Biology subjects

Abdulkader, S. P.

Publications and source records attributed to Abdulkader, S. P..

3 recordsLinked to original sources

bioRxiv2024

Effects of D3-preferring agonist PD 128907 on compulsive behaviour and decision making as assessed by the 5C-CPT

BackgroundRepetitive rituals in OCD patients result from pathological doubt, which has been linked to dysfunction in decision-making. First-line drug treatments for OCD are selective serotonin reuptake inhibitors; however, 40% of OCD patients do not respond to these. As brain activity patterns in OCD resemble those in schizophrenic patients, this suggests a dopaminergic component, supported by data showing that the D2/D3 receptor agonist Quinpirole induces compulsive checking in male rats. OCD has proved difficult to model in rodents and the contribution of decision making to compulsive behaviour in such models has not been studied. The five-choice continuous performance task (5C-CPT) measures both decision making and compulsive behaviour, making it possible to evaluate whether OCD models show correlated changes in these two behaviours. Establishing this would provide a new model approach to help develop therapeutic agents for OCD. AimsThe role of dopaminergic D3 receptors in decision making and compulsive behaviour was determined by testing the effect of the preferential D3 agonist PD 128907 on 5C-CPT performance measures. Oldhams method was used to determine the presence of any rate-dependent effect. MethodsFemale Lister hooded rats were trained to criterion in the 5C-CPT (>70% accuracy, < 30% omission and < 40% false alarms). The effects of PD128907 (0.25-1 mg/kg) were then investigated under challenging task conditions. ResultsOldham method revealed: a moderate positive association between baseline perseverative correct responses and the change at 0.05 mg/kg PD 128907; a strong positive association between baseline perseverative false alarm and the change at 0.2 mg/kg; a positive association between baseline total number of perseverative responses and the change at 0.05 mg/kg or 0.2 mg/kg PD 128907; a positive relationship between baseline accuracy and the change at 0.05 mg/kg PD 128907; and a moderate positive association between baseline correct response latency and the change at 0.05 mg/kg or 0.2 mg/kg PD 128907. The angle measurements and the direction of movement (clockwise or counterclockwise) showed how effective is one dose at increasing compulsive behaviour compared with other doses. ConclusionsPD 128907 effects on compulsive like behaviour and decision making in poor performing female lister hooded rats with long correct response latency and high perseveration at baseline (vulnerable population) in the 5C-CPT task matches two key features of OCD compulsions in humans (perseveration and indecision), this suggests that PD 128907 is more effective than Quinpirole in simulating the brain network conditions that underpin OCD. This model could help to develop more successful pharmacological interventions and to generate data translatable to clinical studies.

animal behavior and cognition↗

bioRxiv2023

Rate dependent effects of SKF 38393 and amphetamine on waiting impulsivity in the 5C-CPT

RationaleStimulants are the first-line treatment for attention-deficit/hyperactivity disorder (ADHD). However, the ensuing risk of abuse with stimulants means there is an urgent need for new, low-risk therapeutic agents. D1 receptors play an important role in the cognitive enhancing effects of stimulants and thus may provide a therapeutic target. Previous pre-clinical studies have shown that selective activation of D1 receptors improves sustained attention in the 5C-CPT without improving waiting impulsivity (premature response). ObjectiveThe aim of the present experiment was to compare the effects of the selective D1 receptor agonist SKF 38393 to a standard ADHD treatment (amphetamine) on waiting impulsivity in the 5C-CPT under extended inter-trial intervals. Oldhams method was used to determine the presence of a rate-dependent effect. MethodsAdult female Lister hooded rats were trained to criterion in the 5C-CPT (>70% accuracy, < 30% omission and < 40% false alarms). Effects of the selective D1 receptor agonist SKF 38393 (2-6 mg/kg) or amphetamine (0.1-0.4 mg/kg) were investigated under behavioural manipulations to challenge inhibitory response control. ResultsThe highest dose of SKF 38393 and the two highest doses of amphetamine improved waiting impulsivity in a baseline dependent manner. The clockwise movement of the regression line indicates that, as the dose increases, the magnitude of improvement increases in a manner consistent with baseline performance. ConclusionsThese findings support further clinical investigation of D1 receptor modulators to facilitate the discovery of improved medications for impulsive behaviour related disorders such as ADHD. The concept of rate dependency applies to effects of SKF 38393 or amphetamine on waiting impulsivity. Oldhams correlation method may present an opportunity to enhance the translational value of research in the preclinical laboratory to the clinic.

animal behavior and cognition↗

bioRxiv2023

The dopamine inhibitor GBR12909 improves attention and compulsive behaviour in female rats

BackgroundStimulants such as methylphenidate are the first-line treatment for attention deficit hyperactivity disorder (ADHD). A principal mechanism of action for these drugs is to reduce dopamine reuptake in the striatum. However, the ensuing risk of abuse with such stimulants means there is an urgent need for new, low-risk therapeutic agents. GBR12909 is a highly selective dopamine reuptake inhibitor, making it an important experimental tool. Indeed, this drug completed Phase II clinical trials for treatment of cocaine abuse. Understanding such drugs has the potential to expand our understanding of the striatal dopamine contribution to impulsivity, attention and compulsive behaviour and will help the development of novel targeted treatments for ADHD without an abuse risk. AimsThe aim of this work was to examine the role of low doses of GBR12909 on attention, impulsivity and compulsive behaviour as measured by 5C-CPT. Oldhams methods was used to determine the presence of a rate-dependent effect. MethodsFemale Lister hooded rats were trained to criterion in the 5C-CPT (>70% accuracy, < 30% omission and < 40% false alarms). Effects of GBR12909 (0.25-1 mg/kg) were investigated on attention, impulsivity and compulsive behaviour under challenging task conditions. ResultsThe two lowest doses of GBR12909 improved selective attention in a rate-dependent manner while the highest dose of GBR 12909 showed a tendency toward improving compulsive behaviour in a baseline-dependent manner. However, GBR 12909 impaired waiting impulsivity in a baseline-dependent manner. ConclusionsGBR12909 has a clearly beneficial effect on attention and compulsive behaviour in the female rat. These findings support further clinical investigation of GBR-type dopamine uptake blockers or GBR analogues to facilitate the discovery of medications for inattentive ADHD, stimulant abuse, compulsive drug seeking behaviour and obsessive-compulsive disorder.

animal behavior and cognition↗