Use of intracranial self-stimulation to evaluate abuse-related and abuse-limiting effects of monoamine releasers in rats

Br J Pharmacol. 2013 Feb;168(4):850-62. doi: 10.1111/j.1476-5381.2012.02214.x.


Background and purpose: Monoamine releasers constitute a class of drugs that promote the release of dopamine (DA), serotonin (5-HT) and/or norepinephrine. Although some drugs in this class are well-known drugs of abuse (amphetamine, methamphetamine), others are thought to have reduced (3,4-methylenedioxy-N-methylamphetamine [MDMA]) or no (fenfluramine) abuse potential. The purpose of this study was to further elucidate the role of dopamine versus serotonin selectivity on expression of abuse-related effects produced by monoamine releasers in an assay of intracranial self-stimulation (ICSS) in rats.

Experimental approach: This study evaluated effects produced in a frequency-rate ICSS procedure by 11 monoamine releasers that vary in selectivity to release DA versus 5-HT.

Key results: Efficacy of monoamine releasers to facilitate ICSS correlated with DA-selectivity, such that DA-selective releasers exclusively facilitated ICSS, a 5-HT-selective releaser exclusively depressed ICSS, and mixed-action releasers both facilitated low ICSS rates and depressed high ICSS rates. Fixed-proportion mixtures of a DA-selective releaser and a 5-HT-selective releaser recapitulated effects of mixed-action releasers. Efficacy of monoamine releasers to facilitate ICSS also correlated with previously published data on efficacy to maintain self-administration in rhesus monkeys responding under a progressive-ratio schedule of reinforcement.

Conclusions and implications: These data support the importance of selectivity for DA versus 5-HT in determining abuse potential of monoamine releasers and demonstrate a novel correlation between rat ICSS and nonhuman primate self-administration measures of abuse-related effects. Taken together, these results support the use of ICSS in rats as an experimental tool to study the expression and pharmacological determinants of abuse-related effects of monoamine releasers.

Publication types

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

MeSH terms

  • Animals
  • Behavior, Animal / drug effects*
  • Biogenic Monoamines / metabolism*
  • Deep Brain Stimulation*
  • Dose-Response Relationship, Drug
  • Illicit Drugs / pharmacology*
  • Male
  • Rats
  • Rats, Sprague-Dawley
  • Reinforcement, Psychology
  • Self Stimulation
  • Substance-Related Disorders / metabolism*
  • Substance-Related Disorders / psychology


  • Biogenic Monoamines
  • Illicit Drugs