Acquisition, Expression, and Reinstatement of Ethanol-Induced Conditioned Place Preference in Mice: Effects of Opioid Receptor-Like 1 Receptor Agonists and Naloxone

Abstract

The ability of the two opioid receptor-like receptor 1 (ORL1) agonists nociceptin (5 nmol i.c.v.) and synthetic (1S,3aS)-8-(2,3,3a,4,5,6-hexahydro-1H-phenalen-1-yl)-1-phenyl-1,3,8-triaza-spiro[4.5]decan-4-one hydrochloride (Ro 64-6198; 0.1, 0.3, and 1.0 mg/kg i.p.) and the opioid antagonist naloxone (0.1, 1.0, and 10.0 mg/kg s.c.) to modify ethanolinduced conditioned place preference was examined in NMRI male mice. The ORL1 agonists were found to significantly reduce the acquisition, expression, and ethanolinduced reinstatement of conditioned place preference. Unlike the ORL1 agonists, naloxone at the doses relevant for opioid receptor blockade failed to significantly influence the acquisition of ethanol-induced conditioned place preference. However, naloxone at 1.0 but not 0.1 mg/kg s.c. potently blocked the expression of ethanol-induced conditioned place preference and significantly inhibited ethanol-induced reinstatement of the conditioned place preference after extinction. Separate experiments indicated that nociceptin and Ro 64-6198 are both devoid of reinforcing or aversive properties. Naloxone, however, at 1.0 and 10.0 mg/kg, produced conditioned place aversion, indicating motivational properties of its own. Both nociceptin and Ro 64-6198 reduced locomotor activity after acute administration. However, tolerance developed very quickly to this effect and already after three i.c.v. (or i.p.) injections, there was no significant reduction of locomotor activity. It is concluded that ORL1 agonists can modulate the acquisition, expression, and reinstatement of the conditioned reinforcing effects of ethanol with no reinforcing or aversive properties of their own. This property might be a potential advantage in the treatment of alcoholism compared with nonselective opioid antagonist naltrexone.Relapse to alcohol use after periods of abstinence is a common feature of alcoholism. Animal models have contributed to the identification of factors that may underlie the motivational aspects of ethanol and that contribute to relapse to ethanol taking. Drug-seeking behavior for ethanol can be initiated or maintained not only by the primary, reinforcing effects of the drugs themselves but also by secondary, drug-associated stimuli (for review, see O'Brien, 1975). The most common experimental model used to study relapse to drug seeking has been the reinstatement procedure. After training to make a response to self-administer a drug and the subsequent extinction of the acquired response, an acute noncontingent injection of test drug (or acute stress) results in the reinstatement of responding (Carroll and Comer, 1996). The conditioned place preference (CPP) procedure provides an alternative experimental approach to examine mechanisms underlying relapse. In this procedure a particular stimulus context or test environment is paired with the effects of the drug, without the animal having to learn to make an explicit response to obtain the drug. In the test trial, the animal is allowed to freely move between the test envir...

The Nociceptin/Orphanin FQ Receptor Agonist Ro 64-6198 Reduces Alcohol Self-Administration and Prevents Relapse-Like Alcohol Drinking

“…nociceptin, Ro 64-6198 administered intraperitoneally (i.p.) reduces acquisition and reinstatement of alcoholinduced place preference in place conditioning experiments but when administered alone did not produce either place preference or place aversion (Kuzmin et al, 2003;Shoblock et al, 2005).…”

“…This peptide also reduced the effects of footshock stress on ethanolseeking behavior (Martin-Fardon et al, 2000). In place conditioning experiments, nociceptin reduced alcoholinduced conditioned place preference and reinstatement of acquired place preference after extinction (Ciccocioppo et al, 1999;Kuzmin et al, 2003). The peptide alone did not affect place preference, suggesting that it is devoid of 'motivational' properties (Devine et al, 1996;Ciccocioppo et al, 1999;Kuzmin et al, 2003).…”

“…Several studies have demonstrated that the endogenous nociceptin/opioid receptor-like 1 (ORL-1) receptor system is involved in the rewarding effects of ethanol (Ciccocioppo et al, 1999(Ciccocioppo et al, , 2004Martin-Fardon et al, 2000;Kuzmin et al, 2003). Thus, nociceptin injected intracerebroventricularly (i.c.v.)…”

“…Non-peptide ORL-1 receptor agonists may represent novel candidates for the development of alternative pharmacotherapy to treat alcoholism that may be effective in a different group of subjects. Compared to naltrexone, ORL-1 receptor agonists do not have apparent aversive effects as evaluated in animal models (Devine et al, 1996;Kuzmin et al, 2003;Shoblock et al, 2005). In addition, ORL-1 agonists have marked anxiolytic and antistress actions (Jenck et al, 2000;MartinFardon et al, 2000) and could have certain advantages over opiate antagonists, which can be anxiogenic (Lee and Rodgers, 1990).…”

Kappa‐opioid receptors differentially regulate low and high levels of ethanol intake in female mice

“…One such antagonist, naltrexone, has been shown in numerous single center and multicenter placebo‐controlled clinical trials to improve treatment outcomes for alcoholics by decreasing relapse (Anton et al., 1999; Guardia et al., 2002; Heinala et al., 2001; Latt, Jurd, Houseman, & Wutzke, 2002; Oslin, Liberto, O'Brien, Krois, & Norbeck, 1997; Volpicelli, Alterman, Hayashida, & O'Brien, 1992), craving (Chick et al., 2000; Heinala et al., 2001; Volpicelli et al., 1992), days of drinking (Monti et al., 2001; O'Malley et al., 1992; Volpicelli et al., 1992) and number of drinks if the patient drank during treatment (Anton et al., 1999; Chick et al., 2000; Monti et al., 2001). Consistent with these clinical findings, there have also been reports from preclinical studies in laboratory animals that describe naltrexone‐induced decreases in ethanol intake (Froehlich, Harts, Lumeng, & Li, 1987, 1990; Hubbell et al., 1986; Myers & Lankford, 1996; Parkes & Sinclair, 2000; Phillips, Wenger, & Dorow, 1997; Reid & Hunter, 1984), ethanol self‐administration (Heyser, Roberts, Schulteis, & Koob, 1999; Samson & Doyle, 1985; Sinden, Marfaing‐Jallat, & Le Magnen, 1983; Williams, Kane, & Woods, 2001), and the expression of ethanol‐induced conditioned place preference (Bechtholt & Cunningham, 2005; Cunningham, Henderson, & Bormann, 1998; Kuzmin, Sandin, Terenius, & Ogren, 2003; Middaugh & Bandy, 2000). Nevertheless, naltrexone is not always effective in humans (Gastpar et al., 2002; Kranzler, Modesto‐Lowe, & Van Kirk, 2000; Krystal, Cramer, Krol, Kirk, & Rosenheck, 2001).…”