Intrinsic Membrane Plasticity via Increased Persistent Sodium Conductance of Cholinergic Neurons in the Rat Laterodorsal Tegmental Nucleus Contributes to Cocaine-Induced Addictive Behavior

Eur J Neurosci. 2015 May;41(9):1126-38. doi: 10.1111/ejn.12855. Epub 2015 Feb 24.

Abstract

The laterodorsal tegmental nucleus (LDT) is a brainstem nucleus implicated in reward processing and is one of the main sources of cholinergic afferents to the ventral tegmental area (VTA). Neuroplasticity in this structure may affect the excitability of VTA dopamine neurons and mesocorticolimbic circuitry. Here, we provide evidence that cocaine-induced intrinsic membrane plasticity in LDT cholinergic neurons is involved in addictive behaviors. After repeated experimenter-delivered cocaine exposure, ex vivo whole-cell recordings obtained from LDT cholinergic neurons revealed an induction of intrinsic membrane plasticity in regular- but not burst-type neurons, resulting in increased firing activity. Pharmacological examinations showed that increased riluzole-sensitive persistent sodium currents, but not changes in Ca(2+) -activated BK, SK or voltage-dependent A-type potassium conductance, mediated this plasticity. In addition, bilateral microinjection of riluzole into the LDT immediately before the test session in a cocaine-induced conditioned place preference (CPP) paradigm inhibited the expression of cocaine-induced CPP. These findings suggest that intrinsic membrane plasticity in LDT cholinergic neurons is causally involved in the development of cocaine-induced addictive behaviors.

Keywords: addiction; conditioned place preference; mesocorticolimbic circuitry; neuroplasticity; persistent sodium channel.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cholinergic Neurons / drug effects
  • Cholinergic Neurons / metabolism*
  • Cholinergic Neurons / physiology
  • Cocaine / toxicity
  • Cocaine-Related Disorders / metabolism*
  • Cocaine-Related Disorders / physiopathology
  • Female
  • Large-Conductance Calcium-Activated Potassium Channels / metabolism
  • Male
  • Neuronal Plasticity*
  • Potassium Channels, Voltage-Gated / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Riluzole / pharmacology
  • Small-Conductance Calcium-Activated Potassium Channels / metabolism
  • Sodium / metabolism*
  • Sodium Channel Blockers / metabolism
  • Tegmentum Mesencephali / cytology
  • Tegmentum Mesencephali / metabolism*
  • Tegmentum Mesencephali / physiopathology

Substances

  • Large-Conductance Calcium-Activated Potassium Channels
  • Potassium Channels, Voltage-Gated
  • Small-Conductance Calcium-Activated Potassium Channels
  • Sodium Channel Blockers
  • Riluzole
  • Sodium
  • Cocaine