Differential involvement of prelimbic and infralimbic medial prefrontal cortex in discrete cue-induced reinstatement of 3,4-methylenedioxymethamphetamine (MDMA; ecstasy) seeking in rats

Psychopharmacology (Berl). 2012 Dec;224(3):377-85. doi: 10.1007/s00213-012-2762-5. Epub 2012 Jun 19.


Rationale: The amphetamine derivative 3,4-methylenedioxymethamphetamine (MDMA; ecstasy) is a widely abused drug, particularly in adolescent and young adult populations. Although it was shown that MDMA-associated cues reinstate extinguished MDMA seeking in an animal relapse model, there is little information regarding the neural mechanisms underlying this behavior.

Objectives: Because the medial prefrontal cortex (mPFC) plays an important role in relapse to cocaine and methamphetamine seeking, we tested the effects of lidocaine inactivation of prelimbic (PL) and infralimbic (IL) subregions of mPFC on cue-induced relapse to MDMA seeking.

Methods: Rats were trained to respond for MDMA infusions (0.50 mg/kg/infusion, i.v.) paired with a discrete cue in daily 2-h sessions. Responding was reinforced contingent on a modified fixed ratio 5 schedule of reinforcement. Cue-induced reinstatement tests were conducted after responding was extinguished in the absence of MDMA and the conditioned cues. Prior to reinstatement tests, rats received bilateral microinjections of either lidocaine (100 μg/0.5 μl/side) or physiological saline (0.5 μl/side) delivered to either PL or IL mPFC.

Results: Microinjections of lidocaine into PL completely blocked reinstatement of MDMA-seeking behavior compared with saline microinjections into the same region. Lidocaine microinjections did not, however, have an effect on food-maintained responding, ruling out a nonspecific disruption of motor performance. Conversely, lidocaine inactivation of IL had no effect on reinstatement of MDMA seeking or food-maintained responding.

Conclusions: Our results provide direct support for PL activation in reinstatement of MDMA-seeking behavior. Moreover, akin to cocaine seeking, there appears to be differential involvement of PL and IL subregions in this behavior.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural

MeSH terms

  • Amphetamine-Related Disorders / physiopathology
  • Amphetamine-Related Disorders / psychology*
  • Animals
  • Behavior, Addictive / physiopathology
  • Behavior, Addictive / psychology*
  • Behavior, Animal / drug effects*
  • Conditioning, Operant / drug effects
  • Cues*
  • Drug-Seeking Behavior / drug effects*
  • Eating / drug effects
  • Extinction, Psychological / drug effects
  • Feeding Behavior / drug effects
  • Hallucinogens / administration & dosage
  • Hallucinogens / pharmacology*
  • Infusions, Intravenous
  • Lidocaine / administration & dosage
  • Limbic System / drug effects*
  • Limbic System / physiopathology
  • Male
  • Microinjections
  • N-Methyl-3,4-methylenedioxyamphetamine / administration & dosage
  • N-Methyl-3,4-methylenedioxyamphetamine / pharmacology*
  • Prefrontal Cortex / drug effects*
  • Prefrontal Cortex / physiopathology
  • Rats
  • Rats, Sprague-Dawley
  • Recurrence
  • Reinforcement Schedule
  • Time Factors


  • Hallucinogens
  • Lidocaine
  • N-Methyl-3,4-methylenedioxyamphetamine