Acute and Chronic Nicotine Exposures Differentially Affect Central Serotonin 2A Receptor Function: Focus on the Lateral Habenula

Nicotine addiction is a serious public health problem causing millions of deaths worldwide. Serotonin (5-hydroxytryptamine; 5-HT) is involved in central nervous system (CNS) nicotine effects, and it has been suggested as a promising pharmacological target for smoking cessation. In this regard, what is particularly interesting are the 5-HT2A receptors (5-HT2ARs) and the lateral habenula (LHb), a central area in nicotine addiction that we showed to be under a strong 5-HT2AR-modulation. Single-cell extracellular recording of LHb neurons was used to study the 5-HT2AR function by intravenously administrating the potent agonist TCB-2. Acute nicotine (2 mg/kg, intraperitoneal, i.p.) and chronic nicotine (6 mg/kg/day for 14 days) differently affected both the 5-HT2AR-immuno reactive (IR) neuron number and the 5-HT2AR immunostaining area in the different brain areas studied. After acute nicotine, TCB-2 cumulative doses (5–640 µg/kg, intravenous, i.v.) bidirectionally affected the activity of 74% of LHb recorded neurons. After chronic nicotine treatment, TCB-2 was only capable of decreasing the LHb firing rate. The expression of 5-HT2AR under acute and chronic nicotine exposure was studied in the LHb and in other brain areas involved in nicotine effects in rats by using immunohistochemistry. These data reveal that acute and chronic nicotine differentially affect the 5-HT2AR function in different brain areas and this might be relevant in nicotine addiction and its treatment.

Download Full-text

Lateral Habenula 5-HT2C Receptor Function Is Altered by Acute and Chronic Nicotine Exposures

International Journal of Molecular Sciences ◽

10.3390/ijms22094775 ◽

2021 ◽

Vol 22 (9) ◽

pp. 4775

Author(s):

Cristiano Bombardi ◽

Francis Delicata ◽

Claudio Tagliavia ◽

Annamaria Grandis ◽

Massimo Pierucci ◽

...

Keyword(s):

Drug Target ◽

Nicotine Addiction ◽

The Other ◽

Nicotine Exposure ◽

Receptor Function ◽

Lateral Habenula ◽

Nicotine Treatment ◽

Chronic Nicotine ◽

Chronic Nicotine Treatment

Serotonin (5-HT) is important in some nicotine actions in the CNS. Among all the 5-HT receptors (5-HTRs), the 5-HT2CR has emerged as a promising drug target for smoking cessation. The 5-HT2CRs within the lateral habenula (LHb) may be crucial for nicotine addiction. Here we showed that after acute nicotine tartrate (2 mg/kg, i.p.) exposure, the 5-HT2CR agonist Ro 60-0175 (5–640 µg/kg, i.v.) increased the electrical activity of 42% of the LHb recorded neurons in vivo in rats. Conversely, after chronic nicotine treatment (6 mg/kg/day, i.p., for 14 days), Ro 60-0175 was incapable of affecting the LHb neuronal discharge. Moreover, acute nicotine exposure increased the 5-HT2CR-immunoreactive (IR) area while decreasing the number of 5-HT2CR-IR neurons in the LHb. On the other hand, chronic nicotine increased both the 5-HT2CR-IR area and 5-HT2CR-IR LHb neurons in the LHb. Western blot analysis confirmed these findings and further revealed an increase of 5-HT2CR expression in the medial prefrontal cortex after chronic nicotine exposure not detected by the immunohistochemistry. Altogether, these data show that acute and chronic nicotine exposure differentially affect the central 5-HT2CR function mainly in the LHb and this may be relevant in nicotine addiction and its treatment.

Download Full-text

Role of the lateral habenula in nicotine addiction: interaction with the dopaminergic system

Intrinsic Activity ◽

10.25006/ia.4.s2-a18.47 ◽

2016 ◽

Vol 4 (Suppl. 2) ◽

pp. A18.47

Author(s):

Massimo Pieruggi

Keyword(s):

Dopaminergic System ◽

Nicotine Addiction ◽

Lateral Habenula

Download Full-text

BDNF and nicotine dependence: associations and potential mechanisms

Reviews in the Neurosciences ◽

10.1515/revneuro-2020-0044 ◽

2020 ◽

Vol 0 (0) ◽

Author(s):

Zeyi Huang ◽

Daichao Wu ◽

Xilin Qu ◽

Meixiang Li ◽

Ju Zou ◽

...

Keyword(s):

Nicotine Dependence ◽

Nicotinic Acetylcholine Receptors ◽

Acetylcholine Receptors ◽

Molecular Mechanisms ◽

Public Health Problem ◽

Nicotine Addiction ◽

Tyrosine Kinase Receptor ◽

Bdnf Expression ◽

High Affinity Receptor ◽

The Brain

AbstractSmoking is the leading preventable cause of death worldwide and tobacco addiction has become a serious public health problem. Nicotine is the main addictive component of tobacco, and the majority of people that smoke regularly develop nicotine dependence. Nicotine addiction is deemed to be a chronic mental disorder. Although it is well known that nicotine binds to the nicotinic acetylcholine receptors (nAChRs) and activates the mesolimbic dopaminergic system (MDS) to generate the pleasant and rewarding effects, the molecular mechanisms of nicotine addiction are not fully understood. Brain-derived neurotrophic factor (BDNF) is the most prevalent growth factor in the brain, which regulates neuron survival, differentiation, and synaptic plasticity, mainly through binding to the high affinity receptor tyrosine kinase receptor B (TrkB). BDNF gene polymorphisms are associated with nicotine dependence and blood BDNF levels are altered in smokers. In this review, we discussed the effects of nicotine on BDNF expression in the brain and summarized the underlying signaling pathways, which further indicated BDNF as a key regulator in nicotine dependence. Further studies that aim to understand the neurobiological mechanism of BDNF in nicotine addcition would provide a valuable reference for quitting smoking and developing the treatment of other addictive substances.

Download Full-text