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Interactive effects of cocaine on HIV infection: implication in HIV-associated neurocognitive disorder and neuroAIDS.

Dahal S, Chitti SV, Nair MP, Saxena SK - Front Microbiol (2015)

Bottom Line: Cocaine abuse during HIV infection enhances the production of platelet monocyte complexes (PMCs), which may cross transendothelial barrier, and result in HIV-associated neurocognitive disorder (HAND).HAND is characterized by neuroinflammation, including astrogliosis, multinucleated giant cells, and neuronal apoptosis that is linked to progressive virus infection and immune deterioration.Cocaine and viral proteins are capable of eliciting signaling transduction pathways in neurons, involving in mitochondrial membrane potential loss, oxidative stress, activation of JNK, p38, and ERK/MAPK pathways, and results in downstream activation of NF-κB that leads to HAND.

View Article: PubMed Central - PubMed

Affiliation: CSIR-Centre for Cellular and Molecular Biology , Hyderabad, India.

ABSTRACT
Substantial epidemiological studies suggest that not only, being one of the reasons for the transmission of the human immunodeficiency virus (HIV), but drug abuse also serves its role in determining the disease progression and severity among the HIV infected population. This article focuses on the drug cocaine, and its role in facilitating entry of HIV into the CNS and mechanisms of development of neurologic complications in infected individuals. Cocaine is a powerfully addictive central nervous system stimulating drug, which increases the level of neurotransmitter dopamine (DA) in the brain, by blocking the dopamine transporters (DAT) which is critical for DA homeostasis and neurocognitive function. Tat protein of HIV acts as an allosteric modulator of DAT, where as cocaine acts as reuptake inhibitor. When macrophages in the CNS are exposed to DA, their number increases. These macrophages release inflammatory mediators and neurotoxins, causing chronic neuroinflammation. Cocaine abuse during HIV infection enhances the production of platelet monocyte complexes (PMCs), which may cross transendothelial barrier, and result in HIV-associated neurocognitive disorder (HAND). HAND is characterized by neuroinflammation, including astrogliosis, multinucleated giant cells, and neuronal apoptosis that is linked to progressive virus infection and immune deterioration. Cocaine and viral proteins are capable of eliciting signaling transduction pathways in neurons, involving in mitochondrial membrane potential loss, oxidative stress, activation of JNK, p38, and ERK/MAPK pathways, and results in downstream activation of NF-κB that leads to HAND. Tat-induced inflammation provokes permeability of the blood brain barrier (BBB) in the platelet dependent manner, which can potentially be the reason for progression to HAND during HIV infection. A better understanding on the role of cocaine in HIV infection can give a clue in developing novel therapeutic strategies against HIV-1 infection in cocaine using HIV infected population.

No MeSH data available.


Related in: MedlinePlus

Mechanism of Dopamine reuptake by DAT receptor (A) and blocking of the DAT receptor by cocaine and HIV Tat protein (B). (A). Dopamine, transmits brain signals by flowing from presynaptic neuron into the synaptic cleft and attaching to a receptor (DRD 1,5, and DRD 2,3,4) on postsynaptic neuron. In general, excess dopamine is recycled into the presynaptic neuron by a dopamine transporter (DAT) on the surface of the presynaptic neuron. The recycled dopamine is then degraded into homovanillic acid via monoamine oxidase (MOA). (B-a). In this case of cocaine drug abuse, the drug (cocaine) attaches to the DAT and blocks the normal recycling of dopamine, causing an increase of dopamine levels in the spaces between neurons that lead to inflammation. (B-b). The dopamine recycling is also inhibited by the Tat protein of HIV by bringing about conformational changes in DAT. The high concentration of dopamine in the synaptic cleft causes inflammation.
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Figure 3: Mechanism of Dopamine reuptake by DAT receptor (A) and blocking of the DAT receptor by cocaine and HIV Tat protein (B). (A). Dopamine, transmits brain signals by flowing from presynaptic neuron into the synaptic cleft and attaching to a receptor (DRD 1,5, and DRD 2,3,4) on postsynaptic neuron. In general, excess dopamine is recycled into the presynaptic neuron by a dopamine transporter (DAT) on the surface of the presynaptic neuron. The recycled dopamine is then degraded into homovanillic acid via monoamine oxidase (MOA). (B-a). In this case of cocaine drug abuse, the drug (cocaine) attaches to the DAT and blocks the normal recycling of dopamine, causing an increase of dopamine levels in the spaces between neurons that lead to inflammation. (B-b). The dopamine recycling is also inhibited by the Tat protein of HIV by bringing about conformational changes in DAT. The high concentration of dopamine in the synaptic cleft causes inflammation.

Mentions: Dopamine is a neurotransmitter that is produced from amino acid tyrosine and belongs to the catecholamine family. DA synthesis occurs in the cytoplasm of the neuron and then it is transported within the secretary vesicles of the neuron for storage and subsequent discharge. Once put away at nerve terminals, DA is prepared to be released into the synaptic cleft and subsequently, a greater part of it is recaptured by the dopamine transporter (DAT), which is present in the pre synaptic membrane (Figure 3A, Giros et al., 1992; Rudnick, 2011). The high concentrations of DA at synaptic cleft causes apoptosis or inflammation to the tissue. There are three main pathways controlled by DA, firstly the pathway of the nigro striatal system, secondly the forebrain that includes cerebral cortex, nucleus accumbens and other limbic structure and finally tubero-infundibular pathway, in which DA release occurs directly in the portal system.


Interactive effects of cocaine on HIV infection: implication in HIV-associated neurocognitive disorder and neuroAIDS.

Dahal S, Chitti SV, Nair MP, Saxena SK - Front Microbiol (2015)

Mechanism of Dopamine reuptake by DAT receptor (A) and blocking of the DAT receptor by cocaine and HIV Tat protein (B). (A). Dopamine, transmits brain signals by flowing from presynaptic neuron into the synaptic cleft and attaching to a receptor (DRD 1,5, and DRD 2,3,4) on postsynaptic neuron. In general, excess dopamine is recycled into the presynaptic neuron by a dopamine transporter (DAT) on the surface of the presynaptic neuron. The recycled dopamine is then degraded into homovanillic acid via monoamine oxidase (MOA). (B-a). In this case of cocaine drug abuse, the drug (cocaine) attaches to the DAT and blocks the normal recycling of dopamine, causing an increase of dopamine levels in the spaces between neurons that lead to inflammation. (B-b). The dopamine recycling is also inhibited by the Tat protein of HIV by bringing about conformational changes in DAT. The high concentration of dopamine in the synaptic cleft causes inflammation.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4562305&req=5

Figure 3: Mechanism of Dopamine reuptake by DAT receptor (A) and blocking of the DAT receptor by cocaine and HIV Tat protein (B). (A). Dopamine, transmits brain signals by flowing from presynaptic neuron into the synaptic cleft and attaching to a receptor (DRD 1,5, and DRD 2,3,4) on postsynaptic neuron. In general, excess dopamine is recycled into the presynaptic neuron by a dopamine transporter (DAT) on the surface of the presynaptic neuron. The recycled dopamine is then degraded into homovanillic acid via monoamine oxidase (MOA). (B-a). In this case of cocaine drug abuse, the drug (cocaine) attaches to the DAT and blocks the normal recycling of dopamine, causing an increase of dopamine levels in the spaces between neurons that lead to inflammation. (B-b). The dopamine recycling is also inhibited by the Tat protein of HIV by bringing about conformational changes in DAT. The high concentration of dopamine in the synaptic cleft causes inflammation.
Mentions: Dopamine is a neurotransmitter that is produced from amino acid tyrosine and belongs to the catecholamine family. DA synthesis occurs in the cytoplasm of the neuron and then it is transported within the secretary vesicles of the neuron for storage and subsequent discharge. Once put away at nerve terminals, DA is prepared to be released into the synaptic cleft and subsequently, a greater part of it is recaptured by the dopamine transporter (DAT), which is present in the pre synaptic membrane (Figure 3A, Giros et al., 1992; Rudnick, 2011). The high concentrations of DA at synaptic cleft causes apoptosis or inflammation to the tissue. There are three main pathways controlled by DA, firstly the pathway of the nigro striatal system, secondly the forebrain that includes cerebral cortex, nucleus accumbens and other limbic structure and finally tubero-infundibular pathway, in which DA release occurs directly in the portal system.

Bottom Line: Cocaine abuse during HIV infection enhances the production of platelet monocyte complexes (PMCs), which may cross transendothelial barrier, and result in HIV-associated neurocognitive disorder (HAND).HAND is characterized by neuroinflammation, including astrogliosis, multinucleated giant cells, and neuronal apoptosis that is linked to progressive virus infection and immune deterioration.Cocaine and viral proteins are capable of eliciting signaling transduction pathways in neurons, involving in mitochondrial membrane potential loss, oxidative stress, activation of JNK, p38, and ERK/MAPK pathways, and results in downstream activation of NF-κB that leads to HAND.

View Article: PubMed Central - PubMed

Affiliation: CSIR-Centre for Cellular and Molecular Biology , Hyderabad, India.

ABSTRACT
Substantial epidemiological studies suggest that not only, being one of the reasons for the transmission of the human immunodeficiency virus (HIV), but drug abuse also serves its role in determining the disease progression and severity among the HIV infected population. This article focuses on the drug cocaine, and its role in facilitating entry of HIV into the CNS and mechanisms of development of neurologic complications in infected individuals. Cocaine is a powerfully addictive central nervous system stimulating drug, which increases the level of neurotransmitter dopamine (DA) in the brain, by blocking the dopamine transporters (DAT) which is critical for DA homeostasis and neurocognitive function. Tat protein of HIV acts as an allosteric modulator of DAT, where as cocaine acts as reuptake inhibitor. When macrophages in the CNS are exposed to DA, their number increases. These macrophages release inflammatory mediators and neurotoxins, causing chronic neuroinflammation. Cocaine abuse during HIV infection enhances the production of platelet monocyte complexes (PMCs), which may cross transendothelial barrier, and result in HIV-associated neurocognitive disorder (HAND). HAND is characterized by neuroinflammation, including astrogliosis, multinucleated giant cells, and neuronal apoptosis that is linked to progressive virus infection and immune deterioration. Cocaine and viral proteins are capable of eliciting signaling transduction pathways in neurons, involving in mitochondrial membrane potential loss, oxidative stress, activation of JNK, p38, and ERK/MAPK pathways, and results in downstream activation of NF-κB that leads to HAND. Tat-induced inflammation provokes permeability of the blood brain barrier (BBB) in the platelet dependent manner, which can potentially be the reason for progression to HAND during HIV infection. A better understanding on the role of cocaine in HIV infection can give a clue in developing novel therapeutic strategies against HIV-1 infection in cocaine using HIV infected population.

No MeSH data available.


Related in: MedlinePlus