5 research outputs found
Vitamin D 3 Receptor Activation Rescued Corticostriatal Neural Activity and Improved Motor Function in –D 2 R Tardive Dyskinesia Mice Model
Haloperidol-induced dyskinesia has been linked to a reduction in dopamine activity characterized
by the inhibition of dopamine receptive sites on D2-receptor (D2R). As a result of D2R inhibition,
calcium-linked neural activity is affected and seen as a decline in motor-cognitive function after
prolonged haloperidol use in the treatment of psychotic disorders. In this study, we have elucidated
the relationship between haloperidol-induced tardive dyskinesia and the neural activity in
motor cortex (M1), basal nucleus (CPu), prefrontal cortex (PFC) and hippocampus (CA1). Also, we
explored the role of Vitamin D3 receptor (VD3R) activation as a therapeutic target in improving
motor-cognitive functions in dyskinetic mice. Dyskinesia was induced in adult BALB/c mice after
28 days of haloperidol treatment (10 mg/Kg; intraperitoneal). We established the presence of abnormal
involuntary movements (AIMs) in the haloperidol treated mice (−D2) through assessment
of the threshold and amplitude of abnormal involuntary movements (AIMs) for the Limbs (Li) and
Orolingual (Ol) area (Li and Ol AIMs). As a confirmatory test, the dyskinetic mice (−D2) showed
high global AIMs score when compared with the VD3RA intervention group (−D2/+VDR) for Li and Ol AIMs. Furthermore, in the behavioral tests, the dyskinetic mice exhibited a decrease in latency
of fall (LOF; Rotarod-P < 0.05), climbing attempts (Cylinder test; P < 0.05) and latency of Turning
(Parallel bar test; LOT-P < 0.05) when compared with the control. The reduced motor function in
dyskinetic mice was associated with a decline in CPu-CA1 burst frequencies and an increase in
M1-PFC cortical activity. However, after VD3RA intervention (−D2/+VDR), 100 mg/Kg for 7 days,
CPu-CA1 burst activity was restored leading to a decrease in abnormal movement, and an increase
in motor function. Ultimately, we deduced that VD3RA activation reduced the threshold of abnormal
movement in haloperidol induced dyskinesia
Vitamin D3 Receptor Activation Rescued Corticostriatal Neural Activity and Improved Motor-Cognitive Function in −D2R Parkinsonian Mice Model
Background: fourth generation antipsychotics have been implicated in the blockade of calcium
signalling through inhibition of dopamine receptive sites on dopaminergic D2 Receptor (D2R). As a
result of the abnormal calcium signalling associated with D2R inhibition, changes occur in the motor
and memory neural axis leading to the observed behavioural deficits after prolonged haloperidol.
Thus, Vitamin D3 receptor (VD3R), a calcium controlling receptor in the striatum can be targeted
to relief the neurological symptoms associated with haloperidol (−D2R) induced PD. Aim:
This study sets to investigate the role of VD3R activation in vitro and in vivo after haloperidolinduced
Dopaminergic (D2R) blockade. In addition, we examined the associated neural activity
and behavioural changes in parkinsonian and VDRA intervention mice. Methods: Dopaminergic
D2R inhibition was investigated in vitro using Melanocytes isolated from the scale of a Tilapia. In
four separate set ups, the cells were cultured in calcium free Ringer’s solution as follows; 300 μM
haloperidol, 100 μM VD3, 100 mM calcium chloride and a combination of 300 μM haloperidol
and 100 μM VD3. Subsequently, dopaminergic vesicle accumulation and calcium signalling were observed in bright field microscopy using blue and green fluorescence probes. In the second phase,
PD was induced in adult BALB/c mice (−D2; n = 8) after 14 days of intraperitoneal haloperidol
treatment (10 mg/Kg). A set of n = 4 mice were untreated (−D2) while the other group (n = 4) received
100 mg/Kg of VD3 for 7 days (−D2/+VDR). The control groups (n = 4 each) were treated with
normal saline (NS) and VD3 (+VDR) for 14 days. At the end of the treatment phase, the animals
were assessed in Rotarod, parallel bar-, cylinder-, Y-Maze-, one trial place recognition- and novel
object recognition-(NOR) tests. Neural activity was measured using chronic electrode implants
placed in the M1 (motor cortex), CPu (striatum), CA1 (hippocampus) and PFC (prefrontal cortex).
Neural activity was compared with the outcomes of behavioural tests for memory and motor functions
and data was expressed as mean ± SEM (analysed using ANOVA with Tukey post-hoc test,
significant level was set at 0.05). Results/Discussion: in vitro outcomes show that VDR increase
calcium signalling and reverses the effect of haloperidol; specifically by reducing dopaminergic
vesicle accumulation in the cell body. Similarly, in vivo neural recordings suggest an increase in
calcium hyperpolarization currents in the CPu and PFC of intervention mice (−D2/+VDR) when
compared with the parkinsonian mice (−D2). These animals (−D2/+VDR) also recorded an improvement
in spatial working memory and motor function versus the Parkinsonian mice (−D2).
These outcomes suggest the role of CPu-PFC corticostriatal outputs in the motor-cognitive decline
seen in parkinsonian mice. Similarly, VDRA reduced the neural deficits through restoration of calcium
currents (burst activities) in the intervention mice (−D2/+VDR). Conclusion: VDRA treatment
reduced the motor-cognitive defects observed in haloperidol induced PD. Our findings suggest the
role of VDRA in restoration of calcium currents associated with PFC and CPu corticostriatal outputs
seen as burst frequencies in in vivo neural recording
Vitamin D 3 Receptor Activation Rescued Corticostriatal Neural Activity and Improved Motor Function in –D 2 R Tardive Dyskinesia Mice Model
Haloperidol-induced dyskinesia has been linked to a reduction in dopamine activity characterized
by the inhibition of dopamine receptive sites on D2-receptor (D2R). As a result of D2R inhibition,
calcium-linked neural activity is affected and seen as a decline in motor-cognitive function after
prolonged haloperidol use in the treatment of psychotic disorders. In this study, we have elucidated the relationship between haloperidol-induced tardive dyskinesia and the neural activity in
motor cortex (M1), basal nucleus (CPu), prefrontal cortex (PFC) and hippocampus (CA1). Also, we
explored the role of Vitamin D3 receptor (VD3R) activation as a therapeutic target in improving
motor-cognitive functions in dyskinetic mice. Dyskinesia was induced in adult BALB/c mice after
28 days of haloperidol treatment (10 mg/Kg; intraperitoneal). We established the presence of abnormal involuntary movements (AIMs) in the haloperidol treated mice (−D2) through assessment
of the threshold and amplitude of abnormal involuntary movements (AIMs) for the Limbs (Li) and
Orolingual (Ol) area (Li and Ol AIMs). As a confirmatory test, the dyskinetic mice (−D2) showed
high global AIMs score when compared with the VD3RA intervention group (−D2/+VDR) for Li and Ol AIMs. Furthermore, in the behavioral tests, the dyskinetic mice exhibited a decrease in latency
of fall (LOF; Rotarod-P < 0.05), climbing attempts (Cylinder test; P < 0.05) and latency of Turning
(Parallel bar test; LOT-P < 0.05) when compared with the control. The reduced motor function in
dyskinetic mice was associated with a decline in CPu-CA1 burst frequencies and an increase in
M1-PFC cortical activity. However, after VD3RA intervention (−D2/+VDR), 100 mg/Kg for 7 days,
CPu-CA1 burst activity was restored leading to a decrease in abnormal movement, and an increase
in motor function. Ultimately, we deduced that VD3RA activation reduced the threshold of abnormal movement in haloperidol induced dyskinesia
Vitamin D 3 Receptor Activation Rescued Corticostriatal Neural Activity and Improved Motor - Cognitive Function in − D 2 R Parkinsonian Mice Model
fourth generation antipsychotics have been implicated in the blockade of calcium
signalling through inhibition of dopamine receptive sites on dopaminergic D
2
Receptor (D
2
R). As a
result of the
abnormal calcium signalling associated with D
2
R inhibition, changes occur in the m
o-
tor and memory neural axis leading to the observed behavioural deficits after prolonged halope
r-
idol. Thus, Vitamin D
3
receptor (VD
3
R), a calcium controlling receptor in the
striatum can be ta
r-
geted to relief the neurological symptoms associated with haloperidol (
−
D
2
R) induced PD.
Aim:
This study sets to investigate the role of VD3R activation
in vitro
and
in vivo
after haloperidol
-
induced Dopaminergic (D
2
R) blockade. In addi
tion, we examined the associated neural activity
and behavioural changes in parkinsonian and VDRA intervention mice.
Methods: Dopaminergic
D
2
R inhibition was investigated
in vitro
using Melanocytes isolated from the scale of a Tilapia. In
four separate set ups, the cells were cultured in calcium free Ringer’s solution as follows; 300
μM
haloperidol, 100
μM VD
3
, 100
mM calcium chloride and a combination of 300
μM haloperidol
and
100
μM VD
3
. Subsequently, dopaminergic vesicle accumulation and calcium signalling were observed in bright field microscopy using blue and green fluorescence probes. In the second phase,
PD was induced in adult BALB/c mice (
−
D
2
; n
=
8) after 14 days of
intraperitoneal haloperidol
treatment (10
mg/Kg). A set of n
=
4 mice were untreated (
−
D
2
) while the other group (n
=
4) r
e-
ceived 100
mg/Kg of VD
3
for 7
days (
−
D
2
/+VDR). The control groups (n
=
4 each) were treated with
normal saline (NS) and VD
3
(+VDR) fo
r 14 days. At the end of the treatment phase, the animals
were assessed in Rotarod, parallel bar
-
, cylinder
-
, Y
-
Maze
-
, one trial place recognition
-
and novel
object recognition
-
(NOR) tests. Neural activity was measured
using chronic electrode implants
plac
ed in the M1 (motor cortex), CPu (striatum), CA1 (hippocampus) and PFC (prefrontal cortex).
Neural activity was compared with the outcomes of behavioural tests for memory and motor fun
c-
tions and data was expressed as mean
±
SEM (analysed using ANOVA with T
ukey post
-
hoc test,
significant level was set at 0.05).
Results/Discussion:
in vitro
outcomes show that VDR increase
calcium signalling and reverses the effect of haloperidol; specifically by reducing dopaminergic
vesicle accumulation in the cell body. Sim
ilarly,
in vivo
neural recordings
suggest an increase in
calcium hyperpolarization currents in the CPu and PFC of intervention mice (
−
D
2
/+VDR) when
compared with the parkinsonian mice (
−
D
2
). These animals (
−
D
2
/+VDR) also recorded an i
m-
provement in spatial
working memory and motor function versus the Parkinsonian mice (
−
D
2
).
These outcomes suggest
the role of CPu
-
PFC corticostriatal outputs in the motor
-
cognitive decline
seen in parkinsonian mice. Similarly, VDRA reduced the neural deficits through restorati
on of ca
l-
cium currents (burst activities) in the intervention mice (
−
D
2
/+VDR).
Conclusion: VDRA treatment
reduced the motor
-
cognitive defects observed in haloperidol induced PD. Our findings suggest the
role of VDRA in restoration of calcium currents assoc
iated with PFC and CPu
corticostriatal ou
t-
puts seen as burst frequencies in
in vivo
neural recording