Neurovascular effects of cocaine: relevance to addiction.

Cocaine is a highly addictive drug, and its use is associated with adverse medical consequences such as cerebrovascular accidents that result in debilitating neurological complications. Indeed, brain imaging studies have reported severe reductions in cerebral blood flow (CBF) in cocaine misusers when compared to the brains of healthy non-drug using controls. Such CBF deficits are likely to disrupt neuro-vascular interaction and contribute to changes in brain function.

Astrocytes mediate cerebral blood flow and neuronal response to cocaine in prefrontal cortex.

Cocaine affects both cerebral blood vessels and neuronal activity in brain. Cocaine can also disrupt astrocytes, which are involved in neurovascular coupling process that modulates cerebral hemodynamics in response to neuronal activity. However, separating neuronal and astrocytic effects from cocaine's direct vasoactive effects is challenging, partially due to limitations of neuroimaging techniques to differentiate vascular from neuronal and glial effects at high temporal and spatial resolutions.

Dynamic 3D imaging of cerebral blood flow in awake mice using self-supervised-learning-enhanced optical coherence Doppler tomography.

Cerebral blood flow (CBF) is widely used to assess brain function. However, most preclinical CBF studies have been performed under anesthesia, which confounds findings. High spatiotemporal-resolution CBF imaging of awake animals is challenging due to motion artifacts and background noise, particularly for Doppler-based flow imaging.

Cocaine's cerebrovascular vasoconstriction is associated with astrocytic Ca increase in mice.

Human and animal studies have reported widespread reductions in cerebral blood flow associated with chronic cocaine exposures. However, the molecular and cellular mechanisms underlying cerebral blood flow reductions are not well understood. Here, by combining a multimodal imaging platform with a genetically encoded calcium indicator, we simultaneously measured the effects of acute cocaine on neuronal and astrocytic activity, tissue oxygenation, hemodynamics and vascular diameter changes in the mouse cerebral cortex.

Memantine Attenuates Cocaine and neuroHIV Neurotoxicity in the Medial Prefrontal Cortex.

Individuals with substance use disorder are at a higher risk of contracting HIV and progress more rapidly to AIDS as drugs of abuse, such as cocaine, potentiate the neurotoxic effects of HIV-associated proteins including, but not limited to, HIV-1 trans-activator of transcription (Tat) and the envelope protein Gp120. Neurotoxicity and neurodegeneration are hallmarks of HIV-1-associated neurocognitive disorders (HANDs), which are hypothesized to occur secondary to excitotoxicity from NMDA-induced neuronal calcium dysregulation, which could be targeted with NMDA antagonist drugs. Multiple studies have examined how Gp120 affects calcium influx and how cocaine potentiates this influx; however, they mostly focused on single cells and did not analyze effects in neuronal and vascular brain networks.

Cocaine's effects on the reactivity of the medial prefrontal cortex to ventral tegmental area stimulation: optical imaging study in mice.

Background And Aims: The prefrontal cortex (PFC) is modulated by dopaminergic and glutamatergic neurons that project from the ventral tegmental area (VTA) and disruption of this modulation might facilitate impulsive behaviors during cocaine intoxication. Here, we assessed the effects of acute cocaine (30 mg/kg, i.p.

Ca channel blockade reduces cocaine's vasoconstriction and neurotoxicity in the prefrontal cortex.

Cocaine profoundly affects both cerebral blood vessels and neuronal activity in the brain. The vasoconstrictive effects of cocaine, concurrently with its effects on neuronal [Ca] 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.

Cocaine Reduces the Neuronal Population While Upregulating Dopamine D2-Receptor-Expressing Neurons in Brain Reward Regions: Sex-Effects.

Addiction to cocaine is associated with dysfunction of the dopamine mesocortical system including impaired dopamine-2 receptor (D2r) signaling. However, the effects of chronic cocaine on neuronal adaptations in this system have not been systematically examined and data available is mostly from males. Here, we investigated changes in the total neuronal density and relative concentration of D2r-expressing neurons in the medial prefrontal cortex (mPFC), dorsal striatum (Dstr), nucleus accumbens (NAc), and ventral tegmental area (VTA) in both male and female mice passively exposed to cocaine for two weeks.

Optical imaging of stimulation-evoked cortical activity using GCaMP6f and jRGECO1a.

Background: Genetically encoded calcium indicators (GECIs), especially the GCaMP-based green fluorescence GECIs have been widely used for detection of neuronal activity in rodents by measuring intracellular neuronal Ca changes. More recently, jRGECO1a, a red shifted GECI, has been reported to detect neuronal Ca activation. This opens the possibility of using dual-color GECIs for simultaneous interrogation of different cell populations.

Interactions between stimuli-evoked cortical activity and spontaneous low frequency oscillations measured with neuronal calcium.

Spontaneous brain activity has been widely used to map brain connectivity. The interactions between task-evoked brain responses and the spontaneous cortical oscillations, especially within the low frequency range of ~0.1 ​Hz, are not fully understood.

In vivo detection of tumor boundary using ultrahigh-resolution optical coherence angiography and fluorescence imaging.

Accurate detection of early tumor margin is of great preclinical and clinical implications for predicting the survival rate of subjects and assessing the response of tumor microenvironment to chemotherapy or radiation therapy. Here, we report a multimodality optical imaging study on in vivo detection of tumor boundary by analyzing neoangiogenesis of tumor microenvironment (microangiography), microcirculatory blood flow (optical Doppler tomography) and tumor proliferation (green fluorescent protein [GFP] fluorescence). Microangiography demonstrates superior sensitivity (77.

Hemodynamic and neuronal responses to cocaine differ in awake versus anesthetized animals: Optical brain imaging study.

Cocaine is a highly addictive drug with complex pharmacological effects. Most preclinical imaging studies investigating the effects of cocaine in the brain have been performed under anesthesia, which confounds findings. To tackle this problem, we used optical imaging to compare the effects of cocaine in the awake versus the anesthetized states.

Cocaine-induced ischemia in prefrontal cortex is associated with escalation of cocaine intake in rodents.

Cocaine-induced vasoconstriction reduces blood flow, which can jeopardize neuronal function and in the prefrontal cortex (PFC) it may contribute to compulsive cocaine intake. Here, we used integrated optical imaging in a rat self-administration and a mouse noncontingent model, to investigate whether changes in the cerebrovascular system in the PFC contribute to cocaine self-administration, and whether they recover with detoxification. In both animal models, cocaine induced severe vasoconstriction and marked reductions in cerebral blood flow (CBF) in the PFC, which were exacerbated with chronic exposure and with escalation of cocaine intake.

Enhanced neuronal and blunted hemodynamic reactivity to cocaine in the prefrontal cortex following extended cocaine access: optical imaging study in anesthetized rats.

Cocaine addiction is associated with dysfunction of the prefrontal cortex (PFC), which facilitates relapse and compulsive drug taking. To assess if cocaine's effects on both neuronal and vascular activity contribute to PFC dysfunction, we used optical coherence tomography and multi-wavelength laser speckle to measure vascularization and hemodynamics and used GCaMP6f to monitor intracellular Ca levels ([Ca ] ) as a marker of neuronal activity. Rats were given short (1 hour; ShA) or long (6 hours; LgA) access cocaine self-administration.

Cerebrovascular adaptations to cocaine-induced transient ischemic attacks in the rodent brain.

Occurrence of transient ischemic attacks (TIA) and cerebral strokes is a recognized risk associated with cocaine abuse. Here, we use a rodent model along with optical imaging to study cocaine-induced TIA and the associated dynamic changes in cerebral blood flow velocity (CBFv) and cerebrovasculature. We show that chronic cocaine exposure in mice resulted in marked cortical hypoperfusion, in significant arterial and venous vasoconstriction, and in a sensitized vascular response to an acute cocaine injection.

Cocaine-Induced Abnormal Cerebral Hemodynamic Responses to Forepaw Stimulation Assessed by Integrated Multi-wavelength Spectroimaging and Laser Speckle Contrast Imaging.

Simultaneous imaging of cerebral hemodynamic changes in response to functional activation during drug intoxication provides a valuable strategy to assess cocaine induced neurovascular dysfunction. However, this requires tools with sufficient spatiotemporal resolution and adequate signal to noise ratio (SNR). Though several technologies have been developed to address this demand during functional brain activation, their spatiotemporal resolution has been compromised to preserve SNR.

Quantitative imaging of microvascular blood flow networks in deep cortical layers by 1310 nm μODT.

There is growing interest in new neuroimage techniques that permit not only high-resolution quantification of cerebral blood flow velocity (CBFv) in capillaries, but also a large field of view to map the CBFv network dynamics. Such image capabilities are of great importance for decoding the functional difference across multiple cortical layers under stimuli. To tackle the limitation of optical penetration depth, we present a new ultrahigh-resolution optical coherence Doppler tomography (μODT) system at 1310 nm and compare it with a prior 800 nm μODT system for mouse brain 3D CBFv imaging.

Cranial window implantation on mouse cortex to study microvascular change induced by cocaine.

Cocaine-induced stroke is among the most serious medical complications associated with cocaine's abuse. However, the extent to which chronic cocaine may induce silent microischemia predisposing the cerebral tissue to neurotoxicity has not been investigated; in part, because of limitations of current neuroimaging tools, that is, lack of high spatiotemporal resolution and sensitivity to simultaneously measure cerebral blood flow (CBF) in vessels of different calibers quantitatively and over a large field of view (FOV). Optical coherence tomography (OCT) technique allows us to image three dimensional (3D) cerebrovascular network (including artery, vein, and capillary), and provides high resolution angiography of the cerebral vasculature and quantitative CBF velocity (CBFv) within the individual vessels in the network.

Ultrasensitive detection of 3D cerebral microvascular network dynamics in vivo.

Despite widespread applications of multiphoton microscopy in microcirculation, its small field of view and inability to instantaneously quantify cerebral blood flow velocity (CBFv) in vascular networks limit its utility in investigating the heterogeneous responses to brain stimulations. Optical Doppler tomography (ODT) provides 3D images of CBFv networks, but it suffers poor sensitivity for measuring capillary flows. Here we report on a new method, contrast-enhanced ODT with Intralipid that significantly improves quantitative CBFv imaging of capillary networks by obviating the errors from long latency between flowing red blood cells (low hematocrit ~20% in capillaries).

Chronic cocaine dampens dopamine signaling during cocaine intoxication and unbalances D1 over D2 receptor signaling.

Dopamine increases triggered by cocaine and consequent stimulation of dopamine receptors (including D1 and D2) are associated with its rewarding effects. However, while facilitation of D1 receptor (D1R) signaling enhances the rewarding effects of cocaine, facilitation of D2R signaling decreases it, which indicates that for cocaine to be rewarding it must result in a predominance of D1R over D2R signaling. Moreover, the transition to compulsive cocaine intake might result from an imbalance between D1R and D2R signaling.

Quantitative imaging of red blood cell velocity invivo using optical coherence Doppler tomography.

We present particle counting ultrahigh-resolution optical Doppler tomography (pc-μODT) that enables accurate imaging of red blood cell velocities (ν(RBC)) of cerebrovascular networks by detecting the Doppler phase transients induced by the passage of a RBC through a capillary. We apply pc-μODT to image the response of capillary ν(RBC) to mild hypercapnia in mouse cortex. The results show that ν(RBC) in normocapnia (ν(N) = 0.