Inhibition of Dopamine Receptor in Neonate Hippocampus: Immunolocalization of Post Synaptic Density Protein-95 and Dopamine Receptor in vivo

The effect of haloperidol on neonatal dopaminergic neurotransmission in the hippocampus of postnatal day 20 rats (P.20) was investigated in this study. Haloperidol blocked dopamine receptors (D2R) and inhibited D2R on the membrane of neonate neurons. For this study the 0.5 ml (20 mg/kg) of haloperidol was administered to pregnant female animals intraperitoneally a week before delivery. At day P.20, 5 control animals and 5 haloperidol treated animals were taken to the behavioral studies room for the Y maze and Novel object recognition test, which was done 7 am in the morning before mating. Electrophysiology was done with 2 control pups and 2 treated pups. Electrodes were implanted in the brain at the hippocampal region 2 mm beneath the bregma, 2 mm lateral to the midline. Anterior Posterior (AP=0), Medial Lateral (ML=2 mm). Also immunolocalization and immunofluorescence of post synaptic density protein (PSD-95), hippocampal morphology and hippocampal neurons have been done respectively. Results from this study showed a decline in memory index for the Y maze as a result of the effect of D2R blockade thereby inhibiting neurotransmission in newborns. Electrophysiology result in this study showed an increase in the root mean square (RMS) of control pups. The increase in RMS is equivalent to increase in wave burst pattern caused by neuronal excitation. Immunochemistry result showed an increase in the number of PSD-95 in the hippocampus of an increase in tyrosine hydroxylase in the hippocampus of the treated neonatal rats when compared to the control neonatal rats Immunofluorescence showed decline in the number of neurons in the haloperidol treated rats and it also caused hippocampal damage in terms of morphology. Furthermore, results from electrophysiology showed a statistical significant difference with P value 0.04229 (P<0.05) using the student t-test. These findings suggest that D2R inhibition may cause decline in memory function, impair learning in newborns and disrupt neonatal dopaminergic neurotransmissio

Neural and behavioural changes in male periadolescent mice after prolonged nicotine-MDMA treatment

The interaction between MDMA and Nicotine affects multiple brain centres and neurotransmitter systems (serotonin, dopamine and glutamate) involved in motor coordination and cognition. In this study, we have elucidated the effect of prolonged (10 days) MDMA, Nicotine and a combined Nicotine-MDMA treatment on motor-cognitive neural functions. In addition, we have shown the correlation between the observed behavioural change and neural structural changes induced by these treatments in BALB/c mice.We observed that MDMA (2 mg/Kg body weight; subcutaneous) induced a decline in motor function, while Nicotine (2 mg/Kg body weight; subcutaneous) improved motor function in male periadolescent mice. In combined treatment, Nicotine reduced the motor function decline observed in MDMA treatment, thus no significant change in motor function for the combined treatment versus the control. Nicotine or MDMA treatment reduced memory function and altered hippocampal structure. Similarly, a combined Nicotine-MDMA treatment reduced memory function when compared with the control. Ultimately, the metabolic and structural changes in these neural systems were seen to vary for the various forms of treatment. It is noteworthy to mention that a combined treatment increased the rate of lipid peroxidation in brain tissue

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

Kolaviron was protective against sodium azide (NaN 3 )induced oxidative stress in the prefrontal cortex

Kolaviron is a phytochemical isolated from Garcina kola (G. kola); a common oral masticatory agent in Nigeria (West Africa). It is a bioflavonoid used - as an antivi- ral, anti-inflammatory and antioxidant - in relieving the symp- toms of several diseases and infections. In this study we have evaluated the neuroprotective and regenerative effect of kolaviron in neurons of the prefrontal cortex (Pfc) before or after exposure to sodium azide (NaN 3 ) induced oxidative stress. Separate groups of animals were treated as follows; kolaviron (200 mg/Kg) for 21 days; kolaviron (200 mg/Kg for21days)followedbyNaN 3 treatment (20 mg/Kg for 5days);NaN 3 treatment (20 mg/Kg for 5 days) followed by kolaviron (200 mg/Kg for 21 days); 1 ml of corn-oil (21 days- vehicle); NaN 3 treatment (20 mg/Kg for 5 days). Exploratory activity associated with Pfc function was assessed in the open field test (OFT) following which the microscopic anatomy of the prefrontal cortex was examined in histology (Haematoxylin and Eosin) and antigen retrieval Immunohis- tochemistry to show astroglia activation (GFAP), neuronal metabolism (NSE), cytoskeleton (NF) and cell cycle dysreg- ulation (p53). Subsequently, we quantified the level of Glucose-6-phosphate dehydrogenase (G6PDH) and lactate dehydrogenase (LDH) in the brain tissue homogenate as a measure of stress-related glucose metabolism. Kolaviron (Kv) and Kolaviron/NaN 3 treatment caused no prominent change in astroglia density and size while NaN 3 and NaN 3 / Kv induced astroglia activation and scar formation (astrogliosis) in the Pfc when compared with the control. Sim- ilarly, Kolaviron and Kv/NaN 3 did not alter NSE expression (glucose metabolism) while NaN 3 and NaN 3 /Kv treatment increased cortical NSE expression; thus indicating stress related metabolism. Further studies on enzymes of glu- cose metabolism (G6PDH and LDH) showed that NaN 3 increased LDH while kolaviron reduced LDH in the brain tissue homogenate (P<0.001). In addition kolaviron treatment before (P<0.001) or after ( P <0.05) NaN 3 treatment also reduced LDH expression; thus supporting its role in suppression of oxidative stress. Interestingly, NF deposition increased in the Pfc after kolaviron treatment while Kv/NaN 3 showed no sig- nificant change in NF when compared with the control. In furtherance, NaN 3 and NaN 3 /Kv caused a decrease in NF deposition (degeneration). Ultimately, the protective effect of KV administered prior to NaN 3 treatment was confirmed through p53 expression; which was similar to the control. However, NaN 3 and NaN 3 /Kv caused an increase in p53 expression in the Pfc neurons (cell cycle dysregulation). We conclude that kolaviron is not neu- rotoxic when used at 200 mg/Kg BW. Furthermore, 200 mg/Kg of kolaviron administered prior to NaN 3 treatment (Kv/NaN 3 ) was neuroprotective when com- pared with Kolaviron administered after NaN 3 treatment (NaN 3 /Kv). Some of the observed effects of kolaviron administered before NaN 3 treatment includes reduction of astroglia activation, absence of astroglia scars, anti- oxidation (reduced NSE and LDH), prevention of neu- rofilament loss and cell cycle regulatio

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

GABAA receptor plasticity in neuropathic pain: pain and memory effects in adult female rats

Background Neuropathic pain has been shown to increase excitability of neurons. This indicates altered inhibitory mechanism of the nervous system. Objective This work was aimed to assess GABAA receptors plasticity in the brain and spinal cord. Materials and methods Fifteen adult female rats were used. Ten animals have their sciatic nerve ligated with no treatment (LIG), and with diazepam treatment for 14 days (LIG+GABA) and the other five were used as the sham group. Pain was assessed using a hot plate and formalin test, while the spatial memory was assessed using Y-maze. At the end of the treatment, the animals were euthanized and fixed using the transcardial perfusion fixation method. The spinal cord, cingulate cortex, and the hippocampus were serially sectioned and stained for GABAA receptor immunohistochemically. Quantification was done using ImageJ software. Data were analyzed using oneway analysis of variance and Newman Tukey post-hoc test significant level was set at P less than 0.05. Results A low level of pain was observed in LIG and LIG+GABA animals on both formalin and hot plate test compared with the control. Memory impairment was found only in the LIG+GABA group. Stereology counting showed that GABAA receptors reduced in the dentate gyrus of the hippocampus of LIG-treated animals which was reversed in LIG+GABA, but in the cingulate cortex, GABAA receptors were increased in LIG animals and LIG+GABA more than the control while the spinal cord shows no significant difference. Conclusion GABAA agonist treatment did not alleviate the symptoms of neuropathic pain due to GABA signaling changing to excitatory in nature