d-Cycloserine accelerates the extinction of cocaine-induced conditioned place preference in C57bL/c mice

Abstract

Recently, it was shown that d-cycloserine (DCS; a NMDA partial agonist) facilitated extinction of fear as well as cocaine conditioned place preference (CPP) in rats. Methods The present study examined the effects of DCS (15mg/kg i.p and 30 mg/kg i.p) on extinction and renewal of cocaine-induced CPP in C57bL/c mice. In parallel we examined the effects of DCS on locomotor activity. Results Extinction to cocaine CPP was significantly faster with DCS than with vehicle treatment (3 sessions, versus 6 sessions respectively). After extinction was achieved; mice were retested for CPP 1 and 2 weeks later. All animals maintained extinction to CPP one week later but at 2 weeks the vehicle and the 15mg/kg DCS treated animals maintained the extinction but the 30mg/kg DCS treated mice had renewed CPP. During induction of cocaine CPP, mice displayed enhanced locomotor activity following treatment with cocaine, as expected based on previous literature. During extinction, there were no differences in locomotor activity between the vehicle and the 15mg/kg DCS treated mice whereas the 30mg/kg DCS treated animal showed significant locomotor activity inhibition. These results corroborate in mice the previously reported acceleration of extinction to cocaine induced CPP by DCS in rats. However we also show that the higher DCS doses facilitated CPP reestablishment after extinction. Thus while DCS could be beneficial in accelerating the extinction to conditioned responses in addiction it could, at higher doses, increase the risk of relapse. Thus studies evaluating the beneficial therapeutic effects of DCS should assess not only the short-term effects but also the potential of longer lasting undesirable effects.

Altered Acquisition and Extinction of Amphetamine-Paired Context Conditioning in Genetic Mouse Models of Altered NMDA Receptor Function

“…This persistent conditioned hyperactivity in the SRÀ/À subjects supports the conclusion that intact NMDA receptor signaling is critical to extinction learning. This genetic evidence builds upon pharmacological findings with augmented GMS activation (Paolone et al, 2009;Thanos et al, 2009;Myers and Carlezon, 2010) in models of drug-associated conditioning and suggests that NMDA receptor hypofunction may be a pathophysiological feature that increases susceptibility to addiction by inhibiting the extinction of conditioned behavior. Acquisition of behavioral sensitization was also affected by altered GMS activation, with the GlyT1À/ + subjects showing a hastened rate of acquisition and the SRÀ/À subjects showing a delayed rate.…”

“…Recent research has demonstrated that inhibiting presynaptic glutamate inhibitory autoreceptors, and thus augmenting glutamatergic synaptic neurotransmission, reduced craving in cocaine-addicted patients (Amen et al, 2011). Preclinical work with the GMS partial agonist Dcycloserine demonstrates that the selective potentiation of NMDA receptor signaling may be an effective means of enhancing extinction of drug conditioning (Paolone et al, 2009;Thanos et al, 2009;Myers and Carlezon, 2010), in a manner similar to the extinction of conditioned fear in agoraphobic patients (Ressler et al, 2004).…”

“…Specifically, potentiation of NMDA receptor neurotransmission, with the GMS partial agonist D-cycloserine, has been used as a strategy to facilitate the extinction of place conditioning (Paolone et al, 2009;Thanos et al, 2009;Myers and Carlezon, 2010). These findings point to the potential therapeutic benefit of enhancing NMDA receptor signaling, but questions remain as to whether aberrant NMDA receptor function may contribute to genetic susceptibility to addiction.…”

Neuroanatomical Structures Underlying the Extinction of Drug-Seeking Behavior

“…Unfortunately, most of what is known about the neural mechanisms of extinction learning was derived from studies that use aversive conditioning (e.g., footshock) or appetitive conditioning with natural rewards (e.g., food). The extinction of conditioned fear in both animals and humans [69][70][71][72][73][74][75][76][77][78][79][80] as well as a cocaine CPP [81][82][83] can be facilitated by the cognitive enhancing drug D-4-amino-3-isoxazolidone [D-cycloserine (DCS)], which is a partial agonist at the strychnine-insensitive glycine site of Nmethyl-D-aspartate (NMDA) receptors [84,85]. Nic Dhonnchadha and colleagues recently found that DCS enhances the extinction learning process and inhibits reacquisition of drug self-administration in rats trained to self-administer cocaine [86].…”

“…Facilitation of glutamatergic transmission enhances extinction of drug-seeking behavior [81,83,[186][187][188]. It is likely that additional neurotransmitter systems, including dopamine and acetylcholine, are also involved in the extinction of drug-cue/context associations [3,[189][190][191].…”