Beschreibung:
<jats:title>Abstract</jats:title><jats:p>Both the opioid antagonist naltrexone and corticotropin‐releasing factor type‐1 receptor (<jats:styled-content style="fixed-case">CRF</jats:styled-content>‐<jats:styled-content style="fixed-case">R</jats:styled-content>1) antagonists have been investigated for the treatment of alcoholism. The current study examines the combination of naltrexone and <jats:styled-content style="fixed-case">CP</jats:styled-content>154526 to reduce intermittent access ethanol drinking [intermittent access to alcohol (<jats:styled-content style="fixed-case">IAA</jats:styled-content>)] in <jats:styled-content style="fixed-case">C</jats:styled-content>57<jats:styled-content style="fixed-case">BL</jats:styled-content>/6<jats:styled-content style="fixed-case">J</jats:styled-content> male mice, and if these compounds reduce drinking via serotonergic mechanisms in the dorsal raphe nucleus (<jats:styled-content style="fixed-case">DRN</jats:styled-content>). Systemic injections and chronic intracerebroventricular infusions of naltrexone, <jats:styled-content style="fixed-case">CP</jats:styled-content>154526 or <jats:styled-content style="fixed-case">CP</jats:styled-content>376395 transiently decreased <jats:styled-content style="fixed-case">IAA</jats:styled-content> drinking. Immunohistochemistry revealed <jats:styled-content style="fixed-case">CRF</jats:styled-content>‐<jats:styled-content style="fixed-case">R</jats:styled-content>1 or μ‐opioid receptor immunoreactivity was co‐localized in tryptophan hydroxylase (<jats:styled-content style="fixed-case">TPH</jats:styled-content>)‐immunoreactive neurons as well as non‐<jats:styled-content style="fixed-case">TPH</jats:styled-content> neurons in the <jats:styled-content style="fixed-case">DRN</jats:styled-content>. Mice with a history of <jats:styled-content style="fixed-case">IAA</jats:styled-content> or continuous access to alcohol were microinjected with artificial cerebral spinal fluid, naltrexone, <jats:styled-content style="fixed-case">CP</jats:styled-content>154526 or the combination into the <jats:styled-content style="fixed-case">DRN</jats:styled-content> or the median raphe nucleus (<jats:styled-content style="fixed-case">MRN</jats:styled-content>). Either intra‐<jats:styled-content style="fixed-case">DRN</jats:styled-content> naltrexone or <jats:styled-content style="fixed-case">CP</jats:styled-content>154526 reduced <jats:styled-content style="fixed-case">IAA</jats:styled-content> in the initial 2 hours of fluid access, but the combination did not additively suppress <jats:styled-content style="fixed-case">IAA</jats:styled-content>, suggesting a common mechanism via which these two compounds affect intermittent drinking. These alcohol‐reducing effects were localized to the <jats:styled-content style="fixed-case">DRN</jats:styled-content> of <jats:styled-content style="fixed-case">IAA</jats:styled-content> drinkers, as intra‐<jats:styled-content style="fixed-case">MRN</jats:styled-content> injections only significantly suppressed water drinking, and continuous access drinkers were not affected by <jats:styled-content style="fixed-case">CRF</jats:styled-content>‐<jats:styled-content style="fixed-case">R</jats:styled-content>1 antagonism. Extracellular serotonin was measured in the medial prefrontal cortex (<jats:styled-content style="fixed-case">mPFC</jats:styled-content>) using <jats:italic>in vivo</jats:italic> microdialysis after intra‐<jats:styled-content style="fixed-case">DRN</jats:styled-content> microinjections in another group of mice. Intra‐<jats:styled-content style="fixed-case">DRN CP</jats:styled-content>154526 increased serotonin impulse flow to the <jats:styled-content style="fixed-case">mPFC</jats:styled-content> while naltrexone did not. This suggests the <jats:styled-content style="fixed-case">mPFC</jats:styled-content> may not be an essential location to intermittent drinking, as evidenced by different effects on serotonin signaling to the forebrain yet similar behavioral findings.</jats:p>