Modulation of Cocaine Self-Administration in the Rat Through D-3 Dopamine Receptors

Metabotropic glutamate 2/3 receptors (mGluR2/3) are emerging targets for the reduction of stress that contributes to drug relapse. The effect of a history of cocaine escalation on stress reactivity during abstinence and the role of mGlu2/3 receptors in stress in these animals were tested. Experiment 1FRats trained to self-administer cocaine, under short (ShA, 1-h) or long (LgA, 6-h) access conditions, or noncaloric food pellets (Ctrl, 1-h), were tested for stress reactivity in the shock-probe defensive burying test following 1, 14, 42, or 84 days of abstinence. Experiment 2FExperimentally naive rats receiving the mGlu2/3 receptor agonist LY379268 (0, 0.3, 1.0, or 3.0 mg/kg) were tested in the defensive burying test to establish the anxiolytic efficacy of this compound in this model. Experiment 3FRats with a history of ShA vs LgA cocaine self-administration, or a history of operant responding reinforced by noncaloric food pellets, were tested in the defensive burying test, following administration of LY379268 (0.3, 1.0, or 3.0 mg/kg) at 14 days of abstinence. LgA rats exhibited a two-to threefold increase in defensive burying at 1, 14, and 42 days of abstinence compared to ShA or control animals. LY379268 (3.0 mg/kg) reduced burying in all groups, whereas the 1.0-mg/kg dose reduced burying only in the LgA group. A robust and enduring increase in stress reactivity developed in rats with a history of daily 6-h access to cocaine. The anxiolytic-like effects of LY379268 identify mGlu2/3 receptors as targets for ameliorating stress-associated relapse risk, and point toward the possibility that a history of cocaine escalation in rats may modify glutamatergic function.

Section: Drugsmentioning

confidence: 99%

Rats with Extended Access to Cocaine Exhibit Increased Stress Reactivity and Sensitivity to the Anxiolytic-Like Effects of the mGluR 2/3 Agonist LY379268 during Abstinence

Aujla

Martin‐Fardon

Weiss

2007

“…For instance, in rats trained to self-administer cocaine, D 3 Rpreferring agonists quinelorane,PD 128,907) enhanced the reinforcing efficacy of this drug and D 3 Rpreferring antagonists (l-nafadotride, (+)-AJ 76, (+)-UH 232) had the opposite effect Koob, 1993, 1995;Richardson et al, 1993;Smith et al, 1995;Parsons et al, 1996;Caine et al, 1997Caine et al, , 1999, although a more selective D 3 R antagonist, SB-277011-A, was inactive in this respect (Di Ciano et al, 2003). The D 3 R-preferring agonists were selfadministered (Caine and Koob, 1993;Parsons et al, 1996); they induced conditioned place preference (CPP) (Mallet and Beninger, 1994;Chaperon and Thiébot, 1996;Khroyan et al, 1997; but see Khroyan et al, 1995;Rodríguez de Fonseca et al, 1995), and/or they generalized from the damphetamine or the cocaine stimulus effects in drugdiscrimination tasks (Acri et al, 1995;Bevins et al, 1997;Baker et al, 1998;Garner and Baker, 1999), indicating that the stimulation of D 3 R may exert reinforcing effects and induce some of the subjective effects of psychostimulants.…”

Section: Introductionmentioning

confidence: 99%

Effects of a Dopamine D3 Receptor Ligand, BP 897, on Acquisition and Expression of Food-, Morphine-, and Cocaine-induced Conditioned Place Preference, and Food-seeking Behavior in Rats

Duarte

Lefebvre

Chaperon

et al. 2003

The present study addressed the role of dopaminergic D 3 receptors (D 3 R) in motivational processes in rats. The effects of the selective D 3 R partial agonist, BP 897 (0.25-1 mg/kg, i.p.), on the establishment and the expression of conditioned place preference (CPP) supported by food, morphine (4 mg/kg, s.c.), or cocaine (2 mg/kg, s.c.) were investigated using an unbiased, one-compartment, placeconditioning procedure. When administered alone, BP 897 (0.05-2 mg/kg, i.p.) did not support CPP; on the contrary, conditioned place avoidance (CPA) was observed at 1 mg/kg, suggesting that this dose of BP 897 could be perceived as aversive. When given before each cocaine injection during the conditioning phase, BP 897 (1 mg/kg) prevented the establishment of CPP, and a single administration of BP 897 (0.5 and 1 mg/kg) before the test session impaired the expression of cocaine CPP. In contrast, neither the establishment nor the expression of food-and morphine-CPP were significantly altered by BP 897 (up to 1 mg/kg), whereas the full but less selective D 3 /D 2 R agonists, 7-OH-DPAT (0.5-2 mg/kg, s.c.) and quinelorane (1 mg/kg, s.c.), prevented the acquisition of food CPP. In a within-session extinction schedule of lever pressing for food, BP 897 (0.06-2 mg/kg) was ineffective in potentiating response reinstatement induced by the noncontingent delivery of two food pellets, in contrast with quinelorane and 7-OH-DPAT where previous studies showed to be efficient in this respect (Duarte et al, 2003). These results indicate that BP 897 has no positive appetitive value on its own, and that a moderate degree of stimulation of D 3 R is not sufficient to modulate food-primed food-seeking behavior or alter incentive motivation for food, morphine, and/or their associated cues. However, D 3 R are likely involved in the perception of the rewarding value of cocaine and cocaine-paired cues. This suggests that the appetitive effects of cocaine are subserved by mechanisms different, at least in part, from those of morphine and food, and that D 3 R play a role only in the former.

“…D 3 receptor activation appears to enhance cocaine-induced reinforcement (Parsons et al, 1996). Congruently, it has been hypothesized that blockade of D 3 receptors may selectively block drug reward and relapse (Sokoloff et al, 1992a, b;Caine and Koob, 1993).…”

Section: Introductionmentioning

confidence: 99%

The Novel Dopamine D3 Receptor Antagonist NGB 2904 Inhibits Cocaine's Rewarding Effects and Cocaine-Induced Reinstatement of Drug-Seeking Behavior in Rats

Newman

Gilbert

et al. 2005

145

177

Accumulating evidence indicates that dopamine (DA) D 3 receptor antagonists appear highly promising in attenuating cocaine reward and relapse in preclinical models of addiction. In the present study, we investigated the effects of the novel D 3 -selective antagonist NGB 2904 (N-(4-[4-{2,3-dichlorophenyl}-1-piperazinyl]butyl)-3-fluorenylcarboxamide) on cocaine self-administration, cocaine-enhanced brain stimulation reward (BSR), and cocaine-triggered reinstatement of drug-seeking behavior in male Long-Evans rats. We found that: (1) acute intraperitoneal (i.p.) administration of NGB 2904 (0.1-10 mg/kg) failed to alter cocaine self-administration (0.5 mg/kg/infusion) under fixed-ratio 2 (FR2) reinforcement, but 1 or 5 mg/kg NGB 2904 significantly lowered the break-point for cocaine self-administration under progressive-ratio (PR) reinforcement; (2) cocaine (1, 2, and 10 mg/kg) significantly enhanced electrical BSR (decreased brain reward thresholds), while NGB 2904 significantly inhibited the enhancement of BSR elicited by 2 mg/kg, but not 10 mg/kg of cocaine; (3) NGB 2904 alone neither maintained self-administration behavior nor altered brain reward thresholds; and (4) NGB 2904 significantly inhibited cocaine-triggered reinstatement of extinguished drug-seeking behavior, but not sucrose-plus-sucrose-cue-triggered reinstatement of sucrose-seeking behavior. Overall, these data show that the novel D 3 -selective antagonist NGB 2904 attenuates cocaine's rewarding effects as assessed by PR self-administration, BSR, and cocaine-triggered reinstatement of cocaine-seeking behavior. Owing to these properties and to its lack of rewarding effects (as assessed by BSR and by substitution during drug self-administration), NGB 2904 merits further investigation as a potential agent for treatment of cocaine addiction.