Effects of extended-access self-administration and deprivation on breakpoints maintained by cocaine in rats

Increased drug availability can precipitate a rapid transition to compulsive drug use in both vulnerable humans and laboratory animals. Recent studies have shown that despite equivalent levels of psychomotor sensitization, only rats with prolonged, but not limited, access to cocaine self-administration respond to the priming effects of cocaine on drug seeking, as measured in a within-session reinstatement model of drug craving. In this model, drug seeking is first extinguished and then reinstated by non-contingent presentations of the drug alone in the absence of response-contingent stimuli. Here, we assessed the generality of this observation in rats with daily short (1 h, ShA) vs long access (6 h, LgA) to i.v. heroin self-administration. As expected, heroin intake by LgA rats (n ¼ 24) increased over time to become excessive compared to heroin intake by ShA rats (n ¼ 24). After escalation, LgA rats tended to be less sensitive to heroin-induced locomotion (7.5-30 mg, i.v.) than ShA rats. In contrast, only LgA rats, not ShA rats, responded to the priming effects of heroin, as measured by the ability of heroin alone (7.5-30 mg, i.v.) to reinstate extinguished drug-seeking behavior. Finally, during the course of heroin intake escalation, a large proportion of LgA rats developed self-injury (mostly targeting the nails and digit tips of the forepaws), a negative consequence not seen in ShA rats. This study reproduces and extends previous research on compulsive cocaine use by showing that heroin-induced reinstatement is also specific to compulsive drug use and dissociable from heroin-induced reward and psychomotor sensitization. Neuropsychopharmacology (2007) 32, 616-624.

Section: Introductionmentioning

confidence: 96%

Section: Introductionmentioning

confidence: 99%

Heroin-Induced Reinstatement is Specific to Compulsive Heroin Use and Dissociable from Heroin Reward and Sensitization

Lenoir¹,

Ahmed²

2006

“…First, LgA rats persist more than ShA rats in seeking the drug despite the fact that their behavior is no longer rewarded (Ahmed et al, 2000). Second, LgA rats show an increased motivation to work to obtain the drug compared to ShA rats, as measured under a progressive ratio schedule of drug self-administration (Paterson and Markou, 2003;Lenoir and Ahmed, unpublished results; but see, Liu et al, 2005). Third, when foraging for the drug, LgA rats ignore signals of potential dangers and thus take increased risks to obtain the drug (Vanderschuren and Everitt, 2004).…”

Section: Introductionmentioning

confidence: 97%

“…Based on previous work using continuous access to drug selfadministration (Deneau et al, 1969;Johanson et al, 1976;Bozarth and Wise, 1985;Wolffgramm, 1991), we and others have recently developed and begun to validate an animal model of the transition to compulsive drug use (Ahmed and Koob, 1998;Mantsch et al, 2001;Paterson and Markou, 2003;Roth and Carroll, 2004;Vanderschuren and Everitt, 2004;Liu et al, 2005). Differential access to intravenous i.v.…”

Section: Introductionmentioning

confidence: 99%

Dissociation of Psychomotor Sensitization from Compulsive Cocaine Consumption

Ahmed¹,

Cador²

2005

146

143

The transition from drug use to drug addiction is associated with a process of escalation, whereby drug use becomes excessive and difficult to control. Several mechanisms have been advanced to explain escalating patterns of drug use as opposed to nonescalating patterns. Although current evidence favors hedonic tolerance, there remains some dispute about the contribution of behavioral sensitization to cocaine intake escalation. Here, we concurrently assessed the ability of cocaine to induce psychomotor sensitization and drug-seeking behavior in animals with 1-h (short access or ShA) vs 6-h (long access or LgA) access to intravenous (i.v.) cocaine selfadministration. As expected, cocaine intake by LgA rats escalated over time and became excessive compared to cocaine intake by ShA rats, which remained low and stable. Despite escalated levels of cocaine consumption, however, LgA rats were not more sensitized to cocaine than ShA rats. The dose-effect function for cocaine-induced locomotion (0.125-1 mg, i.v.) was shifted to the left in LgA rats by the same amount as in ShA rats after cocaine self-administration. In contrast, LgA rats were much more responsive than ShA rats to the motivational effects of cocaine, as measured by the ability of i.v. cocaine to reinstate extinguished drug-seeking behavior. This study demonstrates a dissociation of psychomotor sensitization from the change in motivation underlying the transition to compulsive cocaine consumption, and therefore suggests that responsiveness to the motivational effects of the drug, not psychomotor sensitization, would represent a specific behavioral marker of the transition to and maintenance of compulsive cocaine use.

“…With 1 h of access per day (short access or ShA), rate of drug intake is low and stable over time. In contrast, with 6 or more hours of access per day (long access or LgA), rate of drug intake gradually escalates above initial levels (Ahmed and Koob, 1998;Ahmed et al, 2000;Mantsch et al, 2001;Paterson and Markou, 2003;Walker et al, 2003;Ferrario et al, 2005;Liu et al, 2005;Perry et al, 2006). The intensity of drug intake escalation is influenced by both the unit dose and the daily duration of drug access (Mantsch et al, 2004;Wee et al, 2007).…”

Section: Introductionmentioning

confidence: 99%

Supply of a Nondrug Substitute Reduces Escalated Heroin Consumption

Lenoir

Ahmed

2007

Escalation of drug consumptionFa hallmark of addictionFhas been hypothesized to be associated with a relative devaluation of alternative nondrug rewards and thus with a decrease in their ability to compete with or to substitute for the drug. In a behavioral economic framework, decreased substitutability of nondrug rewards for drug would explain why drug consumption is behaviorally dominant and relatively resistant to change (eg price-inelastic) in drug-addicted individuals. The goal of the present study was to test this hypothesis using a validated rat model of heroin intake escalation. Escalation was precipitated by long (6 h, long access (LgA)), but not short (1 h, short access (ShA)), daily access to i.v. heroin self-administration. After escalation, the effects of price (ie fixed-ratio value) on heroin consumption were assessed under two alternative reward conditions: in the presence or absence of a nondrug substitute for heroin (ie four freely available chow pellets). As expected, escalated heroin consumption by LgA rats was less sensitive to price than heroin consumption by ShA rats, showing that heroin had acquired greater reinforcing strength during escalation. However, supplying a substitute during access to heroin was sufficient to reverse this post-escalation increase in the reinforcing effectiveness of heroin. Thus, escalated heroin consumption is not associated with a decreased sensitivity to competing nondrug rewards. Escalated drug use may therefore persist, not so much because of a relative devaluation of nondrug substitutes, but because of a loss or reduction of their availability.