Poster Session I
Cognitive deficits (attention, working memory, and cognitive flexibility) are considered a core symptom cluster in schizophrenia (SZ); predictive of functional outcome yet not alleviated by current drug and behavioral interventions. Thus, there is a need for further studies on animal models to reveal more efficacious pharmacotherapies. A significant contributor to cognitive impairments seen in SZ may be the elevated levels of kynurenic acid (KYNA), observed in the brains of patients with SZ.
... A is an endogenous, astrocyte-derived metabolite that negatively modulates a7 nicotinic acetylcholine receptors (a7nAChRs) at physiological concentrations and, at higher concentrations, blocks the glycine B site of the NMDA receptor. We have reported that acute administration of KYNA's bioprecursor Lkynurenine (KYN; 100 mg/kg) in intact adult rats increases extracellular KYNA (B1,500%), decreases extracellular glutamate (GLU) levels (B30%) in the prefrontal cortex (PFC), and behaviorally results in an impairment of the prefrontallymediated attentional set shifting task. We investigated three issues: (1) whether the impairing effects of acute KYNA elevations can be generalized to another PFC-mediated task, the Delay Non-Match to Position (DNMTP) working memory task; (2) whether KYNA-induced working memory deficits would be alleviated by the administration of the a7nAChRpositive modulator galantamine (GAL). Our previous results indicated that KYN's reduction of GLU release is restored to basal levels following administration of GAL, and that GAL normalizes performance in a set shifting task in a different KYNA-based animal model of SZ; and (3) the relative roles of a7nAChRs vs NMDA receptors in performance in the DNMTP task.To this end, we determined, in a separate group of intact animals, the effects of an acute administration of 4chlorokynurenine (4-ClKYN), a bioprecursor of the selective glycine B antagonist 7-chlorokynurenic acid (7-ClKYNA),. We predicted working memory deficits following 4-ClKYN but, in contrast to the effects of KYN, we expected no restoration of performance following co-administration of GAL. Methods: Acquisition training in the Delayed Non-Match to Position (DNMTP) task began, in 2 groups of adult male Wistar rats, at postnatal day (PD) 56. After acquisition and baseline performance was established at each of the 3 delay periods (5, 10, and 15 s), rats received a series of drug challenges. Rats in the first group (N ¼ 8) received an acute injection (i.p.) of 0 (vehicle), 25 or 100 mg/kg KYN (dose order randomized) 50 min prior to the session, with a minimum of 48 h between test days to assure complete return to basal performance levels. After completing the KYN dose response curve, animals were tested again 50 min following injection of KYN (100 mg/kg) + GAL (3 mg/kg). Following the same protocol, a second group of rats (N ¼ 8) received 0 (vehicle), 25 or 100 mg/kg 4-ClKYN, or 4-ClKYN (100 mg/kg) + GAL (3 mg/kg). Results: In both groups of rats, performance under the control condition was delay-dependent. In the KYN-treated group, accuracy was 95, 87, and 82% at 5, 10, and 15 s, respectively. Elevation of KYNA via acute administration of KYN resulted in significant deficits in performance and, as expected, the detrimental effects were largest for the higher dose and longest delays. Compared to vehicle treatment, 25 mg/kg KYN significantly reduced accuracy (by 12%) only at the longest delay (15 s), while 100 mg/kg significantly reduced accuracy at 5 s (by 11%), 10 s (by 14%), and during the 15 s delay (by 33%; dropping to chance levels). Compared to vehicle, acute KYN (both 25 and 100 mg/kg) produced a four-fold increase (from B9 to B40) in sample phase omissions during the first 15 min of the task. The detrimental effects of 4-ClKYN were more severe than those caused by KYN. Vehicle treatment accuracy was 96%, 87%, and 77% at 5, 10, and 15 s. 25 mg/kg 4-ClKYN reduced accuracy (by 33%) at the 15 s delay, while 100 mg/kg 4-ClKYN significantly reduced accuracy overall (by 60%) as well as at all delays, well below chance performance, 5 s (by 54%), 10 s (by 60%), and 15 s delays (by 70%). There was no significant increase in omissions following acute administration of 4-ClKYN. Notably, the deficits following acute administration of 100 mg/kg KYN were fully prevented by co-administration of GAL. In contrast, the deficits following 100 mg/kg 4-ClKYNA were unaffected by treatment with GAL. Conclusions: Collectively, these findings suggest a role for both a7nAChRs and NMDA receptors in the mediation of working memory. Acute elevation of KYNA in adult rats results in significantly reduced, delay-dependent performance in the DNMTP task. This deficit appears to result from KYNA's negative allosteric modulation of a7nAChRs, as performance accuracy was normalized by GAL. Acute elevation of the glycine B antagonist 7-ClKYNA resulted in even more severe deficits in performance, and these impairments were not reversed by co-administration of GAL. Considering evidence for impairments in both nicotinic and glutamatergic transmission in SZ, these data in animals provide support for the continued focus on the a7nAChR and NMDA receptor as targets for cognition enhancement in SZ. Background: Metabolic syndrome may be related to dietary folate, its pharmacogenetically regulated metabolism, and Abstracts S109 ACNP 52nd Annual Conference atypical antipsychotic (AAP) exposure. We examined how folate supplementation would affect metabolic measures and endothelial functioning (RHI) in AAP treated schizophrenia subjects meeting NCEP-ATP-III metabolic syndrome criteria. Methods: Subjects were given 5 mg/day open label folate for 3 months. Baseline and 3 month measurements included RHI, BMI, fasting metabolic laboratory measures, Creactive protein, homocysteine, IL-6, and leptin. DNA was gentoyped for the methylenetetrahydrofolate reductase (MTHFR) 677C/T and catechol-O-methyltransferase (COMT) 158 Val/Met variants. Results: Thirty-five subjects with a mean age of 50±9 years and 70% Caucasian. After 3 months supplementation, RHI improved by 20% (p ¼ 0.02), mean homocysteine decreased 14% (p ¼ 0.006), and IL-6 decreased 13% (p ¼ 0.09). Subjects exercised 15% less during the study (p ¼ 0.05). At baseline 61% met endothelial dysfunction criteria (RHIo1.67), which decreased to 27% (p ¼ 0.0006) at endpoint. The MTHFR 677C/C + COMT 158Met/Met subjects had a 44% RHI improvement versus 10% improvement for MTHFR 677T/COMT Val allele carriers (p ¼ 0.06). The MTHFR 677C/C + COMT 158Met/Met group also showed significant reduction in those meeting endothelial dysfunction (83% baseline and 16% endpoint), compared to the MTHFR T + COMT Val allele carriers (54% baseline and 31% endpoint[p ¼ 0.001]). Conclusions: Folate may reduce AAP-associated metabolic risks and we report significant reductions in the number of subjects meeting endothelial dysfunction. This is remarkable given that ALL subjects met metabolic syndrome criteria. This may prove as a useful avenue to reducing CVD risk. Those with the MTHFR T or COMT Met alleles may not benefit from folate, but this needs further follow up.