Chronic lithium treatment rectifies maladaptive dopamine release in the nucleus accumbens

<jats:title>Abstract</jats:title><jats:sec><jats:label/><jats:p>Chronic lithium treatment effectively reduces behavioral phenotypes of mania in humans and rodents. The mechanisms by which lithium exerts these actions are poorly understood. Pre‐clinical and clinical evidence have implicated increased mesolimbic dopamine (<jats:styled-content style="fixed-case">DA</jats:styled-content>) neurotransmission with mania. We used fast‐scan cyclic voltammetry to characterize changes in extracellular <jats:styled-content style="fixed-case">DA</jats:styled-content> concentrations in the nucleus accumbens (<jats:styled-content style="fixed-case">NA</jats:styled-content>c) core evoked by 20 and 60 Hz electrical stimulation of the ventral tegmental area (<jats:styled-content style="fixed-case">VTA</jats:styled-content>) in C57<jats:styled-content style="fixed-case">BL</jats:styled-content>6/J mice treated either acutely or chronically with lithium. The effects of chronic lithium treatment on the availability of <jats:styled-content style="fixed-case">DA</jats:styled-content> for release were assessed by depleting readily releasable <jats:styled-content style="fixed-case">DA</jats:styled-content> using short inter‐train intervals, or administering <jats:italic>d</jats:italic>‐amphetamine acutely to mobilize readily releasable <jats:styled-content style="fixed-case">DA</jats:styled-content>. Chronic, but not acute, lithium treatment decreased the amplitude of <jats:styled-content style="fixed-case">DA</jats:styled-content> responses in the <jats:styled-content style="fixed-case">NA</jats:styled-content>c following 60 Hz pulse train stimulation. Neither lithium treatment altered the kinetics of <jats:styled-content style="fixed-case">DA</jats:styled-content> release or reuptake. Chronic treatment did not impact the progressive reduction in the amplitude of <jats:styled-content style="fixed-case">DA</jats:styled-content> responses when, using 20 or 60 Hz pulse trains, the <jats:styled-content style="fixed-case">VTA</jats:styled-content> was stimulated every 6 s to deplete <jats:styled-content style="fixed-case">DA</jats:styled-content>. Specifically, the amplitude of <jats:styled-content style="fixed-case">DA</jats:styled-content> responses to 60 Hz pulse trains was initially reduced compared to control mice, but by the fifth pulse train, there was no longer a treatment effect. However, chronic lithium treatment attenuated <jats:italic>d</jats:italic>‐amphetamine‐induced increases in <jats:styled-content style="fixed-case">DA</jats:styled-content> responses to 20 Hz pulse trains stimulation. Our data suggest that long‐term administration of lithium may ameliorate mania phenotypes by normalizing the readily releasable <jats:styled-content style="fixed-case">DA</jats:styled-content> pool in <jats:styled-content style="fixed-case">VTA</jats:styled-content> axon terminals in the <jats:styled-content style="fixed-case">NA</jats:styled-content>c.</jats:p></jats:sec><jats:sec><jats:label/><jats:p> <jats:boxed-text content-type="graphic" position="anchor"><jats:graphic xmlns:xlink="http://www.w3.org/1999/xlink" mimetype="image/png" position="anchor" specific-use="enlarged-web-image" xlink:href="graphic/jnc13769-fig-0005-m.png"><jats:alt-text>image</jats:alt-text></jats:graphic></jats:boxed-text> </jats:p><jats:p><jats:bold>Read the Editorial Highlight</jats:bold> for this article on <jats:ext-link xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="http://dx.doi.org/10.1111/jnc.13846">Page 520</jats:ext-link>.</jats:p></jats:sec>