Modulation of neuronal excitability by serotonin-NMDA interactions in prefrontal cortex

Mol Cell Neurosci. 2008 Jun;38(2):290-9. doi: 10.1016/j.mcn.2008.03.003. Epub 2008 Mar 25.


Both serotonin and NMDA signaling in prefrontal cortex (PFC) are implicated in mental disorders, including depression and anxiety. To understand their potential contributions to PFC neuronal excitability, we examined the effect of co-activation of 5-HT and NMDA receptors on action potential firing elicited by depolarizing current injection in PFC pyramidal neurons. In the presence of NMDA, a low concentration of the 5-HT(1A) agonist 8-OH-DPAT substantially reduced the number of spikes, and a low concentration of the 5-HT(2A/C) agonist alpha-Me-5HT significantly enhanced it, while both agonists were ineffective when applied alone. The 8-OH-DPAT effect on firing was mediated by inhibition of protein kinase A (PKA), whereas the alpha-Me-5HT effect was mediated by activation of protein kinase C (PKC). Moreover, the extracellular signal-regulated kinase (ERK), a signaling molecule downstream of PKA and PKC, was involved in both 5-HT(1A) and 5-HT(2A/C) modulation of neuronal excitability. Biochemical evidence showed that 5-HT(1A) decreased, whereas 5-HT(2A/C) increased the activation of ERK in an NMDA-dependent manner. In animals exposed to acute stress, the enhancing effect of 5-HT(2A/C) on firing was lost, while the decreasing effect of 5-HT(1A) on firing was intact. Concomitantly, the effect of 5-HT(2A/C), but not 5-HT(1A), on ERK activation was abolished in stressed animals. Taken together, our results demonstrate that distinct 5-HT receptor subtypes, by interacting with NMDA receptors, differentially regulate PFC neuronal firing, and the complex effects of 5-HT receptors on excitability are selectively altered under stressful conditions, which are often associated with mental disorders.

Publication types

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

MeSH terms

  • 8-Hydroxy-2-(di-n-propylamino)tetralin / pharmacology
  • Action Potentials / drug effects
  • Action Potentials / physiology
  • Animals
  • Excitatory Amino Acid Agonists / pharmacology
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • MAP Kinase Signaling System / physiology
  • N-Methylaspartate / pharmacology
  • Organ Culture Techniques
  • Prefrontal Cortex / cytology
  • Prefrontal Cortex / physiology*
  • Pyramidal Cells / drug effects
  • Pyramidal Cells / physiology*
  • Rats
  • Rats, Sprague-Dawley
  • Receptor, Serotonin, 5-HT1A / metabolism
  • Receptor, Serotonin, 5-HT2A / metabolism
  • Receptors, N-Methyl-D-Aspartate / metabolism*
  • Serotonin / metabolism*
  • Serotonin Receptor Agonists / pharmacology
  • Stress, Physiological / metabolism*
  • Stress, Physiological / physiopathology*
  • Swimming


  • Excitatory Amino Acid Agonists
  • Receptor, Serotonin, 5-HT2A
  • Receptors, N-Methyl-D-Aspartate
  • Serotonin Receptor Agonists
  • Receptor, Serotonin, 5-HT1A
  • Serotonin
  • N-Methylaspartate
  • 8-Hydroxy-2-(di-n-propylamino)tetralin
  • Extracellular Signal-Regulated MAP Kinases