Role for D-Serine within the Ventral Tegmental Area in the Development of Cocaine's Sensitization

Abstract

Repeated exposure to cocaine results in motor sensitization that, in the ventral tegmental area (VTA), is associated to enhanced glutamate release, which in turn leads to enhanced calcium levels in dopaminergic neurons. Calcium influx activates calcium-calmodulindependent protein kinases such as CaMKII. D-Serine could participate on these effects, and the objective was to discern the role of VTA D-serine after a sensitizing regimen of cocaine (10 mg/kg daily), and to discern consequent expression changes in CaMKII and its activated form. For this purpose, D-serine, sodium benzoate (inhibitor of D-amino acid oxidase, the degradating enzyme of D-serine), and 7-chlorokynurenate (inhibitor of the glycine site of NMDA receptors) were injected into the VTA (in either the induction or expression phase of sensitization), and activation state of CaMKII was assessed through blotting. The findings indicated that intra-VTA administration of D-serine (5 mM) and sodium benzoate (100 and 200 mg/ml) during the induction phase (not expression) reliably augmented the expression of behavioral sensitization to cocaine, providing evidence that D-serine in the VTA participates in the initiation of motor sensitization to this psychostimulant drug. Intra-VTA infusions of D-serine, sodium benzoate and 7-chlorokynurenate did not elicit a motor effect of their own. Confirming the important role of NMDA receptors and their activation at the glycine site, the employment of 7-chlorokynurenate (2 and 5 mg/ml) led to blocking of the development of sensitization to cocaine. CaMKII within the VTA was found to participate in D-serine's effects because this kinase, that is activated after repeated cocaine, was further activated after co-treatment with D-serine or sodium benzoate. Besides CaMKII activity was otherwise reduced by 7-chlorokynurenate.

Glycine site N-methyl-D-aspartate receptor antagonist 7-CTKA produces rapid antidepressant-like effects in male rats

“…We chose these doses based on our previous study 20 and on another report that demonstrated effective antagonism of the NMDA receptor. 21 We purchased LY294002 (10 nM/0.5 µl) from Sigma and dissolved it in saline containing 50% DMSO, as described in previous reports. 6,22 Rapamycin (50 µg/0.5 µl) was also purchased from Sigma and dissolved in saline containing 5% DMSO, as described in a previous report.…”

NMDA receptor glycine modulatory site in the ventral tegmental area regulates the acquisition, retrieval, and reconsolidation of cocaine reward memory

“…The glycine binding site affinity of the NMDA receptor R1 subunit in the central nervous system in transgenic mice significantly decreased through a point mutation and resulted in decreased sensitivity to alcohol in behavioral experiments (Kiefer et al 2003). Fernandez-Espejo et al (2008) found that repeated exposure to cocaine resulted in motor sensitization associated with enhanced glutamate release in the VTA. The glycine binding site in the VTA Fig.…”

“…Two groups of rats received bilateral 7-CTKA (0 and 5 μg/μl) microinjections into the VTA 10 min before every cocaine administration. Another two groups of rats received bilateral 7-CTKA (0 and 5 μg/μl) microinjections into the SN 10 min before every cocaine administration (Fernandez-Espejo et al 2008). The rats were alternately conditioned to cocaine in one compartment and saline in the other compartment.…”

“…7-CTKA (5 μg/μl) was bilaterally infused into the VTA or SN (1 μl/side) at a rate of 0.5 μl/ min, and the injector was kept in place for another 2 min to allow diffusion. The dose of 7-CTKA was based on previous reports (Fernandez-Espejo et al 2008). At the end of the experiments, the rats were anesthetized with sodium pentobarbital (100 mg/kg, i.p.)…”

The neurobiology of D-amino acid oxidase and its involvement in schizophrenia

“…Direct evidence that local actions of endogenous brain DAO are functional is, to our knowledge, limited to a pharmacological study showing that DAO inhibition localized to the ventral tegmental area augments NMDAR-dependent behaviours. 95 Apart from NMDAR modulation, other roles of DAO substrates, and thus of DAO itself, may exist. D-serine antagonizes a-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid glutamate receptors, 96 suggesting that D-serine and DAO could be involved in both positive and negative modulatory effects at glutamatergic synapses.…”