Reduced d-serine levels in the nucleus accumbens of cocaine-treated rats hinder the induction of NMDA receptor-dependent synaptic plasticity

Abstract

Cocaine seeking behaviour and relapse have been linked to impaired potentiation and depression at excitatory synapses in the nucleus accumbens, but the mechanism underlying this process is poorly understood. We show that, in the rat nucleus accumbens core, D-serine is the endogenous coagonist of N-methyl-D-aspartate receptors, and its presence is essential for N-methyl-D-aspartate receptor-dependent potentiation and depression of synaptic transmission. Nucleus accumbens core slices obtained from cocaine-treated rats after 1 day of abstinence presented significantly reduced D-serine concentrations, increased expression of the D-serine degrading enzyme, D-amino acid oxidase, and downregulated expression of serine racemase, the enzyme responsible for D-serine synthesis. The D-serine deficit was associated with impairment of potentiation and depression of glutamatergic synaptic transmission, which was restored by slice perfusion with exogenous D-serine. Furthermore, in vivo administration of D-serine directly into the nucleus accumbens core blocked behavioural sensitization to cocaine. These results provide evidence for a critical role of D-serine signalling in synaptic plasticity relevant to cocaine addiction.

Inhibition of Lactate Transport Erases Drug Memory and Prevents Drug Relapse

“…Astrocytes clear synaptic transmitters from the cleft and recycle glutamate to modulate excitatory and inhibitory synaptic transmission. Astrocytes also release glutamate (39)(40)(41), the N-methyl-D-aspartate (NMDA) receptor agonist D-serine (42,43), and astrocyte-derived neurotrophic factors (44), all of which have been shown to be involved in addiction-related behaviors, including cue-induced drug-seeking behavior (45)(46)(47), the extinction of drug memory (46,48), and the incubation of drug-seeking behavior (6,49). In the present study, we found that astrocyte-neuron lactate shuttle mediated the reconsolidation of cocaine reward memory.…”

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). These findings suggest that D-serine, GMS agonists, or NMDAR-positive modulators may be effective treatments for individuals with schizophrenia who also suffer from comorbid substance dependence, as they may decrease the salience of drug-associated cues in the absence of drug.…”

Intraneuronal Aβ accumulation induces hippocampal neuron hyperexcitability through A-type K+ current inhibition mediated by activation of caspases and GSK-3

“…Coronal slices (300- to 400-μm thick) containing the hippocampi were prepared using standard procedures (Podda et al, 2004, 2008; Curcio et al, 2013). Briefly, the animals were anesthetized with halothane (Sigma) and decapitated.…”