Serotonergic treatment normalizes midbrain dopaminergic neuron increase after periaqueductal gray stimulation

Abstract

Background: Electrical stimulation of the dorsolateral periaqueductal gray (dlPAG) in rats has been shown to elicit panic-like behaviour and can be a useful tool for modelling anticipatory fear and agoraphobia. Methods: In this study, we further analysed our previous data on the effects of escitalopram (a selective serotonin reuptake inhibitor, SSRI) and buspirone (a 5-HT1A receptor partial agonist) on dlPAG-induced anticipatory fear behaviour in a rat model using freezing as a measure. We then used tyrosine hydroxylase (TH) immunohistochemistry to probe the effects on dopaminergic neurons. Results: Although acute treatment of escitalopram, but not buspirone, was effective in reducing anticipatory freezing behaviour, chronic administrations of both drugs were comparably effective. We found that the number of dopaminergic neurons in the ventral tegmental area (VTA) was lowered in both chronic buspirone and escitalopram groups. We showed a strong correlation between the number of dopaminergic neurons and freezing in the VTA. We further showed positive correlations between dopaminergic neurons in the VTA and substantia nigra pars compacta in escitalopram and buspirone groups, respectively. Limitations: Although our data strongly hint to a role of dopaminergic mechanisms in the dlPAG induced fear response, more in-depth studies with larger sample sizes are needed to understand the neuronal mechanisms underlying the interactions between serotonergic drugs and dopaminergic cell number and fear behavior. Conclusion: Chronic treatment with an SSRI and a 5-HT1A agonist decrease the number of dopaminergic neurons in the VTA. These effects seem to be associated with reduced dlPAG-induced anticipatory freezing behaviour.

Distribution and inter-regional relationship of amyloid-beta plaque deposition in a 5xFAD mouse model of Alzheimer’s disease

“…We also did not detect Aβ deposition in the periaqueductal gray of 5xFAD mice, which contradicts the findings in a post-mortem AD brain study that observed senile plaques in the periaqueductal gray in 81% of samples ( Parvizi et al, 2000 ). The periaqueductal gray is a major component of brainstem that has pivotal roles in autonomic function, behavior, memory formation, and emotional response to aversive events ( Lim et al, 2008 ; Lim et al, 2010 ; Temel et al, 2012 ; Tan et al, 2020b ). The absence of Aβ deposition in the periaqueductal gray in 5xFAD mice might represent an inability to recapitulate the Aβ pathological characteristics of human AD.…”

“…The experiment was conducted as previously described to evaluate locomotor function ( Lim et al, 2016 ; Tan et al, 2020b ). The test was conducted in an enclosed square arena (40 cm × 40 cm × 40 cm) in dim light condition (30 ± 5 lux).…”

Prelimbic Cortical Stimulation Induces Antidepressant-like Responses through Dopaminergic-Dependent and -Independent Mechanisms

“…After 21 days of CUS, animals were subjected to electrical stimulation (1 h daily HFS for two weeks; from CUS day [22][23][24][25][26][27][28][29][30][31][32][33][34][35][36] and behavioral testing to assess anxiety, anhedonia, behavioral despair or antidepressant-like activities. Behavioral testing was conducted on specific days in weeks 4 and 5 of CUS (i.e., CUS day [20][21][22][23][24][25][26][27][28][29][30][31][32][33][34][35]. Stressors were applied continuously throughout the entire experiment except during the behavioral testing.…”

“…Blood samples were collected on the day before the CUS procedure and after 1 h of HFS PrL on the day of sacrifice. The sucrose intake test was conducted after 3 weeks of CUS (on day [20][21][22] and at week 4 after HFS PrL (on day [30][31][32]. Animals were categorized as either susceptible or resilient to CUS-induced depression based on the sucrose intake test after week 3 of CUS.…”

“…Animals immediately received an injection of sodium pentobarbital (Dorminal 20%, Alfasan, Woerden, Holland) and then intracardially perfused with 4% paraformaldehyde fixative solution. Brains were removed and serially cut into 30 µm coronal sections and stored at −80 • C. Histological staining for tyrosine hydroxylase-immunoreactive (TH-ir) cells was carried out as previously described [32]. In brief, brain sections were incubated with rabbit antityrosine hydroxylase (ab112, 1:1000; Abcam, Cambridge, MA, USA) overnight at 4 • C with constant shaking.…”