Berberine hydrochloride attenuates voluntary methamphetamine consumption and anxiety-like behaviors via modulation of oxytocin receptors in methamphetamine addicted rats

Physiol Behav. 2019 Jul 1:206:157-165. doi: 10.1016/j.physbeh.2019.03.024. Epub 2019 Mar 25.


Objective: Methamphetamine (METH) addiction is recognized as one of the major public health concerns, with no approved pharmacological agents for treatment. Berberine hydrochloride, an isoquinoline alkaloid in plants, induces antipsychotic and anxiolytic effects. Hence, we hypothesized that berberine may modulate the METH-induced rewarding effects.

Materials and methods: In this study, three groups of rat including control (N = 10), METH + vehicle (N = 10), and METH + berberine (N = 10) were kept in separate cages one day before expriments. METH (20 mg/L) was dissolved in tap water inside a bottle, while there was only tap water in the control bottle. Two groups received free METH solutions for two weeks (up to 12 mg/kg). Afterwards, they were abstianced for three weeks. Only one group received 100 mg/kg/day of berberine. After three weeks, locomotor activity and anxiety (elevated plus maze test) were evaluated, then the two-bottles choice model was used for one week to evaluate drug preferences. Finally, the brain of rats was removed for evaluation of oxytocin receptor expression via immunofluorescence staining method.

Results: The results showed that METH preference was lower in the berberine + METH group during drug intake compared to the METH group (P < .05). During withdrawal, berberine reduced anxiety-like behaviors (P < .05) and decreased locomotor activity versus the METH group (P < .001). Also, berberine increased numbers of oxytocin receptors in comparison with the METH group (P < .01).

Conclusion: Considering the modulation of oxytocin receptors, berberine may be considered as a potential therapeutic agent for METH addiction.

Keywords: Anxiety; Berberine hydrocholoride; Drug preference; Methamphetamine addiction; Oxytocin receptor.

MeSH terms

  • Amphetamine-Related Disorders / metabolism
  • Animals
  • Anti-Anxiety Agents / pharmacology*
  • Anti-Anxiety Agents / therapeutic use
  • Anxiety / drug therapy*
  • Anxiety / metabolism
  • Behavior, Animal / drug effects*
  • Berberine / pharmacology*
  • Berberine / therapeutic use
  • Central Nervous System Stimulants / administration & dosage*
  • Drug-Seeking Behavior / drug effects
  • Hippocampus / drug effects
  • Hippocampus / metabolism
  • Locomotion / drug effects
  • Methamphetamine / administration & dosage*
  • Nucleus Accumbens / drug effects
  • Nucleus Accumbens / metabolism
  • Rats
  • Receptors, Oxytocin / metabolism*
  • Self Administration


  • Anti-Anxiety Agents
  • Central Nervous System Stimulants
  • Receptors, Oxytocin
  • Berberine
  • Methamphetamine