Potentiation of synaptic strength and intrinsic excitability in the nucleus accumbens after 10 days of morphine withdrawal

J Neurosci Res. 2012 Jun;90(6):1270-83. doi: 10.1002/jnr.23025. Epub 2012 Mar 2.


Neuroadaptations in the nucleus accumbens (NAc) are associated with the development of drug addiction. Plasticity in synaptic strength and intrinsic excitability of NAc medium spiny neurons (MSNs) play critical roles in addiction induced by different classes of abused drugs. However, it is unknown whether morphine exposure influences synaptic strength, intrinsic excitability or both in NAc. Here we show that chronic withdrawal (10 days after the last injection) from repeated morphine exposure elicited potentiation in both glutamatergic synaptic strength and intrinsic excitability of MSNs in NAc shell (NAcSh). The potentiation of synaptic strength was demonstrated by an increase in the frequency of miniature excitatory postsynaptic currents (mEPSCs), a decrease in the paired-pulse ratio (PPR), and an increase in the ratio of α-amino-3-hydroxy-5-methyl-isoxazole propionic acid receptors (AMPAR)- to N-methyl-D-aspartate receptors (NMDAR)-mediated currents. The potentiation of intrinsic excitability was mediated by inhibition of the sustained potassium currents via extrasynaptic NMDAR activation. The function of the presynaptic group II metabotropic glutamate receptors (mGluR2/3) was downregulated, enhancing the probability of glutamate release on synaptic terminals during chronic morphine withdrawal. Pretreatment with the mGluR2/3 agonist LY379268 completely blocked potentiation of both synaptic strength and intrinsic excitability. These results suggest that chronic morphine withdrawal downregulates mGluR2/3 to induce potentiation of MSN glutamatergic synapse via increased glutamate release, leading to potentiation of intrinsic excitability. Such potentiation of both synaptic strength and intrinsic excitability might contribute to neuroadaptations induced by morphine application.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 2-Amino-5-phosphonovalerate / pharmacology
  • 6-Cyano-7-nitroquinoxaline-2,3-dione / pharmacology
  • Amino Acids / pharmacology
  • Analysis of Variance
  • Animals
  • Bridged Bicyclo Compounds, Heterocyclic / pharmacology
  • Disease Models, Animal
  • Down-Regulation / drug effects
  • Electric Stimulation / methods
  • Excitatory Amino Acid Agonists / pharmacology
  • Excitatory Amino Acid Antagonists / pharmacology
  • Excitatory Postsynaptic Potentials / drug effects
  • Excitatory Postsynaptic Potentials / physiology*
  • In Vitro Techniques
  • Male
  • Morphine / adverse effects*
  • Narcotics / adverse effects*
  • Neurons / drug effects
  • Neurons / physiology
  • Neuroprotective Agents
  • Nucleus Accumbens / drug effects
  • Nucleus Accumbens / pathology*
  • Patch-Clamp Techniques
  • Rats
  • Rats, Sprague-Dawley
  • Substance Withdrawal Syndrome / etiology
  • Substance Withdrawal Syndrome / pathology*
  • Synapses / drug effects
  • Synapses / physiology*
  • Xanthines / pharmacology


  • Amino Acids
  • Bridged Bicyclo Compounds, Heterocyclic
  • Excitatory Amino Acid Agonists
  • Excitatory Amino Acid Antagonists
  • LY 379268
  • Narcotics
  • Neuroprotective Agents
  • Xanthines
  • propentofylline
  • 6-Cyano-7-nitroquinoxaline-2,3-dione
  • 2-Amino-5-phosphonovalerate
  • Morphine