{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T00:06:58Z","timestamp":1792109218163,"version":"4.4.0"},"reference-count":50,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2024,5,14]],"date-time":"2024-05-14T00:00:00Z","timestamp":1715644800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Behav. Neurosci."],"abstract":"<jats:sec><jats:title>Background<\/jats:title><jats:p>Drug seeking behavior occurs in response to environmental contexts and drug-associated cues. The presence of these pervasive stimuli impedes abstinence success. \u03b2-adrenergic receptors (\u03b2-ARs) have a long-standing historical implication in driving processes associated with contextual memories, including drug-associated memories in substance use disorders. However, sex differences in the role of \u03b2-adrenergic receptors in drug memories remain unknown.<\/jats:p><\/jats:sec><jats:sec><jats:title>Hypothesis<\/jats:title><jats:p>Prior reports indicate a selective role for \u03b22-ARs in retrieval and retention of contextual drug memories in males, and substantial sex differences exist in the expression of \u03b2-ARs of male and female rats. Therefore, we hypothesized that there are sex differences in selective recruitment of \u03b2-ARs during different stages of memory encoding and retrieval.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>The role of \u03b2-ARs in driving retrieval and learning of contextual cocaine memories was investigated using cocaine conditioned place preference (CPP) in adult male and female Sprague\u2013Dawley rats. Rats were infused directly to the dorsal hippocampus with Propranolol (\u03b21 and \u03b22) or ICI-118,551 (\u03b21) and\/or Betaxolol (\u03b22), immediately prior to testing (retrieval), or paired to each cocaine (10\u2009mg\/kp, IP) conditioning session (learning).<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>In males, administration of either \u03b21, \u03b22, or combined \u03b21 and \u03b22-ARs before the initial CPP testing reduced the expression of a CPP compared to vehicle administration. In females, \u03b22-ARs transiently decreased CPP memories, whereas \u03b21 had long lasting but not immediate effects to decrease CPP memories. Additionally, \u03b21 and combined \u03b21 and \u03b22-ARs had immediate and persistent effects to decrease CPP memory expression. DG Fos\u2009+\u2009neurons predicted cocaine CPP expression in males, whereas CA1 and CA3 Fos\u2009+\u2009neurons predicted cocaine CPP expression in females.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>There are significant sex differences in the role of dorsal hippocampus \u03b2-ARs in the encoding and expression of cocaine conditioned place preference. Furthermore, sub regions of the dorsal hippocampus appear to activate differently between male and female rats during CPP. Therefore DG, CA3, and CA1 may have separate region- and sex-specific impacts on driving drug- associated, or context-associated cues.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fnbeh.2024.1379866","type":"journal-article","created":{"date-parts":[[2024,5,14]],"date-time":"2024-05-14T04:31:49Z","timestamp":1715661109000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":5,"title":["Sex differences in hippocampal \u03b2-adrenergic receptor subtypes drive retrieval, retention, and learning of cocaine-associated memories"],"prefix":"10.3389","volume":"18","author":[{"given":"Melanie M.","family":"Berry","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Beau","family":"Miller","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Silvia","family":"Kelsen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carlee","family":"Cockrell","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amy Stave","family":"Kohtz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2024,5,14]]},"reference":[{"key":"ref9001","doi-asserted-by":"publisher","first-page":"180","DOI":"10.1038\/s41386-021-01131-1","article-title":"Prefrontal-hippocampal interactions supporting the extinction of emotional memories: the retrieval stopping model","volume":"47","author":"Anderson","year":"2021","journal-title":"Neuropsychopharmacol."},{"key":"ref1","doi-asserted-by":"publisher","first-page":"73","DOI":"10.1007\/7854_2010_93","article-title":"Females are more vulnerable to drug abuse than males: evidence from preclinical studies and the role of ovarian hormones","volume":"8","author":"Anker","year":"2011","journal-title":"Curr. Top. Behav. Neurosci."},{"key":"ref9002","doi-asserted-by":"publisher","first-page":"166","DOI":"10.1038\/mp.2012.24","article-title":"Increased vulnerability of the brain norepinephrine system of females to corticotropin-releasing factor overexpression","volume":"18","author":"Bangasser","year":"2012","journal-title":"Mol. Psychiatry."},{"key":"ref2","doi-asserted-by":"publisher","first-page":"36","DOI":"10.1016\/j.yfrne.2007.07.003","article-title":"Sex differences in drug abuse","volume":"29","author":"Becker","year":"2008","journal-title":"Front. Neuroendocrinol."},{"key":"ref3","doi-asserted-by":"publisher","first-page":"242","DOI":"10.1124\/pr.115.011163","article-title":"Sex differences in animal models: focus on addiction","volume":"68","author":"Becker","year":"2016","journal-title":"Pharmacol. Rev."},{"key":"ref9003","doi-asserted-by":"publisher","first-page":"12","DOI":"10.1016\/j.euroneuro.2019.12.112","article-title":"Sex differences in the vulnerability to cocaine\u2019s addictive effects after early-life stress in mice","volume":"32","author":"Castro-Zavala","year":"2020","journal-title":"Eur. Neuropsychopharmacol."},{"key":"ref4","doi-asserted-by":"publisher","first-page":"845","DOI":"10.3389\/fphar.2021.686845","article-title":"Blockade of \u03b2-Adrenergic Receptors by Propranolol Disrupts Reconsolidation of Drug Memory and Attenuates Heroin Seeking","volume":"12","author":"Chen","year":"2021","journal-title":"Front. Pharmacol."},{"key":"ref9004","first-page":"74","article-title":"Conditioned craving and arousal in cocaine addiction: a preliminary report","volume":"81","author":"Childress","year":"1988","journal-title":"PubMed"},{"key":"ref5","doi-asserted-by":"publisher","first-page":"112771","DOI":"10.1016\/j.bbr.2020.112771","article-title":"Contextual processing elicits sex differences in dorsal hippocampus activation following footshock and context fear retrieval","volume":"393","author":"Colon","year":"2020","journal-title":"Behav. Brain Res."},{"key":"ref6","doi-asserted-by":"publisher","first-page":"3233","DOI":"10.1098\/rstb.2008.0090","article-title":"Context-induced relapse to drug seeking: a review","volume":"363","author":"Crombag","year":"2008","journal-title":"Philos. Trans. R. Soc. B Biol. Sci."},{"key":"ref7","doi-asserted-by":"publisher","first-page":"51","DOI":"10.2217\/17455057.4.1.51","article-title":"Sex Differences in Drug Addiction: A Review of Animal and Human Studies","volume":"4","author":"Fattore","year":"2008","journal-title":"Womens Health"},{"key":"ref9005","doi-asserted-by":"publisher","first-page":"107089","DOI":"10.1016\/j.nlm.2019.107089","article-title":"The dorsal hippocampus mediates synaptic destabilization and memory lability in the amygdala in the absence of contextual novelty","volume":"166","author":"Ferrara","year":"2019","journal-title":"Neurobiol. Learn. Mem."},{"key":"ref8","doi-asserted-by":"publisher","first-page":"94","DOI":"10.1016\/j.bbr.2015.08.030","article-title":"Dissociation of \u03b21- and \u03b22-adrenergic receptor subtypes in the retrieval of cocaine-associated memory","volume":"296","author":"Fitzgerald","year":"2016","journal-title":"Behav. Brain Res."},{"key":"ref9","doi-asserted-by":"publisher","first-page":"296","DOI":"10.1038\/sj.npp.1300579","article-title":"The Role of the Dorsomedial Prefrontal Cortex, Basolateral Amygdala, and Dorsal Hippocampus in Contextual Reinstatement of Cocaine Seeking in Rats. Neuropsychopharmacology","volume":"30","author":"Fuchs","year":"2005","journal-title":"Neuropsychopharmacology"},{"key":"ref10","doi-asserted-by":"publisher","first-page":"689","DOI":"10.1016\/S0306-4522(97)00233-9","article-title":"Sex differences in dendritic atrophy of CA3 pyramidal neurons in response to chronic restraint stress","volume":"81","author":"Galea","year":"1997","journal-title":"Neuroscience"},{"key":"ref9006","doi-asserted-by":"publisher","first-page":"617","DOI":"10.1093\/bja\/ael238","article-title":"\u03b2 2 Adrenergic antagonist inhibits cerebral cortical oxygen delivery after severe haemodilution in rats","volume":"97","author":"Hare","year":"2006","journal-title":"Br. J. Anaesth."},{"key":"ref11","doi-asserted-by":"publisher","first-page":"14","DOI":"10.1007\/s002130100693","article-title":"Preference for a cocaine-associated environment is attenuated by augmented accumbal serotonin in cocaine withdrawn rats","volume":"156","author":"Harris","year":"2001","journal-title":"Psychopharmacology"},{"key":"ref12","doi-asserted-by":"publisher","first-page":"303","DOI":"10.1038\/npp.1993.66","article-title":"Beta-Adrenergic Antagonists Attenuate Somatic and Aversive Signs of Opiate Withdrawal","volume":"9","author":"Harris","year":"","journal-title":"Neuropsychopharmacology"},{"key":"ref13","doi-asserted-by":"publisher","first-page":"131","DOI":"10.1007\/bf02244345","article-title":"\u03b2-adrenergic antagonists attenuate withdrawal anxiety in cocaine-and morphine-dependent rats","volume":"113","author":"Harris","year":"","journal-title":"Psychopharmacology"},{"key":"ref14","doi-asserted-by":"publisher","first-page":"75","DOI":"10.1016\/S0893-133X(00)00184-6","article-title":"Augmented Accumbal Serotonin Levels Decrease the Preference for a Morphine Associated Environment During Withdrawal","volume":"24","author":"Harris","year":"2001","journal-title":"Neuropsychopharmacology"},{"key":"ref9007","doi-asserted-by":"publisher","first-page":"e57010","DOI":"10.7554\/eLife.57010","article-title":"Noradrenergic projections from the locus coeruleus to the amygdala constrain fear memory reconsolidation","volume":"9","author":"Haubrich","year":"2020","journal-title":"ELife"},{"key":"ref15","doi-asserted-by":"publisher","first-page":"226","DOI":"10.1002\/hipo.22826","article-title":"Involvement of the dorsal hippocampus in expression and extinction of cocaine-induced conditioned place preference","volume":"28","author":"Hitchcock","year":"2018","journal-title":"Hippocampus"},{"key":"ref16","doi-asserted-by":"publisher","first-page":"109","DOI":"10.1126\/sciadv.aax1532","article-title":"New medications for the treatment of cocaine dependence","volume":"45","author":"Kampman","year":"2009","journal-title":"Ann. Ist. Super. Sanita"},{"key":"ref17","doi-asserted-by":"publisher","first-page":"397","DOI":"10.1038\/npp.2016.174","article-title":"Sex Differences in Context Fear Generalization and Recruitment of Hippocampus and Amygdala during Retrieval","volume":"42","author":"Keiser","year":"2017","journal-title":"Neuropsychopharmacology"},{"key":"ref18","doi-asserted-by":"publisher","first-page":"29","DOI":"10.1016\/j.drugalcdep.2012.12.025","article-title":"Sex differences in cocaine\/heroin users: Drug-use triggers and craving in daily life","volume":"132","author":"Kennedy","year":"2013","journal-title":"Drug Alcohol Depend."},{"key":"ref19","doi-asserted-by":"publisher","first-page":"408","DOI":"10.1038\/npp.2016.150","article-title":"Cocaine Seeking During Initial Abstinence Is Driven by Noradrenergic and Serotonergic Signaling in Hippocampus in a Sex-Dependent Manner","volume":"42","author":"Kohtz","year":"2017","journal-title":"Neuropsychopharmacology"},{"key":"ref20","doi-asserted-by":"publisher","first-page":"1485","DOI":"10.3390\/brainsci12111485","article-title":"Paired housing or a socially-paired context decreases ethanol conditioned place preference in male rats","volume":"12","author":"Lorenz","year":"2022","journal-title":"Brain Sci."},{"key":"ref21","doi-asserted-by":"publisher","first-page":"121","DOI":"10.1007\/s00213-002-1183-2","article-title":"Biological basis of sex differences in drug abuse: preclinical and clinical studies","volume":"164","author":"Lynch","year":"2002","journal-title":"Psychopharmacology"},{"key":"ref22","doi-asserted-by":"publisher","first-page":"2431","DOI":"10.1523\/JNEUROSCI.1598-03.2004","article-title":"The Role of the Dorsal Hippocampus in the Acquisition and Retrieval of Context Memory Representations","volume":"24","author":"Matus-Amat","year":"2004","journal-title":"J. Neurosci."},{"key":"ref23","doi-asserted-by":"publisher","first-page":"401","DOI":"10.1037\/0735-7044.120.2.401","article-title":"Dorsal hippocampus inhibition disrupts acquisition and expression, but not consolidation, of cocaine conditioned place preference","volume":"120","author":"Meyers","year":"2006","journal-title":"Behav. Neurosci."},{"key":"ref24","doi-asserted-by":"publisher","first-page":"303","DOI":"10.1038\/npp.2013.187","article-title":"Inhibition of Hippocampal \u03b2-Adrenergic Receptors Impairs Retrieval But Not Reconsolidation of Cocaine-Associated Memory and Prevents Subsequent Reinstatement","volume":"39","author":"Otis","year":"2013","journal-title":"Neuropsychopharmacology"},{"key":"ref25","doi-asserted-by":"publisher","first-page":"119","DOI":"10.3389\/fnbeh.2018.00119","article-title":"Prefrontal Neuronal Excitability Maintains Cocaine-Associated Memory During Retrieval","volume":"12","author":"Otis","year":"2018","journal-title":"Front. Behav. Neurosci."},{"key":"ref26","doi-asserted-by":"publisher","first-page":"1912","DOI":"10.1038\/npp.2011.77","article-title":"Inhibition of \u03b2-Adrenergic Receptors Induces a Persistent Deficit in Retrieval of a Cocaine-Associated Memory Providing Protection against Reinstatement","volume":"36","author":"Otis","year":"2011","journal-title":"Neuropsychopharmacology"},{"key":"ref27","doi-asserted-by":"publisher","first-page":"103","DOI":"10.1038\/nature21376","article-title":"Prefrontal cortex output circuits guide reward seeking through divergent cue encoding","volume":"543","author":"Otis","year":"2017","journal-title":"Nature"},{"key":"ref9008","volume-title":"Paxinos and Watson\u2019s the rat brain in stereotaxic coordinates","author":"Paxinos","year":"2014"},{"key":"ref28","doi-asserted-by":"publisher","first-page":"231","DOI":"10.1016\/0006-8993(85)90857-1","article-title":"Quantitative autoradiographic mapping of serotonin receptors in the rat brain. II. Serotonin-2 receptors","volume":"346","author":"Pazos","year":"1985","journal-title":"Brain Res."},{"key":"ref29","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.neulet.2014.02.063","article-title":"Differential effects of dorsal hippocampal inactivation on expression of recent and remote drug and fear memory","volume":"569","author":"Raybuck","year":"2014","journal-title":"Neurosci. Lett."},{"key":"ref30","doi-asserted-by":"publisher","first-page":"380","DOI":"10.1016\/j.biopsych.2011.10.028","article-title":"Neural Signature of Reconsolidation Impairments by Propranolol in Humans","volume":"71","author":"Schwabe","year":"2012","journal-title":"Biol. Psychiatry"},{"key":"ref31","doi-asserted-by":"publisher","first-page":"43","DOI":"10.1007\/s00429-008-0191-3","article-title":"Noradrenergic transmission in the extended amygdala: role in increased drug-seeking and relapse during protracted drug abstinence","volume":"213","author":"Smith","year":"2008","journal-title":"Brain Struct. Funct."},{"key":"ref32","doi-asserted-by":"publisher","first-page":"239","DOI":"10.1016\/S0376-8716(99)00055-1","article-title":"Predictors of cardiovascular response to smoked cocaine in humans","volume":"57","author":"Sofuoglu","year":"2000","journal-title":"Drug Alcohol Depend."},{"key":"ref9009","volume-title":"Effects of single compared with pair housing on hypothalamic-pituitary-adrenal axis activity and low-dose heroin place conditioning in adult male Sprague-Dawley rats","author":"Turner","year":"2014"},{"key":"ref8003","doi-asserted-by":"publisher","first-page":"711","DOI":"10.1242\/jeb.205.6.711","article-title":"Oocyte apoptosis during the transition from ovary-like tissue to testes during sex differentiation of juvenile zebrafish","volume":"205","author":"Uchida","year":"2002","journal-title":"J. Exp. Biol"},{"key":"ref8002","doi-asserted-by":"publisher","first-page":"1520","DOI":"10.1038\/s41593-018-0246-6","article-title":"Volitional social interaction prevents drug addiction in rat models","volume":"21","author":"Venniro","year":"2018","journal-title":"Nat. Neurosci"},{"key":"ref8001","doi-asserted-by":"publisher","first-page":"798","DOI":"10.1016\/j.psyneuen.2009.11.005","article-title":"Community-dwelling cocaine-dependent men and women respond differently to social stressors versus cocaine cues","volume":"35","author":"Waldrop","year":"2010","journal-title":"Psychoneuroendocrinology"},{"key":"ref9010","doi-asserted-by":"publisher","first-page":"1336","DOI":"10.1016\/j.cub.2010.06.068","article-title":"The hippocampus plays a selective role in the retrieval of detailed contextual memories","volume":"20","author":"Wiltgen","year":"2010","journal-title":"Curr. Biol."},{"key":"ref9011","doi-asserted-by":"publisher","first-page":"4035","DOI":"10.1523\/jneurosci.10-12-04035.1990","article-title":"Naturally occurring fluctuation in dendritic spine density on adult hippocampal pyramidal neurons","volume":"10","author":"Woolley","year":"1990","journal-title":"J. Neurosci."},{"key":"ref33","doi-asserted-by":"publisher","first-page":"200","DOI":"10.1038\/s41386-018-0208-4","article-title":"Sex differences in hippocampal cognition and neurogenesis","volume":"44","author":"Yagi","year":"2018","journal-title":"Neuropsychopharmacology"},{"key":"ref34","doi-asserted-by":"publisher","first-page":"119","DOI":"10.1016\/j.lfs.2003.12.004","article-title":"Sexual dimorphism in the induction of LTP: Critical role of tetanizing stimulation","volume":"75","author":"Yang","year":"2004","journal-title":"Life Sci."},{"key":"ref35","doi-asserted-by":"publisher","first-page":"890","DOI":"10.1016\/j.neuroscience.2009.06.068","article-title":"Social and physical environment alter cocaine conditioned place preference and dopaminergic markers in adolescent male rats","volume":"163","author":"Zakharova","year":"2009","journal-title":"Neuroscience"},{"key":"ref36","doi-asserted-by":"publisher","first-page":"1831","DOI":"10.1007\/s00429-013-0605-8","article-title":"Fos expression induced by cocaine-conditioned cues in male and female rats","volume":"219","author":"Zhou","year":"2013","journal-title":"Brain Struct. 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