Biology subjects

Arban, R.

Publications and source records attributed to Arban, R..

3 recordsLinked to original sources

bioRxiv2025

Modulation of negative affective biases in male rats may predict the rapid and sustained antidepressant effects of different NMDA antagonists

Affective biases influence cognitive and emotional behaviour and play a significant role in major depressive disorder. We have shown that the NMDA antagonist and rapid-acting antidepressant, ketamine, selectively modulates affective biases, a neuropsychological effect which may underlie its efficacy. Clinical studies with different NMDA antagonists have found mixed effects but the reasons for these differences in efficacy are not understood. This study used a rat model of negative affective biases to investigate if different NMDA antagonists also differentially modulated affective biases. Dose-response experiments using the NMDA antagonists lanicemine, memantine, CP101,606, phencyclidine (PCP) and ephenidine, and ketamine metabolite, (2R,6R)-hydroxynorketamine (HNK), were performed to test their acute and sustained (24hrs) effects, and specificity of affective bias modulation. Our results showed that HNK, PCP, lanicemine, and ephenidine acutely attenuate negative biases. HNK, CP-101,606, and ephenidines effects were sustained at 24hrs post-treatment with a positive bias observed for HNK and a tendency towards a positive affective bias for CP101,606 and ephenidine. Lanicemines effects were sustained at 24hrs but only at the highest dose and PCP and memantine had no effects. Considering these findings in the context of clinical observations, we suggest that the ability to induce a sustained modulation of affective biases corresponds with therapeutic effects. The differences in efficacy observed with NMDA antagonists may be related to their ion trapping properties and those with very high and low ion trapping properties are less effective than those with more moderate ion trapping effects such as ketamine or ephenidine or the subunit selective antagonist, CP101,606.

pharmacology and toxicology↗

bioRxiv2020

Effects of pro-depressant and immunomodulatory drugs on biases in decision-making in the rat judgement bias task

Studies in human and non-human species suggest that decision-making behaviour can be biased by affective state, also termed an affective bias. To study these behaviours in non-human species, judgement bias tasks have been developed. Animals are trained to associate specific cues (tones) with a positive or negative/less positive outcome. Animals are then presented with intermediate ambiguous cues and affective biases quantified by observing whether animals make more optimistic or more pessimistic choices. Here we use a high versus low reward judgement bias task and test whether pharmacologically distinct compounds, which induce negative biases in learning and memory, have similar effects on decision-making: tetrabenazine (0.0-1.0mg/kg), retinoic acid (0.0-10.0mg/kg) and rimonabant (0.0-10.0mg/kg). We also tested immunomodulatory compounds: interferon- (0-100units/kg), lipopolysaccharide (0.0-10.0g/kg) and corticosterone (0.0-10.0mg/kg). We observed no specific effects in the judgement bias task with any acute treatment except corticosterone which induced a negative bias. We have previously observed a similar lack of effect with acute but not chronic psychosocial stress and so next tested decision-making behaviour following chronic interferon-alpha. Animals developed a negative bias which was sustained even after treatment was ended. These data suggest that decision-making behaviour in the task is sensitive to chronic but not acute effects of most pro-depressant drugs or immunomodulators, but exogenous administration of acute corticosterone induces pessimistic behaviour. This work supports our hypothesis that biases in decision-making develop over a different temporal scale to those seen with learning and memory which may be relevant in the development and perpetuation of mood disorders. Graphical abstract and textDecision-making bias in rats, measured using a judgement bias task, is not altered by acute treatments with pro-depressant or immunomodulatory drugs, but becomes more negative following chronic treatment. The time course of change in decision-making bias reflects the subjective reporting of changes in depression symptoms in humans treated with these drugs. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=163 SRC="FIGDIR/small/358655v1_ufig1.gif" ALT="Figure 1"> View larger version (55K): org.highwire.dtl.DTLVardef@93dd2corg.highwire.dtl.DTLVardef@19d7e41org.highwire.dtl.DTLVardef@cc1ac1org.highwire.dtl.DTLVardef@1f0775c_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2020

Role of the medial prefrontal cortex in the effects of rapid acting antidepressants on affective biases in a rodent decision-making task

Major Depressive Disorder is a significant and costly cause of global disability. Until the discovery of the rapid acting antidepressant (RAAD) effects of ketamine, treatments were limited to drugs that have delayed clinical benefits. The mechanism of action of ketamine is currently unclear but one hypothesis is that it may involve neuropsychological effects mediated through modulation of affective biases (where cognitive processes such as learning and memory and decision-making are modified by emotional state). Previous work has shown that affective biases in a rodent decision-making task are differentially altered by ketamine, compared to conventional, delayed onset antidepressants. This study sought to further investigate these effects by comparing ketamine with other NMDA antagonists using this decision-making task. We also investigated the subtype selective GluN2B antagonist, CP-101,606 and muscarinic antagonist scopolamine which have both been shown to have RAAD effects. Both CP-101,606 and scopolamine induced similar positive biases in decision-making to ketamine, but the same effects were not seen with other NMDA antagonists. Using targeted medial prefrontal cortex (mPFC) infusions, these effects were localised to the mPFC. In contrast, the GABAA agonist, muscimol, induced general disruptions to behaviour. These data suggest that ketamine and other RAADs mediate a specific effect on affective bias which involves the mPFC. Non-ketamine NMDA antagonists lacked efficacy and we also found that temporary inactivation of the mPFC did not fully recapitulate the effects of ketamine, suggesting a specific mechanism.

neuroscience↗