Dorsal Raphe Nucleus Serotoninergic Neurons Mediate Morphine Rewarding Effect and Conditioned Place Preference

Fu, Bo; Yao, Jun-Qi; Chang, Lu; Wang, Bin; Li, Zeqi; Huang, Ming; Tian, Tian; Liu, Shaojun

doi:10.1016/j.neuroscience.2021.10.031

Cited by 5 publications

(5 citation statements)

References 39 publications

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“…However, this speculation seemed to conflict with our study that instead of producing analgesia, inhibiting DR GABA+ neurons significantly increased the sensitivity to mechanical stimulation, and morphine treatment reversed the mechanical hyperalgesia induced by photoinhibition of DR GABA+ neurons. Interestingly, a recent study using in vivo electrophysiological recordings showed that morphine directly activated 5-HT neurons by increasing the firing rate of putative 5-HT neurons without affecting DR GABA+ neurons [ 29 ]. Activation of the 5-HT system has been suggested as a useful strategy for the treatment of pain and comorbid chronic pain-related depression [ 30 , 31 ].…”

Section: Discussionmentioning

confidence: 99%

Divergent modulation of pain and anxiety by GABAergic neurons in the ventrolateral periaqueductal gray and dorsal raphe

Xie

Chen

et al. 2022

Neuropsychopharmacol.

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The ventrolateral periaqueductal gray (vlPAG) collaborates with the dorsal raphe (DR) in pain regulation and emotional response. However, the roles of vlPAG and DR γ-aminobutyric acid (GABA)-ergic neurons in regulating nociception and anxiety are contradictory and poorly understood. Here, we observed that pharmacogenetic co-activation of vlPAG and DR GABAergic (vlPAG-DRGABA+) neurons enhanced sensitivity to mechanical stimulation and promoted anxiety-like behavior in naïve mice. Simultaneous inhibition of vlPAG-DRGABA+ neurons showed adaptive anti-nociception and anti-anxiety effects on mice with inflammatory pain. Notably, vlPAGGABA+ and DRGABA+ neurons exhibited opposing effects on the sensitivity to mechanical stimulation in both naïve state and inflammatory pain. In contrast to the role of vlPAGGABA+ neurons in pain processing, chemogenetic inhibition and chronic ablation of DRGABA+ neurons remarkably promoted nociception while selectively activating DRGABA+ neurons ameliorated inflammatory pain. Additionally, utilizing optogenetic technology, we observed that the pronociceptive effect arising from DRGABA+ neuronal inhibition was reversed by the systemic administration of morphine. Our results collectively provide new insights into the modulation of pain and anxiety by specific midbrain GABAergic subpopulations, which may provide a basis for cell type-targeted or subregion-targeted therapies for pain management.

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Section: Discussionmentioning

confidence: 99%

Divergent modulation of pain and anxiety by GABAergic neurons in the ventrolateral periaqueductal gray and dorsal raphe

Xie

Chen

et al. 2022

Neuropsychopharmacol.

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“…It is known that the LHb‐DRN (dorsal raphe nucleus, a major source of serotonin) circuit contributes to the regulation of behavioural and physiological mechanisms, including reward, pain sensitivity and cognition 27 . DRN serotonergic neurons interact with the mesolimbic dopaminergic system and regulate the reward effect of addictive drugs 28 . It is also possible that LHb activation would suppress cocaine‐enhanced behaviours through the serotonergic pathway of LHb‐DRN.…”

Section: Discussionmentioning

confidence: 99%

“…16 Consistent with previous studies, the present study revealed interact with the mesolimbic dopaminergic system and regulate the reward effect of addictive drugs. 28 It is also possible that LHb activation would suppress cocaine-enhanced behaviours through the serotonergic pathway of LHb-DRN.…”

Section: Glutamatergic Input From Lh To Lhbmentioning

confidence: 99%

A hypothalamus‐habenula circuit regulates psychomotor responses induced by cocaine

Ahn,

Jang,

Ryu

et al. 2023

Addiction Biology

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Administration of cocaine increases synaptic dopamine levels by blocking dopamine reuptake and leads to increased locomotor activity and compulsive drug‐seeking behaviour. It has been suggested that the lateral hypothalamus (LH) or lateral habenula (LHb) is involved in drug‐seeking behaviours. To explore the role of the LH and the LHb in cocaine‐induced psychomotor responses, we tested whether modulation of the LH or the LH‐LHb circuit affects cocaine‐induced locomotion. Cocaine‐induced locomotor activity and dopamine release were suppressed by the activation of the LH with 2‐[2,6‐difluoro‐4‐[[2‐[(phenylsulfonyl)amino]ethyl]thio]phenoxy]acetamide (PEPA), an AMPA receptor agonist. When the LH was inhibited by microinjection of a GABA receptor agonists mixture prior to cocaine injection, the cocaine's effects were enhanced. Furthermore, optogenetic activation of the LH‐LHb circuit attenuated the cocaine‐induced locomotion, while optogenetic inhibition of the LH‐LHb circuit increased it. In vivo extracellular recording found that the LH sent a glutamatergic projection to the LHb. These findings suggest that the LH glutamatergic projection to the LHb plays an active role in the modulation of cocaine‐induced psychomotor responses.

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“…[77] DRN 5-HT neurons also have a multifaceted role with respect to reward processing, encoding both reward and aversion signals, [129,130] and there are some contradictory findings about the reward property of the activation of DRN 5-HT neurons. [132][133][134][135][136][137][138] Furthermore, the activity of DRN 5-HT neurons is positively associated with physiological [95][96][97]100] and behavioral arousal levels. [104][105][106][107] On the other hand, these neurons are linked to behavioral inhibition, specifically acting to suppress impulsive behavior.…”

Section: Behavioral Inhibition and Impulsivitymentioning

confidence: 99%

“…[ 132 ] Additionally, activation of either Pet‐1‐ or Tph2‐positive 5‐HT neurons in the DRN causes place preference in the CPP test [ 133 ] and the real‐time place preference (RPP) test. [ 134 ] On the other hand, other studies reported that photoactivation of DRN 5‐HT neurons did not induce self‐administration behavior in ePet1‐Cre mice [ 135,136 ] and Tph2‐ChR2 transgenic mice, [ 137 ] nor lead to place preference in the RPP test in SERT‐Cre mice. [ 138 ]…”

Section: The Drn and Other Traits That Could Affect Aggressive Behaviormentioning

confidence: 99%

Aggression modulator: Understanding the multifaceted role of the dorsal raphe nucleus

Mitsui,

Takahashi

2024

BioEssays

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Aggressive behavior is instinctively driven behavior that helps animals to survive and reproduce and is closely related to multiple behavioral and physiological processes. The dorsal raphe nucleus (DRN) is an evolutionarily conserved midbrain structure that regulates aggressive behavior by integrating diverse brain inputs. The DRN consists predominantly of serotonergic (5‐HT:5‐hydroxytryptamine) neurons and decreased 5‐HT activity was classically thought to increase aggression. However, recent studies challenge this 5‐HT deficiency model, revealing a more complex role for the DRN 5‐HT system in aggression. Furthermore, emerging evidence has shown that non‐5‐HT populations in the DRN and specific neural circuits contribute to the escalation of aggressive behavior. This review argues that the DRN serves as a multifaceted modulator of aggression, acting not only via 5‐HT but also via other neurotransmitters and neural pathways, as well as different subsets of 5‐HT neurons. In addition, we discuss the contribution of DRN neurons in the behavioral and physiological aspects implicated in aggressive behavior, such as arousal, reward, and impulsivity, to further our understanding of DRN‐mediated aggression modulation.

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Dorsal Raphe Nucleus Serotoninergic Neurons Mediate Morphine Rewarding Effect and Conditioned Place Preference

Cited by 5 publications

References 39 publications

Divergent modulation of pain and anxiety by GABAergic neurons in the ventrolateral periaqueductal gray and dorsal raphe

Divergent modulation of pain and anxiety by GABAergic neurons in the ventrolateral periaqueductal gray and dorsal raphe

A hypothalamus‐habenula circuit regulates psychomotor responses induced by cocaine

Aggression modulator: Understanding the multifaceted role of the dorsal raphe nucleus

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