D2 receptor sensitization: Neurobiological basis of increase sensitivity of stress on stimulant induced impaired behavioural sensetization

Stress is associated with high risk of psychological disorders and cognitive impairment. Psychostimulants are also known to potentiate cognition & ameliorate depression, but their long-term use causes behavioural sensitization. The locomotor response to psychostimulant potentiated after repeated exposure to stressful stimulus & dopamine is thought to play a major role in sensitization-like phenomena. The present study is conducted to visualize responsiveness of dopamine D2 receptors by challenge dose of haloperidol following long term psychostimulant administration in restrained & unrestrained rats. Behavioural Effects of oral repeated administration of methylphenidate (10mg/kg/day 2 times daily) & modafinil (75mg/kg/day once daily) in restrained (exposed to immobilization stress for 2 hours daily) and unrestrained rats were monitored to observe locomotor sensitization, by using familiar environment of home cage (performed after every two days) and novel environment of open field (weekly) however, exploratory activity in Head Dip Test and cognitive activity in passive avoidance test (PAT) were carried out weekly for 35 days (till the behavioral sensitization produced). Effects of haloperidol challenge dose (1 mg/kg i.p.) were monitored after 35 days of treatment using Home Cage, Open Field, Head Dip and PAT, 30-, 60-, 90- & 120-minutes post injection. The result shows increase in locomotor activity in drug treated rats potentiated by restrained stress and sensitization effect was significant in 3rd week of psychostimulant administration and was more pronounced in modafinil treated rats. Exploratory activity in Head dip test reduced by restrained stress whereas potentiated by MOD & MPH in unrestrained rats. In restrained rats only MOD prevents stress-induced effect on exploratory behaviour. Restrained stress produced cognitive deficits but MOD and MPH improved cognitive performance in PAT. Challenge dose of haloperidol ameliorated motor activity in familiar and novel environment, impaired cognition in PAT and decreased activity in head dip test, effect was more pronounced in psychostimulant treated restrained mice. This study will be beneficial for the understanding of neurobiological basis of the effect of psychostimulants on stress induced motor and cognitive deficits so helpful to investigate drugs that could prevent psychostimulant induced behavioural sensitization in stressful environment