l-701324 and Cognition-Disorders

Opiate addiction is associated with complex cognitive impairment, which contributes to the development of compulsive drug use and relapses. Dopamine and N-methyl-D-aspartate receptors play critical roles in opiate-induced cognitive deficits. However, the roles of D1 and D3 receptors in the N-methyl-D-aspartate/glycineB receptor-regulated cognitive behaviors induced by morphine remain unknown.. The 5-choice serial reaction time task was used to investigate the cognitive profiles associated with repeated morphine administration in D1 (D1-/-)- and D3 (D3-/-)-receptor knockout mice. The expression of phosphorylated NR1, Ca2+/calmodulin-dependent protein kinase II (CaMKII), and cAMP response element-binding protein (CREB) in the brain was examined by western blotting. D1-/- and D3-/- mice were treated with the N-methyl-D-aspartate/glycineB site agonist l-aminocyclopropanecarboxylic acid and the antagonist L-701,324 to chronically disrupt N-methyl-D-aspartate receptor function and investigate their effects on morphine-induced cognitive changes.. Repeated morphine administration impaired attentional function and caused impulsive and compulsive behaviors. D1-/- mice exhibited hardly any premature nosepokes. D3-/- mice showed robustly increased morphine-induced impulsive behavior. The numbers of premature responses were decreased by L-701,324 administration and increased by ACPC administration; these effects were completely abolished in D1-/- mice due to their inability to perform reward-based tasks. In contrast, the inhibitory effects of L-701,324 on impulsive behavior were significantly augmented in D3-/- mice.. N-methyl-D-aspartate/glycineB site functions may contribute to morphine-induced cognitive deficits, especially those related to impulsive behavior. D1 and D3 receptors may have contrasting effects with respect to modulating impulsive behavior. D3 receptors have inhibitory effects on impulsive behaviors, and these effects are clearly mediated by N-methyl-D-aspartate/glycineB receptor and μ-opioid receptor interactions.

Topics: Analgesics, Opioid; Analysis of Variance; Animals; Choice Behavior; Cognition Disorders; Cyclopentanes; Excitatory Amino Acid Antagonists; Gene Expression Regulation; Impulsive Behavior; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Morphine; Opioid-Related Disorders; Quinolones; Reaction Time; Receptors, Dopamine D1; Receptors, Dopamine D3; Receptors, Glycine; Receptors, N-Methyl-D-Aspartate

A recent clinical study demonstrated that sodium benzoate (SB), a prototype competitive d-amino acid oxidase inhibitor, was effective in the treatment of several symptoms, such as positive and negative symptoms, and cognitive impairment in medicated patients with schizophrenia. The objective of the study was to examine the effects of SB on behavioural abnormalities such as pre-pulse inhibition (PPI) deficits and hyperlocomotion in mice after a single administration of the N-methyl-D-aspartate (NMDA) receptor antagonist, phencyclidine (PCP).. The effects of SB on behavioural abnormalities (PPI deficits and hyperlocomotion) in mice after PCP administration were examined. Furthermore, effects of SB on tissue levels of amino acids were also examined.. A single oral dose of SB (100, 300, or 1000 mg/kg) attenuated PPI deficits in mice after administration of PCP (3.0 mg/kg, s.c.) in a dose-dependent manner. In contrast, L-701,324 (10 mg/kg), an antagonist at the glycine site of the NMDA receptor, did not affect the effect of SB (1000 mg/kg) on PCP-induced PPI deficits. Furthermore, a single oral dose of SB (1000 mg/kg) significantly attenuated the hyperlocomotion in mice after administration of PCP (3.0 mg/kg, s.c.). However, a single oral dose of SB (1000 mg/kg) caused no changes to D-serine levels in plasma or in the frontal cortex, hippocampus, and striatum of these animals.. This study suggests that SB induced antipsychotic effects in the PCP model of schizophrenia, although it did not increase D-serine levels in the brain.

Topics: Animals; Antipsychotic Agents; Behavior, Animal; Chromatography, Liquid; Cognition Disorders; D-Amino-Acid Oxidase; Drug Interactions; Excitatory Amino Acid Antagonists; Hyperkinesis; Male; Mice; Models, Animal; Motor Activity; Phencyclidine; Prepulse Inhibition; Quinolones; Receptors, N-Methyl-D-Aspartate; Serine; Sodium Benzoate