title: Heantos-4, a natural plant extract used in the treatment of drug addiction, modulates T-type calcium channels and thalamocortical burst-firing.
abstract: Heantos-4 is a refined combination of plant extracts currently approved to treat opiate addiction in Vietnam. In addition to its beneficial effects on withdrawal and prevention of relapse, reports of sedation during clinical treatment suggest that arousal networks in the brain may be recruited during Heantos administration. T-type calcium channels are implicated in the generation of sleep rhythms and in this study we examined whether a Heantos-4 extraction modulates T-type calcium channel currents generated by the Cav3.1, Cav3.2 and Ca3.3 subtypes. Utilizing whole-cell voltage clamp on exogenously expressed T-type calcium channels we find that Heantos inhibits Cav3.1 and Cav3.3 currents, while selectively potentiating Cav3.2 currents. We further examined the effects of Heantos-4 extract on low-threshold burst-firing in thalamic neurons which contribute to sleep oscillations. Using whole-cell current clamp in acute thalamic brain slices Heantos-4 suppressed rebound burst-firing in ventrobasal thalamocortical neurons, which express primarily Cav3.1 channels. Conversely, Heantos-4 had no significant effect on the burst-firing properties of thalamic reticular neurons, which express a mixed population of Cav3.2 and Cav3.3 channels. Examining Heantos-4 effects following oral administration in a model of absence epilepsy revealed the potential to exacerbate seizure activity. Together, the findings indicate that Heantos-4 has selective effects both on specific T-type calcium channel isoforms and distinct populations of thalamic neurons providing a putative mechanism underlying its effects on sedation and on the thalamocortical network.
authors.affiliation: Michael Smith Laboratories and Djavad Mowafaghian Centre for Brain Health, University of British Columbia, 219-2185 East Mall, Vancouver, BC, V6T 1Z4, Canada.
authors.forename: Stuart M
authors.initials: SM
authors.lastname: Cain
authors.affiliation: Department of Psychiatry, University of British Columbia, Vancouver, Canada.
authors.forename: Soyon
authors.initials: S
authors.lastname: Ahn
authors.affiliation: Michael Smith Laboratories and Djavad Mowafaghian Centre for Brain Health, University of British Columbia, 219-2185 East Mall, Vancouver, BC, V6T 1Z4, Canada.
authors.forename: Esperanza
authors.initials: E
authors.lastname: Garcia
authors.affiliation: Michael Smith Laboratories and Djavad Mowafaghian Centre for Brain Health, University of British Columbia, 219-2185 East Mall, Vancouver, BC, V6T 1Z4, Canada.
authors.forename: Yiming
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Michael Smith Laboratories and Djavad Mowafaghian Centre for Brain Health, University of British Columbia, 219-2185 East Mall, Vancouver, BC, V6T 1Z4, Canada.
authors.forename: Zeina
authors.initials: Z
authors.lastname: Waheed
authors.affiliation: Michael Smith Laboratories and Djavad Mowafaghian Centre for Brain Health, University of British Columbia, 219-2185 East Mall, Vancouver, BC, V6T 1Z4, Canada.
authors.forename: John R
authors.initials: JR
authors.lastname: Tyson
authors.affiliation: Michael Smith Laboratories and Djavad Mowafaghian Centre for Brain Health, University of British Columbia, 219-2185 East Mall, Vancouver, BC, V6T 1Z4, Canada.
authors.forename: Yi
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Institute of Chemistry, Vietnam Academy of Science and Technology, Hanoi, Vietnam.
authors.forename: Tran
authors.initials: T
authors.lastname: Van Sung
authors.affiliation: Department of Psychiatry, University of British Columbia, Vancouver, Canada.
authors.forename: Anthony G
authors.initials: AG
authors.lastname: Phillips
authors.affiliation: Michael Smith Laboratories and Djavad Mowafaghian Centre for Brain Health, University of British Columbia, 219-2185 East Mall, Vancouver, BC, V6T 1Z4, Canada. snutch@msl.ubc.ca.|Department of Psychiatry, University of British Columbia, Vancouver, Canada. snutch@msl.ubc.ca.
authors.forename: Terrance P
authors.initials: TP
authors.lastname: Snutch
mesh_terms: D000200:Action Potentials; D000818:Animals; D020747:Calcium Channels, T-Type / Q000378:metabolism*; D002540:Cerebral Cortex / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D004832:Epilepsy, Absence / Q000473:pathology / Q000503:physiopathology; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D015640:Ion Channel Gating / Q000187:drug effects; D008297:Male; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D008517:Phytotherapy; D010936:Plant Extracts / Q000494:pharmacology / Q000627:therapeutic use*; D020033:Protein Isoforms / Q000378:metabolism; D017208:Rats, Wistar; D019966:Substance-Related Disorders / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology*; D013788:Thalamus / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology
chemical_list: D020747:Calcium Channels, T-Type; D010936:Plant Extracts; D020033:Protein Isoforms; C497043:heantos
keywords: Addiction; Burst firing; Calcium; Epilepsy; Heantos-4; T-type; Thalamocortical; Thalamus