A progressive ratio schedule of self-stimulation testing in rats reveals profound augmentation of d-amphetamine reward by food restriction but no effect of a "sensitizing" regimen of d-amphetamine

Psychopharmacology (Berl). 2004 Aug;175(1):106-13. doi: 10.1007/s00213-003-1768-4. Epub 2004 Feb 20.


Rationale: Prior research indicates that psychostimulant-induced sensitization is not expressed in lateral hypothalamic electrical self-stimulation (LHSS)-based measures of drug reward, although the augmenting effect of chronic food restriction is. Neuroadaptations within the brain dopamine system have been identified in both psychostimulant-sensitized and food-restricted animals. Consequently, a variant of the LHSS paradigm in which responding is particularly sensitive to changes in dopaminergic tone may be best suited to detect and compare effects of chronic d-amphetamine and food restriction. Instrumental responding on a progressive ratio (PR) schedule is more sensitive to dopaminergic manipulations than is responding on a continuous reinforcement (CRF) schedule, but has not previously been used to examine chronic psychostimulant and food restriction effects on LHSS-based measures of drug reward.

Objective: The first aim of this study was to determine whether a regimen of d-amphetamine treatment, that produces locomotor sensitization (5 mg/kg per day x5 days), increases the reward-potentiating effect of d-amphetamine in a PR LHSS protocol. The second aim, was to determine whether chronic food restriction produces a marked increase in the reward-potentiating effect of d-amphetamine in the PR LHSS protocol and, if so, whether it is reversible in parallel with body weight recovery when free feeding is restored.

Method: Reward-potentiating effects of a challenge dose of d-amphetamine (0.25 mg/kg, IP) were measured in terms of the break point of LHSS responding on a PR schedule of reinforcement, in ad libitum fed and food-restricted rats.

Results: A regimen of d-amphetamine treatment that produced locomotor sensitization did not increase the break point for LHSS in the presence or absence of d-amphetamine. Chronic food restriction produced a marked increase in the break point-increasing effect of d-amphetamine (3-fold), which returned to baseline in parallel with body weight recovery over a 4-week period of restored free-feeding.

Conclusions: A locomotor-sensitizing regimen of d-amphetamine treatment does not increase the rewarding effect of LH electrical stimulation or the reward-potentiating effect of d-amphetamine in a PR LHSS protocol. The augmenting effect of chronic food restriction on drug reward is mechanistically and functionally different from psychostimulant sensitization and may be controlled by signals associated with adipose depletion and repletion.

Publication types

  • Comparative Study
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Behavior, Animal
  • Dextroamphetamine / pharmacology*
  • Dopamine Agents / pharmacology*
  • Eating / drug effects
  • Electric Stimulation
  • Food Deprivation / physiology
  • Male
  • Motor Activity / drug effects
  • Motor Activity / physiology
  • Rats
  • Rats, Sprague-Dawley
  • Reinforcement Schedule*
  • Reward*
  • Self Stimulation / drug effects*
  • Self Stimulation / physiology
  • Time Factors


  • Dopamine Agents
  • Dextroamphetamine