Priming threshold: a novel quantitative measure of the reinstatement of cocaine self-administration

Norman, Andrew B.; Norman, Mantana K.; Hall, J. F.; Tsibulsky, Vladimir L.

doi:10.1016/s0006-8993(99)01423-7

Cited by 53 publications

(42 citation statements)

References 18 publications

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“…Until it is overcome, conclusions about the model's value to patients, or about its lack thereof, are premature. Table 1 Preclinical studies of reinstatement in rats Blocked by Naltrexone (opioid antagonist) Nicotine antibodies (Lindblom et al 2002) ABT-431 (D 1 agonist) (Self et al 2000) Flupenthixol (DA antagonist) (Shaham and Stewart 1996) Naltrindole (δ-opioid antagonist) (Ciccocioppo et al, 2002) Baclofen (GABA B agonist) (Campbell et al 1999) Haloperidol (D 2 antagonist) (Ettenberg et al 1996) Buprenorphine (opioid partial agonist) (Comer et al, 1993) Naltrexone (opioid antagonist) (Shaham and Stewart, 1996) Eticlopride (D 1 antagonist) (Khroyan et al 2000) Raclopride (D 2 antagonist) (Shaham and Stewart 1996) Flupenthixol (DA antagonist) (Khroyan et al 2000) SCH 23390 (D 1 antagonist) (Shaham and Stewart 1996) Nemonapride (D 1 antagonist) (Khroyan et al 2000) Ro 60-0175 (5-HT 2C agonist) (Grottick et al 2000) SCH 23390 (D 1 antagonist) (Norman et al 1999) SCH 39166 (ecopipam) (D 1 antagonist) (Khroyan et al 2000) SKF 81297, 83959, 82958, or 38393 (D 1 agonists or partial agonists) (Self et al 1996;Khroyan et al 2000) SR 141617A (cannabinoid antagonist) …”

Section: Resultsmentioning

confidence: 99%

The reinstatement model and relapse prevention: a clinical perspective

2003

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Objectives-This commentary assesses the degree to which the reinstatement model is homologous to the human experience of relapse.Results-A review of the literature suggests that the relationship is less clear than is often assumed, largely due to a lack of prospective data on the precipitants and process of relapse (especially relapse to heroin or cocaine abuse). However, reinstatement does not need to resemble relapse to have immediate clinical value; predictive validity as a medication screen would be sufficient. Whether the model has predictive validity is unknown, because, to date, very few clinical trials have tested medications that are effective in the reinstatement model, and even fewer have used designs comparable to those of reinstatement experiments. A clinical trial comparable to a reinstatement experiment would enroll participants who are already abstinent, and its main outcome measure would be propensity to undergo a specific type of relapse (e.g., relapse induced by stress or cues).Conclusions-Until clinical and preclinical work are more comparable, criticisms of the reinstatement model's presumed shortcomings are premature.The reinstatement model has generated a body of preclinical data that grows increasingly substantial and impressive (Shaham et al. 2003). Yet opinions remain divided about its relation to clinical realities (Marlatt 1996;Bergman and Katz 1998). In this commentary, we address the issues of whether reinstatement resembles relapse, whether it can be useful without resembling relapse, and why neither of those questions can yet be answered satisfactorily. We have drawn on clinical literature and on our own experiences working with substance abusers. Does reinstatement resemble relapse? MaybeIn most published discussions of the reinstatement model, attention is drawn to the fact that the most widely studied precipitants of reinstatement in rats (drug priming, drug-associated cues, and stress) are provocatively similar to the precipitants of relapse in humans. This is typically taken as a point of commonality between the reinstatement model and the real-life experiences of recovered addicts. It is tempting to agree without further consideration; the assertion that priming, cues, and stress precipitate relapse is intuitively appealing and seems to accord with clinical experience. But how strong is the evidence that most relapses are precipitated by any of those three factors?No definitive answer can be found in the clinical literature. Relapse is usually described retrospectively, with weeks or months intervening between the event and its recollection. This leaves ample time for the introduction of recall bias and the formation of post hoc explanations for the reporter's behavior. As an only slightly tangential illustration of the problem, consider the intuitively plausible prediction that abused children are at increased risk for later addiction. The prediction is confirmed when adult addicts are asked retrospectively about their childhoods -but not when abused and nonabused c...

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Section: Resultsmentioning

confidence: 99%

The reinstatement model and relapse prevention: a clinical perspective

2003

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“…The effects our anti-cocaine mAb in rats can be compared with those of competitive antagonists of dopamine receptors that also have been demonstrated to increase the rate of self-administration of cocaine (Koob et al, 1987;Gerber and Wise, 1989;Corrigall and Coen, 1991;Caine and Koob, 1994;Mello and Negus, 1996;Norman et al, 1999) and increase the cocaine priming threshold (Norman et al, 2002). Although the effects of mAb 2E2, in acting as a pharmacokinetic/ chemical antagonist, were qualitatively similar to those of competitive dopamine receptor antagonists, there were noticeable quantitative differences between these two different types of antagonists.…”

Section: Discussionmentioning

confidence: 99%

The Effect of a Chimeric Human/Murine Anti-Cocaine Monoclonal Antibody on Cocaine Self-Administration in Rats

Norman¹,

Norman²,

Buesing³

et al. 2008

J Pharmacol Exp Ther

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The predominantly human sequence anti-cocaine monoclonal antibody (mAb), 2E2, has high affinity and specificity for cocaine and antagonizes cocaine distribution to the brain in mice. To determine whether 2E2 can alter the self-administration of cocaine in rats, both cocaine-induced reinstatement (priming) of self-administration, and the rates of cocaine consumption were assessed during daily sessions. After self-administration training, the rats' cocaine priming threshold values were stable over a 2-week baseline period. Furthermore, the rates of cocaine consumption at unit doses of 0.3 and 3.0 mol/kg were steady within sessions and stable between sessions. Then, 2E2 (120 mg/kg i.v.) or an equivalent dose of nonspecific human polyclonal IgG (control) was infused and daily sessions continued. 2E2 produced an initial, approximately 3-fold, increase in the cocaine priming threshold that declined toward baseline values over the subsequent 3 weeks, with an effect t 1/2 of approximately 4 days. In contrast to the substantial increase in the cocaine priming threshold, 2E2 produced only modest dose-dependent increases (42 and 18%) in the cocaine consumption rates, and these also gradually declined toward baseline values. There was no significant effect of the control IgG on the priming threshold or rates of consumption of cocaine. After infusion, antibody blood concentrations declined over time, and a two-compartment pharmacokinetic model generated values for the distribution and elimination half-lives of 0.5 and 11.6 days for 2E2 and 0.4 and 6.0 days for control IgG. 2E2 had a long-lasting effect on cocaine-induced priming, which may predict its efficacy as an immunotherapy for cocaine abuse.The drug-induced reinstatement (priming) of drug selfadministration behavior represents an animal model of some aspects of the relapse process (de Wit and Stewart, 1981;Shalev et al., 2002) in addicts. The cumulative concentration of cocaine is a critical determinant of the probability of reinstating cocaine self-administration in rats (Norman et al., , 2002. Because the site of action for cocaine is presumably in the brain, decreasing the drug concentrations reaching the brain would be expected to decrease the probability of relapse. Antibodies with high affinity and specificity for cocaine are hypothesized to sequester cocaine in the peripheral circulation and reduce its entry to the brain (Kosten and Owens, 2005). Pharmacokinetic antagonism is defined as a decrease in the concentration of an agonist at its site of action. Typically, the mechanism by which this is achieved is by increasing the rate of agonist clearance (Rang et al., 2007). Although this may occur with antibody Fab fragments targeting slowly cleared drugs such as digoxin (Bateman, 2004), this would not occur with monoclonal antibodies (mAb) targeting rapidly cleared drugs such as cocaine or nicotine (Keyler et al., 2005). Antibodies generally act as chemical antagonists by binding to and thereby reversibly inactivating drugs. As a consequence, anti-drug an...

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“…Furthermore, the potency of such agents was shown to correlate significantly with their in vitro affinity and functional activity on DA D 3 , but not D 2 receptors (Caine et al, 1997;Spealman, 1996). In the case of drug priming-induced relapse to cocaine seeking, evidence suggests that blockade of D 2 -like receptors by haloperidol (Ettenberg, 1990) or blockade of DA D 1 -like receptors by SCH 23390 (Norman et al, 1999) attenuates cocaine seeking. Furthermore, activation of D 1 -like receptors by direct agonists can inhibit cocaine seeking (Self et al, 1996(Self et al, , 2000.…”

Section: Discussionmentioning

confidence: 99%

Selective Antagonism at Dopamine D3 Receptors Prevents Nicotine-Triggered Relapse to Nicotine-Seeking Behavior

Andreoli

Tessari

Pilla

et al. 2003

Neuropsychopharmacol

134

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Drugs of abuse, including, nicotine have been shown to enhance brain reward functions in the mesocortico-limbic dopamine (DA) system in general, and the nucleus accumbens in particular. The latter occupies a prominent position in the ventral striatum and expresses a high density of DA D 3 receptors. As such, the present study aimed at investigating the effect of the selective D 3 receptor antagonist SB-277011-A on both the stable maintenance of intravenous nicotine self-administration and nicotine-triggered relapse to nicotine-seeking behavior in the rat. SB-277011-A (3-10 mg/kg i.p.) significantly reduced reinstatement of nicotine-seeking behavior without affecting nicotine self-administration per se. These results suggest that DA D 3 receptors are involved in the reinstatement of nicotine-seeking behavior independently of any interaction with the primary reinforcing effects of nicotine itself. These findings point toward the potential use of selective DA D 3 receptor antagonists for the pharmacotherapeutic management of relapse to drug-seeking behaviors.

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Priming threshold: a novel quantitative measure of the reinstatement of cocaine self-administration

Cited by 53 publications

References 18 publications

The reinstatement model and relapse prevention: a clinical perspective

The reinstatement model and relapse prevention: a clinical perspective

The Effect of a Chimeric Human/Murine Anti-Cocaine Monoclonal Antibody on Cocaine Self-Administration in Rats

Selective Antagonism at Dopamine D3 Receptors Prevents Nicotine-Triggered Relapse to Nicotine-Seeking Behavior

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