Regulation of the ventral tegmental area by the bed nucleus of the stria terminalis is required for expression of cocaine preference

<jats:title>Abstract</jats:title><jats:p>Lateral hypothalamus (<jats:styled-content style="fixed-case">LH</jats:styled-content>) orexin neurons are essential for the expression of a cocaine place preference. However, the afferents that regulate the activity of these orexin neurons during reward behaviors are not completely understood. Using tract tracing combined with Fos staining, we examined <jats:styled-content style="fixed-case">LH</jats:styled-content> afferents for <jats:styled-content style="fixed-case">F</jats:styled-content>os induction during cocaine preference in rats. We found that the ventral bed nucleus of the stria terminalis (v<jats:styled-content style="fixed-case">BNST</jats:styled-content>) was a major input to the <jats:styled-content style="fixed-case">LH</jats:styled-content> orexin cell field that was significantly <jats:styled-content style="fixed-case">F</jats:styled-content>os‐activated during cocaine conditioned place preference (<jats:styled-content style="fixed-case">CPP</jats:styled-content>). Inactivation of the v<jats:styled-content style="fixed-case">BNST</jats:styled-content> with baclofen plus muscimol blocked expression of cocaine <jats:styled-content style="fixed-case">CPP</jats:styled-content>. Surprisingly, such inactivation of the v<jats:styled-content style="fixed-case">BNST</jats:styled-content> also increased <jats:styled-content style="fixed-case">F</jats:styled-content>os induction in <jats:styled-content style="fixed-case">LH</jats:styled-content> orexin neurons; as activity in these cells is normally associated with increased preference, this result indicates that a v<jats:styled-content style="fixed-case">BNST</jats:styled-content>–orexin connection is unlikely to be responsible for <jats:styled-content style="fixed-case">CPP</jats:styled-content> that is dependent on v<jats:styled-content style="fixed-case">BNST</jats:styled-content> activity. Because previous studies have revealed that v<jats:styled-content style="fixed-case">BNST</jats:styled-content> regulates dopamine cells in the ventral tegmental area (<jats:styled-content style="fixed-case">VTA</jats:styled-content>), which is known to be involved in <jats:styled-content style="fixed-case">CPP</jats:styled-content> and other reward functions, we tested whether v<jats:styled-content style="fixed-case">BNST</jats:styled-content> afferents to the <jats:styled-content style="fixed-case">VTA</jats:styled-content> are necessary for cocaine <jats:styled-content style="fixed-case">CPP</jats:styled-content>. We found that disconnection of the v<jats:styled-content style="fixed-case">BNST</jats:styled-content> and <jats:styled-content style="fixed-case">VTA</jats:styled-content> (using local microinjections of baclofen plus muscimol unilaterally into the v<jats:styled-content style="fixed-case">BNST</jats:styled-content> and contralateral <jats:styled-content style="fixed-case">VTA</jats:styled-content>) significantly attenuated expression of cocaine preference. However, blocking ionotropic glutamatergic afferents to the <jats:styled-content style="fixed-case">VTA</jats:styled-content> from the v<jats:styled-content style="fixed-case">BNST</jats:styled-content> did not significantly reduce cocaine preference. These results indicate that a non‐glutamatergic v<jats:styled-content style="fixed-case">BNST</jats:styled-content>–<jats:styled-content style="fixed-case">VTA</jats:styled-content> projection is involved in expression of cocaine preference.</jats:p>