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The Journal of Neuroscience, January 9, 2008, 28(2):529-542; doi:10.1523/JNEUROSCI.2666-07.2008

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Behavioral/Systems/Cognitive
Dopamine and Corticotropin-Releasing Factor Synergistically Alter Basolateral Amygdala-to-Medial Prefrontal Cortex Synaptic Transmission: Functional Switch after Chronic Cocaine Administration

Luis Orozco-Cabal, Jie Liu, Sebastian Pollandt, Kady Schmidt, Patricia Shinnick-Gallagher, and Joel P. Gallagher

Department of Pharmacology and Toxicology, The University of Texas Medical Branch, Galveston, Texas 77555-1031

Correspondence should be addressed to Dr. Joel P. Gallagher, Department of Pharmacology and Toxicology, The University of Texas Medical Branch, 301 University Boulevard, Galveston, TX 77555-1031. Email: jpgallag{at}utmb.edu

Basolateral amygdala (BLA) neurons provide a major excitatory input to medial prefrontal cortex (mPFC)–layer V pyramidal neurons. Under stressful conditions, commonly associated with chronic cocaine abuse, altered BLA-to-mPFC synaptic transmission could lead to defective emotional information processing and decision making within the mPFC and result in misguided and inappropriate behaviors. We examined the effects of cocaine administered chronically in vivo on EPSCs recorded from a putative BLA–mPFC pathway in vitro and their modulation by dopamine (DA), corticotropin-releasing factor (CRF), and their combination (DA plus CRF). In saline-treated animals, activation of D_1/5 receptors depressed BLA–mPFC EPSCs, whereas CRF₁ receptor activation alone had no effect on EPSCs. Activating D_1/5 and CRF₁ receptors in combination, however, worked synergistically through presynaptic and postsynaptic mechanisms to depress EPSCs to levels greater than D_1/5 receptor activation alone. After chronic cocaine administration, the function of DA_1/5 and CRF receptors switched from inhibitory to excitatory. In slices from cocaine-treated animals, putative BLA–mPFC EPSCs were depressed through a presynaptic mechanism. Now, activation of either D_1/5 or CRF₂ receptors increased the cocaine-induced, depressed EPSCs. Additionally, simultaneous activation of presynaptic D_1/5 and CRF₂ receptors led to further enhancement of EPSCs. These data indicate that CRF acting synergistically with DA normally potentiates D_1/5-induced synaptic depression. However, after chronic cocaine, the combined synergistic actions of DA and CRF switched polarity to enhance facilitation of BLA–mPFC glutamatergic transmission. Also unmasked after acute withdrawal from chronic cocaine are endogenous, tonic-inhibitory D₂-like and tonic-facilitatory CRF₂ receptor actions. These multiple functional and receptor changes may underlie the altered, possibly aberrant, decision-making process after chronic cocaine.

Key words: addiction; CRF; dopamine; glutamate; SKF81297; NBI30775; Astressin₂B; stress

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Received Jan. 7, 2007; revised Dec. 5, 2007; accepted Dec. 5, 2007.

Correspondence should be addressed to Dr. Joel P. Gallagher, Department of Pharmacology and Toxicology, The University of Texas Medical Branch, 301 University Boulevard, Galveston, TX 77555-1031. Email: jpgallag{at}utmb.edu

This article has been cited by other articles:

				T. L. Kash, W. P. Nobis, R. T. Matthews, and D. G. Winder Dopamine Enhances Fast Excitatory Synaptic Transmission in the Extended Amygdala by a CRF-R1-Dependent Process J. Neurosci., December 17, 2008; 28(51): 13856 - 13865. [Abstract] [Full Text] [PDF]

				J. Stewart Psychological and neural mechanisms of relapse Phil Trans R Soc B, October 12, 2008; 363(1507): 3147 - 3158. [Abstract] [Full Text] [PDF]

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