 97 Surprisingly, injections of an opioid antagonist into the VTA have relatively little effect. 98 It remains unclear why many studies have shown that the VTA is one of the most sensitive brain sites for intracerebral self administration of opioid agonists, whereas it is one of the least effective sites for disrupting IV heroin self-administration studies with an intracerebral injection of opioid antagonists. Lesions offer a third method for identifying critical brain areas responsible for the reinforcing effects of opioids. Zito et al. 99 showed that the size of a kainic acid–induced lesion of the NAcc correlated with impaired heroin self-administration. This effect is site specific because lesions of other areas, such as the lateral hypothalamus, do not necessarily affect heroin self administration. 100 More recent studies have attempted to de fine the relative contribution of subregions within the ventral striatum comparing acquisition of heroin self-administration after excitotoxic lesions of the NAcc core or shell. Rats with lesions of the NAcc core lesion group showed impairments in acquisition, whereas the group with lesions of the NAcc shell was similar to controls. This effect was found either with acqui sition of low-dose heroin on a simple fixed-ratio schedule 101 or with acquisition of a second-order schedule with a high injec tion dose. 102 These data suggest a relatively greater role for the NAcc core in the acquisition of heroin-seeking behavior.

Figure 3-6. Cannabinoid receptor expression in the rat brain. Areas with brightest colors indicate a greater expression. Cannabinoid receptors are ex pressed in high numbers in the cerebellum (Cer), hippocampus (Hipp), globus pallidus (GP), external globus pallidus (Ep), and the substantia nigra pars reticulate (SNr). Sp Cd, spinal cord. (Courtesy of Dr Allyn Howlett.) Copyright © 2024 Wolters Kluwer, Inc. Unauthorized reproduction of the content is prohibited.