Heantos-4, a natural plant extract used in the treatment of drug addiction, modulates T-type calcium channels and thalamocortical burst-firing.

Stuart M Cain,John R Tyson,Anthony G Phillips,Yiming Zhang,Yi Yang,Zeina Waheed,Tran Van Sung,Esperanza Garcia,Soyon Ahn,Terrance P Snutch

doi:10.1186/s13041-016-0274-7

Stuart M Cain, John R Tyson + Show 8 more

Open Access

https://doi.org/10.1186/s13041-016-0274-7

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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.

Highlights

Opiate dependence is estimated to affect 15 million people worldwide and opiate overdose is believed to result in approximately 69,000 mortalities per year [1]
Heantos differentially modulates T-type calcium channel subtypes To assess whether Heantos directly alters T-type calcium channel currents, individual CaV3.1, CaV3.2 and CaV3.3 isoforms were exogenously expressed in HEK293 cells
The voltage-dependent kinetics of CaV3.2 currents were altered by Heantos-4 application with the tau of activation increased between −45 mV and -20 mV and the tau of inactivation increased between −40 mV and 0 mV (Fig. 2d and e)

Summary

Introduction

Opiate dependence is estimated to affect 15 million people worldwide and opiate overdose is believed to result in approximately 69,000 mortalities per year [1]. While pharmacological therapies can be utilized during rehabilitation to reduce cravings (methodone, buprenorphine, suboxone), block of the rewarding effects (naltrexone) or lessen the negative symptoms of opioid withdrawal (antiemetics, sedatives, antidepressants), relapse rates remain. Heantos-4, which is the Greek term for “Plants” is a mixture of organic herbs developed in Vietnam and recently approved for the clinical alleviation of withdrawal symptoms in individuals dependent upon opiates [4]. Preliminary observations indicate that it aids in the reduction in relapse rates. A sedative effect of Heantos has been reported by patients during the first few days of treatment. There is little current understanding of how Heantos mediates its effects on opioid withdrawal, relapse or sedation. Recent findings show that oral administration of Heantos-4 reduces drug-seeking behaviors in animal models of

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