Ca2+ channel blockade reduces cocaine’s vasoconstriction and neurotoxicity in the prefrontal cortex

AbstractCocaine profoundly affects both cerebral blood vessels and neuronal activity in the brain. The vasoconstrictive effects of cocaine, concurrently with its effects on neuronal [Ca2+]i accumulation are likely to jeopardize neuronal tissue that in the prefrontal cortex (PFC) could contribute to impaired self-regulation and compulsive cocaine consumption. Here we used optical imaging to study the cerebrovascular and neuronal effects of acute cocaine (1 mg/kg i.v.) and to examine whether selective blockade of L-type Ca2+ channels by Nifedipine (NIF) (0.5 mg/kg i.v.) would alleviate cocaine’s effects on hemodynamics (measured with cerebral blood volume, HbT), oxygenation (measured with oxygenated hemoglobin, HbO2) and neuronal [Ca2+]i, which were concomitantly measured in the PFC of naive rats. Our results show that in the PFC acute cocaine significantly reduced flow delivery (HbT), increased neuronal [Ca2+]i accumulation and profoundly reduced tissue oxygenation (HbO2) and these effects were significantly attenuated by NIF pretreatment. They also show that cocaine-induced vasoconstriction is distinct from its increase of neuronal [Ca2+]i accumulation though both of them contribute to hypoxemia and both effects were attenuated by NIF. These results provide evidence that blockade of voltage-gated L-type Ca2+ channels might be beneficial in preventing vasoconstriction and neurotoxic effects of cocaine and give support for further clinical investigations to determine their value in reducing cocaine’s neurotoxicity in cocaine use disorders.

Download Full-text

DETECTION OF Ca2+-DEPENDENT NEURONAL ACTIVITY SIMULTANEOUSLY WITH DYNAMIC CHANGES IN CEREBRAL BLOOD VOLUME AND TISSUE OXYGENATION FROM THE LIVE RAT BRAIN

Journal of Innovative Optical Health Sciences ◽

10.1142/s1793545809000498 ◽

2009 ◽

Vol 02 (02) ◽

pp. 189-200 ◽

Cited By ~ 2

Author(s):

CONGWU DU ◽

ZHONGCHI LUO ◽

MEI YU ◽

HELENE BENVENISTE ◽

MELISSA TULLY ◽

...

Keyword(s):

Rat Brain ◽

Blood Volume ◽

Neuronal Activity ◽

Cerebral Blood Volume ◽

Tissue Oxygenation ◽

Simultaneous Detection ◽

Fluorescence Emission ◽

High Temporal Resolution ◽

Functional Changes ◽

The Brain

We present a catheter-based optical diffusion and fluorescence (ODF) probe to study the functional changes of the brain in vivo. This ODF probe enables the simultaneous detection of the multi-wavelength absorbance and fluorescence emission from the living rat brain. Our previous studies, including a transient stroke experiment of the rat brain as well as the brain response to cocaine, have established the feasibility of simultaneously determining changes in cerebral blood volume (CBV), tissue oxygenation ( S t O 2) and intracellular calcium ([ Ca 2+]i, using the fluorescence indicator Rhod2). Here, we present our preliminary results of somatosensory response to electrical forepaw stimulation obtained from the rat cortical brain by using the ODF probe, which indicate that the probe could track brain activation by directly detecting [ Ca 2+]i along with separately distinguishing CBV and S t O 2 in real time. The changes of CBV, S t O 2 and [ Ca 2+]i are comparable with the blood-oxygen-level-dependent (BOLD) response to the stimulation obtained using functional magnetic resonance imaging (fMRI). However, the high temporal resolution of the optical methodology is advanced, thus providing a new modality for brain functional studies to understand the hemodynamic changes that underlie the neuronal activity.

Download Full-text

Review of Self-regulation of the Brain and Behavior.

Contemporary Psychology ◽

10.1037/023440 ◽

1985 ◽

Vol 30 (12) ◽

pp. 999-999

Author(s):

Gerald S. Wasserman

Keyword(s):

Self Regulation ◽

Brain And Behavior ◽

And Behavior ◽

The Brain

Download Full-text

Glia in Peril: The Neurotoxic Effects of Antipsychotic Medication on the Brain

PsycEXTRA Dataset ◽

10.1037/e590382013-001 ◽

2013 ◽

Author(s):

Anthony A. Arellano

Keyword(s):

Antipsychotic Medication ◽

Neurotoxic Effects ◽

The Brain

Download Full-text

SPECIFIC PROPERTIES OF TUBULIN IN THE PREFRONTAL CORTEX IN CONTROL, SCHIZOPHRENIA AND VASCULAR DEMENTIA

"Medical & pharmaceutical journal "Pulse" ◽

10.26787/nydha-2686-6838-2020-22-11-65-71 ◽

2020 ◽

pp. 65-71

Author(s):

Burbaeva G.Sh. ◽

Androsova L.V. ◽

Vorobyeva E.A. ◽

Savushkina O.K.

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Prefrontal Cortex ◽

Vascular Dementia ◽

Binding Activity ◽

Nephelometric Method ◽

Rate Of Polymerization ◽

Mental Diseases ◽

And Control ◽

The Brain

The aim of the study was to evaluate the rate of polymerization of tubulin into microtubules and determine the level of colchicine binding (colchicine-binding activity of tubulin) in the prefrontal cortex in schizophrenia, vascular dementia (VD) and control. Colchicine-binding activity of tubulin was determined by Sherlinе in tubulin-enriched extracts of proteins from the samples. Measurement of light scattering during the polymerization of the tubulin was carried out using the nephelometric method at a wavelength of 450-550 nm. There was a significant decrease in colchicine-binding activity and the rate of tubulin polymerization in the prefrontal cortex in both diseases, and in VD to a greater extent than in schizophrenia. The obtained results suggest that not only in Alzheimer's disease, but also in other mental diseases such as schizophrenia and VD, there is a decrease in the level of tubulin in the prefrontal cortex of the brain, although to a lesser extent than in Alzheimer's disease, and consequently the amount of microtubules.

Download Full-text

Activation of Melanocortin-4 Receptor by a Synthetic Agonist Inhibits Ethanolinduced Neuroinflammation in Rats

Current Pharmaceutical Design ◽

10.2174/1381612825666191216145153 ◽

2020 ◽

Vol 25 (45) ◽

pp. 4799-4805 ◽

Cited By ~ 3

Author(s):

Osvaldo Flores-Bastías ◽

Gonzalo I. Gómez ◽

Juan A. Orellana ◽

Eduardo Karahanian

Keyword(s):

Prefrontal Cortex ◽

Alcohol Consumption ◽

Ethanol Intake ◽

Neuroinflammatory Response ◽

Agonist Peptide ◽

Melanocortin 4 Receptor ◽

Tnf Α ◽

Cord Injury ◽

High Ethanol ◽

The Brain

Background: High ethanol intake induces a neuroinflammatory response resulting in the subsequent maintenance of chronic alcohol consumption. The melanocortin system plays a pivotal role in the modulation of alcohol consumption. Interestingly, it has been shown that the activation of melanocortin-4 receptor (MC4R) in the brain decreases the neuroinflammatory response in models of brain damage other than alcohol consumption, such as LPS-induced neuroinflammation, cerebral ischemia, glutamate excitotoxicity, and spinal cord injury. Objectives: In this work, we aimed to study whether MC4R activation by a synthetic MC4R-agonist peptide prevents ethanol-induced neuroinflammation, and if alcohol consumption produces changes in MC4R expression in the hippocampus and hypothalamus. Methods: Ethanol-preferring Sprague Dawley rats were selected offering access to 20% ethanol on alternate days for 4 weeks (intermittent access protocol). After this time, animals were i.p. administered an MC4R agonist peptide in the last 2 days of the protocol. Then, the expression of the proinflammatory cytokines interleukin 6 (IL-6), interleukin 1-beta (IL-1β), and tumor necrosis factor-alpha (TNF-α) were measured in the hippocampus, hypothalamus and prefrontal cortex. It was also evaluated if ethanol intake produces alterations in the expression of MC4R in the hippocampus and the hypothalamus. Results: Alcohol consumption increased the expression of MC4R in the hippocampus and the hypothalamus. The administration of the MC4R agonist reduced IL-6, IL-1β and TNF-α levels in hippocampus, hypothalamus and prefrontal cortex, to those observed in control rats that did not drink alcohol. Conclusion: High ethanol consumption produces an increase in the expression of MC4R in the hippocampus and hypothalamus. The administration of a synthetic MC4R-agonist peptide prevents neuroinflammation induced by alcohol consumption in the hippocampus, hypothalamus, and prefrontal cortex. These results could explain the effect of α-MSH and other synthetic MC4R agonists in decreasing alcohol intake through the reduction of the ethanol-induced inflammatory response in the brain.

Download Full-text

025 Sleep Disruption on an Orbital Shaker alters Glutamate in Prairie Vole Prefrontal Cortex

SLEEP ◽

10.1093/sleep/zsab072.024 ◽

2021 ◽

Vol 44 (Supplement_2) ◽

pp. A11-A12

Author(s):

Carolyn Jones ◽

Randall Olson ◽

Alex Chau ◽

Peyton Wickham ◽

Ryan Leriche ◽

...

Keyword(s):

Autism Spectrum Disorder ◽

Prefrontal Cortex ◽

Early Life ◽

Autism Spectrum ◽

Prairie Vole ◽

Sleep Disruption ◽

Glutamatergic Synapses ◽

The Brain ◽

Orbital Shaker

Abstract Introduction Glutamate concentrations in the cortex fluctuate with the sleep wake cycle in both rodents and humans. Altered glutamatergic signaling, as well as the early life onset of sleep disturbances have been implicated in neurodevelopmental disorders such as autism spectrum disorder. In order to study how sleep modulates glutamate activity in brain regions relevant to social behavior and development, we disrupted sleep in the socially monogamous prairie vole (Microtus ochrogaster) rodent species and quantified markers of glutamate neurotransmission within the prefrontal cortex, an area of the brain responsible for advanced cognition and complex social behaviors. Methods Male and female prairie voles were sleep disrupted using an orbital shaker to deliver automated gentle cage agitation at continuous intervals. Sleep was measured using EEG/EMG signals and paired with real time glutamate concentrations in the prefrontal cortex using an amperometric glutamate biosensor. This same method of sleep disruption was applied early in development (postnatal days 14–21) and the long term effects on brain development were quantified by examining glutamatergic synapses in adulthood. Results Consistent with previous research in rats, glutamate concentration in the prefrontal cortex increased during periods of wake in the prairie vole. Sleep disruption using the orbital shaker method resulted in brief cortical arousals and reduced time in REM sleep. When applied during development, early life sleep disruption resulted in long-term changes in both pre- and post-synaptic components of glutamatergic synapses in the prairie vole prefrontal cortex including increased density of immature spines. Conclusion In the prairie vole rodent model, sleep disruption on an orbital shaker produces a sleep, behavioral, and neurological phenotype that mirrors aspects of autism spectrum disorder including altered features of excitatory neurotransmission within the prefrontal cortex. Studies using this method of sleep disruption combined with real time biosensors for excitatory neurotransmitters will enhance our understanding of modifiable risk factors, such as sleep, that contribute to the altered development of glutamatergic synapses in the brain and their relationship to social behavior. Support (if any) NSF #1926818, VA CDA #IK2 BX002712, Portland VA Research Foundation, NIH NHLBI 5T32HL083808-10, VA Merit Review #I01BX001643

Download Full-text

Glia Not Neurons: Uncovering Brain Dysmaturation in a Rat Model of Alzheimer’s Disease

Biomedicines ◽

10.3390/biomedicines9070823 ◽

2021 ◽

Vol 9 (7) ◽

pp. 823

Author(s):

Ekaterina A. Rudnitskaya ◽

Tatiana A. Kozlova ◽

Alena O. Burnyasheva ◽

Natalia A. Stefanova ◽

Nataliya G. Kolosova

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Prefrontal Cortex ◽

Brain Structures ◽

Time Frame ◽

Oxys Rats ◽

Unknown Etiology ◽

Suitable Model ◽

Model Of Alzheimer’S Disease ◽

The Brain

Sporadic Alzheimer’s disease (AD) is a severe disorder of unknown etiology with no definite time frame of onset. Recent studies suggest that middle age is a critical period for the relevant pathological processes of AD. Nonetheless, sufficient data have accumulated supporting the hypothesis of “neurodevelopmental origin of neurodegenerative disorders”: prerequisites for neurodegeneration may occur during early brain development. Therefore, we investigated the development of the most AD-affected brain structures (hippocampus and prefrontal cortex) using an immunohistochemical approach in senescence-accelerated OXYS rats, which are considered a suitable model of the most common—sporadic—type of AD. We noticed an additional peak of neurogenesis, which coincides in time with the peak of apoptosis in the hippocampus of OXYS rats on postnatal day three. Besides, we showed signs of delayed migration of neurons to the prefrontal cortex as well as disturbances in astrocytic and microglial support of the hippocampus and prefrontal cortex during the first postnatal week. Altogether, our results point to dysmaturation during early development of the brain—especially insufficient glial support—as a possible “first hit” leading to neurodegenerative processes and AD pathology manifestation later in life.

Download Full-text

Cannabidiol Has a Unique Effect on Global Brain Activity: A Pharmacological, Functional MRI Study in Awake Mice

10.21203/rs.3.rs-253550/v1 ◽

2021 ◽

Author(s):

Aymen Sadaka ◽

Ana Ozuna ◽

Richard Ortiz ◽

Praveen Kulkarni ◽

Clare Johnson ◽

...

Keyword(s):

Prefrontal Cortex ◽

Brain Activity ◽

Stress Disorders ◽

Functional Coupling ◽

Specific Information ◽

Imaging Data ◽

Post Traumatic Stress ◽

Brain Areas ◽

Dose Dependent ◽

The Brain

Abstract Background: The phytocannabinoid cannabidiol (CBD) is a potential treatment for post-traumatic stress disorders. How does CBD interact with the brain to alter behavior? We hypothesized that CBD would produce a dose-dependent reduction in brain activity and functional coupling in neural circuitry associated with fear and defense. Methods: During the scanning session awake mice were given vehicle or CBD (3, 10, or 30 mg/kg I.P.) and imaged for 10 min post treatment. Mice were also treated with the 10 mg/kg dose of CBD and imaged one hr later for resting state BOLD functional connectivity (rsFC). Imaging data were registered to a 3D MRI mouse atlas providing site-specific information on 138 different brain areas. Blood samples were collected for CBD measurements.Results: CBD produced a dose-dependent polarization of activation along the rostral-caudal axis of the brain. The olfactory bulb and prefrontal cortex showed an increase in positive BOLD whereas the brainstem and cerebellum showed a decrease in BOLD signal. This negative BOLD affected many areas connected to the ascending reticular activating system (ARAS). The ARAS was decoupled to much of the brain but was hyperconnected to the olfactory system and prefrontal cortex. The pattern of ARAS connectivity closely overlapped with brain areas showing high levels N-acyl-phosphatidylethanolamines-specific phospholipase D (NAPE-PLD) messenger RNA.Conclusion: The CBD-induced decrease in ARAS activity is consistent with an emerging literature suggesting that CBD reduces autonomic arousal under conditions of emotional and physical stress. The putative target and mechanism of action is NAPE-PLD the enzyme responsible for the biosynthesis of lipid signaling molecules like anandamide.

Download Full-text

Unilateral Antegrade Cerebral Perfusion Through the Right Axillary Artery Provides Uniform Flow Distribution to Both Hemispheres of the Brain

Circulation ◽

10.1161/circ.100.suppl_2.ii-309 ◽

1999 ◽

Vol 100 (suppl_2) ◽

Author(s):

Jian Ye ◽

Guangping Dai ◽

Lawrence N. Ryner ◽

Piotr Kozlowski ◽

Luojia Yang ◽

...

Keyword(s):

Cerebral Blood Volume ◽

Axillary Artery ◽

Circulatory Arrest ◽

Flow Distribution ◽

Mr Perfusion ◽

Mr Perfusion Imaging ◽

Regional Cerebral Blood Volume ◽

The Right ◽

The Brain ◽

Antegrade Cerebral Perfusion

Background —Bilateral antegrade cerebral perfusion (ACP) has decreased in popularity over the past decade because of its complexity and the risk of cerebral embolism. We used magnetic resonance (MR) perfusion imaging to assess flow distribution in both hemispheres of the brain during unilateral ACP through the right carotid artery via a cannula placed in the right axillary artery in conjunction with hypothermic circulatory arrest. Methods and Results —Twelve pigs were randomly exposed to 120 minutes of either bilateral ACP through both carotid arteries (n=6) or unilateral ACP through the right axillary artery (n=6) at pressures of 60 to 65 mm Hg at 15°C, followed by 60 minutes of cardiopulmonary bypass at 37°C. MR perfusion images were acquired every 30 minutes before, during, and after ACP. The brain was perfusion fixed for histopathology. During initial normothermic cardiopulmonary bypass, MR perfusion imaging showed a uniform distribution of flow in the brain. In both the bilateral and unilateral ACP groups, the same pattern was maintained, with an increase in regional cerebral blood volume during ACP and reperfusion. The changes in regional cerebral blood volume and mean transit time were similar in both hemispheres during and after unilateral ACP. No difference was observed between the 2 groups. Histopathology showed normal morphology in all regions of the brain in both groups. Conclusions —Both bilateral ACP and unilateral ACP provide uniform blood distribution to both hemispheres of the brain and preserve normal morphology of the neurons after prolonged hypothermic circulatory arrest.

Download Full-text