Clinical Textbook of Addictive Disorders 3rd ed - R. Frances, S. Miller, A. Mack (Guilford, 2005) WW

1. The Neurobiology of Substance Dependence 13that produce feelings of pleasure (Kosten & Kleber, 1984). An individual whois adequately dosed with naltrexone does not obtain any pleasure from addictiveopioids and is less motivated to use them. An interesting neurobiologicaleffect of naltrexone is that it appears to increase the number of available muopiate receptors, which may help to renormalize the imbalance between thereceptors and G-protein coupling to cyclic AMP (Kosten, 1990). Naltrexone isalso sometimes used to detoxify patients rapidly from opioid dependence. Inthis situation, while naltrexone keeps the addictive opioid molecules away fromthe mu receptors, clonidine may help to suppress the opioid-induced excessiveNA output that is a primary cause of withdrawal (Kosten, 1990). Clonidine iscapable of this withdrawal relief because alpha-adrenergic autoreceptors are colocalizedwith mu opiate receptors on the neurons of the LC, and both receptortypes inhibit cyclic AMP synthesis through similar inhibitory G proteins.Buprenorphine’s action on the mu opioid receptors elicits two differenttherapeutic responses within the brain cells, depending on the dose. At lowdoses, buprenorphine has effects like methadone, but at high doses, it behaveslike naltrexone, blocking the receptors so strongly that it can precipitate withdrawalin highly dependent patients (i.e., those maintained on more than 40mg methadone daily). Several clinical trials have shown that buprenorphine isas effective as methadone, when used in sufficient doses (Kosten, Schottenfeld,Ziedonis, & Falcioni, 1993; Oliveto, Feingold, Schottenfeld, Jatlow, & Kosten,1999; Schottenfeld, Pakes, Oliveto, Ziedonis, & Kosten, 1997). Buprenorphinehas a safety advantage over methadone, since high doses precipitate withdrawalrather than the suppression of consciousness and respiration seen in overdosesof methadone and heroin. Thus, buprenorphine has less overdose potentialthan methadone, since it blocks other opioids and even itself as the dosageincreases. Finally, buprenorphine can be given three times per week, simplifyingobserved ingestion during the early weeks of treatment.SUMMARYDependence and addiction are most appropriately understood as chronic medicaldisorders, with frequent recurrences to be expected. The neurobiology ofthese disorders is becoming well understood, but much remains unknown aboutthe genomic mechanisms that predispose to addictions and that are activated,perhaps irreversibly, by long-term drug use. The mesolimbic reward systemappears to be central to the development of the direct clinical consequences ofchronic abuse, including tolerance, dependence, and addiction. Other brainareas and neurochemicals, including cortisol, also are relevant to dependenceand relapse. Pharmacological interventions for addiction are highly effective foropiates, and we have illustrated three different approaches using an agonist, anantagonist, or a partial agonist. However, given the complex biological, psycho-