Interhemispheric regulation of the rat medial prefrontal cortical glutamate stress response: role of local GABA- and dopamine-sensitive mechanisms

Psychopharmacology (Berl). 2017 Feb;234(3):353-363. doi: 10.1007/s00213-016-4468-6. Epub 2016 Nov 7.


Rationale: We previously reported that stressors increase medial prefrontal cortex (PFC) glutamate (GLU) levels as a result of activating callosal neurons located in the opposite hemisphere and that this PFC GLU stress response is regulated by GLU-, dopamine- (DA-), and GABA-sensitive mechanisms (Lupinsky et al. 2010).

Objectives: Here, we examine the possibility that PFC DA regulates the stress responsivity of callosal neurons indirectly by acting at D1 and D2 receptors located on GABA interneurons.

Methods: Microdialysis combined with drug perfusion (reverse dialysis) or microinjections was used in adult male Long-Evans rats to characterize D1, D2, and GABAB receptor-mediated regulation of the PFC GABA response to tail-pinch (TP) stress.

Results: We report that TP stress reliably elicited comparable increases in extracellular GABA in the left and right PFCs. SCH23390 (D1 antagonist; 100 μM perfusate concentration) perfused by reverse microdialysis attenuated the local GABA stress responses equally in the left and right PFCs. Intra-PFC raclopride perfusion (D2 antagonist; 100 μM) had the opposite effect, not only potentiating the local GABA stress response but also causing a transient elevation in basal (pre-stress) GABA. Moreover, unilateral PFC raclopride microinjection (6 nmol) attenuated the GLU response to TP stress in the contralateral PFC. Finally, intra-PFC baclofen perfusion (GABAB agonist; 100 μM) inhibited the local GLU and GABA stress responses.

Conclusions: Taken together, these findings implicate PFC GABA interneurons in processing stressful stimuli, showing that local D1, D2, and GABAB receptor-mediated changes in PFC GABA transmission play a crucial role in the interhemispheric regulation of GLU stress responsivity.

Keywords: Baclofen; Callosal neurons; GABA; Hemispheric specialization; Raclopride; SCH23390.

MeSH terms

  • Animals
  • Baclofen / pharmacology
  • Benzazepines / pharmacology
  • Corpus Callosum / cytology
  • Corpus Callosum / drug effects
  • Corpus Callosum / metabolism
  • Dopamine / metabolism*
  • Dopamine Antagonists / pharmacology
  • Functional Laterality
  • GABA-B Receptor Agonists / pharmacology
  • Glutamic Acid / metabolism*
  • Interneurons / drug effects
  • Interneurons / metabolism*
  • Male
  • Microdialysis
  • Neurons / drug effects
  • Neurons / metabolism
  • Prefrontal Cortex / drug effects
  • Prefrontal Cortex / metabolism*
  • Raclopride / pharmacology
  • Rats
  • Rats, Long-Evans
  • Receptors, Dopamine D1 / antagonists & inhibitors
  • Receptors, Dopamine D1 / drug effects
  • Receptors, Dopamine D1 / metabolism*
  • Receptors, Dopamine D2 / drug effects
  • Receptors, Dopamine D2 / metabolism*
  • Receptors, GABA-B
  • Stress, Psychological / metabolism*
  • gamma-Aminobutyric Acid / metabolism*


  • Benzazepines
  • DRD2 protein, rat
  • Dopamine Antagonists
  • GABA-B Receptor Agonists
  • Receptors, Dopamine D1
  • Receptors, Dopamine D2
  • Receptors, GABA-B
  • SCH 23390
  • Glutamic Acid
  • Raclopride
  • gamma-Aminobutyric Acid
  • Baclofen
  • Dopamine

Grant support