Anxiolytic effects of 5-HT1A receptors and anxiogenic effects of 5-HT2C receptors in the amygdala of mice

doi:10.1016/j.neuropharm.2011.09.002

Neuropharmacology

Volume 62, Issue 1, January 2012, Pages 474-484

https://doi.org/10.1016/j.neuropharm.2011.09.002 Get rights and content

Abstract

The aim of the present study is to test a hypothesis that 5-HT_1A and 5-HT_2C receptors in the amygdala play an important role in the regulation of anxiety behaviors. We examined alterations in anxiety-like behaviors after manipulation of the expression of 5-HT_1A and 5-HT_2C receptors in the amygdala using recombinant adenovirus approaches. Recombinant adenoviruses containing a 5-HT_1A promoter-controlled 5-HT_1A antisense sequence or a 5-HT_2C promoter-controlled 5-HT_2C sense sequence were injected into the amygdala. Elevated plus-maze (EPM) and open field tests were conducted to determine anxiety-like behavior and locomotor activity. Reductions in the expression of 5-HT_1A receptors in the amygdala significantly attenuated the time spent in the open arms of EPM and time spent in the center of an open field. Reduction in the percent of time spent in the open arms of EPM is negatively correlated with the density of 5-HT_1A receptors in the central amygdala. On the other hand, increased expression of 5-HT_2C receptors reduced the time spent in the open arms of EPM and time spent in the center of an open field. The reductions in the time spent and distance traveled in the open arms of EPM were correlated to the density of 5-HT_2C receptors in the basolateral nucleus of amygdala. These data suggest that amygdaloid 5-HT_1A receptors produce anxiolytic and 5-HT_2C receptors produce anxiogenic effects. Together, the present results demonstrate the important role of the amygdaloid 5-HT_1A and 5-HT_2C receptors in the regulation of anxiety-like behaviors.

This article is part of a Special Issue entitled ‘Anxiety and Depression’.

Highlights

► Altering 5-HT_1A and 5-HT_2C receptor expressions in the amygdala by Ad-Easy. ► Reduction of 5-HT_1A receptors in the amygdala increased anxiety-like behaviors. ► Increase of 5-HT_2C receptors in the amygdala increased anxiety-like behaviors. ► 5-HT_1A receptors in the CeA and 5-HT_2C receptors in the BLA regulate anxiety.

Introduction

Serotonin (5-HT) is known to regulate anxiety behaviors. Among the fifteen 5-HT receptors, 5-HT_1A and 5-HT_2C receptors have gained particular attention. 5-HT_1A receptor agonists produce anxiolytic effects (De Vry, 1995, Lacivita et al., 2008). Mice with a genetic deficit in 5-HT_1A receptors showed an increase in anxiety-like behaviors (Gross et al., 2000, Heisler et al., 1998, Olivier et al., 2001, Ramboz et al., 1998). On the other hand, a 5-HT agonist with a relatively high affinity for 5-HT_2C receptors, m-chlorophenylpiperazine (mCPP), induces anxiogenic effects (Gibson et al., 1994), which can be blocked by 5-HT_2C receptor antagonists (Bagdy et al., 2001, Hackler et al., 2007). 5-HT_2C receptor knockout mice displayed decreases in anxiety-like behavior (Heisler et al., 2007). These data suggest that activation of 5-HT_1A receptors may play anxiolytic effects, whereas stimulation of 5-HT_2C receptors produces an anxiogenic effect. However, the mechanisms and neurocircuitries mediating these effects of 5-HT_1A and 5-HT_2C receptors are still unclear.

The amygdala is known as a fear center. It is involved in the regulation of emotions and fear learning and memory (LeDoux, 2000). The amygdala can be divided into two subregions, the basolateral complex (including the lateral, basolateral and basomedial nuclei) and the centromedial subdivision (containing the central nucleus, medial nucleus and part of the bed nucleus of stria terminalis) (LeDoux, 2000, Sah et al., 2003). Evidence suggests that the basolateral complex receives sensory inputs of fear stimuli and conveys the information to the central nucleus, which further sends signals to other brain regions to express fear behaviors (LeDoux, 2000). The basolateral complex is vital for the acquisition of fear memory, whereas the central nucleus may be related to the expression of the fear memory. 5-HT_1A and 5-HT_2C receptors are relatively abundant in the amygdala. The 5-HT_1A receptors are mainly located in the central nucleus, whereas 5-HT_2C receptors are rich in the basolateral nucleus (Li et al., 1997, Li et al., 2000, Li et al., 2003). Our previous study demonstrated that 5-HT_1A receptors are decreased and 5-HT_2C receptors are increased in the amygdala of mice lacking 5-HT transporters (Li et al., 2000, Li et al., 2003). Consistent with the results, the 5-HT transporter knockout mice showed an increase in anxiety-like behaviors (Holmes et al., 2003b). Furthermore, stress-induced increases in c-fos expression in the amygdala are blunted in 5-HT_2C receptor knockout mice (Heisler et al., 2007). These data suggest that the amygdaloid 5-HT_1A and 5-HT_2C receptors may be involved in the regulation of anxiety-like behaviors.

Several studies have been reported on the role of amygdaloid 5-HT_1A (Gonzalez et al., 1996, Graeff et al., 1993, Zangrossi and Graeff, 1994) and 5-HT_2C receptors (Campbell and Merchant, 2003, Christianson et al., 2010, de Mello Cruz et al., 2005) in the regulation of anxiety-like behaviors in rats using pharmacological approaches. The results from these studies were not consistent, especially those concerning the effects of amygdaloid 5-HT_1A receptors on anxiety-like behaviors. For example, Graeff et al. reported an anxiogenic effect of activation of 5-HT_1A receptor in the amygdala (Graeff et al., 1993). On the other hand, Gonzalez et al. and Zangrossi and Graeff showed that activation of 5-HT_1A receptors in the amygdala did not alter anxiety-like behaviors tested by the EPM (Gonzalez et al., 1996, Graeff et al., 1993, Zangrossi and Graeff, 1994). Furthermore, these data were contradictory with the data observed in 5-HT_1A knockout mice and serotonin transporter knockout mice. In these mice, a lack or reduction of 5-HT_1A receptors in the amygdala increased anxiety-like behaviors (Gross et al., 2000, Heisler et al., 1998, Holmes et al., 2003a, Li et al., 2000, Olivier et al., 2001, Ramboz et al., 1998). In contrast, the effects of 5-HT_2C receptors in the amygdala were more consistent. Two studies reported that activation of 5-HT_2C receptors in the basolateral amygdala produced an anxiogenic effects in EPM test (Campbell and Merchant, 2003, de Mello Cruz et al., 2005), although locomotor activity was also reduced by the 5-HT_2C receptor agonists. Furthermore, Christianson et al. reported recently that 5-HT_2C receptors in the BLA are related to uncontrollable traumatic stress-induced anxiety-like behavior in rats (Christianson et al., 2010). To date, no study has reported using molecular approaches to investigate the effects of 5-HT_1A and 5-HT_2C receptors in the amygdala on the anxiety-like behaviors.

The aim of the present studies was to test the hypothesis that amygdaloid 5-HT_1A and 5-HT_2C receptors are related to anxiolytic and anxiogenic effects, respectively. Recombinant adenoviruses containing a 5-HT_1A promoter-controlled 5-HT_1A antisense sequence (P_1A-5-HT_1A-AS-Ad) or a 5-HT_2C promoter-controlled 5-HT_2C sense sequence (P_2C-5-HT_2C-S-Ad) was used to manipulate the expression of 5-HT_1A receptors and 5-HT_2C receptors in the amygdala. Since expression of 5-HT_1A antisense and 5-HT_2C sense sequences was controlled by 5-HT_1A and 5-HT_2C promoter, respectively, the alterations in the expression of 5-HT_1A and 5-HT_2C receptors selectively occurred in the 5-HT_1A and 5-HT_2C receptor-positive cells, respectively. The EPM, a typical test for anxiety-like behavior, was used to examine the impact of amygdaloid 5-HT_1A and 5-HT_2C receptor expression. Another behavioral test, the open field test, was used to exclude possible changes in the locomotor activity and was also used as an indicator for anxiety-like behavior in mice by measuring time spent in the center of the open field. These studies provided direct evidence concerning the involvement of amygdaloid 5-HT_1A and 5-HT_2C receptors in the regulation of anxiety behaviors.

Section snippets

Generation of recombinant adenovirus containing 5-HT_2C promoter-controlled 5-HT_2C sense sequence (P_2C-5-HT_2C-S-Ad)

Recombinant adenovirus containing 5-HT_1A promoter-controlled 5-HT_1A antisense sequence (P_1A-5-HT_1A-AS-Ad) was generated and evaluated, as described previously (Li et al., 2004). To generate P_2C-5-HT_2C-S-Ad, a fragment of 5-HT_2C promoter sequence (Forward primer: 5′-AGTTGCAGCCATCCTTTCTG-3′ and reverse primer: 5′-GCAAGTCGACCTCCTGTGG-3′ encoding 28–1822 bp, Access No. S62283) and the 5-HT_2C sense sequence (Forward primer: 5′-GGAGGTCGACTTGCCGGC-3′ and reverse primer: 5′-

Evaluation of P_2C-5-HT_2C-S-Ad

To manipulate the expression of 5-HT_2C receptors, we generated a recombinant adenovirus containing 5-HT_2C receptor sense sequence that is controlled by the 5-HT_2C promoter. In the process of the generation of P_2C-5-HT_2C-S-Ad, we found that the 5′ UTR of the 5-HT_2C receptor mRNA is required for the in vivo expression of 5-HT_2C receptors. Similar to the recombinant adenovirus containing 5-HT_1A receptor sequences shown in previous publication (Li et al., 2004), the P_2C-5-HT_2C-S-Ad only spreads in

Discussion

Stimulation of 5-HT_1A receptors and 5-HT_2C receptors produce anxiolytic and anxiogenic effects, respectively (Holmes, 2008). However, the neurocircuitries and brain regions mediating these effects are still unclear. In the present studies, we provide the first direct evidence, using molecular approaches, to demonstrate the involvement of amygdaloid 5-HT_1A and 5-HT_2C receptors in the regulation of anxiety-like behaviors. Reduced expression of 5-HT_1A receptors in the central nucleus of the

Acknowledgments

The authors thank Dr. Bert Vogelstin in The Johns Hopkins oncology center for kindly providing adenoviral vectors and Dr. Tong-Chuan He for his excellent technical advice in the generation of recombinant adenovirus. The authors thank Kate Davis and Yan Liu for their important technical assistance with the experiments. The authors also thank Dr. Nancy A Muma in the University of Kansas, who kindly provided feedback and proof-reading of the manuscript. The studies were supported by USPHS MH72938

References (42)

K. Abe et al.
Stimulation of basolateral amygdaloid serotonin 5-HT(2C) receptors promotes the induction of long-term potentiation in the dentate gyrus of anesthetized rats
Neuroscience Letters
(2009)
B.M. Campbell et al.
Serotonin 2C receptors within the basolateral amygdala induce acute fear-like responses in an open-field environment
Brain Research
(2003)
J.P. Christianson et al.
5-hydroxytryptamine 2C receptors in the basolateral amygdala are involved in the expression of anxiety after uncontrollable traumatic stress
Biological Psychiatry
(2010)
A.M. Cornelio et al.
Anxiogenic-like effects of mCPP microinfusions into the amygdala (but not dorsal or ventral hippocampus) in mice exposed to elevated plus-maze
Behavioural Brain Research
(2007)
I. Ehrlich et al.
Amygdala inhibitory circuits and the control of fear memory
Neuron
(2009)
E.L. Gibson et al.
Evidence that mCPP-induced anxiety in the plus-maze is mediated by postsynaptic 5-HT2C receptors but not by sympathomimetic effects
Neuropharmacology
(1994)
L.E. Gonzalez et al.
5-HT1A and benzodiazepine receptors in the basolateral amygdala modulate anxiety in the social interaction test, but not in the elevated plus-maze
Brain Research
(1996)
F.G. Graeff et al.
Role of the amygdala and periaqueductal gray in anxiety and panic
Behavioural Brain Research
(1993)
C. Gross et al.
Altered fear circuits in 5-HT1A receptor KO mice
Biological Psychiatry
(2000)
A. Holmes
Genetic variation in cortico-amygdala serotonin function and risk for stress-related disease
Neuroscience and Biobehavioral Reviews
(2008)

A. Holmes et al.

Behavioral profile of wild mice in the elevated plus-maze test for anxiety

Physiology & Behavior

(2000)

Q. Li et al.

Autoradiographic evidence for differential G-protein coupling of 5-HT1A receptors in rat brain: lack of effect of repeated injections of fluoxetine

Brain Research

(1997)

M.J. Millan

The neurobiology and control of anxious states

Progress in Neurobiology

(2003)

M. Toth

5-HT1A receptor knockout mouse as a genetic model of anxiety

European Journal of Pharmacology

(2003)

G. Bagdy et al.

Anxiety-like effects induced by acute fluoxetine, sertraline or m-CPP treatment are reversed by pretreatment with the 5-HT2C receptor antagonist SB-242084 but not the 5-HT1A receptor antagonist WAY-100635

International Journal of Neuropsychopharmacology

(2001)

A.P. de Mello Cruz et al.

Behavioral effects of systemically administered MK-212 are prevented by ritanserin microinfusion into the basolateral amygdala of rats exposed to the elevated plus-maze

Psychopharmacology (Berl)

(2005)

J. De Vry

5-HT 1A receptor agonists: recent developments and controversial issues

Psychopharmacology (Berl)

(1995)

S. Duvarci et al.

Characterization of fear memory reconsolidation

Journal of Neuroscience

(2004)

F.G. Graeff et al.

The dual role of serotonin in defense and the mode of action of antidepressants on generalized anxiety and panic disorders

Cent Nerv Syst Agents Med Chem

(2010)

L. Groenink et al.

5-HT1A receptor and 5-HT1B receptor knockout mice in stress and anxiety paradigms

Behavioural Pharmacology

(2003)

E.A. Hackler et al.

5-Hydroxytryptamine2C receptor contribution to m-chlorophenylpiperazine and N-methyl-beta-carboline-3-carboxamide-induced anxiety-like behavior and limbic brain activation

Journal of Pharmacology and Experimental Therapeutics

(2007)

Cited by (62)

Pharmacological evaluation of the anxiolytic-like effects of an aqueous extract of the Raphanus sativus L. sprouts in mice
2023, Biomedicine and Pharmacotherapy
Raphanus sativus L. (Brassicaceae), commonly known as radish, is consumed worldwide as a vegetable. However, its benefits on mental health are unknown. The aim of this study was to evaluate its anxiolytic-like effects and safety using different experimental models. An aqueous extract of R. sativus sprouts (AERSS) was pharmacologically evaluated by intraperitoneal route (i.p.) at 10, 30, and 100 mg/kg and orally (p.o.) at 500 mg/kg on behavior by using open-field and plus-maze tests. In addition, its acute toxicity (LD₅₀) was determined by the Lorke's method. Diazepam (1 mg/kg, i.p.) and buspirone (4 mg/kg, i.p.) were the reference drugs. A significant and anxiolytic-like dosage of AERSS (30 mg/kg, i.p.) resembling the effects of reference drugs was chosen to explore the involvement of GABA_A/BDZs site (flumazenil, 5 mg/kg, i.p.) and serotonin 5-HT_1A receptors (WAY100635, 1 mg/kg, i.p.) as a possible mechanism of action. A 500 mg/kg, p.o. dosage of AERSS produced an anxiolytic-like response equivalent to 100 mg/kg, i.p. No acute toxicity was observed since a LD₅₀ > 2000 mg/kg, i.p. The phytochemical analysis allowed the identification and quantification of major presence of sulforaphene (2500 µM), sulforaphane (15 µM), iberin (0.75 µM), and indol-3-carbinol (0.75 µM), as major constituents. Both the GABA_A/BDZs site and serotonin 5-HT_1A receptors were involved in the anxiolytic-like activity of AERSS, depending on the pharmacological parameter or the experimental assay tested. Our results demonstrate that the anxiolytic activity of R. sativus sprouts involves GABA_A/BDZs site and serotonin 5-HT_1A receptors supporting its health benefits in the treatment of anxiety beyond the satisfaction of basic nutritional needs.
Repeated early-life exposure to anaesthesia and surgery causes subsequent anxiety-like behaviour and gut microbiota dysbiosis in juvenile rats
2023, British Journal of Anaesthesia
Early exposure to general anaesthetics for multiple surgeries or procedures might negatively affect brain development. Recent studies indicate the importance of microbiota in the development of stress-related behaviours. We determined whether repeated anaesthesia and surgery in early life cause gut microbiota dysbiosis and anxiety-like behaviours in rats.
Sprague Dawley rats received skin incisions under sevoflurane 2.3 vol% three times during the first week of life. After 4 weeks, gut microbiota, anxiety-related behaviours, hippocampal serotonergic activity, and plasma stress hormones were tested. Subsequently, we explored the effect of faecal microbiota transplantation from multiple anaesthesia/surgery exposed rats after administration of a cocktail of antibiotics on anxiety-related behaviours.
Anxiety-like behaviours were observed in rats with repeated anaesthesia/surgery exposures: In the OF test, multiple anaesthesia/surgery exposures induced a decrease in the time spent in the centre compared to the Control group (P<0.05, t=3.05, df=16, Cohen’s d=1.44, effect size=0.58). In the EPM test, rats in Multiple AS group travelled less (P<0.05, t=5.09, df=16, Cohen’s d=2.40, effective size=0.77) and spent less time (P<0.05, t=3.58, df=16, Cohen’s d=1.69, effect size=0.65) in the open arms when compared to the Control group. Repeated exposure caused severe gut microbiota dysbiosis, with exaggerated stress response (P<0.01, t=4.048, df=16, Cohen's d=−1.91, effect size=−0.69), a significant increase in the hippocampal concentration of 5-hydroxytryptamine (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) (P<0.05; for 5-HT: t=3.33, df=18, Cohen’s d=−1.49, effect size=−0.60; for 5-HIAA: t=3.12, df=18, Cohen’s d=−1.40, effect size=−0.57), and changes in gene expression of serotonergic receptors later in life (for Htr1a: P<0.001, t=4.49, df=16, Cohen’s d=2.24, effect size=0.75; for Htr2c: P<0.01, t=3.72, df=16, Cohen’s d=1.86, effect size=0.68; for Htr6: P<0.001, t=7.76, df=16, Cohen’s d=3.88, effect size=0.89). Faecal microbiota transplantation led to similar anxiety-like behaviours and changes in the levels of 5-hydroxytryptamine and 5-hydroxyindoleacetic acid.
Gut microbiota dysbiosis caused by early repeated exposure to anaesthesia and surgery affects long-term anxiety emotion behaviours in rats.
Biased agonism in drug discovery: Is there a future for biased 5-HT<inf>1A</inf> receptor agonists in the treatment of neuropsychiatric diseases?
2021, Pharmacology and Therapeutics
Serotonin (5-HT) is one of the fundamental neurotransmitters that contribute to the information essential for an organism's normal, physiological function. Serotonin acts centrally and systemically. The 5-HT_1A receptor is the most widespread serotonin receptor, and participates in many brain-related disorders, including anxiety, depression, and cognitive impairments. The 5-HT_1A receptor can activate several different biochemical pathways and signals through both G protein-dependent and G protein-independent pathways. Preclinical experiments indicate that distinct signaling pathways in specific brain regions may be crucial for antidepressant-like, anxiolytic-like, and procognitive responses. Therefore, the development of new ligands that selectively target a particular signaling pathway(s) could open new possibilities for more effective and safer pharmacotherapy. This review discusses the current state of preclinical studies focusing on the concept of functional selectivity (biased agonism) regarding the 5-HT_1A receptor and its role in antidepressant-like, anxiolytic-like, and procognitive regulation. Such work highlights not only the differential effects of targeted autoreceptors, vs. heteroreceptors, but also the importance of targeting specific downstream intracellular signaling processes, thereby enhancing favorable over unfavorable signaling activation.
Blockade of pre-synaptic and post-synaptic GABA<inf>B</inf> receptors in the lateral habenula produces different effects on anxiety-like behaviors in 6-hydroxydopamine hemiparkinsonian rats
2021, Neuropharmacology
Although the output of the lateral habenula (LHb) controls the activity of midbrain dopaminergic and serotonergic systems, which are implicated in the pathophysiology of anxiety, it is not known how blockade of GABA_B receptors in the region affects anxiety-like behaviors, particularly in Parkinson's disease-related anxiety. In this study, unilateral 6-hydroxydopamine lesions of the substantia nigra pars compacta in rats induced anxiety-like behaviors, led to hyperactivity of LHb neurons and decreased the level of extracellular dopamine (DA) in the basolateral amygdala (BLA) compared to sham-lesioned rats. Intra-LHb injection of pre-synaptic GABA_B receptor antagonist CGP36216 produced anxiolytic-like effects, while the injection of post-synaptic GABA_B receptor antagonist CGP35348 induced anxiety-like responses in both groups. Further, intra-LHb injection of CGP36216 decreased the firing rate of the neurons, and increased the GABA/glutamate ratio in the LHb and release of DA and serotonin (5-HT) in the BLA; conversely, CGP35348 increased the firing rate of the neurons and decreased the GABA/glutamate ratio and release of DA and 5-HT in sham-lesioned and the lesioned rats. However, the doses of the antagonists producing these behavioral effects in the lesioned rats were lower than those in sham-lesioned rats, and the duration of action of the antagonists on the firing rate of the neurons and release of the neurotransmitters was prolonged in the lesioned rats. Collectively, these findings suggest that pre-synaptic and post-synaptic GABA_B receptors in the LHb are involved in the regulation of anxiety-like behaviors, and degeneration of the nigrostriatal pathway up-regulates function and/or expression of these receptors.
Serotonergic modulation of basolateral amygdala nucleus in the extinction of reward-driven learning: The role of 5-HT bioavailability and 5-HT<inf>1A</inf> receptor
2021, Behavioural Brain Research
Serotonin (5-HT) neurotransmission has been associated with reward-related behaviour. Moreover, the serotonergic system modulates the basolateral amygdala (BLA), a structure involved in reward encoding, and reward prediction error. However, the role played by 5-HT on BLA during a reward-driven task has not been fully elucidated. In this paper, we investigated whether serotonergic modulation of the BLA is involved in reward-driven learning. To this end, we trained Long Evans rats in an operant conditioning task, and examined the effects of fluoxetine treatment (a selective serotonin reuptake inhibitor, 10 mg/kg) in combination with BLA lesions with NMDA (20 mg/mL) on extinction learning. We also investigated whether intra-BLA injection of the serotonergic 5-HT_1A receptor agonist 8-OH DPAT, or antagonist WAY-100635, alters extinction performance. We found that fluoxetine treatment strongly accelerated extinction learning, while BLA lesions partially reverted this effect and slightly impaired consolidation of extinction. Stimulation and inhibition of 5-HT_1A receptors in BLA induced opposite effects to those of fluoxetine, impairing or accelerating extinction performance, respectively. Our findings suggest that 5-HT modulates reward-driven learning, and 5-HT_1A receptors located in the BLA are relevant for extinction.
PNU282987 alleviates Aβ-induced anxiety and depressive-like behaviors through upregulation of α7nAChR by ERK-serotonin receptors pathway
2020, Neuroscience Letters
Citation Excerpt :
#p < 0.05, compared with control mice, *p < 0.05 compared with Aβ1−42-injected mice. Anxiety and depression-like behaviors have been reported to be regulated by 5-HT1AR and 5-HT2CR in the amygdala [6]. Therefore, we assessed the effect of Aβ1−42 on 5-HT1AR and 5-HT2CR levels.
Patients with Alzheimer's disease often undergo anxiety and depression. Our previous studies have shown that α7nAChR protects against Aβ-induced neurotoxicity via downregulation of p38 and JNK MAPKs, but the role of α7nAChR on Aβ-induced anxiety and depressive-like behaviors and the effect of α7nAChR on the regulation of MAPKs pathways remain unknown. To examine the effects of α7nAChR and MAPKs pathways on Aβ-induced anxiety and depression-like behaviors and to explore their relationships between them, elevated plus maze, open field and forced swim tests were performed. Protein levels of 5-HT_1A receptor, 5-HT_2C receptor, α7nAChR, t-ERK1/2 and p-ERK1/2 in the amygdala were analyzed by western blotting and immunostaining. Our study found out that Aβ oligomers induced anxiety and depression-like behaviors in C56BL/6 mice with open field, elevated plus maze and forced swim tests. However, activation of α7nAChR or inhibition of ERK pathways showed significant antidepressant and anxiolytic-like effects on Aβ-injected mice. Moreover, Aβ significantly decreased the level of 5-HT_1A receptor but increased the level of 5-HT_2C receptor in the basolateral amygdala. Treatment with α7nAChR agonist PNU282987 or ERK inhibitor U0126 reversed Aβ-induced 5-HT_1A and 5-HT_2C receptor changes. Moreover, activation of α7nAChR inhibited ERK pathway in the amygdala of Aβ₁₋₄₂-injected mice. Our study provides a new insight into the mechanism of α7nAChR in Aβ-induced depression and anxiety-related symptoms through the regulation of ERK1/2 pathway and the potential association with serotonin receptors. Together, our data suggests that α7nAChR is protective against Aβ-induced anxiety and depression-like behaviors in mice.

View all citing articles on Scopus

¹: Present address: Chongqing University of Medical Science, Chongqing, China.

View full text

Anxiolytic effects of 5-HT1A receptors and anxiogenic effects of 5-HT2C receptors in the amygdala of mice

Abstract

Highlights

Introduction

Section snippets

Generation of recombinant adenovirus containing 5-HT2C promoter-controlled 5-HT2C sense sequence (P2C-5-HT2C-S-Ad)

Evaluation of P2C-5-HT2C-S-Ad

Discussion

Acknowledgments

Neuroscience Letters

Brain Research

Biological Psychiatry

Behavioural Brain Research

Neuron

Neuropharmacology

Brain Research

Behavioural Brain Research

Biological Psychiatry

Neuroscience and Biobehavioral Reviews

Physiology & Behavior

Brain Research

Progress in Neurobiology

European Journal of Pharmacology

Anxiety-like effects induced by acute fluoxetine, sertraline or m-CPP treatment are reversed by pretreatment with the 5-HT2C receptor antagonist SB-242084 but not the 5-HT1A receptor antagonist WAY-100635

International Journal of Neuropsychopharmacology

Behavioral effects of systemically administered MK-212 are prevented by ritanserin microinfusion into the basolateral amygdala of rats exposed to the elevated plus-maze

Psychopharmacology (Berl)

5-HT 1A receptor agonists: recent developments and controversial issues

Psychopharmacology (Berl)

Characterization of fear memory reconsolidation

Journal of Neuroscience

The dual role of serotonin in defense and the mode of action of antidepressants on generalized anxiety and panic disorders

Cent Nerv Syst Agents Med Chem

5-HT1A receptor and 5-HT1B receptor knockout mice in stress and anxiety paradigms

Behavioural Pharmacology

5-Hydroxytryptamine2C receptor contribution to m-chlorophenylpiperazine and N-methyl-beta-carboline-3-carboxamide-induced anxiety-like behavior and limbic brain activation

Journal of Pharmacology and Experimental Therapeutics

Anxiolytic effects of 5-HT_1A receptors and anxiogenic effects of 5-HT_2C receptors in the amygdala of mice

Generation of recombinant adenovirus containing 5-HT_2C promoter-controlled 5-HT_2C sense sequence (P_2C-5-HT_2C-S-Ad)

Evaluation of P_2C-5-HT_2C-S-Ad