ABSTRACT
The present study investigated the pharmacological mechanisms of the antidepressant-like effects of amantadine in mice and their influence on hippocampal neurogenesis. To improve the translational validity of preclinical results, reproducibility across laboratories and replication in other animal models and species are crucial. Single amantadine administration at doses of 50 and 75 mg/kg resulted in antidepressant-like effects in mice in the tail suspension test (TST), reflected by an increase in immobility time. The effects of amantadine were seen at doses that did not alter locomotor activity. The tyrosine hydroxylase inhibitor α-methyl-ρ-tyrosine did not influence the anti-immobility effect of amantadine in the TST. Pretreatment with the α1 adrenergic receptor antagonist prazosin, ß adrenergic receptor antagonist propranolol, α2 adrenergic receptor antagonist yohimbine, and α2 adrenergic receptor agonist clonidine did not alter the antidepressant-like effect of amantadine. However, amantadine's effect was blocked by the dopamine D2 receptor antagonist haloperidol and glutamate receptor agonist N-methyl-D-aspartate (NMDA). Repeated amantadine administration (50 mg/kg) also exerted an antidepressant-like effect, paralleled by an increase in hippocampal neurogenesis. The present results demonstrate that the antidepressant-like effects of amantadine may be mediated by its actions on D2 and NMDA receptors and likely involve hippocampal neurogenesis.
Subject(s)
Adrenergic Agonists/pharmacology , Adrenergic Antagonists/pharmacology , Amantadine/pharmacology , Antidepressive Agents/pharmacology , Behavior, Animal/drug effects , Excitatory Amino Acid Agonists/pharmacology , Receptors, Dopamine D2/drug effects , Receptors, N-Methyl-D-Aspartate/drug effects , Amantadine/administration & dosage , Animals , Antidepressive Agents/administration & dosage , Enzyme Inhibitors/pharmacology , Hippocampus/drug effects , Male , Mice , Neurogenesis/drug effects , alpha-Methyltyrosine/pharmacologyABSTRACT
Schizophrenia is one of the most debilitating and costly illnesses worldwide. First-generation antipsychotics such as chlorpromazine and haloperidol succeeded in controlling the positive symptoms of schizophrenia, but had significant extrapyramidal effects that led to the search for new agents and the release of second-generation (or atypical) antipsychotics. These drugs had a lower risk of adverse motor symptoms. Therapeutic drug monitoring has become a useful tool to optimize schizophrenia treatment and HPLC-MS/MS has been considered the primary technique to monitor antipsychotics. This review comprises three sections: schizophrenia pathophysiology and treatment; recent advances in LC-MS/MS methods designed to measure levels of antipsychotics and their metabolites in plasma samples (selectivity, matrix effect and sensitivity); and the importance of therapeutic drug monitoring.
ABSTRACT
Diabetes is a chronic disease associated with depression whose pathophysiological mechanisms that associate these conditions are not fully elucidated. However, the activation of the indoleamine-2,3-dioxygenase (IDO), an enzyme that participate of the tryptophan metabolism leading to a decrease of serotonin (5-HT) levels and whose expression is associated with an immune system activation, has been proposed as a common mechanism that links depression and diabetes. To test this hypothesis, diabetic (DBT) and normoglycemic (NGL) groups had the cytokines (TNFα, IL-1ß, and IL-6) and 5-HT and norepinephrine (NE) levels in the hippocampus (HIP) evaluated. Moreover, the effect of the selective serotonin reuptake inhibitor fluoxetine (FLX), IDO direct inhibitor 1-methyl-tryptophan (1-MT), anti-inflammatory and IDO indirect inhibitor minocycline (MINO), or non-selective cyclooxygenase inhibitor ibuprofen (IBU) was evaluated in DBT rats submitted to the modified forced swimming test (MFST). After the behavioral test, the HIP was obtained for IDO expression by Western blotting analysis. DBT rats exhibited a significant increase in HIP levels of TNFα, IL-1ß, and IL-6 and a decrease in HIP 5-HT and NA levels. They also presented a depressive-like behavior which was reverted by all employed treatments. Interestingly, treatment with MINO, IBU, or FLX but not with 1-MT reduced the increased IDO expression in the HIP from DBT animals. Taken together, our data support our hypothesis that neuroinflammation in the HIP followed by IDO activation with a consequent decrease in the 5-HT levels can be a possible pathophysiological mechanism that links depression to diabetes.
