Acute, but not chronic, exposure to d-cycloserine facilitates extinction and modulates spontaneous recovery of a conditioned taste aversion

Abstract

D-cycloserine, the glutamate N-methyl-D-aspartate receptor partial agonist, has been reported to facilitate the extinction of learned fears acquired in both naturalistic and laboratory settings. The current study extended this literature by evaluating the ability of either chronic or acute administrations of DCS to modulate the extinction and spontaneous recovery of a conditioned taste aversion (CTA). Twenty-three hour fluid-deprived Sprague-Dawley rats acquired a strong CTA following 3 pairings of a conditioned stimulus (CS; 0.3% oral saccharin) + unconditioned stimulus [US; 81 mg/kg (i.p.) lithium chloride (LiCl)]. In separate groups of rats, we then employed 2 different extinction paradigms: (1) CS-only (CSO-EXT) in which saccharin was presented every-other day, or (2) Explicitly Unpaired (EU-EXT) in which both saccharin and LiCl were presented but on alternate days. Previous studies have indicated that the EU-EXT procedure speeds up the extinction process. Further, spontaneous recovery of a CTA emerges following CSO-EXT but the EU-EXT paradigm causes a suppression of spontaneous recovery. DCS (15 mg/kg, i.p.) was administered immediately after daily liquid presentations (saccharin or water, alternate days) during the extinction period. In an acute drug manipulation, DCS (15 mg/kg, i.p.) or saline control injections were administered for 4 days only. This was done during one of 3 different phases of extinction [i.e., static (2–5%), early dynamic (8–16%), or middle dynamic (20–40%) saccharin reacceptance]. Other animals assigned to the chronic DCS condition received daily DCS (15 mg/kg, i.p.) throughout extinction. Changes in saccharin drinking in these animals were compared to the data from rats that received no drug (saline controls). Once rats met our criterion for asymptotic extinction (90% reacceptance of the CS) they entered a 30-day latency period during which they received water for 1 hr/day. The day after the completion of the latency period, a final opportunity to drink saccharin was provided (spontaneous recovery test). Saline-treated control rats that went through the EU-EXT procedure achieved asymptotic extinction more quickly than did the CSO-EXT rats and did not exhibit a spontaneous recovery of the CTA. Chronic DCS treatments did not significantly reduce the time to achieve asymptotic CTA extinction in rats exposed to either CSO or EU extinction methods. Further, animals treated with DCS throughout EU-EXT exhibited a spontaneous recovery of the CTA whereas the saline-treated, EU-EXT rats did not. Thus, chronic DCS treatment did not shorten the time to extinguish a CTA and this treatment eliminated the ability of EU-EXT to block spontaneous recovery of the CTA. Acute DCS treatments were more effective in reducing the time required to extinguish a CTA than were chronic drug treatments. Moreover, the timing of these acute DCS treatments affected spontaneous recovery of the CTA depending on the extinction method employed. Acute DCS administrations later in extinction were more effective in reducing...

Persistent reduction of cocaine seeking by pharmacological manipulation of adenosine A1 and A2A receptors during extinction training in rats

“…All cocaine self-administration and extinction procedures were the same except that animals were treated with vehicle or CPA (0.1 mg/kg, ip) 4 h after the end of each 4 h extinction training session with the first treatment administered 4 h after the first extinction training session. We chose to administer the A1AR agonist 4 h post extinction based on the pharmacokinetics of CPA (Mathot et al 1993) and other experiments examining similar effects (Hammond et al 2012; Mickley et al 2012). …”

Effects of Augmenting N-Methyl-D-Aspartate Receptor Signaling on Working Memory and Experience-Dependent Plasticity in Schizophrenia: An Exploratory Study Using Acute d-cycloserine

“…Additionally, multiple rodent studies found that beneficial cognitive effects following a single dose of DCS did not persist with chronic dosing. [47][48][49] This suggests that prolonged DCS administration may lead to desensitization of the NMDAR, which could also account for prior negative findings.…”

“…DCS binds to the NMDAR glycine-modulatory site and augments NMDAR signaling at low doses by increasing channel open time and open probability. 45,46 Given evidence that repeated DCS dosing may desensitize the NMDAR complex, [47][48][49] we used a single dose of DCS. In our prior study among healthy adults, acute DCS enhanced experience-dependent plasticity, 50 as demonstrated by enhanced visual evoked potentials (VEPs) following high-frequency visual stimulation (HFvS) and enhanced learning on 2 cortico-striatal dependent learning tasks: the weather prediction task (WPT) 51 and information integration task (IIT).…”

Augmenting Transcranial Direct Current Stimulation With D-Cycloserine for Depression

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