Mechanisms of withdrawal-associated increases in heroin self-administration: pharmacologic modulation of heroin vs food choice in heroin-dependent rhesus monkeys

“However, preference between two commodities can vary as function of ratio value (Williams and Woods, 2000; Hursh and Silberberg, 2008), and future studies will be required to explore the degree to which the present results generalize to choice under other response requirements.”

“…other abused drugs, and it has been suggested that activity of these neurotransmitter systems opposes the positive-reinforcing effects of abused drugs and contributes to aversive, dysphoric, and/or anxiogenic effects of withdrawal (Koob and Le Moal, 2001; Koob et al, 2004; Walker and Koob, 2008).”

“…of clonidine or the related a-2 agonist ST-91 in rats attenuated acquisition of withdrawal-induced place aversions (Schulteis et al, 1998; Delfs et al, 2000) and withdrawal-induced suppression of responding maintained by food or electrical brain stimulation (Sparber and Meyer, 1978;…”

“However, the k-antagonist norbinaltorphimine did decrease escalated ethanol self-administration in ethanol-dependent rats (Walker and Koob, 2008).”

“…in rats (Heinrichs et al, 1995; Stinus et al, 2005). k-Receptors appear to play only a minor role in expression of somatic withdrawal signs in rats (Maldonado et al, 1992a), and the effects of k-antagonists on motivational and mood-related aspects of opioid withdrawal have not been evaluated.”

“…and motivational signs of opioid withdrawal, such as conditioned place aversions and reductions in rates of foodmaintained responding, appear to be mediated by reductions in midbrain dopamine release in regions such as nucleus accumbens (Stinus et al, 1990; Acquas et al, 1991; Criner et al, 2007).”

“For example, withdrawal in opioid-dependent rats or rhesus monkeys increased rates of morphine-maintained responding under a chain schedule (Thompson and Schuster, 1964), breakReceived 3 June 2008; revised 19 July 2008; accepted 20 July 2008 *Correspondence: Dr SS Negus, Department of Pharmacology…”

“However, drug self-administration procedures are useful for predicting determinants of drug-taking behavior in humans (Ator and Griffiths, 2003; Mello, 2005), and by extension, these procedures should be especially useful for investigating mechanisms that underlie the role of dependence and withdrawal in generating ad…”

“…signs (Brugger et al, 1998; Iredale et al, 2000; Lu et al, 2000; Skelton et al, 2007) as well as withdrawalinduced place aversions in rats (Heinrichs et al, 1995; Stinus et al, 2005). k-Receptors appear to play only a minor role in expression of somatic withdrawal signs in rats (Maldonado…”

“Second, choice studies provide a rate-independent measure of reinforcing efficacy (percent heroin choice), and as a result, effects of withdrawal or pharmacologic manipulations on choice can be dissociated from effects on response rates (Griffiths et al, 1975; Negus, 2003).”

“Clonidine reduces at least some somatic/autonomic withdrawal signs in rats, nonhuman primates, and humans (Tseng et al, 1975; Gold et al, 1979; Redmond and Huang, 1982; Jasinski et al, 1985; Katz, 1986; Sell et al, 2005).”

“…and Deneau, 1963; Blasig and Herz, 1977; O’Brien, 2006), and different withdrawal signs appear to be mediated by anatomically distinct receptor populations integrated into neural circuits that employ different neurotransmitters (Maldonado et al, 1992b; Koob and Le Moal, 2001; Frenois et al, 2002).”

“Clonidine reduces at least some somatic/autonomic withdrawal signs in rats, nonhuman primates, and humans (Tseng et al, 1975; Gold et al, 1979; Redmond and Huang, 1982; Jasinski et al, 1985; Katz, 1986; Sell et al, 2005).”

“Clonidine reduces at least some somatic/autonomic withdrawal signs in rats, nonhuman primates, and humans (Tseng et al, 1975; Gold et al, 1979; Redmond and Huang, 1982; Jasinski et al, 1985; Katz, 1986; Sell et al, 2005).”

“…and motivational signs of opioid withdrawal, such as conditioned place aversions and reductions in rates of foodmaintained responding, appear to be mediated by reductions in midbrain dopamine release in regions such as nucleus accumbens (Stinus et al, 1990; Acquas et al, 1991; Criner et al, 2007).”

“…in rats (Heinrichs et al, 1995; Stinus et al, 2005). k-Receptors appear to play only a minor role in expression of somatic withdrawal signs in rats (Maldonado et al, 1992a), and the effects of k-antagonists on motivational and mood-related aspects of opioid withdrawal have not been evaluated.”

“…opioid withdrawal, and it agrees with previous findings that CRF1 receptor antagonists attenuated both somatic withdrawal signs (Brugger et al, 1998; Iredale et al, 2000; Lu et al, 2000; Skelton et al, 2007) and withdrawal-induced place aversions (Heinrichs et al, 1995; Stinus et al, 2005) in rats.”

“First, we and others have shown previously that either spontaneous or precipitated opioid withdrawal dramatically increases choice of morphine or heroin over food (Spragg, 1940; Griffiths et al, 1975; Negus, 2006; Negus, in press).”

“Opioid addiction is thought to be motivated, at least in part, by the development of physical dependence and by negative reinforcing effects associated with the avoidance of drug withdrawal (Tatum et al, 1929; Koob and Le Moal, 2001).”

“In support of this proposition, CRF antagonists including antalarmin blocked some somatic withdrawal signs (Brugger et al, 1998; Iredale et al, 2000; Lu et al, 2000; Skelton et al, 2007) as well as withdrawalinduced place aversions in rats (Heinrichs et al, 1995; Stinus et al, 2005). k-Receptors appear to play only a…”

“…opioid withdrawal, and it agrees with previous findings that CRF1 receptor antagonists attenuated both somatic withdrawal signs (Brugger et al, 1998; Iredale et al, 2000; Lu et al, 2000; Skelton et al, 2007) and withdrawal-induced place aversions (Heinrichs et al, 1995; Stinus et al, 2005) in rats.”

“First, we and others have shown previously that either spontaneous or precipitated opioid withdrawal dramatically increases choice of morphine or heroin over food (Spragg, 1940; Griffiths et al, 1975; Negus, 2006; Negus, in press).”

“Future studies with more selective indirect or direct dopamine agonists would be useful for addressing this issue (eg Chartoff et al, 2006).”

“Clonidine also blocked acquisition of withdrawal-induced place aversions and attenuated withdrawal-induced disruption of operant responding in rats (Sparber and Meyer, 1978; Schaefer and Michael, 1983; Schulteis et al, 1998).”

“This agrees with previous findings that clonidine also failed to alter the discriminative stimulus effects of opioid withdrawal in animals (Gellert and Holtzman, 1979; France and Woods, 1989) or the craving and other subjective effects elicited by withdrawal in humans (Jasinski et al, 1985; Walsh et al, 2003).”

“This agrees with previous findings that clonidine also failed to alter the discriminative stimulus effects of opioid withdrawal in animals (Gellert and Holtzman, 1979; France and Woods, 1989) or the craving and other subjective effects elicited by withdrawal in humans (Jasinski et al, 1985; Walsh et al, 2003).”

“Doses and treatment intervals were based on previous studies with these drugs in rhesus monkeys (Katz, 1986; Negus and Mello, 2002; Negus et al, 2002; Negus, 2003; Broadbear et al, 2004; Mello et al, 2006).”

“…exposure also activates systems that employ the neurotransmitters CRF (Iredale et al, 2000; Skelton et al, 2007) and dynorphin (Rattan et al, 1992; Nylander et al, 1995), and it has been proposed that increased activity in CRF and/or dynorphinergic systems may contribute to aversive states of…”

“The efficacy-dependent effects of m-receptor ligands on opioid self-administration in opioid-dependent monkeys correlates well with the efficacy-dependent ability of these same ligands to suppress or precipitate somatic withdrawal signs (eg Woods and Gmerek, 1985).”

“…chronic opioid exposure also activates systems that employ the neurotransmitters CRF (Iredale et al, 2000; Skelton et al, 2007) and dynorphin (Rattan et al, 1992; Nylander et al, 1995), and it has been proposed that increased activity in CRF and/or dynorphinergic systems may contribute to…”

“In a previous study that provided a more detailed assessment of somatic withdrawal signs in group-housed rhesus monkeys, clonidine also had no effect on ‘vocalization,’ and clonidine effects on ‘lying on side’ and ‘cooperativity’ were small and biphasic (Katz, 1986).”

“…can be fully suppressed by treatment with relatively high-efficacy m-agonists, including morphine, heroin, and methadone, and partially suppressed by treatment with the lower efficacy m-agonist buprenorphine (Thompson and Schuster, 1964; Griffiths et al, 1975; Griffiths et al, 1981; Negus, 2006).”

“…All rights reserved 0893-133X/09 $32.00 www.neuropsychopharmacology.org points maintained by morphine delivery under progressiveratio schedules (Yanagita, 1978; Carrera et al, 1999), and choice of morphine or heroin over food in choice procedures (Spragg, 1940; Griffiths et al, 1975; Negus, 2006).”

“032 mg/kg per injection heroin was available (Negus, 2005; Negus, 2006).”

“Doses and treatment intervals were based on previous studies with these drugs in rhesus monkeys (Katz, 1986; Negus and Mello, 2002; Negus et al, 2002; Negus, 2003; Broadbear et al, 2004; Mello et al, 2006).”

“Clonidine also blocked acquisition of withdrawal-induced place aversions and attenuated withdrawal-induced disruption of operant responding in rats (Sparber and Meyer, 1978; Schaefer and Michael, 1983; Schulteis et al, 1998).”

“However, these findings contrast with reports that administration of clonidine or the related a-2 agonist ST-91 in rats attenuated acquisition of withdrawal-induced place aversions (Schulteis et al, 1998; Delfs et al, 2000) and withdrawal-induced suppression of responding maintained by food or electrical brain stimula…”

“…opioid withdrawal, and it agrees with previous findings that CRF1 receptor antagonists attenuated both somatic withdrawal signs (Brugger et al, 1998; Iredale et al, 2000; Lu et al, 2000; Skelton et al, 2007) and withdrawal-induced place aversions (Heinrichs et al, 1995; Stinus et al, 2005) in rats.”

“Studies were conducted in five adult male rhesus monkeys (Macaca mulatta) that had been surgically implanted with double-lumen catheters using aseptic procedures as described previously (Negus and Mello, 2004).”

“…with previous findings that clonidine also failed to alter the discriminative stimulus effects of opioid withdrawal in animals (Gellert and Holtzman, 1979; France and Woods, 1989) or the craving and other subjective effects elicited by withdrawal in humans (Jasinski et al, 1985; Walsh et al, 2003).”

“This possibility is further supported by data suggesting that opioid self-administration may not rely on dopaminergic substrates in non-dependent animals (Koob et al, 1986).”

“These effects are generally thought to reflect an ability of a-2 noradrenergic agonists to bind autoreceptors and suppress withdrawal-induced increases in norepinephrine release by brain stem noradrenergic neurons (Aghajanian, 1982; Delfs et al, 2000; Van Bockstaele et al, 2008).”

“Doses and treatment intervals were based on previous studies with these drugs in rhesus monkeys (Katz, 1986; Negus and Mello, 2002; Negus et al, 2002; Negus, 2003; Broadbear et al, 2004; Mello et al, 2006).”

“However, preference between two commodities can vary as function of ratio value (Williams and Woods, 2000; Hursh and Silberberg, 2008), and future studies will be required to explore the degree to which the present results generalize to choice under other response requirements.”

“…increases in heroin choice contrasts with the finding that amphetamine and the monoamine uptake blocker cocaine completely reversed the discriminative stimulus effects of Neuropsychopharmacology morphine withdrawal in rhesus monkeys (Sell and France, 2002; McMahon et al, 2004).”

“In contrast to clonidine, amphetamine decreased the discriminative stimulus effects of opioid withdrawal but did not attenuate somatic withdrawal signs in rhesus monkeys (Sell and France, 2002; McMahon et al, 2004; Sell et al, 2005).”

“In support of this proposition, CRF antagonists including antalarmin blocked some somatic withdrawal signs (Brugger et al, 1998; Iredale et al, 2000; Lu et al, 2000; Skelton et al, 2007) as well as withdrawalinduced place aversions in rats (Heinrichs et al, 1995; Stinus et al, 2005). k-Receptors…”

“Cocaine has also been reported to decrease some opioid withdrawal signs in humans (Kosten and Kosten, 1989; Rosen et al, 1992).”

“Cocaine has also been reported to decrease some opioid withdrawal signs in humans (Kosten and Kosten, 1989; Rosen et al, 1992).”

“Clonidine reduces at least some somatic/autonomic withdrawal signs in rats, nonhuman primates, and humans (Tseng et al, 1975; Gold et al, 1979; Redmond and Huang, 1982; Jasinski et al, 1985; Katz, 1986; Sell et al, 2005).”

“…κ receptors reduced naltrexone-precipitated morphine withdrawal in mice (Simonin et al. 1998), and 5′- guanidinonaltrindole, a κ antagonist, had no effect on the withdrawal-induced increase in heroin choice over food in a choice self-administration paradigm in rhesus monkeys (Negus and Rice 2009).”

“However, using this choice model, a study in rhesus monkeys failed to show positive effects with a CRF1 receptor antagonist (although one of three monkeys did respond) and a k-opioid receptor antagonist, but it did show positive results with opioid substitution drugs (Negus and Rice, 2009).”

“…serve as an important negative reinforcement mechanism for the self-administration of some drugs, examination of how the reinforcing effects of a drug might change under conditions of withdrawal might be a valuable additional component of abuse liability assessment (e.g., Negus and Rice, 2009).”

“…expression of reinforcing effects in preclinical self-administration procedures (Thompson and Schuster, 1964; Yanagita, 1978; Carrera et al., 1999; Negus and Rice, 2009; O’Connor et al., 2011) and expression of abuse-related subjective and reinforcing effects in humans (Lasagna et al., 1955;…”

“failed to modify withdrawal-induced choice of heroin over food in non-human primates with 21-h access to heroin [389], suggesting KORs may not regulate opiate withdrawal-induced heroin seeking.”

“…and behavioral evidence suggests that this class of drugs would also attenuate the reinforcing effects of opioids, unlike adrenergic agents Group © 2015 Society for the Study of Addiction Addiction Biology that do not decrease opioid self-administration in laboratory animals (Negus & Rice 2009).”

“Furthermore, acute treatment with another long-acting KOR antagonist, 5′-guanidonaltrindole, also failed to block withdrawal-associated increases in heroin versus food choice in nonhuman primates [84].”

“Both conditioned and unconditioned heroin or morphine withdrawal has previously been demonstrated to increase responding for heroin in rats (Shaham et al, 1996; Kenny et al, 2006) and heroin choices in monkeys, especially at the lowest doses of heroin tested (Negus, 2006; Negus and Rice, 2009).”

“In addition, withdrawal from heroin increases the choice of heroin in nonhuman primates, even at low doses (Negus 2006, Negus & Rice 2009).”

“Withdrawal-associated increases in heroin self-administration relative to food choice in heroin-dependent rhesus monkeys was suppressed by morphine, but not NE agonism, DA release or KOR agonists [485].”

“Also, our hypothesis is further supported by recent studies showing that opioid agonist methadone reduces early withdrawal-associated increases in heroin self-administration in heroindependent monkeys (Negus, 2006; Negus and Rice, 2009).”

“However, drugs targeting withdrawal signs did not reduce heroin choice in monkeys (Negus and Rice 2009) and have not yet successfully translated to the clinic.”

“First, we and others have shown earlier that opioid withdrawal increases choice of heroin or morphine over food in opioid-dependent monkeys (Spragg, 1940; Griffiths et al, 1975; Negus, 2006; Negus and Rice, 2009).”

“Moreover, agonists at these receptors serve as reinforcers in self-administration paradigms (Justinova et al. 2008; Negus and Rice 2009).”

“1C shows that morphine administered by continuous infusion during the withdrawal period dose-dependently and completely prevented withdrawal-associated increases in heroin choice (Negus and Rice, 2009).”

“Furthermore, administration of nonopioid agents that decreased withdrawal (10 mg/kg/day antalarmin and 0.032 mg/kg/h clonidine) did not reverse withdrawalassociated increases in the relative reinforcing effects of heroin (Negus and Rice 2009).”

“, 1996), increase reinforcing effects in preclinical assays of self-administration (Thompson and Schuster, 1964; Yanagita, 1978; Carrera et al., 1999; Negus and Rice, 2009), and increase the expression of abuse-related subjective effects and reinforcing effects in humans (Comer et al.”

“For example, monkeys with a history of drug self-administration will choose heroin over a food reward (Negus and Rice, 2009) and will even administer drug to the point of death (Downs et al., 1979).”

“For example, in heroin-dependent rhesus monkeys responding under a choice procedure for either food or heroin, discontinuation of daily heroin administration concurrently increased withdrawal scores and choice of heroin over food (Negus 2006; Negus and Rice (2009).”

“1994) elevated self-stimulation thresholds (Schaefer and Michael 1985), and elevated and persistent heroin-seeking behavior (Hutcheson et al. 2001; Lenoir and Ahmed 2007; Gerak et al. 2009; Negus 2006; Negus and Rice 2009).”

“We have reported previously that the relative reinforcing effects of mu opioid agonists may be influenced by the degree of opioid dependence (Negus 2006; Negus and Rice 2009).”

“Historically, NHPs have not been widely used in the study of delay discounting.”

“Despite compelling behavioral data to suggest that MOPrs mediate key aspects of opiate dependence-related processes (Matthes et al. 1996; Negus and Rice 2009), inconsistent findings have pointed to increases, decreases or a lack of change in MOPr mRNA (Brodsky et al.”

“…LY2456302 had no significant effect on self-administration of morphine or heroin or oxycodone, heroin vs. food choice, and CPP induced by repeated morphine administration (Bossert et al., 2019; Brice-Tutt et al., 2022; Glick et al., 1995; Negus et al., 1993; Negus and Rice, 2009; Xi et al., 1998).”

“…and behavioral abstinence syndrome when drug is withdrawn, and one common component of withdrawal from many addictive drugs is a decrease in the reinforcing effectiveness of non-drug reinforcers such as food and social interaction (Emmett-Oglesby et al. 1990; Negus and Rice 2009; Spragg 1940).”

“In fact, even a lower dose, 10 mg/kg, has been reported to partially block heroin choice precipitated in rhesus macaques by heroinwithdrawal [29].”

“, 2002), selectivity of possible therapeutic drugs (Ginsburg and Lamb, 2006; Banks and Negus, 2010), drugs and drug combinations (Meisch and Lemaire, 1990), and effects of withdrawal or tolerance (Negus and Rice, 2009).”

“…on drug reinforcement may be especially useful in studies examining the effects of subchronic drug exposure and termination on drug reinforcement, because drug withdrawal may reduce rates of operant responding (Griffiths et al., 1975; Negus & Rice, 2009; Wade-Galuska, Galuska, & Winger, 2011).”

“In contrast to stimulants like cocaine (Banks & Negus, 2010), physical dependence and its associated withdrawal are strong drivers of drug choice with opioids like heroin (e.g., Negus, 2006; Negus & Rice, 2009).”

“1C and previous preclinical studies [23, 24, 37, 77, 78].”

“…escalated drug use in single schedules often do not show corroborative drug preference changes in choice procedures (Caprioli, Zeric, Thorndike, & Venniro, 2015; Lenoir, Serre, Cantin, & Ahmed, 2007; Schwartz et al., 2017; c.f. Lenoir, Cantin, Vanhille, Serre, & Ahmed, 2013; Negus & Rice, 2009 ).”