D-cycloserine in Prelimbic Cortex Reverses Scopolamine-Induced Deficits in Olfactory Memory in Rats

Abstract

A significant interaction between N-methyl-D-aspartate (NMDA) and muscarinic receptors has been suggested in the modulation of learning and memory processes. The present study further investigates this issue and explores whether d-cycloserine (DCS), a partial agonist at the glycine binding site of the NMDA receptors that has been regarded as a cognitive enhancer, would reverse scopolamine (SCOP)-induced amnesia in two olfactory learning tasks when administered into the prelimbic cortex (PLC). Thus, in experiment 1, DCS (10 µg/site) was infused prior to acquisition of odor discrimination (ODT) and social transmission of food preference (STFP), which have been previously characterized as paradigms sensitive to PLC muscarinic blockade. Immediately after learning such tasks, SCOP was injected (20 µg/site) and the effects of both drugs (alone and combined) were tested in 24-h retention tests. To assess whether DCS effects may depend on the difficulty of the task, in the STFP the rats expressed their food preference either in a standard two-choice test (experiment 1) or a more challenging three-choice test (experiment 2). The results showed that bilateral intra-PLC infusions of SCOP markedly disrupted the ODT and STFP memory tests. Additionally, infusions of DCS alone into the PLC enhanced ODT but not STFP retention. However, the DCS treatment reversed SCOP-induced memory deficits in both tasks, and this effect seemed more apparent in ODT and 3-choice STFP. Such results support the interaction between the glutamatergic and the cholinergic systems in the PLC in such a way that positive modulation of the NMDA receptor/channel, through activation of the glycine binding site, may compensate dysfunction of muscarinic neurotransmission involved in stimulus-reward and relational learning tasks.

Comparative Pro-cognitive and Neurochemical Profiles of Glycine Modulatory Site Agonists and Glycine Reuptake Inhibitors in the Rat: Potential Relevance to Cognitive Dysfunction and Its Management

“…Rats reared in isolation took longer to habituate to a novel environment, but this hyperactivity, thought to reflect a mesolimbic hyperdopaminergic state analogous to that in psychosis [97], was unaffected by S18841. Current antipsychotics reverse the isolation-induced hyperactivity, at least in part, through antagonism of dopamine D 2 receptors [46,49,98].…”

d-cycloserine prevents relational memory deficits and suppression of long-term potentiation induced by scopolamine in the hippocampus

“…Juvenile demonstrator rats were used in order to avoid fighting and favor social interaction (Vale-Martinez et al, 2002). Procedures for housing, food restriction and habituation are explained in detail elsewhere (Portero-Tresserra et al, 2013a). All procedures were carried out in compliance with the European Community Council Directive for care and use of laboratory animals (86/609/ECC) and with the Generalitat de Catalunya authorization (DOGC 2450 7/8/1997, DARP protocol number 5959).…”

“…The rats received 10µg/hemisphere of DCS (Sigma-Aldrich, Madrid, Spain) or phosphatebuffered saline (PBS; 0.1M, pH 7.4) infusions 20 min before STFP acquisition and 40µg/hemisphere SCOP (Scopolamine Hydrobromide USP, Sigma-Aldrich, Madrid, Spain) or PBS immediately after the social learning session. The solutions were infused bilaterally in a volume of 0.5 µl / hemisphere for 2 min (plus 1 min to allow for diffusion) following procedures described previously (Portero-Tresserra, et al, 2013a). The dose of DCS selected has been established previously to facilitate olfactory learning tasks when injected into the PLC or the basolateral amygdala (Portero-Tresserra et al, 2013a,b;Villarejo-Rodríguez et al, 2010), and other learning tasks, such as extinction of fear conditioning and appetitive learning, when injected into the basolateral amygdala or the infralimbic cortex (Peters & de Vries 2013;Walker et al 2002).…”

“…The number of times each observer sniffed the muzzle, body or anogenital region of the demonstrator, fighting and grooming (social interaction), and the number of forepaws (jar climbs during STFP test) were recorded (JVC, Everio Model GZ-X900). To rule out olfactory alterations due to the DCS and SCOP infusions, an additional olfactory perception test (described in Portero-Tresserra et al, 2013a) was conducted.…”

“…Perfusions and brains' post fixation were performed as explained elsewhere (Carballo-Marquez et al, 2009). Coronal 40-µm sections were cut on a cryostat (Shandom Cryotome FSE, Thermo Electron Corporation, Massachusetts, USA), mounted and processed for acetylcholinesterase histochemistry and examined essentially as described previously (Portero-Tresserra et al, 2013a).…”