Methamphetamine (METH) enhances dopamine (DA) transmission in the mesolimbic system implicated in its reinforcing effects. Our previous studies have shown that acupuncture attenuates drug-seeking behaviors by modulating GABAergic transmission in the ventral tegmental area and DA release in the nucleus accumbens (NAc) of the striatum. The effects of acupuncture on METH-induced behaviors and its mediation by neural pathways remain a relatively understudied area of research. The central amygdala (CeA) plays a critical role in physiological and behavioral responses to somatosensory and drug stimuli and has been implicated in negative reinforcement. Thus, we evaluated the role of the CeA in acupuncture effects on locomotor activity, positive affective states, and DA release in the NAc following acute administration of METH. Acupuncture at acupoint HT7 reduced locomotor activity, 50-kHz ultrasonic vocalizations (USVs), and NAc DA release following systemic injection of METH, which was prevented by electrolytic lesions or optogenetic inhibition of the CeA. Acupuncture alone excited CeA neurons and reversed the suppression of CeA neurons induced by METH. These results suggest that acupuncture can relieve psychomotor responses and positive affective states following METH by inhibiting NAc DA release and this effect is mediated by activation of CeA neurons.
Nociceptive signals interact with various regions of the brain, including those involved in physical sensation, reward, cognition, and emotion. Emerging evidence points to a role of nociception in the modulation of the mesolimbic reward system. The mechanism by which nociception affects dopamine (DA) signaling and reward is unclear. The lateral hypothalamus (LH) and the lateral habenula (LHb) receive somatosensory inputs and are structurally connected with the mesolimbic DA system. Here, we show that the LH–LHb pathway is necessary for nociceptive modulation of this system using male Sprague Dawley rats. Our extracellular single-unit recordings and head-mounted microendoscopic calcium imaging revealed that nociceptive stimulation by tail pinch excited LHb and LH neurons, which was inhibited by chemical lesion of the LH. Tail pinch increased activity of GABA neurons in ventral tegmental area, decreased the extracellular DA level in the nucleus accumbens ventrolateral shell in intact rats, and reduced cocaine-increased DA concentration, which was blocked by disruption of the LH. Furthermore, tail pinch attenuated cocaine-induced locomotor activity, 22 and 50 kHz ultrasonic vocalizations, and reinstatement of cocaine-seeking behavior, which was inhibited by chemogenetic silencing of the LH–LHb pathway. Our findings suggest that nociceptive stimulation recruits the LH–LHb pathway to inhibit mesolimbic DA system and drug reinstatement.SIGNIFICANCE STATEMENTThe LHb and the LH have been implicated in processing nociceptive signals and modulating DA release in the mesolimbic DA system. Here, we show that the LH–LHb pathway is critical for nociception-induced modulation of mesolimbic DA release and cocaine reinstatement. Nociceptive stimulation alleviates extracellular DA release in the mesolimbic DA system, cocaine-induced psychomotor activities, and reinstatement of cocaine-seeking behaviors through the LH–LHb pathway. These findings provide novel evidence for sensory modulation of the mesolimbic DA system and drug addiction.
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