d-Cycloserine administered directly to infralimbic medial prefrontal cortex enhances extinction memory in sucrose-seeking animals
Introduction
Extinction training can be used to develop and strengthen the inhibition of undesirable conditioned responses. This type of training involves exposure to various cues that trigger the conditioned response, but in the absence of the unconditioned stimulus that was originally paired with those cues. With repeated cue exposure, the conditioned response is suppressed, owing to this new inhibitory extinction memory (Quirk et al., 2006). Pharmacological adjuncts can be administered before or after the training session to enhance extinction memory consolidation and promote the effects of behavioral therapy. For example, the N-methyl-D-aspartate (NMDA) receptor partial agonist, d-cycloserine (DCS), has been used effectively for this purpose in the extinction of pathological fear, and in some cases, the extinction of drug-associated cues in addicts (Santa Ana et al., 2009, Choi et al., 2010). In general, however, there are relatively few reports on the efficacy of DCS as an extinction memory enhancer in appetitive learning paradigms. This raises the question of whether the same pharmacological strategies can be applied to extinction therapy in different patient populations.
Preclinical animal models have been incredibly helpful in delineating the neurobiological mechanisms and neurocircuitry of extinction memory. Much of this work has been done in Pavlovian-conditioned fear models, where extinction memory has been shown to rely on NMDA receptors (Baker and Azorlosa, 1996, Lee et al., 2006, Burgos-Robles et al., 2007). Specifically, NMDA receptor-mediated bursting in infralimbic medial prefrontal neurons is critical for extinction memory consolidation (Burgos-Robles et al., 2007). Consistent with this, infralimbic lesions performed prior to Pavlovian fear conditioning do not disrupt the expression of fear during conditioning, nor do they disrupt the short-term memory for extinction, but long-term extinction memory is specifically impaired (Morgan et al., 1993). Hence, the infralimbic cortex is especially important for the consolidation of extinction memory. That infralimbic neuronal bursting and extinction memory formation can be disrupted with NMDA antagonists indicates an endogenous requirement of these receptors, but does little in the way of therapy. Stimulating NMDA receptors directly is problematic owing to their susceptibility to induce seizure (Ghasemi and Schachter, 2011). The co-agonist DCS provides an ideal mechanism for enhancing NMDA-receptor function, in that it facilitates channel opening in response to endogenous glutamate (Pitkanen et al., 1994, Dravid et al., 2010).
Recently, infusion of DCS directly into the infralimbic cortex effectively enhanced extinction memory in a Pavlovian-conditioned fear model (Chang and Maren, 2011). To our knowledge, this was the first demonstration of an infralimbic site of action for the extinction-memory enhancing effects of DCS. While there are a few mixed reports on the effects of systemic DCS on the extinction of operant appetitive memories (Vengeliene et al., 2008, Shaw et al., 2009, Vurbic et al., 2011), no studies have yet addressed the role of infralimbic NMDA receptors in the extinction of operant responding for rewards. A lesion study by Rhodes and Killcross (2004) suggests that the infralimbic cortex may play a similar role in suppressing conditioned food-seeking responses as it does for conditioned fear, suggesting that these mechanisms may generalize across reward and punishment. We first set out to verify that extinction memory in sucrose-seeking rats depends on endogenous NMDA receptors under the parameters used in our self-administration model. Thereafter we sought to enhance extinction memory by the direct infusion of DCS into the infralimbic cortex.
Section snippets
Subjects
Male, Wistar rats (Harlan; Sulzfeld, German) weighing approximately 280–300 g at the start of the experiment were housed in a temperature- and humidity-controlled vivarium on a 12 h reverse light–dark cycle (7.00 am lights off). Food and water were available ad libitum throughout the experiment. Behavioral sessions were conducted during the dark phase, at the same time of the day each day. The study was approved by the Animal Care committee at the VU University of Amsterdam.
Drugs and microinfusions
Both
CPP disrupts extinction memory formation in sucrose-seeking animals
Rats were trained to self-administer sucrose over a period of 3 weeks and were then assigned to saline (SAL) and CPP treatment groups (n = 10/group) based on their average responding over the last three FR4 sessions. These groups were not statistically different in the number of total active (532 ± 32 SAL, 514 ± 23 CPP) or inactive (6 ± 1 SAL, 4 ± 1 CPP) responses (p-values > 0.1). Twenty-two hours after the last sucrose self-administration session, rats were injected with SAL or CPP (5 mg/kg, i.p.) and 2h
Discussion
Here we investigated the role of NMDA receptors, particularly within the infralimbic medial prefrontal cortex, in extinction memory formation in a sucrose-seeking self-administration model. The NMDA-receptor antagonist CPP administered prior to the first extinction training session disrupted extinction memory recall on a long-term memory test 24 h later, without disrupting performance during training. This profile suggests that NMDA receptors do not mediate the expression of the conditioned
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