D-serine treatment reduces cocaine-primed reinstatement in rats following extended access to cocaine self-administration

Abstract

The most intractable feature of drug addiction is the high rate of relapse, even following extended periods of abstinence from drug-taking. Evidence suggests that allowing rats extended access to cocaine self-administration leads to behavioral characteristics in these animals that are consistent with the development of addiction in humans. In the current study, rats were allowed to selfadminister cocaine over a total of 22 daily sessions, the final 7 of which were long-access (LgA) sessions of 6 hours duration. Assessments of reinstatement of drug-seeking behavior were made following reintroduction to the drug-taking environment and noncontingent priming with either CS or cocaine in both extinguished and abstinent subject groups. Three separate groups of rats were treated with either saline or D-serine (100mg/kg i.p.) administered 2 hrs prior to, or immediately following, each extinction training session. Saline-treated LgA rats were resistant to the effects of extinction training to reduce noncontingent priming of reinstatement of drug-seeking behavior with either CS or cocaine. In contrast, treatment with D-serine either before or immediately following the sessions resulted in a significant enhancement in the ability of extinction training to reduce cocaine-primed reinstatement of drug-seeking behavior. These results suggest that D-serine can act to enhance the consolidation of extinction learning in LgA rats, and is therefore a promising adjunctive agent along with behavioral therapy for the treatment of cocaine addiction.The development of an effective treatment regimen for the state of addiction to psychostimulants such as cocaine and amphetamines has proved to be problematic, and currently there is no FDA approved treatment for this condition. A prominent feature of addiction is the propensity for relapse, and craving is thought to be a contributing factor for this component of the disease (Jaffe et al., 1989;Ehrman et al., 1992). One therapeutic approach showing efficacy involves behavioral therapy, including the attempt to restructure past experiences and learn new behaviors that would decrease the frequency and/or severity of relapse in individuals attempting to remain abstinent (Dutra et al., 2008;Waldron and Turner, 2008). Enhancing the effectiveness of such psychosocial treatments through the use of adjunctive pharmacotherapy such as cognitive enhancement is therefore a reasonable

Availability of N-Methyl-d-Aspartate Receptor Coagonists Affects Cocaine-Induced Conditioned Place Preference and Locomotor Sensitization: Implications for Comorbid Schizophrenia and Substance Abuse

“…Furthermore, D-serine administration during extinction training has been shown to attenuate drug-induced reinstatement of cocaine self-administration (Kelamangalath et al, 2009;Kelamangalath and Wagner, 2010;Hammond et al, 2013). It also is possible that D-serine treatment had no effect on cocaine-induced reinstatement due to upregulation of its degradation enzyme, as cocaine has been shown to increase D-amino-acid oxidase levels (Curcio et al, 2013).…”

“…Specifically, modulation of the mesocorticolimbic dopamine system (the circuit in the brain responsible for reward processing) by glutamatergic inputs from cortical and subcortical regions appears to regulate aspects of maladaptive drug seeking (see Carlezon and Thomas, 2009, for a review). Furthermore, extinction of both cocaine-induced conditioned place preference (CPP) and cocaine self-administration has been shown to be NMDARdependent and can be enhanced by treatment with the partial GMS agonist D-cycloserine (Paolone et al, 2009;Thanos et al, 2011) or D-serine (Kelamangalath et al, 2009;Kelamangalath and Wagner, 2010;Hammond et al, 2013). Thus, we have hypothesized that the high comorbid substance abuse in schizophrenia results from shared NMDAR-mediated pathophysiology (Coyle, 2006;Benneyworth and Coyle, 2012).…”

Cyclin-Dependent Kinase Inhibitor 1a (p21) Modulates Response to Cocaine and Motivated Behaviors

“…The experimental design for the cocaine self-administration assay using male SpragueDawley rats was described in Kelamangalath and Wagner (2010). Briefly, animals were allowed to self-administer cocaine in an operant environment (Med Associates Inc.) containing both active and inactive levers.…”

Analysis of free d-serine in mammals and its biological relevance

“…It has well been established that conditioned fear or drug seeking behavior is eradicated by being replaced by subsequent learning of harmless or alternative cues. This extinction phenomena have been applied as the behavioral therapies to the treatment of phobias, obsessive-compulsive disorder, posttraumatic stress disorder (PTSD) or drug abuse, and have newly been shown to be facilitated by the NMDA receptor glycine site agonists in their animal models [167][168][169][170][171][172]. In several randomized placebo-controlled clinical trials for phobia [173], social anxiety disorder [174], obsessive-compulsive disorder [175], PTSD [176] or panic disorder [126], low dose of d-cycloserine, a partial agonist for the glycine site of the NMDA receptor, in combination with a conventional cognitive behavioral therapy (CBT) has been reported to be more effective in ameliorating fear or anxiety compared with CBT alone.…”