Effects of Acute and Chronic Restraint Stress on Reinstatement of Extinguished Methamphetamine-induced Conditioned Place Preference in Rats

Introduction: Methamphetamine (METH) is a neurotoxic psychostimulant with highly addictive potential that leads to compulsive drug use and vulnerability to relapse. Environmental cues, such as drug exposure, peer influence, and social stress, are the powerful triggers of drug relapse. In  this  study,  we  tried  to  find  out  the effect of acute and chronic restraint stress on reinstatement of extinguished METH-induced Conditioned Place  Preference  (CPP)  in  rats.  Methods: Subcutaneous (SC) administration of METH (0.125, 0.25, 0.5, 1, 2 and 4 mg/kg) could induce CPP and it was found that  METH with the dose of 0.5 mg/kg was more potent than other doses. In  extinction phase,  rats  were  put  in  the  CPP  box  for  30  min  per  day  for  8 consecutive days.  After  extinction,  animals  were  exposed  to restraint stress (3-h period, as an acute stress) 60  min  before  subcutaneous  administration  of  ineffective  dose  of  METH  (0.125  mg/kg)  in  order  to  reinstate  the  extinguished  METH-induced CPP. For induction of the chronic stress during extinction phase, the animals were exposed to the restraint stress for one hour per day. Results: The results showed that the effective dose of METH to induce CPP was 0.5 mg/kg.  Based on the results, physical  stress  (restraint stress) whether acute and chronic, can  significantly  induce  reinstatement  of METH-induced CPP (P˂0.001) in extinguished animals.  Conclusion: Additionally, the chronic restraint stress could reduce duration of extinction (maintenance) of METH-induced CPP. It seems that exposure to the stress induces the relapse in abstinent amphetamine, but acute and chronic situation have a different reaction.