Enhanced cocaine-induced locomotor sensitization and intrinsic excitability of NAc medium spiny neurons in adult but not in adolescent rats susceptible to diet-induced obesity

Psychopharmacology (Berl). 2016 Mar;233(5):773-84. doi: 10.1007/s00213-015-4157-x. Epub 2015 Nov 27.


Rationale: Basal and diet-induced differences in mesolimbic function, particularly within the nucleus accumbens (NAc), may contribute to human obesity; these differences may be more pronounced in susceptible populations.

Objectives: We examined differences in cocaine-induced behavioral plasticity in rats that are susceptible vs. resistant to diet-induced obesity and basal differences in striatal neuron function in adult and in adolescent obesity-prone and obesity-resistant rats.

Methods: Susceptible and resistant outbred rats were identified based on "junk-food" diet-induced obesity. Then, the induction and expression of cocaine-induced locomotor sensitization, which is mediated by enhanced striatal function and is associated with increased motivation for rewards and reward-paired cues, were evaluated. Basal differences in mesolimbic function were examined in selectively bred obesity-prone and obesity-resistant rats (P70-80 and P30-40) using both cocaine-induced locomotion and whole-cell patch clamping approaches in NAc core medium spiny neurons (MSNs).

Results: In rats that became obese after eating junk-food, the expression of locomotor sensitization was enhanced compared to non-obese rats, with similarly strong responses to 7.5 and 15 mg/kg cocaine. Without diet manipulation, obesity-prone rats were hyper-responsive to the acute locomotor-activating effects of cocaine, and the intrinsic excitability of NAc core MSNs was enhanced by ∼60 % at positive and negative potentials. These differences were present in adult, but not adolescent rats. Post-synaptic glutamatergic transmission was similar between groups.

Conclusions: Mesolimbic systems, particularly NAc MSNs, are hyper-responsive in obesity-prone individuals, and interactions between predisposition and experience influence neurobehavioral plasticity in ways that may promote weight gain and hamper weight loss in susceptible rats.

Keywords: Cocaine; Excitability; Nucleus accumbens; Obesity; Sensitization; Striatum.

Publication types

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

MeSH terms

  • Aging
  • Animals
  • Central Nervous System Stimulants / pharmacology*
  • Cocaine / pharmacology*
  • Diet
  • Dose-Response Relationship, Drug
  • Glutamates / physiology
  • Male
  • Motor Activity / drug effects*
  • Neostriatum / cytology
  • Neostriatum / drug effects
  • Neurons / drug effects*
  • Nucleus Accumbens / cytology
  • Nucleus Accumbens / drug effects*
  • Obesity / genetics
  • Obesity / physiopathology*
  • Patch-Clamp Techniques
  • Rats
  • Rats, Sprague-Dawley
  • Synaptic Transmission / drug effects


  • Central Nervous System Stimulants
  • Glutamates
  • Cocaine