title: Cocaine Seeking During Initial Abstinence Is Driven by Noradrenergic and Serotonergic Signaling in Hippocampus in a Sex-Dependent Manner.
abstract: There is evidence for sex differences in cocaine addiction from both clinical and preclinical studies. In particular, preclinical studies indicate that females may be more sensitive than males to stress-induced drug seeking. The dorsal hippocampus (DH) is prominently involved in the stress response, as are the locus coeruleus norepinephrine (LC-NE) and dorsal raphe serotonin (DR 5-HT) systems. Moreover, DH receives strong inputs from LC-NE and DR 5-HT neurons. We hypothesized that the stress associated with non-reinforced drug seeking during early abstinence (on extinction day 1 (ED1)) may contribute to drug seeking via β-adrenergic and 5-HT neurotransmission in DH. We observed decreased drug-seeking behavior on ED1 following 10 mg/kg S-propranolol (β-adrenergic and 5-HT1A/1B receptor antagonist), R-propranolol (5-HT1A/1B receptor antagonist), or racemic propranolol in both male and female rats. ED1 increased Fos expression in DH, LC, and DR, and DH Fos was decreased by systemic S-propranolol. Based on these results, we investigated the effects of blocking 5-HT and β-adrenoceptor transmission in DH on drug seeking during ED1 by infusing a cocktail of WAY100635 plus GR127935 (5-HT1A/1B receptor antagonists), betaxolol plus ICI-118 551 (β1 and β2 antagonists), or S-propranolol alone. In males, WAY100635/GR127935 was most effective in reducing drug-seeking on ED1, whereas betaxolol/ICI-118 551 was ineffective. In contrast, S-propranolol was most effective in females in reducing drug seeking on ED1, and WAY100635/GR127935 and betaxolol/ICI-118 551 were each partially effective. Our results indicate that drug seeking during initial abstinence involves 5-HT and β-adrenergic signaling in female DH, but only 5-HT signaling in male DH.
authors: Brain Health Institute, Rutgers University and Rutgers Biomedical and Health Sciences, Piscataway, NJ, USA.
authors: Amy S
authors: AS
authors: Kohtz
authors: Brain Health Institute, Rutgers University and Rutgers Biomedical and Health Sciences, Piscataway, NJ, USA.
authors: Gary
authors: G
authors: Aston-Jones
mesh_terms: D000319:Adrenergic beta-Antagonists / Q000008:administration & dosage; D000818:Animals; D003042:Cocaine / Q000008:administration & dosage*; D065847:Dorsal Raphe Nucleus / Q000187:drug effects / Q000378:metabolism; D058999:Drug-Seeking Behavior / Q000502:physiology*; D005260:Female; D006624:Hippocampus / Q000187:drug effects / Q000502:physiology*; D008125:Locus Coeruleus / Q000187:drug effects / Q000378:metabolism; D008297:Male; D009638:Norepinephrine / Q000502:physiology*; D011433:Propranolol / Q000008:administration & dosage; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D017207:Rats, Sprague-Dawley; D011943:Receptors, Adrenergic, beta / Q000502:physiology; D044263:Receptors, Serotonin, 5-HT1 / Q000502:physiology; D012646:Self Administration; D012701:Serotonin / Q000502:physiology*; D058829:Serotonin 5-HT1 Receptor Antagonists / Q000008:administration & dosage; D012727:Sex Characteristics; D013315:Stress, Psychological / Q000503:physiopathology*
chemical_list: D000319:Adrenergic beta-Antagonists; D016760:Proto-Oncogene Proteins c-fos; D011943:Receptors, Adrenergic, beta; D044263:Receptors, Serotonin, 5-HT1; D058829:Serotonin 5-HT1 Receptor Antagonists; D012701:Serotonin; D011433:Propranolol; D003042:Cocaine; D009638:Norepinephrine