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      Optogenetic brain‐stimulation reward: A new procedure to re‐evaluate the rewarding versus aversive effects of cannabinoids in dopamine transporter‐Cre mice

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          Abstract

          <p class="first" id="d1634864e144">Despite extensive research, the rewarding effects of cannabinoids are still debated. Here, we used a newly established animal procedure called optogenetic intracranial self-stimulation (ICSS) (oICSS) to re-examine the abuse potential of cannabinoids in mice. A specific adeno-associated viral vector carrying a channelrhodopsin gene was microinjected into the ventral tegmental area (VTA) to express light-sensitive channelrhodopsin in dopamine (DA) neurons of transgenic dopamine transporter (DAT)-Cre mice. Optogenetic stimulation of VTA DA neurons was highly reinforcing and produced a classical "sigmoidal"-shaped stimulation-response curve dependent upon the laser pulse frequency. Systemic administration of cocaine dose-dependently enhanced oICSS and shifted stimulation-response curves upward, in a way similar to previously observed effects of cocaine on electrical ICSS. In contrast, Δ9 -tetrahydrocannabinol (Δ9 -THC), but not cannabidiol, dose-dependently decreased oICSS responding and shifted oICSS curves downward. WIN55,212-2 and ACEA, two synthetic cannabinoids often used in laboratory settings, also produced dose-dependent reductions in oICSS. We then examined several new synthetic cannabinoids, which are used recreationally. XLR-11 produced a cocaine-like increase, AM-2201 produced a Δ9 -THC-like reduction, while 5F-AMB had no effect on oICSS responding. Immunohistochemistry and RNAscope in situ hybridization assays indicated that CB1 Rs are expressed mainly in VTA GABA and glutamate neurons, while CB2 Rs are expressed mainly in VTA DA neurons. Together, these findings suggest that most cannabinoids are not reward enhancing, but rather reward attenuating or aversive in mice. Activation of CB1 R and/or CB2 R in different populations of neurons in the brain may underlie the observed actions. </p>

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          Author and article information

          Contributors
          (View ORCID Profile)
          (View ORCID Profile)
          Journal
          Addiction Biology
          Addiction Biology
          Wiley
          1355-6215
          1369-1600
          February 03 2021
          Affiliations
          [1 ]Addiction Biology Unit, Molecular Targets and Medications Discovery, Intramural Research Program National Institute on Drug Abuse Baltimore Maryland USA
          [2 ]Synaptic Plasticity Section, Intramural Research Program National Institute on Drug Abuse Baltimore Maryland USA
          [3 ]Designer Drug Research Unit, Intramural Research Program National Institute on Drug Abuse Baltimore Maryland USA
          Article
          10.1111/adb.13005
          9308103
          33538103
          2b0252e7-9adb-4f34-992b-6ff16ff2f092
          © 2021

          http://onlinelibrary.wiley.com/termsAndConditions#vor

          http://doi.wiley.com/10.1002/tdm_license_1.1

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