Preclinical Behavioral Models for Addressing Unmet Needs in Opiate Addiction

Clonidine Blocks Acquisition But not Expression of Conditioned Opiate Withdrawal in Rats

“…However, as discussed earlier, although data from the clinical literature support some reductions in subjective/affective components of withdrawal, these symptoms seem less effectively blocked by clonidine than somatic signs. Many current theories of addiction favor a role of affective withdrawal symptomatology and conditioned reinforcement processes in maintaining addiction and promoting relapse after periods of abstention (Childress et al 1994;Jasinski et al 1985;O'Brien et al 1976O'Brien et al , 1993Ramsay and Woods 1997;Schulteis and Koob 1996;Schulteis et al 1997a;Wikler 1973). The inability of clonidine to attenuate effectively either unconditioned or conditioned affective withdrawal symptoms emphasizes a potentially significant limitation in the clinical utility of this and related ␣ 2 -compounds (e.g., lofexidine, Kahn et al 1997;Washton et al 1983) in facilitating complete detoxification and preventing relapse.…”

“…A considerable body of both clinical and preclinical literature suggests that positive (drug reward) and negative (drug withdrawal) affective states can become associated with stimuli in the drug-taking environment and that these conditioned stimuli themselves acquire motivational significance in maintaining compulsive use and in precipitating relapse after periods of abstention (Baldwin and Koob 1993;Childress et al 1994;O'Brien et al 1976O'Brien et al , 1993Ramsay and Woods 1997;Schulteis and Koob 1996;Schulteis et al 1997a;Wikler 1973).…”

“…In addition, recent studies with conditioned place aversion, a behavioral paradigm that serves as a sensitive animal model of affective opiate withdrawal (Hand et al 1988;Schulteis et al 1994), suggested that clonidine administered prior to each conditioning trial could block the acquisition of a conditioned aversion to a distinct environment paired with naloxone-precipitated withdrawal (Kosten 1994;Nader and van der Kooy 1996). Conditioned place aversions can be elicited by administration of opiate antagonists directly into the nucleus accumbens and central nucleus of the amygdala (Stinus et al 1990), critical elements of the brain's reward circuitry that mediate the acute hedonic (rewarding) effects of opiates and other drugs of abuse (see Schulteis and Koob 1996;Schulteis et al 1997a). Therefore, conditioned place aversions seem to be a specific manifestation of neuroadaptation within the affective (emotional) domain.…”

Buprenorphine and a CRF1 Antagonist Block the Acquisition of Opiate Withdrawal-Induced Conditioned Place Aversion in Rats

“…This has been hypothesized to contribute to the motivation for continued use and escalation to compulsive use (Koob and Le Moal, 1997). While it is clear that the induction of dependence is not necessary for the initiation of voluntary self-administration of opiates, once drug self-administration is initiated the negative consequences of drug abstinence may motivate the continued administration of the drug to prevent the appearance of a withdrawal or abstinence syndrome (Schulteis et al, 1997).…”