The use of adjuvant L-arginine in schizophrenia: A behavioural and neurochemical analysis

• Author / Creator

  MacKay, Mary-Anne B

• Schizophrenia is a complex neurodevelopmental illness that often requires a combination of treatments to adequately control its symptoms. Despite the availability of several neuroleptic medications on the market, many patients with schizophrenia remain symptomatic. Research has shifted emphasis towards impaired glutamate signaling as a major contributor to the illness. Drug targets specific to the glutamate-nitric oxide (NO) pathway may offer a promising new approach to treatment. The therapeutic effect of the amino acid L-arginine (Arg), the substrate for the NO-producing enzyme neuronal nitric oxide synthase (nNOS) was examined in this thesis. As an augmenting strategy, Arg was administered (at 6g per day) to patients with schizophrenia in an attempt to improve the efficacy of antipsychotic therapy. Responders to Arg therapy had a reduction in anxiety symptoms that were previously resistant to prescribed medication. The anxiolytic effect of Arg may be directly related to an increase in endogenous central NO production and the downstream induction of cyclic guanosine monophosphate (cGMP)-mediated signaling cascades. L-Arginine also proved to be a safe strategy in the treatment of schizophrenia and did not exacerbate any of the known side-effects that were already present as a result of ongoing antipsychotic therapy. This thesis also investigated genetic influences on glutamate N-methyl-D-aspartate (NMDA) receptor functioning and treatment response to Arg therapy. The Neuronal Period-Arylhydrocarbon Nuclear Translocator (ARNT)-Single-minded (PAS) domain containing 3 (NPAS3) gene codes for a protein that functions as a transcription factor. NPAS3 and its related variants may be important for the development of functional postsynaptic density (PSD-95) scaffolding proteins that directly link the NMDA receptor to the nNOS enzyme in the brain. Variants associated with NPAS3 and schizophrenia were examined to elucidate the integrity of the PSD-95 protein and used to predict the outcome of the effects of adjuvant Arg therapy. Two carriers of a NPAS3 variant who did not respond to Arg treatment may have had compromised NMDA receptor function related to altered neurodevelopmental processes that occurred during early brain development. Participants were also genotyped for the catechol-O-methyltransferase (COMT ) enzyme single nucleotide polymorphism (SNP) p.V158M to explore the relationship between this genetic marker and clinical outcomes. No significant gene-gene interaction between NPAS3 and COMT was determined that would influence treatment response to Arg therapy. Preclinical experiments were also included in this thesis to determine the behavioural and neurochemical mechanisms by which Arg was able to exert its therapeutic effect. Competing metabolic enzymes that utilize Arg as a substrate were investigated by measurement of related amino acids ornithine (Orn) and citrulline (Cit). The immediate potentiation of whole brain Cit levels following Arg administration suggested that NO is produced quickly and NOS enzymes require a much lower concentration of Arg than that of the arginase enzymes. This thesis was also able to confirm the utility of phencyclidine (PCP) as a comprehensive pharmacological model of psychosis and the ability of antipsychotic drugs to reduce PCP-induced hyperlocomotor activity. The administration of Arg alone in a rodent PCP model had no significant effect on hyperlocomotor activity (a behavioural measure of the positive symptoms of psychosis) and it also did not enhance the locomotor-reducing effects of antipsychotic drugs. These results were consistent with the clinical trial data where no significant changes in positive symptoms were also found when augmenting antipsychotic treatment with Arg. Although Arg therapy was unable to potentiate antipsychotic effects in schizophrenia, work presented in this thesis does support the use of Arg as a tolerable and effective strategy that may target intrinsic anxiety in treatment-refractory schizophrenia.

• Subjects / Keywords

  • Schizophrenia
  • Nitric oxide
  • L-arginine

• Graduation date

  Spring 2016

• Type of Item

  Thesis

• Degree

  Doctor of Philosophy

• DOI

  https://doi.org/10.7939/R3ZS2KQ4M

• License

  This thesis is made available by the University of Alberta Libraries with permission of the copyright owner solely for non-commercial purposes. This thesis, or any portion thereof, may not otherwise be copied or reproduced without the written consent of the copyright owner, except to the extent permitted by Canadian copyright law.