Angiotensin II and CRF receptors in the central nucleus of the amygdala mediate hemodynamic response variability to cocaine in conscious rats.
Stress or cocaine evokes either a large increase in systemic vascular resistance (SVR) or a smaller increase in SVR accompanied by an increase in cardiac output (designated vascular and mixed responders, respectively) in Sprague-Dawley rats. We hypothesized that the central nucleus of the amygdala (CeA) mediates this variability. Conscious, freely-moving rats, instrumented for measurement of arterial pressure and cardiac output and for drug delivery into the CeA, were given cocaine (5 mg/kg, iv, 4-6 times) and characterized as vascular (n=15) or mixed responders (n=10). Subsequently, we administered cocaine after bilateral microinjections (100 nl) of saline or selective agents in the CeA. Muscimol (80 pmol), a GABA(A) agonist, or losartan (43.4 pmol), an AT(1) receptor antagonist, attenuated the cocaine-induced increase in SVR in vascular responders, selectively, such that vascular responders were no longer different from mixed responders. The corticotropin releasing factor (CRF) antagonist, alpha-helical CRF(9-41) (15.7 pmol), abolished the difference between cardiac output and SVR in mixed and vascular responders. We conclude that greater increases in SVR observed in vascular responders are dependent on AT(1) receptor activation and, to a lesser extent on CRF receptors. Therefore, AT(1) and CRF receptors in the CeA contribute to hemodynamic response variability to intravenous cocaine.
Watanabe
Mari A
MA
Department of Pharmacological and Physiological Science, St. Louis University School of Medicine, 1402 S. Grand Blvd., St. Louis, MO 63104, USA.
Kucenas
Sarah
S
Bowman
Tamara A
TA
Ruhlman
Melissa
M
Knuepfer
Mark M
MM
D000679:Amygdala / Q000187:drug effects / Q000378:metabolism*; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology; D000818:Animals; D003042:Cocaine / Q000494:pharmacology*; D019970:Cocaine-Related Disorders / Q000378:metabolism* / Q000503:physiopathology; D003243:Consciousness / Q000502:physiology; D003346:Corticotropin-Releasing Hormone / Q000494:pharmacology; D004195:Disease Models, Animal; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology; D018755:GABA Agonists / Q000494:pharmacology; D006439:Hemodynamics / Q000187:drug effects* / Q000502:physiology; D006727:Hormone Antagonists / Q000494:pharmacology; D019808:Losartan / Q000494:pharmacology; D008297:Male; D009118:Muscimol / Q000494:pharmacology; D010446:Peptide Fragments / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D044140:Receptor, Angiotensin, Type 1 / Q000187:drug effects* / Q000378:metabolism; D018019:Receptors, Corticotropin-Releasing Hormone / Q000187:drug effects* / Q000378:metabolism; D014655:Vascular Resistance / Q000187:drug effects / Q000502:physiology; D014661:Vasoconstriction / Q000187:drug effects / Q000502:physiology
D047228:Angiotensin II Type 1 Receptor Blockers; D018765:Dopamine Uptake Inhibitors; D018755:GABA Agonists; D006727:Hormone Antagonists; D010446:Peptide Fragments; D044140:Receptor, Angiotensin, Type 1; D018019:Receptors, Corticotropin-Releasing Hormone; D009118:Muscimol; D003346:Corticotropin-Releasing Hormone; C045089:corticotropin releasing hormone (9-41); D003042:Cocaine; D019808:Losartan