Activation of a hypothalamus-habenula circuit by mechanical stimulation inhibits cocaine addiction-like behaviors

• Published in: Biological research Vol. 56; no. 1; p. 25
• Main Authors: Jang, Han Byeol, Ahn, DanBi, Chang, Suchan, Kim, Hyung Kyu, Lee, Bong Hyo, Kim, Sang Chan, Steffensen, Scott C, Bills, Kyle B, Lee, Hubert, Kim, Hee Young
• Format: Journal Article
• Language: English; Portuguese
• Published: England BioMed Central Ltd 17.05.2023; BioMed Central; Sociedad de Biología de Chile; BMC
• Subjects: Addictive behaviors; Affect (Psychology); Behavior; BIOLOGY; Circuits; Cocaine; Cocaine - metabolism; Cocaine - pharmacology; Cocaine-Related Disorders - metabolism; Cocaine-Related Disorders - therapy; Dopamine; Dopamine - metabolism; Dopamine - pharmacology; Drug abuse; Drug addiction; Electrophysiology; GABA; Genetics; Habenula; Habenula - metabolism; Humans; Hypothalamus; Hypothalamus (lateral); Hypothalamus - metabolism; Immunohistochemistry; Information processing; Lateral habenula; Locomotion; Locomotor activity; Luteinizing hormone; Mechanical stimulation (MS); Mechanical stimuli; Mediation; Mesolimbic system; Neurons; Nucleus accumbens; Optics; Optogenetics; Reinstatement; Ultrasonic vocalization (USVs); Vectors (Biology); γ-Aminobutyric acid; Mechanical stimulation (MS); Lateral habenula; Cocaine; Optogenetics; Ultrasonic vocalization (USVs); Locomotor activity
• ISSN: 0717-6287; 0716-9760; 0717-6287
• DOI: 10.1186/s40659-023-00440-7

Mechanoreceptor activation modulates GABA neuron firing and dopamine (DA) release in the mesolimbic DA system, an area implicated in reward and substance abuse. The lateral habenula (LHb), the lateral hypothalamus (LH), and the mesolimbic DA system are not only reciprocally connected, but also involved in drug reward. We explored the effects of mechanical stimulation (MS) on cocaine addiction-like behaviors and the role of the LH-LHb circuit in the MS effects. MS was performed over ulnar nerve and the effects were evaluated by using drug seeking behaviors, optogenetics, chemogenetics, electrophysiology and immunohistochemistry. Mechanical stimulation attenuated locomotor activity in a nerve-dependent manner and 50-kHz ultrasonic vocalizations (USVs) and DA release in nucleus accumbens (NAc) following cocaine injection. The MS effects were ablated by electrolytic lesion or optogenetic inhibition of LHb. Optogenetic activation of LHb suppressed cocaine-enhanced 50 kHz USVs and locomotion. MS reversed cocaine suppression of neuronal activity of LHb. MS also inhibited cocaine-primed reinstatement of drug-seeking behavior, which was blocked by chemogenetic inhibition of an LH-LHb circuit. These findings suggest that peripheral mechanical stimulation activates LH-LHb pathways to attenuate cocaine-induced psychomotor responses and seeking behaviors.