Tryptophan Supplementation Reduces Schizophrenia-Like Symptoms in Apomorphine Treated Rats: Role of D2, GABA, and...

Schizophrenia is a multifaceted neuropsychiatric disorder characterized by disruptions in dopaminergic, GABAergic, and glutamatergic signaling pathways. While conventional antipsychotics primarily target dopamine D2 receptors, exhibit limited efficacy to alleviate cognitive deficits and negative symptoms and are associated with extrapyramidal side effects. Tryptophan (Trp), the essential amino acid precursor to serotonin, is critical modulator of these circuits. Serotonin acts as a brake on dopamine release and receptor activity. This study investigates the therapeutic potential of Trp supplementation in reducing schizophrenia-like symptoms in apomorphine-treated rats, focusing on the mRNA expression of D2, GABA, and glutamate receptors in nucleus accumbens and caudate. Apomorphine, a dopamine agonist, induces hyperdopaminergic activity, mimicking schizophrenia-like behaviors. In the present study, rats were divided into control, apomorphine-treated, Trp-supplemented and apomorphine plus Trp treated groups. Trp was administered at two different doses (25 and 50 mg/kg). Behavioral assessments were conducted in novel and familiar environments, Morris water maze and elevated plus maze to evaluate motor activity, learning and memory, and anxiety respectively. Results demonstrated that Trp supplementation significantly ameliorated the schizophrenia-like symptoms induced by apomorphine, exhibiting a distinct biphasic pattern: the 25 mg/kg dose was consistently more effective than the 50 mg/kg dose. Specifically, the low dose Trp reduced hyperactivity, improved cognitive performance and anxiolytic effects. In contrast, the 50 mg/kg dose showed a diminished therapeutic effect, likely due to competitive kynurenine pathway activation. Molecular analysis showed that optimal tryptophan treatment decreased the mRNA expression of D2 receptors, enhanced GABA receptor mRNA expression, and stabilized glutamate receptor mRNA levels in key brain regions. These findings suggest that low dose tryptophan supplementation may offer a promising adjunctive treatment for schizophrenia by restoring transcriptional balance of critical neurotransmitter systems.