Nociceptive Stimuli Activate the Hypothalamus–Habenula Circuit to Inhibit the Mesolimbic Reward System and Cocaine-Seeking Behaviors

Abstract

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.

Abnormal functional connectivity in the habenula is associated with subjective hyperarousal state in chronic insomnia disorder

“…Additionally, the lateral habenula has been demonstrated as a key brain region for reward regulation ( 38 ). The lateral habenula has been known to modulate DA release and process nociceptive signals in the mesolimbic DA system ( 39 ). Moreover, recent electrophysiological studies provide evidence that prefrontal and non-prefrontal cortical regions can indirectly convey information to the lateral habenula via a cortico-striosome-pallido-habenular circuit in macaque monkeys ( 40 ).…”

Deep electroacupuncture of neurogenic spots attenuates immobilization stress-induced acute hypertension in rats

“…Electrolytic lesions of rVLM were made before electrical stimulation at a depth of 3 mm, as described previously. 18 Briefly, under isoflurane anesthesia a tungsten electrode, insulated except for 0.5 mm at the tip, was inserted in rVLM. The bilateral electrolytic lesions of rVLM were made by passing ±0.35 mA positive current for 8 s.…”

Mediation of lateral hypothalamus orexin input to lateral habenula in the inhibitory effects of mechanical stimulation on psychomotor responses induced by cocaine

“…As performed in our laboratory, locomotor activity and 50-kHz USVs were recorded simultaneously in customized sound-attenuating chambers ( Kim et al, 2021 ; Lee et al, 2022 ). The chamber consisted of two boxes to minimize exterior noise (inside box: 54 × 38 × 35 cm, outside box: 68 × 50 × 51 cm).…”

“…In addition, LHb neurons encode mRNA for both OX1R and OX2R but with a higher ratio of OX2R ( Huang et al, 2019 ). As our previous studies showed that MS activates an LH–LHb pathway to inhibit the mesolimbic DA system and cocaine addiction–like behaviors ( Chang et al, 2017 ; Ahn et al, 2021 ; Lee et al, 2022 ), we hypothesized that the MS effects on cocaine addiction–like behaviors may be mediated via an orexinergic pathway from the LH to the LHb.…”