Skip to main content
Springer Nature Link
Log in

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

  • Original Investigation
  • Published:
Psychopharmacology Aims and scope Submit manuscript

Abstract

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
$34.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or eBook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

Explore related subjects

Discover the latest articles and news from researchers in related subjects, suggested using machine learning.

References

  • Aguilar-Garcia A, Gonzalez-Frankenberger B, Ramon-Frias T, Mendez-Franco BJ, Perez-de la Mora M (2000) Lack of coupling between GABA release and GABA synthesis in the rat brain via GABAB autoreceptors. Amino Acids 19:63–77

    Article  CAS  PubMed  Google Scholar 

  • Bacon SJ, Headlam AJ, Gabbott PL, Smith AD (1996) Amygdala input to medial prefrontal cortex (mPFC) in the rat: a light and electron microscope study. Brain Res 720:211–219

    Article  CAS  PubMed  Google Scholar 

  • Bagley J, Moghaddam B (1997) Temporal dynamics of glutamate efflux in the prefrontal cortex and in the hippocampus following repeated stress: effects of pretreatment with saline or diazepam. Neuroscience 77:65–73

    Article  CAS  PubMed  Google Scholar 

  • Balla A, Nattini ME, Sershen H, Lajtha A, Dunlop DS, Javitt DC (2009) ABAB/NMDA receptor interaction in the regulation of extracellular dopamine levels in rodent prefrontal cortex and striatum. Neuropharmacology 56:915–921

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Berridge CW, Mitton E, Roth RH (1999) Engagement in a non-escape (displacement) behavior elicits a selective and lateralized suppression of frontal cortical dopaminergic utilization in stress. Synapse 32:187–197

    Article  CAS  PubMed  Google Scholar 

  • Bowery NG, Hill DR, Hudson AL, Doble A, Middlemiss DN, Shaw J, Turnbull M (1980) Baclofen decreases neurotransmitter release in the mammalian CNS by an action at a novel GABA receptor. Nature 283:92–94

    Article  CAS  PubMed  Google Scholar 

  • Bowery NG, Hudson AL, Price GW (1987) GABAA and GABAB receptor site distribution in the rat central nervous system. Neuroscience 20:365–383

    Article  CAS  PubMed  Google Scholar 

  • Brake WG, Flores G, Francis D, Meaney MJ, Srivastava LK, Gratton A (2000) Enhanced nucleus accumbens dopamine and plasma corticosterone stress responses in adult rats with neonatal excitotoxic lesions to the medial prefrontal cortex. Neuroscience 96(4):687–695

    Article  CAS  PubMed  Google Scholar 

  • Carlson JN, Fitzgerald LW, Keller RW, Glick SD (1991) Side and region dependent changes in dopamine activation with various durations of restraint stress. Brain Res 550:313–318

    Article  CAS  PubMed  Google Scholar 

  • Carlson JN, Fitzgerald LW, Keller RW, Glick SD (1993) Lateralized changes in prefrontal cortical dopamine activity induced by controllable and uncontrollable stress in the rat. Brain Res 630:178–187

    Article  CAS  PubMed  Google Scholar 

  • Carr DB, Sesack SR (1998) Callosal terminals in the rat prefrontal cortex: synaptic targets and association with GABA immunoreactive structures. Synapse 29:193–205

    Article  CAS  PubMed  Google Scholar 

  • Carr DB, Sesack SR (2000) Dopamine terminals synapse on callosal projection neurons in the rat prefrontal cortex. J Comp Neurol 425:275–283

    Article  CAS  PubMed  Google Scholar 

  • Del Arco A, Mora F (2000) Endogenous dopamine potentiates the effects of glutamate on extracellular GABA in the prefrontal cortex of the freely moving rat. Brain Res Bull 53:339–345

    Article  CAS  PubMed  Google Scholar 

  • Del Arco A, Mora F (2001) Dopamine release in the prefrontal cortex during stress is reduced by the local activation of glutamate receptors. Brain Res Bull 56:125–130

    Article  CAS  PubMed  Google Scholar 

  • Denenberg VH, Gall JS, Berrebi A, Yutzey DA (1986) Callosal mediation of cortical inhibition in the lateralized rat brain. Brain Res 397:327–332

    Article  CAS  PubMed  Google Scholar 

  • Doherty MD, Gratton A (1999) Effects of medial prefrontal cortical injections of GABA agonists and antagonists on the local and nucleus accumbens dopamine responses to stress. Synapse 32:288–300

    Article  CAS  PubMed  Google Scholar 

  • Feenstra MGP, Botterblom MHA, van Uum JFM (2002) Behavioral arousal and increased dopamine efflux after blockade of NMDA-receptors in the prefrontal cortex are dependent on activation of glutamatergic neurotransmission. Neuropharmacology 42 (6):752–763

  • Ferino F, Thierry AM, Saffroy M, Glowinski J (1987) Inter-hemispheric and subcortical collaterals of medial prefrontal cortical neurons in the rat. Brain Res 417:257–266

    Article  CAS  PubMed  Google Scholar 

  • File SE, Andrews N, Zharkovsky A (1990) Handling habituation and chlordiazepoxide have different effects on GABA and 5-HT function in the frontal cortex and hippocampus. Eur J Pharmacol 190:229–234

    Article  CAS  PubMed  Google Scholar 

  • Gratton A, Sullivan RM (2005) Role of the prefrontal cortex in stress responsivity. In: Steckler T, Kalin N, Reul JMHM (eds) Handbook of stress and the brain. Part 1: the neurobiology of stress, vol. 15. Elsevier Science, Amsterdam, pp. 807–818

    Chapter  Google Scholar 

  • Harte M, O’Connor WT (2004) Evidence for a differential medial prefrontal dopamine D1 and D2 receptor regulation of local and ventral tegmental glutamate and GABA release: a dual probe microdialysis study in the awake rat. Brain Res 1017(1–2):120–129

    Article  CAS  PubMed  Google Scholar 

  • Ishikawa A, Nakamura S (2003) Convergence and interaction of hippocampal and amygdalar projections within the prefrontal cortex in the rat. J Neurosci 23:9987–9995

    CAS  PubMed  Google Scholar 

  • Jayaram P, Steketee JD (2004) Effects of repeated cocaine on medical prefrontal cortical GABAB receptor modulation of neurotransmission in the mesocorticolimbic dopamine system. J Neurochem 90:839–847

    Article  CAS  PubMed  Google Scholar 

  • Johnston GA, Hailstone MH, Freeman CG (1980) Baclofen: stereoselective inhibition of excitant amino acid release. J Pharm Pharmacol 32:230–231

    Article  CAS  PubMed  Google Scholar 

  • Karayannis T, Huerta-Ocampo I, Capogna M (2007) GABAergic and pyramidal neurons of deep cortical layers directly receive and differently integrate callosal input. Cereb Cortex 17:1213–1226

    Article  PubMed  Google Scholar 

  • Kruse MS, Prémont J, Krebs M, Jay TM (2009) Interaction of dopamine D1 with NMDA NR1 receptors in rat prefrontal cortex. European Neuropsychopharmacology 19 (4):296–304

  • Luczynski P, Moquin L, Gratton A (2015) Chronic stress alters the dendritic morphology of callosal neurons and the acute glutamate stress response in the rat medial prefrontal cortex. Stress 18(6):654–667

    Article  CAS  PubMed  Google Scholar 

  • Lupinsky D, Moquin L, Gratton A (2010) Interhemispheric regulation of the medial pre-frontal cortical glutamate stress response in rats. J Neurosci 30:7624–7633

    Article  CAS  PubMed  Google Scholar 

  • Margeta-Mitrovic M, Mitrovic I, Riley RC, Jan LY, Basbaum AI (1999) Immunohistochemical localization of GABAB receptors in the rat central nervous system. J Comp Neurol 405:299–321

    Article  CAS  PubMed  Google Scholar 

  • McDonald AJ (1987) Organization of amygdaloid projections to the mediodorsal thalamus and prefrontal cortex: a fluorescence retrograde transport study in the rat. J Comp Neurol 262:46–58

    Article  CAS  PubMed  Google Scholar 

  • McDonald AJ (1991) Organization of amygdaloid projections to the prefrontal cortex and associated striatum in the rat. Neuroscience 44:1–14

    Article  CAS  PubMed  Google Scholar 

  • McDonald AJ (1996) Glutamate and aspartate immunoreactive neurons of the rat basolateral amygdala: colocalization of excitatory amino acids and projections to the limbic circuit. J Comp Neurol 365:367–379

    Article  CAS  PubMed  Google Scholar 

  • Moghaddam B (1993) Stress preferentially increases extraneuronal levels of excitatory amino acids in the prefrontal cortex: comparison to hippocampus and basal ganglia. J Neurochem 60(5):1650–1657

    Article  CAS  PubMed  Google Scholar 

  • Neff VL, Finlay JM (1997) Dopamine modulation of basal and stress-evoked GABA release in prefrontal cortex in rat. Soc Neurosci Abstr 23:1360

    Google Scholar 

  • Paxinos G, Watson C (1996) The rat brain in stereotaxic coordinates. Academic, New York

    Google Scholar 

  • Santana N, Mengod G, Artigas F (2009) Quantitative Analysis of the Expression of Dopamine D1 and D2 Receptors in Pyramidal and GABAergic Neurons of the Rat Prefrontal Cortex. Cerebral Cortex 19 (4):849–860

  • Santiago M, Machado A, Cano J (1993) Regulation of the prefrontal cortical dopamine release by GABAA and GABAB receptor agonists and antagonists. Brain Res 630:28–31

    Article  CAS  PubMed  Google Scholar 

  • Seamans JK, Durstewitz D, Christie BR, Stevens CF, Sejnowski TJ (2001a) Dopamine D1/D5 receptor modulation of excitatory synaptic inputs to layer V prefrontal cortex neurons. Proc Natl Acad Sci U S A 98:301–306

    Article  CAS  PubMed  Google Scholar 

  • Seamans JK, Gorelova N, Durstewitz D, Yang CR (2001b) Bidirectional dopamine modulation of GABAergic inhibition in prefrontal cortical pyramidal neurons. J Neurosci 21:3628–3638

    CAS  PubMed  Google Scholar 

  • Stalnaker TA, Rodrigo A, Espan A, Berridge CW (2009) Coping behavior causes asymmetric changes in neuronal activation in the prefrontal cortex and amygdale. Synapse 63:82–85

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Steciuk M, Kram M, Kramer GL, Petty F (2000) Immobilization-induced glutamate efflux in medial prefrontal cortex: blockade by (+)-Mk-801, a selective NMDA receptor antagonist. Stress 3:195–199

    Article  CAS  PubMed  Google Scholar 

  • Stevenson C, Sullivan RM, Gratton A (2003) Effects of basolateral amygdala dopamine depletion on the nucleus accumbens and medial prefrontal cortical dopamine responses to stress. Neuroscience 116:285–293

    Article  CAS  PubMed  Google Scholar 

  • Sullivan RM, Gratton A (1998) Relationships between stress-induced increases in medial prefrontal cortical dopamine and plasma corticosterone levels in rats: role of cerebral laterality. Neuroscience 83:81–91

    Article  CAS  PubMed  Google Scholar 

  • Sullivan RM, Gratton A (1999) Lateralized effects of medial prefrontal cortex lesions on neuroendocrine and autonomic stress responses in rats. J Neurosci 19:2834–2840

    CAS  PubMed  Google Scholar 

  • Sullivan RM, Gratton A (2002) Prefrontal cortical regulation of hypothalamic-pituitary-adrenal function in the rat and implications for psychopathology: side matters. Psychoneuroendocrinology 27:99–114

    Article  CAS  PubMed  Google Scholar 

  • Sullivan RM, Szechtman H (1995) Asymmetrical influence of mesocortical dopamine depletion on stress ulcer development and subcortical dopamine systems in rats: implications for psychopathology. Neuroscience 65:757–766

    Article  CAS  PubMed  Google Scholar 

  • Trantham-Davidson H, Neely LC, Lavin A, Seamans JK (2004) Mechanisms underlying differential D1 versus D2 dopamine receptor regulation of inhibition in prefrontal cortex. J Neurosci 24:10652–10659

    Article  CAS  PubMed  Google Scholar 

  • Tseng KY, O’Donnell P (2004) Dopamine-glutamate interactions controlling prefrontal cortical pyramidal cell excitability involves multiple signaling mechanisms. J Neurosci 24:5131–5139

    Article  CAS  PubMed  Google Scholar 

  • Tseng KY, O’Donnell P (2007a) Prefrontal cortical interneurons acquire modulation by D2 dopamine receptors during adolescence. Cereb Cortex 17:1235–1240

    Article  PubMed  Google Scholar 

  • Tseng K, O’Donnell P (2007b) D2 dopamine receptors recruit a GABA component for their attenuation of excitatory synaptic transmission in the adult rat prefrontal cortex. Synapse 61:843–850

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tseng KY, Mallet N, Toreson KL, Le Moine C, Gonon F, O'Donnell P (2006) Excitatory response of prefrontal cortical fast-spiking interneurons to ventral tegmental area stimulation in vivo. Synapse 59 (7):412–417

  • van der Zeyden M, Oldenziel WH, Rea K, Cremers TI, Westerink BH (2008) Microdialysis of GABA and glutamate: analysis, interpretation and comparison with microsensors. Pharmacol Biochem Behav 90:135–147

    Article  PubMed  Google Scholar 

  • Waldmeier PC, Wicki P, Feldtrauer J-J (1993) Release of endogenous glutamate from rat cortical slices in presence of the glutamate uptake inhibitor L-trans-pyrrolidine-2,4-dicarboxylic acid. Naunyn Schmiedeberg’s Arch Pharmacol 348:478–485

    Article  CAS  Google Scholar 

  • Waldmeier PC, Kaupmann K, Urwyler S (2008) Roles of GABA(B) receptor subtypes in presynaptic auto- and heteroreceptor function regulating GABA and glutamate release. J Neural Transm 115:1401–1411

    Article  CAS  PubMed  Google Scholar 

  • Yang CR, Seemans JK (1996) Dopamine D1 receptor actions in layers V-VI rat prefrontal cortex neurons in vitro. Modulation of dendritic-somatic signal integration. J Neurosci 16:1922–1935.

  • Zapata A, Chefer VI, Shippenberg TS (2009) Microdialysis in rodents. Curr Protoc Neurosci. Chapter 7: Unit7.2

  • Zhou F-M, Hablitz JJ (1999) Dopamine modulation of membrane and synaptic properties of interneurons in rat cerebral cortex. J Neurophysiol 81:967–976

    CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This study was made possible by a Canadian Institutes for Health Research (CIHR) grant to A.G. and a Fonds de la recherche en santé du Québec (FRSQ) doctoral fellowship to D.L.

Author information

Authors and Affiliations

  1. Department of Psychiatry, McGill University, Montréal, Québec, H4H 1R3, Canada

    Derek Lupinsky & Alain Gratton

  2. Douglas Institute Research Center, 6875 LaSalle Blvd, Montréal, Québec, H4H 1R3, Canada

    Derek Lupinsky, Luc Moquin & Alain Gratton

Authors
  1. Derek Lupinsky
    View author publications

    You can also search for this author inPubMed Google Scholar

  2. Luc Moquin
    View author publications

    You can also search for this author inPubMed Google Scholar

  3. Alain Gratton
    View author publications

    You can also search for this author inPubMed Google Scholar

Corresponding author

Correspondence to Derek Lupinsky.

Ethics declarations

All procedures were approved by the McGill University Animal Care Committee in accordance with the guidelines of the Canadian Council on Animal Care.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Lupinsky, D., Moquin, L. & Gratton, A. Interhemispheric regulation of the rat medial prefrontal cortical glutamate stress response: role of local GABA- and dopamine-sensitive mechanisms. Psychopharmacology 234, 353–363 (2017). https://doi.org/10.1007/s00213-016-4468-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00213-016-4468-6

Keywords

Profiles

  1. Derek Lupinsky View author profile