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

Abstract

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.

Targeting Endocannabinoid Signaling in the Lateral Habenula as an Intervention to Prevent Mental Illnesses Following Early Life Stress: A Perspective

“…Interestingly, a recent study demonstrated that most cannabinoids suppress the reinforcing effects of optogenetic VTA DA neuron self-stimulation in mice, suggesting that cannabinoid receptor activation, in general, attenuates VTA DA reward or could exert aversive effects. This study also shows that VTA GABA and glutamate neurons express CB1Rs while VTA DA neurons express CB2Rs (Humburg et al, 2021). Given that VTA GABA neurons also provide inhibitory GABAergic input to LHb, it is possible that ELS-induced decreases in MAGL expression and persistent increases in eCB 2AG-CB1R-mediated suppression of VTA GABAergic input to the LHb promotes ELS-associated LHb hyperactivity.…”

β-caryophyllene, an FDA-Approved Food Additive, Inhibits Methamphetamine-Taking and Methamphetamine-Seeking Behaviors Possibly via CB2 and Non-CB2 Receptor Mechanisms

“…However, this view is not supported by our findings that neither CB2-immunostaining nor CB2 mRNA was detected in microglia in either normal healthy subjects ( Zhang et al, 2014 , 2017 , 2019 ) or in mice after acute administration of lipopolysaccharide, an endotoxin that causes severe neuroinflammation and microglia activation ( Zhang et al, 2014 ) or chronic administration of cocaine ( Zhang et al, 2017 ; 2021a ). In contrast, we demonstrated clear CB2 receptor expression in multiple phenotypes of neurons, including VTA DA neurons ( Zhang et al, 2014 , 2017 , 2019 ; Humburg et al, 2021 ), red nucleus glutamate neurons ( Zhang et al, 2021b ), and striatal GABA neurons ( Zhang et al, 2021a ; see a comprehensive review by; Jordan and Xi, 2019 ). Furthermore, chronic cocaine administration significantly up-regulates CB2 receptor expression in VTA DA neurons and NAc D1 receptor-expressing medium-spiny neurons, not in microglia ( Zhang et al, 2014 ; 2021a ).…”

Hippocampal Cannabinoid 1 Receptors Are Modulated Following Cocaine Self-administration in Male Rats

“…Altogether, findings suggest a reciprocal interaction within the endocannabinoid system for modulating the reinforcing and psychomotor effects of cocaine. As discussed previously, this may occur through specificity of neurons expressing CB1Rs and CB2Rs, as recently described in the VTA [28,91,92]. Also, both CBRs are expressed on microglia and modulate neuroinflammatory processes, which may contribute to the pathophysiology of cocaine addiction (reviewed in [93]).…”