Extinction-induced upregulation in AMPA receptors reduces cocaine-seeking behaviour

Sutton, Michael A.; Schmidt, Eric F.; Choi, Kwang Ho; Schad, Christina A.; Whisler, Kim; Simmons, Diana; Karanian, David A.; Monteggia, Lisa M.; Neve, Rachael L.; Self, David W.

doi:10.1038/nature01249

Cited by 303 publications

(299 citation statements)

References 28 publications

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“…Several procedural variables may explain this apparent discrepancy. First, in all previous studies except one (Deroche et al, 1999), daily access time to cocaine was longer than the minimum of the present study (ie 1 h) and ranged between 2 and 6 h (eg de Wit and Stewart, 1981;Erb et al, 1996;De Vries et al, 1998;Lynch and Carroll, 2000;Lu et al, 2004;Fuchs et al, 2004;Schenk and Partridge 1999;Neisewander et al, 1996;Xi et al, 2004;Sutton et al, 2003;Dias et al, 2004). Thus, together with the present findings, this difference may point to the existence of some threshold duration below which most individuals readily learn to take cocaine without becoming responsive to its motivational effects and above which they begin to respond to these effects.…”

Section: Discussioncontrasting

confidence: 40%

Dissociation of Psychomotor Sensitization from Compulsive Cocaine Consumption

Ahmed¹,

Cador²

2005

Neuropsychopharmacol

146

143

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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.

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Section: Discussioncontrasting

confidence: 40%

Dissociation of Psychomotor Sensitization from Compulsive Cocaine Consumption

Ahmed¹,

Cador²

2005

Neuropsychopharmacol

146

143

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“…On the other hand, exposure to cocaine 17-90 days earlier has been reported to either slightly increase GluR1 (Churchill et al, 1999;Scheggi et al, 2002;Lu et al, 2003) and GluR2 protein levels, leave GluR1 (Fitzgerald et al, 1996;Ghasemzadeh et al, 1999) and GluR2 (Fitzgerald et al, 1996;Churchill et al, 1999;Ghasemzadeh et al, 1999;Scheggi et al, 2002) protein and mRNA levels unchanged and decrease GluR3 and GluR4 mRNA levels (Ghasemzadeh et al, 1999). In another study, GluR1 and GluR2/3 protein levels were not increased 1 week following cocaine self-administration unless animals were subjected to an extinction procedure during the withdrawal period (Sutton et al, 2003). While multiple factors can certainly be evoked to explain the different results obtained, the range of findings together with the small magnitude of the effects reported (20-50% of control) suggests that factors other than changes in the overall expression of AMPA receptor subunits are responsible for the enhanced ability of NAcc AMPA to produce locomotion and reinstate drug seeking.…”

Section: Discussionmentioning

confidence: 93%

Previous Exposure to Psychostimulants Enhances the Reinstatement of Cocaine Seeking by Nucleus Accumbens AMPA

Suto

Tanabe

Austin

et al. 2004

Neuropsychopharmacol

103

100

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The effect of previous exposure to psychostimulants on the subsequent self-administration of cocaine as well as reinstatement of this behavior by priming infusions of AMPA into the nucleus accumbens (NAcc) was examined. Rats were exposed to five injections, one injection every third day, of either saline or amphetamine (AMPH: 1.5 mg/kg, i.p.). Starting 10 days later, they were trained to selfadminister cocaine (0.3 mg/kg/infusion, i.v.) and subsequently tested under a progressive ratio (PR) schedule for 4 consecutive days. As expected, rats exposed to AMPH worked more and obtained more cocaine infusions than saline exposed controls on the PR test sessions. Following daily extinction sessions during which saline was substituted for cocaine, the effect of priming infusions of AMPA (0.0, 0.08, or 0.8 nmol/0.5 ml/side) into the NAcc was then examined on two tests: one conducted 4 days after the last cocaine PR test session (2-3 weeks after the last AMPH exposure injection) and the next 4 weeks later. Consistent with previous reports, NAcc AMPA dosedependently reinstated cocaine seeking on both tests regardless of exposure condition. Importantly, this priming effect of NAcc AMPA was significantly enhanced in AMPH compared to saline exposed rats on the first test conducted 2-3 weeks after AMPH. On the second test, conducted 4 weeks after cocaine, reinstatement was similarly enhanced in both groups to levels observed on the first test in AMPH exposed rats. These results indicate that both noncontingent (AMPH) and contingent (cocaine) exposure to psychostimulants enhances the reinstatement of cocaine seeking by NAcc AMPA and appears to do so in a time-dependent manner.

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“…Similarly, a down regulation of NMDA receptor NR1 subunit during abstinence is reversed by extinction [25]. Finally, an extinction induced upregulation of GluR1 AMPA receptors occurs in the nucleus accumbens shell [32], and an upregulation of tyrosine hydroxylase also has been observed in the ventral tegmental area following extinction training [23]. All of these extinction induced neuroadaptations would be expected to act in a compensatory manner in order to counteract the drug induced depression of the synapses in the nucleus accumbens shell [33].…”

Section: Discussionmentioning

confidence: 99%

The effects of extinction training in reducing the reinstatement of drug-seeking behavior: Involvement of NMDA receptors

Kelamangalath

Swant

Stramiello

et al. 2007

Behavioural Brain Research

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Although the process of extinction has been well documented for various forms of behavioral responses, the effects of extinction on the reinstatement of drug seeking behavior are relatively understudied. In this report, the effectiveness of an extinction training protocol to reduce primed reinstatement responses was compared with the effectiveness of an equivalent period of enforced abstinence. We found that extinction training performed in the drug taking environment significantly reduced reinstatement behavior subsequently primed by either contextual cues, conditioned cues, or cocaine infusion. The ability of extinction to reduce cocaine primed reinstatement was blocked by the systemic administration of the competitive NMDAR antagonist ((±)CPP, 5 mg/kg i.p.) administered prior to each extinction training session. Interestingly, this pharmacological intervention had no impact on the effectiveness of extinction to reduce drug-seeking behavior primed by either contextual cues or conditioned cues. These results suggest that an extinction training experience involves multiple mechanisms that can be dissociated into nonNMDAR and NMDAR dependent components with respect to the type of reinstatement (i.e. context-, CS-, or drug-induced) being assessed.

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Extinction-induced upregulation in AMPA receptors reduces cocaine-seeking behaviour

Cited by 303 publications

References 28 publications

Dissociation of Psychomotor Sensitization from Compulsive Cocaine Consumption

Dissociation of Psychomotor Sensitization from Compulsive Cocaine Consumption

Previous Exposure to Psychostimulants Enhances the Reinstatement of Cocaine Seeking by Nucleus Accumbens AMPA

The effects of extinction training in reducing the reinstatement of drug-seeking behavior: Involvement of NMDA receptors

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