Addiction Biology Unit – Publications

@article{pmid40413193,

title = {RDS-04-010: a novel atypical DAT inhibitor that inhibits cocaine taking and seeking and itself has low abuse potential in experimental animals},

author = {Omar Soler-Cedeno and Ewa Galaj and Benjamin Klein and Jianjing Cao and Guo-Hua Bi and Amy Hauck Newman and Zheng-Xiong Xi},

url = {https://pubmed.ncbi.nlm.nih.gov/40413193/},

doi = {10.1038/s41398-025-03391-7},

issn = {2158-3188},

year  = {2025},

date = {2025-05-01},

urldate = {2025-05-01},

journal = {Transl Psychiatry},

volume = {15},

number = {1},

pages = {182},

abstract = {Cocaine use disorder (CUD) is a severe public health problem, and currently, there is no FDA-approved medication for its treatment. Atypical dopamine (DA) transporter (DAT) inhibitors display low addictive liability by themselves and may have therapeutic potential for treatment of psychostimulant use disorders. Here, we report that RDS-04-010, a novel atypical DAT inhibitor that binds to an inward-facing conformation of DAT due to its sulfoxide moiety, displayed distinct pharmacological profiles in animal models of addiction from its sulfide analog, RDS-03-094, a DAT inhibitor that binds to a more outward-facing conformation. Systemic administration of RDS-04-010 dose-dependently inhibited cocaine self-administration, shifted the cocaine self-administration dose-response curve downward, decreased motivation for cocaine seeking under progressive-ratio reinforcement conditions, and inhibited cocaine-primed reinstatement of drug-seeking behavior. RDS-04-010 alone neither altered optical brain-stimulation reward nor evoked reinstatement of drug-seeking behavior. RDS-04-010 substitution for cocaine was not able to maintain self-administration in rats trained to self-administer cocaine. In contrast, RDS-03-094 displayed more cocaine-like reinforcing effects. Its pretreatment upward-shifted both the cocaine self-administration dose-response and optical brain-stimulation reward curves. RDS-03-094 alone was able to reinstate extinguished cocaine-seeking behavior and sustain self-administration during a substitution test. Collectively, these findings suggest that RDS-04-010 is a novel atypical DAT inhibitor with favorable therapeutic potential in reducing cocaine-taking and -seeking behavior with low addictive liability. Moreover, this extensive behavioral evaluation further confirms the role that DAT binding conformation plays in the distinctive profiles of atypical DAT inhibitors that prefer the inward facing conformation.},

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pubstate = {published},

tppubtype = {article}

}

@article{pmid40150927,

title = {ESG-1-60 and ESG-1-61: Novel dopamine D receptor-preferring partial agonists/antagonists that inhibit cocaine taking and seeking in rodents},

author = {Omar Soler-Cedeño and Bradley M Keegan and Hannah Alton and Guo-Hua Bi and Emily Linz and Caleb D Vogt and Emma S Gogarnoiu and Lei Shi and Amy Hauck Newman and Zheng-Xiong Xi},

url = {https://pubmed.ncbi.nlm.nih.gov/40150927/},

doi = {10.1111/bph.70021},

issn = {1476-5381},

year  = {2025},

date = {2025-03-01},

urldate = {2025-03-01},

journal = {Br J Pharmacol},

abstract = {BACKGROUND AND PURPOSE: Preclinical studies suggest that highly selective dopamine D receptor (DR) antagonists or partial agonists hold promise for treating substance use disorders. However, their limited effectiveness in reducing cocaine self-administration is a major drawback. This study investigated whether cariprazine (D receptor-preferring partial agonist) and its analogues ESG-1-60 and ESG-1-61 have enhanced efficacy in reducing cocaine-taking and cocaine-seeking behaviour.



EXPERIMENTAL APPROACH: In vitro BRET experiments were used to characterize the functional efficacies of cariprazine and its analogues. Intravenous cocaine self-administration and reinstatement models were used to evaluate efficacy in reducing cocaine-taking and cocaine-seeking behaviour. Optical intracranial self-stimulation (oICSS) procedures assessed effects on dopamine-dependent behaviour. Open-field locomotion, oral sucrose self-administration and conditioned place-preference were used to evaluate potential unwanted side effects.



KEY RESULTS: BRET functional assays indicated that cariprazine and ESG-1-60 are D receptor-preferring partial agonists, while ESG-1-61 is a D receptor-preferring antagonist/inverse agonist. All three compounds inhibited cocaine self-administration under both fixed-ratio and progressive-ratio reinforcement schedules and reduced cocaine-induced reinstatement of drug-seeking behaviour in both male and female rats. The compounds did not alter locomotor behaviour but suppressed sucrose intake and dopamine-dependent oICSS. Cariprazine and ESG-1-61 produced significant place aversion, while ESG-1-60 did not. Chronic administration of ESG-1-60 inhibited cocaine self-administration.



CONCLUSIONS AND IMPLICATIONS: Novel D receptor-preferring compounds ESG-1-60 and ESG-1-61 were highly effective in reducing cocaine-taking and cocaine-seeking, under various reinforcement conditions. ESG-1-60 warrants further investigation as a new pharmacotherapy for treating cocaine use disorder as it is effective in these models and lacks unwanted behavioural effects.},

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pubstate = {published},

tppubtype = {article}

}

@article{pmid38838841,

title = {Presynaptic and Postsynaptic Mesolimbic Dopamine D_{3} Receptors Play Distinct Roles in Cocaine Versus Opioid Reward in Mice},

author = {Zheng-Xiong Xi and Miriam E Bocarsly and Ewa Galaj and Briana Hempel and Catherine Teresi and Marlisa Shaw and Guo-Hua Bi and Chloe Jordan and Emily Linz and Hannah Alton and Gianluigi Tanda and Zachary Freyberg and Veronica A Alvarez and Amy Hauck Newman},

url = {https://pubmed.ncbi.nlm.nih.gov/38838841/},

doi = {10.1016/j.biopsych.2024.05.020},

issn = {1873-2402},

year  = {2024},

date = {2024-06-01},

urldate = {2024-06-01},

journal = {Biol Psychiatry},

abstract = {Background: Past research has illuminated pivotal roles of dopamine D3 receptors (D_{3}R) in the rewarding effects of cocaine and opioids. However, the cellular and neural circuit mechanisms that underlie these actions remain unclear.



Methods: We employed Cre-LoxP techniques to selectively delete D_{3}R from presynaptic dopamine neurons or postsynaptic dopamine D_{1} receptor (D_{1}R)-expressing neurons in male and female mice. We utilized RNAscope in situ hybridization, immunohistochemistry, real-time polymerase chain reaction, voltammetry, optogenetics, microdialysis, and behavioral assays (n ≥ 8 animals per group) to functionally characterize the roles of presynaptic versus postsynaptic D_{3}R in cocaine and opioid actions.



Results: Our results revealed D_{3}R expression in ∼25% of midbrain dopamine neurons and ∼70% of D_{1}R-expressing neurons in the nucleus accumbens. While dopamine D_{2} receptors (D_{2}R) were expressed in ∼80% dopamine neurons, we found no D_{2}R and D_{3}R colocalization among these cells. Selective deletion of D_{3}R from dopamine neurons increased exploratory behavior in novel environments and enhanced pulse-evoked nucleus accumbens dopamine release. Conversely, deletion of D_{3}R from D_{1}R-expressing neurons attenuated locomotor responses to D_{1}-like and D_{2}-like agonists. Strikingly, deletion of D_{3}R from either cell type reduced oxycodone self-administration and oxycodone-enhanced brain-stimulation reward. In contrast, neither of these D_{3}R deletions impacted cocaine self-administration, cocaine-enhanced brain-stimulation reward, or cocaine-induced hyperlocomotion. Furthermore, D_{3}R knockout in dopamine neurons reduced oxycodone-induced hyperactivity and analgesia, while deletion from D_{1}R-expressing neurons potentiated opioid-induced hyperactivity without affecting analgesia.



Conclusions: We dissected presynaptic versus postsynaptic D_{3}R function in the mesolimbic dopamine system. D_{2}R and D_{3}R are expressed in different populations of midbrain dopamine neurons, regulating dopamine release. Mesolimbic D_{3}R are critically involved in the actions of opioids but not cocaine.



Keywords: Cocaine; Conditional D(3) receptor knockout; Dopamine D(3) receptor; Opioid; Optical brain stimulation reward; Self-administration.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid38374108,

title = {GPR55 is expressed in glutamate neurons and functionally modulates drug taking and seeking in rats and mice},

author = {Yi He and Hui Shen and Guo-Hua Bi and Hai-Ying Zhang and Omar Soler-Cedeño and Hannah Alton and Yihong Yang and Zheng-Xiong Xi},

url = {https://pubmed.ncbi.nlm.nih.gov/38374108/},

doi = {10.1038/s41398-024-02820-3},

issn = {2158-3188},

year  = {2024},

date = {2024-02-01},

urldate = {2024-02-01},

journal = {Transl Psychiatry},

volume = {14},

number = {1},

pages = {101},

abstract = {G protein-coupled receptor 55 (GPR55) has been thought to be a putative cannabinoid receptor. However, little is known about its functional role in cannabinoid action and substance use disorders. Here we report that GPR55 is predominantly found in glutamate neurons in the brain, and its activation reduces self-administration of cocaine and nicotine in rats and mice. Using RNAscope in situ hybridization, GPR55 mRNA was identified in cortical vesicular glutamate transporter 1 (VgluT1)-positive and subcortical VgluT2-positive glutamate neurons, with no detection in midbrain dopamine (DA) neurons. Immunohistochemistry detected a GPR55-like signal in both wildtype and GPR55-knockout mice, suggesting non-specific staining. However, analysis using a fluorescent CB1/GPR55 ligand (T1117) in CB1-knockout mice confirmed GPR55 binding in glutamate neurons, not in midbrain DA neurons. Systemic administration of the GPR55 agonist O-1602 didnt impact ∆-THC-induced analgesia, hypothermia and catalepsy, but significantly mitigated cocaine-enhanced brain-stimulation reward caused by optogenetic activation of midbrain DA neurons. O-1602 alone failed to alter extracellar DA, but elevated extracellular glutamate, in the nucleus accumbens. In addition, O-1602 also demonstrated inhibitory effects on cocaine or nicotine self-administration under low fixed-ratio and/or progressive-ratio reinforcement schedules in rats and wildtype mice, with no such effects observed in GPR55-knockout mice. Together, these findings suggest that GPR55 activation may functionally modulate drug-taking and drug-seeking behavior possibly via a glutamate-dependent mechanism, and therefore, GPR55 deserves further study as a new therapeutic target for treating substance use disorders.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid37479780b,

title = {PPARα and PPARγ are expressed in midbrain dopamine neurons and modulate dopamine- and cannabinoid-mediated behavior in mice},

author = {Briana Hempel and Madeline Crissman and Sruti Pari and Benjamin Klein and Guo-Hua Bi and Hannah Alton and Zheng-Xiong Xi},

url = {https://pubmed.ncbi.nlm.nih.gov/37479780/},

doi = {10.1038/s41380-023-02182-0},

issn = {1476-5578},

year  = {2023},

date = {2023-07-01},

urldate = {2023-07-01},

journal = {Mol Psychiatry},

abstract = {Peroxisome proliferator-activated receptors (PPARs) are a family of nuclear receptors that regulate gene expression. Δ-tetrahydrocannabinol (Δ-THC) is a PPARγ agonist and some endocannabinoids are natural activators of PPARα and PPARγ. However, little is known regarding their cellular distributions in the brain and functional roles in cannabinoid action. Here, we first used RNAscope in situ hybridization and immunohistochemistry assays to examine the cellular distributions of PPARα and PPARγ expression in the mouse brain. We found that PPARα and PPARγ are expressed in ~70% of midbrain dopamine (DA) neurons. In the amygdala, PPARα is expressed in ~60% of glutamatergic neurons, while PPARγ is expressed in ~60%  of GABA neurons. However, no PPARα/γ signal was detected in GABA neurons in the nucleus accumbens. We then used a series of behavioral assays to determine the functional roles of PPARα/γ in the CNS effects of Δ-THC. We found that optogenetic stimulation of midbrain DA neurons was rewarding as assessed by optical intracranial self-stimulation (oICSS) in DAT-cre mice. Δ-THC and a PPARγ (but not PPARα) agonist dose-dependently inhibited oICSS. Pretreatment with PPARα or PPARγ antagonists attenuated the Δ-THC-induced reduction in oICSS and Δ-THC-induced anxiogenic effects. In addition, a PPARγ agonist increased, while PPARα or PPARγ antagonists decreased open-field locomotion. Pretreatment with PPARα or PPARγ antagonists potentiated Δ-THC-induced hypoactivity and catalepsy but failed to alter Δ-THC-induced analgesia, hypothermia and immobility. These findings provide the first anatomical and functional evidence supporting an important role of PPARα/γ in DA-dependent behavior and cannabinoid action.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid36517243,

title = {Cannabinoid CB_{1} Receptors Are Expressed in a Subset of Dopamine Neurons and Underlie Cannabinoid-Induced Aversion, Hypoactivity, and Anxiolytic Effects in Mice},

author = {Xiao Han and Ying Liang and Briana Hempel and Chloe J Jordan and Hui Shen and Guo-Hua Bi and Jin Li and Zheng-Xiong Xi},

url = {https://pubmed.ncbi.nlm.nih.gov/36517243/},

doi = {10.1523/JNEUROSCI.1493-22.2022},

issn = {1529-2401},

year  = {2023},

date = {2023-01-01},

urldate = {2023-01-01},

journal = {J Neurosci},

volume = {43},

number = {3},

pages = {373--385},

abstract = {Cannabinoids modulate dopamine (DA) transmission and DA-related behavior, which has been thought to be mediated initially by activation of cannabinoid CB1 receptors (CB1Rs) on GABA neurons. However, there is no behavioral evidence supporting it. In contrast, here we report that CB1Rs are also expressed in a subset of DA neurons and functionally underlie cannabinoid action in male and female mice. RNAscope in situ hybridization (ISH) assays demonstrated CB1 mRNA in tyrosine hydroxylase (TH)-positive DA neurons in the ventral tegmental area (VTA) and glutamate decarboxylase 1 (GAD1)-positive GABA neurons. The CB1R-expressing DA neurons were located mainly in the middle portion of the VTA with the number of CB1-TH colocalization progressively decreasing from the medial to the lateral VTA. Triple-staining assays indicated CB1R mRNA colocalization with both TH and vesicular glutamate transporter 2 (VgluT2, a glutamate neuronal marker) in the medial VTA close to the midline of the brain. Optogenetic activation of this population of DA neurons was rewarding as assessed by optical intracranial self-stimulation. Δ-tetrahydrocannabinol (Δ-THC) or ACEA (a selective CB1R agonist) dose-dependently inhibited optical intracranial self-stimulation in DAT-Cre control mice, but not in conditional knockout mice with the CB1R gene absent in DA neurons. In addition, deletion of CB1Rs from DA neurons attenuated Δ-THC-induced reduction in DA release in the NAc, locomotion, and anxiety. Together, these findings indicate that CB1Rs are expressed in a subset of DA neurons that corelease DA and glutamate, and functionally underlie cannabinoid modulation of DA release and DA-related behavior. Cannabinoids produce a series of psychoactive effects, such as aversion, anxiety, and locomotor inhibition in rodents. However, the cellular and receptor mechanisms underlying these actions are not fully understood. Here we report that CB1 receptors are expressed not only in GABA neurons but also in a subset of dopamine neurons, which are located mainly in the medial VTA close to the midline of the midbrain and corelease dopamine and glutamate. Optogenetic activation of these dopamine neurons is rewarding, which is dose-dependently inhibited by cannabinoids. Selective deletion of CB1 receptor from dopamine neurons blocked cannabinoid-induced aversion, hypoactivity, and anxiolytic effects. These findings demonstrate that dopaminergic CB1 receptors play an important role in mediating cannabinoid action.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid36054363,

title = {A red nucleus-VTA glutamate pathway underlies exercise reward and the therapeutic effect of exercise on cocaine use},

author = {Yi He and Graziella Madeo and Ying Liang and Cindy Zhang and Briana Hempel and Xiaojie Liu and Lianwei Mu and Shui Liu and Guo-Hua Bi and Ewa Galaj and Hai-Ying Zhang and Hui Shen and Ross A McDevitt and Eliot L Gardner and Qing-Song Liu and Zheng-Xiong Xi},

url = {https://pubmed.ncbi.nlm.nih.gov/36054363/},

doi = {10.1126/sciadv.abo1440},

issn = {2375-2548},

year  = {2022},

date = {2022-09-01},

urldate = {2022-09-01},

journal = {Sci Adv},

volume = {8},

number = {35},

pages = {eabo1440},

abstract = {Physical exercise is rewarding and protective against drug abuse and addiction. However, the neural mechanisms underlying these actions remain unclear. Here, we report that long-term wheel-running produced a more robust increase in c-fos expression in the red nucleus (RN) than in other brain regions. Anatomic and functional assays demonstrated that most RN magnocellular portion (RNm) neurons are glutamatergic. Wheel-running activates a subset of RNm glutamate neurons that project to ventral tegmental area (VTA) dopamine neurons. Optogenetic stimulation of this pathway was rewarding, as assessed by intracranial self-stimulation and conditioned place preference, whereas optical inhibition blocked wheel-running behavior. Running wheel access decreased cocaine self-administration and cocaine seeking during extinction. Last, optogenetic stimulation of the RNm-to-VTA glutamate pathway inhibited responding to cocaine. Together, these findings indicate that physical exercise activates a specific RNm-to-VTA glutamatergic pathway, producing exercise reward and reducing cocaine intake.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid35851573,

title = {Therapeutic potential of PIMSR, a novel CB1 receptor neutral antagonist, for cocaine use disorder: evidence from preclinical research},

author = {Ewa Galaj and Briana Hempel and Allamar Moore and Benjamin Klein and Guo-Hua Bi and Eliot L Gardner and Herbert H Seltzman and Zheng-Xiong Xi},

url = {https://pubmed.ncbi.nlm.nih.gov/35851573/},

doi = {10.1038/s41398-022-02059-w},

issn = {2158-3188},

year  = {2022},

date = {2022-07-01},

urldate = {2022-07-01},

journal = {Transl Psychiatry},

volume = {12},

number = {1},

pages = {286},

abstract = {Cannabinoid CB1 receptors (CB1Rs) have been major targets in medication development for the treatment of substance use disorders. However, clinical trials with rimonabant, a CB1R antagonist/inverse agonist, failed due to severe side effects. Here, we evaluated the therapeutic potential of PIMSR, a neutral CB1R antagonist lacking an inverse agonist profile, against cocaine's behavioral effects in experimental animals. We found that systemic administration of PIMSR dose-dependently inhibited cocaine self-administration under fixed-ratio (FR5), but not FR1, reinforcement, shifted the cocaine self-administration dose-response curve downward, decreased incentive motivation to seek cocaine under progressive-ratio reinforcement, and reduced cue-induced reinstatement of cocaine seeking. PIMSR also inhibited oral sucrose self-administration. Importantly, PIMSR alone is neither rewarding nor aversive as assessed by place conditioning. We then used intracranial self-stimulation (ICSS) to explore the possible involvement of the mesolimbic dopamine system in PIMSR's action. We found that PIMSR dose-dependently attenuated cocaine-enhanced ICSS maintained by electrical stimulation of the medial forebrain bundle in rats. PIMSR itself failed to alter electrical ICSS, but dose-dependently inhibited ICSS maintained by optical stimulation of midbrain dopamine neurons in transgenic DAT-Cre mice, suggesting the involvement of dopamine-dependent mechanisms. Lastly, we examined the CB1R mechanisms underlying PIMSR's action. We found that PIMSR pretreatment attenuated Δ-tetrahydrocannabinol (Δ-THC)- or ACEA (a selective CB1R agonist)-induced reduction in optical ICSS. Together, our findings suggest that the neutral CB1R antagonist PIMSR deserves further research as a promising pharmacotherapeutic for cocaine use disorder.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid35091501,

title = {Elevation of Extracellular Glutamate by Blockade of Astrocyte Glutamate Transporters Inhibits Cocaine Reinforcement in Rats via a NMDA-GluN2B Receptor Mechanism},

author = {Hong-Ju Yang and Briana J Hempel and Guo-Hua Bi and Yi He and Hai-Ying Zhang and Eliot L Gardner and Zheng-Xiong Xi},

url = {https://pubmed.ncbi.nlm.nih.gov/35091501/},

doi = {10.1523/JNEUROSCI.1432-21.2022},

issn = {1529-2401},

year  = {2022},

date = {2022-01-01},

urldate = {2022-01-01},

journal = {J Neurosci},

volume = {42},

number = {11},

pages = {2327--2343},

abstract = {It is well established that glutamate plays an important role in drug-induced and cue-induced reinstatement of drug seeking. However, the role of glutamate in drug reward is unclear. In this study, we systemically evaluated the effects of multiple glutamate transporter (GLT) inhibitors on extracellular glutamate and dopamine (DA) in the nucleus accumbens (NAc), intravenous cocaine self-administration, intracranial brain-stimulation reward (BSR), and reinstatement of cocaine seeking in male and female rats. Among the five GLT inhibitors we tested, TFB-TBOA was the most potent. Microinjections of TFB-TBOA into the NAc, but not the ventral tegmental area (VTA), or dorsal striatum (DS), dose-dependently inhibited cocaine self-administration under fixed-ratio and progressive-ratio (PR) reinforcement schedules, shifted the cocaine dose-response curve downward, and inhibited intracranial BSR. Selective downregulation of astrocytic GLT-1 expression in the NAc by GLT-1 antisense oligonucleotides also inhibited cocaine self-administration. The reduction in cocaine self-administration following TFB-TBOA administration was NMDA GluN2B receptor dependent, and rats self-administering cocaine showed upregulation of GluN2B expression in NAc DA- and cAMP-regulated phosphoprotein 32 (DARPP-32)-positive medium-spiny neurons (MSNs). In contrast, TFB-TBOA, when locally administered into the NAc, VTA, or ventral pallidum (VP), dose-dependently reinstated cocaine-seeking behavior. Intra-NAc TFB-TBOA-evoked drug-seeking was long-lasting and NMDA/AMPA receptor dependent. These findings, for the first time, indicate that glutamate in the NAc negatively regulates cocaine's rewarding effects, while an excess of glutamate in multiple brain regions can trigger reinstatement of drug-seeking behavior. It is well known that glutamate plays an important role in relapse to drug seeking. However, the role of glutamate in drug reward is less clear. Here, we report that TFB-TBOA, a highly potent glutamate transporter (GLT) inhibitor, dose-dependently elevates extracellular glutamate and inhibits cocaine self-administration and brain-stimulation reward (BSR), when administered locally into the nucleus accumbens (NAc), but not other brain regions. Mechanistic assays indicate that cocaine self-administration upregulates NMDA-GluN2B receptor subtype expression in striatal dopaminoceptive neurons and activation of GluN2B by TFB-TBOA-enhanced glutamate inhibits cocaine self-administration. TFB-TBOA also reinstates cocaine-seeking behavior when administered into the NAc, ventral tegmental area (VTA), and ventral pallidum (VP). These findings demonstrate that glutamate differentially regulates cocaine reward versus relapse, reducing cocaine reward, while potentiating relapse to cocaine seeking.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid33789118,

title = {Cannabinoid CB_{2} receptors are expressed in glutamate neurons in the red nucleus and functionally modulate motor behavior in mice},

author = {Hai-Ying Zhang and Hui Shen and Ming Gao and Zegang Ma and Briana J Hempel and Guo-Hua Bi and Eliot L Gardner and Jie Wu and Zheng-Xiong Xi},

url = {https://pubmed.ncbi.nlm.nih.gov/33789118/},

doi = {10.1016/j.neuropharm.2021.108538},

issn = {1873-7064},

year  = {2021},

date = {2021-05-01},

urldate = {2021-05-01},

journal = {Neuropharmacology},

volume = {189},

pages = {108538},

abstract = {Cannabinoids produce a number of central nervous system effects via the CB receptor (CBR), including analgesia, antianxiety, anti-reward, hypoactivity and attenuation of opioid-induced respiratory depression. However, the cellular distributions of the CBRs in the brain remain unclear. We have reported that CBRs are expressed in midbrain dopamine (DA) neurons and functionally regulate DA-mediated behavior(s). Unexpectedly, high densities of CB-like signaling were also found in a neighboring motor structure - the red nucleus (RN) of the midbrain. In the present study, we systematically explored CBR expression and function in the RN. Immunohistochemistry and in situ hybridization assays showed high densities of CBR-immunostaining and mRNA signal in RN magnocellular glutamate neurons in wildtype and CB-knockout, but not CB-knockout, mice. Ex vivo electrophysiological recordings in midbrain slices demonstrated that CBR activation by JWH133 dose-dependently inhibited firing rates of RN magnocellular neurons in wildtype, but not CB-knockout, mice, while having no effect on RN GABA neurons in transgenic GAD67-GFP reporter mice, suggesting CB-mediated effects on glutamatergic neurons. In addition, microinjection of JWH133 into the RN produced robust ipsilateral rotations in wildtype, but not CB-knockout mice, which was blocked by pretreatment with either a CB or DA D1 or D2 receptor antagonist, suggesting a DA-dependent effect. Finally, fluorescent tract tracing revealed glutamatergic projections from the RN to multiple brain areas including the ventral tegmental area, thalamus, and cerebellum. These findings suggest that CBRs in RN glutamate neurons functionally modulate motor activity, and therefore, constitute a new target in cannabis-based medication development for motor disorders.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}