BETAINE ALLEVIATES CUE-INDUCED REINSTATEMENT OF KETAMINE SEEKING VIA AMPK ACTIVATION IN THE NUCLEUS ACCUMBENS CORE
Authors: Hung *Yun Ting , Lee Mei Yi , Chan Ming Huan , Chen Hwei Hsien 
Published: February 2025

Background

Betaine is a functional nutrient with a variety of potential health benefits1.2. It has been shown to attenuate the reinstatement of ketamine-seeking behavior in rats3. Moreover, betaine activates AMP-activated protein kinase (AMPK) and functions as a partial agonist of the NMDA receptor glycine binding site, both of which have been associated with reducing cue-induced reinstatement4.5.6.

Aims & Objectives

The study aimed to both identify the brain regions associated with betaine's reduction effect on cue-induced reinstatement of ketamine seeking and to explore the involvement of NMDA receptor and AMPK in the potential underlying mechanisms.

Methods

Male Sprague-Dawley rats were trained to respond for intravenous ketamine (0.5 mg/kg/infusion) self-administration, followed by extinction. Prior to cue-induced reinstatement, rats received bilateral microinjection of betaine (100 μ g/μ l/side) either into the prelimbic cortex (PrL) or the nucleus accumbens (NAc) core. The impact of pretreatment of 7-chlorokynurenate (7-CK) (20 μ g/μ l/side), an antagonist of NMDA receptor glycine binding site, or dorsomorphin (6 μ g/μ l/side), an AMP-activated protein kinase (AMPK) inhibitor, on betaine's effects in the NAc core regarding cue-induced reinstatement were examined.

Results

Our data demonstrated a significant reduction in cue-induced reinstatement of ketamine-seeking behavior when betaine was administered into the NAc core, with no such effect observed in the PrL. In addition, dorsomorphin, but not 7-CK, blocked the effect of betaine on cue-induced reinstatement of ketamine- seeking behavior.

Discussion & Conclusions

These findings suggest the potential benefits of betaine supplementation for individuals with ketamine use disorder. Moreover, it sheds light on betaine's capacity to mitigate cue-induced reinstatement of ketamine-seeking behavior by activating AMPK in the NAc core.

References

1(Arumugam et al., 2021)

2(Bhatt et al., 2023)

3(Carlezon and Wise, 1996)

4(McGlinchey et al., 2016)

5(Gao et al., 2017)

6(Chen et al., 2021)

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