Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.16.2 (PCP)
 3,761 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Lamotrigine (LTG), a new anticonvulsant, chemically unrelated to current antiepileptic drugs (AEDs), resembles phenytoin (PHT) and carbamazepine (CBZ) in ability to block hindlimb extension in both the maximal electroshock test and leptazol-induced seizures. Results indicate that LTG may be of value in both partial and generalized seizures. In in vitro studies, LTG has been shown to inhibit veratrine-evoked release of glutamate when a threshold depolarizing concentration (4 micrograms/ml) is used, and also inhibits aspartate release when a larger stimulus is given (10 micrograms/ml). However, LTG does not block potassium-evoked transmitter release. LTG is a less potent inhibitor of the release of gamma-aminobutyric acid (GABA), acetylcholine, noradrenaline, and dopamine. LTG blocks the neurotoxicity of kainic acid in vivo, supporting the in vitro findings, and suggests that the anticonvulsant effect of LTG may be due to inhibition of glutamate release. In a test of working memory and phencyclidine (PCP) discrimination studies, LTG had no effect, indicating no sharing of the same PCP-like side effects associated with NMDA receptor blockade. In the gerbil model of global ischemia, high doses of LTG provided protection against damage to the CA1 region of the hippocampus. Analogues of LTG of higher potency to block the release of glutamate may be necessary to ensure protection against ischemic brain damage.
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PMID:Neurochemical and behavioral aspects of lamotrigine. 168 39

There is growing evidence from both uncontrolled and controlled clinical studies that lamotrigine (LTG) significantly augments clozapine (CLZ) in the treatment of refractory schizophrenia (RS) [Dursun, S.M., McIntosh, D., Milliken, H., 1999. Clozapine plus lamotrigine in treatment-resistant schizophrenia. Arch. Gen. Psychiatry 56, 950; Dursun, S.M., Deakin, J.F.W., 2001. Augmenting antipsychotic treatment with lamotrigine or topiramate in patients with treatment-resistant schizophrenia: a naturalistic case-series outcome study. J. Psychopharmacol. 15, 297-301; Tiihonen, J., Hallikainen, T., Ryynanen, O.P., Repo-Tiihonen, E., Kotilinen, I., Eronen, M., Toivonen, P., Wahlbeck, K., Putkonen, A., 2003. Lamotrigine in treatment-resistant schizophrenia; a randomized placebo-controlled cross over trial. Biol. Psychiatry 54, 1241-1248; Kremer, I., Vass, A., Gorelik, I., Bar, G., Blanaru, M., Javitt, D.C., Heresco-Levy, U., 2004. Placebo-controlled trial of lamotrigine added to conventional and atypical antipsychotics in schizophrenia. Biol. Psychiatry. 56, 441-446]. However, the precise mechanism of action of this synergistic augmentation between clozapine and lamotrigine remains unclear. Therefore, the goal of this research is to explore the mechanism of action of this synergistic interaction between CLZ and LTG, utilizing a pharmacological animal model of schizophrenia by using phencyclidine (PCP). The effects of CLZ plus LTG were assessed by measuring PCP-induced hyper-locomotion and stereotyped behaviours in rats. Adult male rats (250-300 g) were pre-treated via intra-peritoneal (i.p.) injection with vehicle or drug 30 min before a PCP (5 mg/kg) or saline challenge. The behaviours were recorded and analysed for a 90-min period using the Etho Vision-computer based system. PCP produced hyper-locomotion, which was maximal at 30 min. LTG (10 mg/kg) significantly increased hyperlocomotion induced with PCP. However, a combination treatment of CLZ (5 mg/kg) plus LTG (10 mg/kg) significantly blocked the potentiation of PCP-induced hyper-locomotion observed with LTG (10 mg/kg) alone. Furthermore, the PCP-induced locomotion in the combination CLZ plus LTG-treated rats was significantly decreased when compared to vehicle. Therefore, LTG at doses that do not induce ataxia enhanced PCP-induced hyper-locomotion in rats, whereas the combination of LTG and CLZ significantly decreased PCP-induced hyper-locomotion consistent with clinical data.
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PMID:Effects of clozapine plus lamotrigine on phencyclidine-induced hyperactivity. 1630 24

Lamotrigine is suggested to have potential as an add-on treatment for patients with schizophrenia. Supporting evidence comes from the efficacy of the drug in models of psychotic-like behaviour induced by N-methyl-D-aspartate (NMDA) receptor antagonists, such as phencyclidine (PCP). These drugs enhance levels of the monoamines in the cortex, which may contribute to their psychotomimetic effects. The ability of lamotrigine to prevent these neurochemical changes has not been examined. We studied PCP-evoked overflow of noradrenaline, dopamine and serotonin in the medial prefrontal cortex of awake rats using microdialysis. Rats were administered lamotrigine or vehicle, followed by PCP. Locomotor activity was also recorded before and after drug treatment. Lamotrigine did not have an influence on basal levels of the monoamines, but significantly reduced PCP-evoked overflow of dopamine and serotonin; PCP-evoked overflow of noradrenaline was also reduced by lamotrigine, but not to a significant degree. In contrast, PCP-induced hyperactivity was unaffected by lamotrigine. It is concluded that lamotrigine can modify PCP-evoked monoamine overflow in the cortex, consistent with an ability to prevent the psychotomimetic effects of NMDA receptor antagonists in rodents and humans. The dissociation between monoamine overflow and locomotor activity suggests the involvement of different brain circuits; relevance to the treatment of schizophrenia is also discussed.
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PMID:Effects of lamotrigine on PCP-evoked elevations in monoamine levels in the medial prefrontal cortex of freely moving rats. 2104 17