lithium-chloride and Cocaine-Related-Disorders

Kappa opioid receptor (KOR) agonists have known anti-addiction properties and can reduce drug seeking. Their potential for clinical use has largely been daunted by their aversive properties mediated through p38 MAPK signaling. Here we examined the therapeutic potential of the KOR agonist U50,488 (U50) to reduce cocaine seeking in a self-administration model. Following cocaine self-administration and 7 days of forced home-cage abstinence, rats were administered a single dose of U50 (5 mg/kg, i.p.) 30 min prior to the first extinction training session, wherein cocaine and the discrete cocaine-paired cues were no longer available. U50 reduced cocaine seeking on this first extinction session, but did not alter extinction training over subsequent days. 2 weeks after U50 treatment, rats underwent a test of cue-induced reinstatement, and rats that had received U50 reinstated less than controls. Central inhibition of p38 MAPK at the time of U50 administration prevented its long-term therapeutic effect on reinstatement, but not its acute reduction in drug seeking on extinction day 1. The long-term therapeutic effect of U50 required operant extinction during U50 exposure, extended to cocaine-primed reinstatement, and was not mimicked by another aversive drug, lithium chloride (LiCl). These data suggest U50 elicits its long-term anti-relapse effects through a KOR-p38 MAPK-specific aversive counterconditioning of the operant cocaine-seeking response. A single, albeit aversive treatment that is able to reduce relapse long-term warrants further consideration of the therapeutic potential of KOR agonists in the treatment of addiction.

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Animals; Cocaine; Cocaine-Related Disorders; Conditioning, Operant; Cues; Drug-Seeking Behavior; Extinction, Psychological; Imidazoles; Infusions, Intraventricular; Lithium Chloride; Male; p38 Mitogen-Activated Protein Kinases; Pyridines; Rats; Receptors, Opioid, kappa; Recurrence; Self Administration

Cocaine addiction is often characterized by a rigid pattern of behavior in which cocaine users continue seeking and taking drug despite negative consequences associated with its use. As such, full acquisition and relapse of drug-seeking behavior may be attributed to a shift away from goal-directed responding and a shift towards the maladaptive formation of rigid and habit-like responses. This rigid nature of habitual responding can be developed with extended training and is typically characterized by insensitivity to changes in outcome value. The present study determined whether cocaine (primary reinforcer) and cocaine associated cues (secondary reinforcer) could be devalued in rats with different histories of cocaine self-administration. Specifically, rats were trained on two schedules of cocaine self-administration (long-access vs. short-access). Following training the cocaine reinforcer was devalued through three separate pairings of lithium chloride with cocaine infusions. Cocaine history did not have an impact on devaluation of cocaine-associated cues. However, the reinforcing properties of cocaine were devalued only in rats on a short-access cocaine schedule but not those trained on a long-access schedule. Taken together this pattern of findings suggests that, in short access rats, devaluation is specific to the primary reinforcer and not associative stimuli such as cues. Importantly, rats that received extended training during self-administration displayed insensitivity to outcome devaluation of the primary reinforcer as well as all associative stimuli, thus displaying rigid behavioral responding similar to behavioral patterns found in addiction. Alternatively, long access cocaine exposure may have altered the devaluation threshold.

Topics: Analysis of Variance; Animals; Cocaine; Cocaine-Related Disorders; Disease Models, Animal; Dopamine Uptake Inhibitors; Drug-Seeking Behavior; Extinction, Psychological; Goals; Habits; Lithium Chloride; Male; Rats, Sprague-Dawley; Self Administration; Time Factors

Rodents suppress intake of saccharin when it is paired with a drug of abuse (Goudie, Dickins, & Thornton, 1978; Risinger & Boyce, 2002). By the authors' account, this phenomenon, referred to as reward comparison, is thought to be mediated by anticipation of the rewarding properties of the drug (P. S. Grigson, 1997; P. S. Grigson & C. S. Freet, 2000). Although a great deal has yet to be discovered regarding the neural basis of reward and addiction, it is known that overexpression of DeltaFosB is associated with an increase in drug sensitization and incentive. Given this, the authors reasoned that overexpression of DeltaFosB should also support greater drug-induced devaluation of a natural reward. To test this hypothesis, NSE-tTA x TetOp-DeltaFosB mice (Chen et al., 1998) with normal or overexpressed DeltaFosB in the striatum were given access to a saccharin cue and then injected with saline, 10 mg/kg cocaine, or 20 mg/kg cocaine. Contrary to the original prediction, overexpression of DeltaFosB was associated with attenuated cocaine-induced suppression of saccharin intake. It is hypothesized that elevation of DeltaFosB not only increases the reward value of drug, but the reward value of the saccharin cue as well.

Topics: Analysis of Variance; Animals; Antimanic Agents; Cocaine; Cocaine-Related Disorders; Conditioning, Operant; Corpus Striatum; Cues; Dopamine Uptake Inhibitors; Eating; Food Preferences; Lithium Chloride; Male; Mice; Mice, Transgenic; Proto-Oncogene Proteins c-fos; Reward; Saccharin; Self Administration; Sweetening Agents