Optogenetic brain‐stimulation reward: A new procedure to re‐evaluate the rewarding versus aversive effects of cannabinoids in dopamine transporter‐Cre mice
Bree A. Humburg, Chloe J. Jordan, Hai‐Ying Zhang, Hui Shen, Xiao Han, Guo-Hua Bi, Briana J. Hempel, Ewa Galaj, Michael H. Baumann, Zheng-Xiong Xi
Addiction Biology February 3, 2021 DOI: 10.1111/adb.13005 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Experimental study Peer reviewed |
|---|---|
| Population | Transgenic dopamine transporter (DAT)-Cre mice |
| Interventions | cannabidiol WIN55 ACEA cocaine |
| Topics | CBD |
| Keywords | Ventral tegmental area Optogenetics Brain stimulation reward Dopamine transporter Pharmacology Channelrhodopsin Δ9-tetrahydrocannabinol Cannabinoid Nucleus accumbens Dopaminergic Receptor |
| Citations | 30 |
| Key findings | Most cannabinoids, including Δ9-THC, WIN55,212-2, and ACEA, dose-dependently decreased optogenetic intracranial self-stimulation responding, indicating reward attenuation or aversion in mice. |
Abstract
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, Δ 9 ‐tetrahydrocannabinol (Δ 9 ‐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 Δ 9 ‐THC‐like reduction, while 5F‐AMB had no effect on oICSS responding. Immunohistochemistry and RNAscope in situ hybridization assays indicated that CB 1 Rs are expressed mainly in VTA GABA and glutamate neurons, while CB 2 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 CB 1 R and/or CB 2 R in different populations of neurons in the brain may underlie the observed actions.
Comparable studies
Other preclinical and animal studies on CBD, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Effects of cannabinoid drugs on the deficit of prepulse inhibition of startle in an animal model of schizophrenia: the SHR strain Spontaneously hypertensive rats (SHRs) and Wistar rats | 2014 | Animal experimental study | |
| Δ-9-Tetrahydrocannabinol and Cannabidiol produce dissociable effects on prefrontal cortical executive function and regulation of affective behaviors Rats | 2018 | Experimental study | |
| Effects of inhaled cannabis high in Δ9-THC or CBD on the aging brain: A translational MRI and behavioral study 19-20 month old mice | 2023 | Randomized controlled trial | |
| Cannabidiol tempers alcohol intake and neuroendocrine and behavioural correlates in alcohol binge drinking adolescent rats. Focus on calcitonin gene‐related peptide's brain levels Adolescent male rats | 2023 | Animal study | |
| Multi-level therapeutic actions of cannabidiol in ketamine-induced schizophrenia psychopathology in male rats. Male rats | 2024 | Experimental study |
Citations in the library
Cited by 2
- PPARα and PPARγ are expressed in midbrain dopamine neurons and modulate dopamine- and cannabinoid-mediated behavior in mice. Molecular Psychiatry October 2023
- Cannabinoid CB1 Receptors Are Expressed in a Subset of Dopamine Neurons and Underlie Cannabinoid-Induced Aversion, Hypoactivity, and Anxiolytic Effects in Mice. Journal of Neuroscience January 18, 2023
Cites 11
- Highway to hell or magic smoke? The dose-dependence of Δ9-THC in place conditioning paradigms. Learning & Memory September 2018
- Evaluation of reinforcing and aversive effects of voluntary Δ9-tetrahydrocannabinol ingestion in rats. Neuropharmacology July 15, 2018
- Chronic Δ9-THC in Rhesus Monkeys: Effects on Cognitive Performance and Dopamine D2/D3 Receptor Availability. Journal of Pharmacology and Experimental Therapeutics February 2018
- Synthetic cannabinoids found in "spice" products alter body temperature and cardiovascular parameters in conscious male rats. Drug and Alcohol Dependence October 1, 2017
- Δ9-THC exposure attenuates aversive effects and reveals appetitive effects of K2/'Spice' constituent JWH-018 in mice. Behavioural Pharmacology June 2014
and 6 more in the library