No abstract

No abstract

Repetitive behavioral phenotypes are a trait of several neuropsychiatric disorders, including obsessive-compulsive disorder (OCD). Such behaviors are typified by complex interactions between cognitive and neurobiological processes which most likely contribute to the suboptimal treatment responses often observed. To this end, exploration of the adenosinergic system may be useful, since adenosine-receptor modulation has previously shown promise to restore control over voluntary behavior and improve cognition in patients presenting with motor repetition. Here, we employed the deer mouse (Peromyscus maniculatus bairdii) model of compulsive-like behavioral persistence, seeking to investigate possible associations between stereotypic motor behavior and cognitive flexibility as measured in the T-maze continuous alternation task (T-CAT). The effect of istradefylline, a selective adenosine A 2A receptor antagonist at two doses (10 and 20 mg kg −1 day −1 ) on the expression of stereotypy and T-CAT performance in high (H) and non-(N) stereotypical animals, was investigated in comparison to a control intervention (six groups; n = 8 or 9 per group). No correlation between H behavior and T-CAT performance was found. However, H but not N animals presented with istradefylline-sensitive spontaneous alternation and stereotypy, in that istradefylline at both doses significantly improved the spontaneous alternation scores and attenuated the stereotypical expression of H animals. Thus, evidence is presented that anti-adenosinergic drug action improves repetitive behavior and spontaneous alternation in stereotypical deer mice, putatively pointing to a shared psychobiological construct underlying naturalistic stereotypy and alterations in cognitive flexibility in deer mice.

No abstract

A significant number of adolescents are considered insufficiently active. This is of concern considering the negative association between physical activity and major depressive disorder (MDD). There is a lack of approved pharmacological treatment options in this population partly due to limited information on the risks associated with lasting effects during early life. Therefore, interest in non-pharmacological strategies is gaining popularity with low-to moderate-intensity exercise being especially attractive for its antidepressant-like effects and augmentation properties in combination with antidepressants. Early-life development might present a unique "window of opportunity" to induce long-term beneficial effects in individuals treated with central acting drugs, such as antidepressants. Therefore, we investigated the bio-behavioural effects of pre-pubertal, low-intensity exercise (EXE) and/or venlafaxine (VEN) on depressive-like behaviour in juvenile (postnatal day 35 (PND35)) and young adult (PND60) stress-sensitive Flinders sensitive line (FSL) rats. Interventions were introduced during pre-pubertal development, that is PND21-34, followed by a 26-day washout/sedentary period, when bio-behavioural analyses were performed in the early adulthood group. VEN, alone or in combination with EXE, proved ineffective in inducing any bio-behavioural changes in either age group. EXE did not induce early-life antidepressant-like effects, despite increasing frontal serotonin (5-HT) and noradrenaline (NA) levels. Later in life (PND60), pre-pubertal exercise reduced immobility and increased coping behaviours, together with increased cortical 5-HT levels, despite a significant reduction in locomotor activity. These findings emphasize a strong serotonergic basis to the observed delayed antidepressant effects of EXE later in life. K E Y W O R D S animal models of depression, behavioural pharmacology, cellular and molecular assays, Juvenile depression, non-pharmacological augmentation 3980 | STEYN ET al.

No abstract

No abstract

ObjectivesThe aim of this study was to repurpose a drug for the treatment of bipolar depression.MethodsA gene expression signature representing the overall transcriptomic effects of a cocktail of drugs widely prescribed to treat bipolar disorder was generated using human neuronal‐like (NT2‐N) cells. A compound library of 960 approved, off‐patent drugs were then screened to identify those drugs that affect transcription most similar to the effects of the bipolar depression drug cocktail. For mechanistic studies, peripheral blood mononuclear cells were obtained from a healthy subject and reprogrammed into induced pluripotent stem cells, which were then differentiated into co‐cultured neurons and astrocytes. Efficacy studies were conducted in two animal models of depressive‐like behaviours (Flinders Sensitive Line rats and social isolation with chronic restraint stress rats).ResultsThe screen identified trimetazidine as a potential drug for repurposing. Trimetazidine alters metabolic processes to increase ATP production, which is thought to be deficient in bipolar depression. We showed that trimetazidine increased mitochondrial respiration in cultured human neuronal‐like cells. Transcriptomic analysis in induced pluripotent stem cell‐derived neuron/astrocyte co‐cultures suggested additional mechanisms of action via the focal adhesion and MAPK signalling pathways. In two different rodent models of depressive‐like behaviours, trimetazidine exhibited antidepressant‐like activity with reduced anhedonia and reduced immobility in the forced swim test.ConclusionCollectively our data support the repurposing of trimetazidine for the treatment of bipolar depression.