Effects of the dopamine/norepinephrine releaser phenmetrazine on cocaine self-administration and cocaine-primed reinstatement in rats

Psychopharmacology (Berl). 2015 Jul;232(13):2405-14. doi: 10.1007/s00213-015-3875-4. Epub 2015 Feb 13.


Rationale: Like other monoamine releasers such as D-amphetamine, chronic treatment with phenmetrazine can attenuate cocaine self-administration in monkeys.

Objectives: The present studies extended this finding to rodents and to cocaine-primed reinstatement, a putative laboratory animal model of relapse.

Methods: In experiment 1, rats self-administered food pellets or injections of 0.19 mg/kg cocaine (i.v.) under a progressive-ratio schedule. When responding was stable, subcutaneous osmotic pumps were implanted containing saline or (+)-phenmetrazine (25 or 50 mg/kg per day). In experiment 2, rats self-administered injections of 0.75 mg/kg cocaine under a fixed-ratio 1 schedule in daily 6-h sessions. When responding was stable, rats were removed from the self-administration environment for 7 days and treated continuously with saline, 5 mg/kg per day D-amphetamine or phenmetrazine (25 or 50 mg/kg per day) via osmotic pumps. Rats were then returned to the self-administration context while treatment continued, and responding was extinguished by removing response-contingent stimulus changes and cocaine injections. Once responding was extinguished, reinstatement tests were conducted using cocaine injections (10 mg/kg i.p.).

Results: Phenmetrazine decreased self-administration of cocaine, but not food pellets, during the 14-day treatment period; effects persisted for several days after treatment was discontinued. Moreover, cocaine-induced increases in responding during the reinstatement test were attenuated by D-amphetamine and both phenmetrazine doses.

Conclusions: These results extend the study of the effects of phenmetrazine on cocaine self-administration to a rodent model, and provide further support for the use of monoamine releasers as agonist medications for cocaine abuse.

Keywords: Agonist therapy; Monoamine; Rat; Reinforcement; Reinstatement; Relapse.

Publication types

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

MeSH terms

  • Animals
  • Cocaine / administration & dosage*
  • Cocaine-Related Disorders / drug therapy
  • Cocaine-Related Disorders / metabolism
  • Dopamine / metabolism*
  • Eating / drug effects
  • Eating / physiology
  • Macaca mulatta
  • Male
  • Norepinephrine / metabolism*
  • Phenmetrazine / pharmacology*
  • Rats
  • Rats, Sprague-Dawley
  • Reinforcement, Psychology*
  • Self Administration


  • Cocaine
  • Dopamine
  • Norepinephrine
  • Phenmetrazine