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Despite widespread cannabis use in humans, few rodent models exist demonstrating significant Δ⁹-tetrahydrocannabinol (THC) self-administration, possibly due to THC's co-occurring aversive effects, which impact drug reinforcement. Cannabis contains a number of phytocannabinoids in addition to THC, one of which, cannabidiol (CBD), has been reported to antagonize some of the aversive effects of THC. Given such effects of CBD, it is possible that it might influence THC intravenous self-administration in rodents. Accordingly, male and female Long-Evans rats were trained to self-administer THC over a 3-week period and then were assessed for the effects of CBD on responding for THC at 1:1 and 1:10 dose ratios or for the establishment of cocaine self-administration (as a positive control for drug self-administration). Consistent with previous research, THC self-administration was modest and only evident in a subset of animals (and unaffected by sex). Cocaine self-administration was high and evident in the majority of animals tested, indicating that the design was sensitive to drug reinforcement. There was no effect of CBD pretreatment on THC intravenous self-administration at any CBD:THC dose ratio. Future developments of animal models of THC self-administration and the examination of factors that affect its display remain important to establish procedures designed to assess the basis for and treatment of cannabis use and abuse. (PsycINFO Database Record

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 CB1Rs are expressed mainly in VTA GABA and glutamate neurons, while CB2Rs 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 CB1R and/or CB2R in different populations of neurons in the brain may underlie the observed actions.

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