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American Journal of Infectious Diseases
Year: 2009  |  Volume: 5  |  Issue: 1  |  Page No.: 26 - 30

Cocaine Exposure Results in Formation of Dendritic Varicosity in Rat Primary Hippocampal Neurons

Honghong Yao, Crystal Bethel-Brown, Anil Kumar and Shilpa Buch    

Abstract: Problem statement: It has been well documented that drugs of abuse such as cocaine can cause enhanced progression of HIV-Associated Neuropathological Disorders (HAND), the underlying mechanisms mediating these effects remain poorly understood. Approach: In present study, we explored the impact of cocaine exposure (I and 10 µM) on the dendritic beading in rat primary hippocampal neurons. Using the approach of transfection with green fluorescent protein, we observed significant dendritic swelling in hippocampal neurons exposed to 10 µM but not 1 µM of cocaine when compared with the saline treated group. Results: Cocaine exposure also resulted in decreased expression of the synaptic plasticity gene, Arc as evidenced by Western blotting. Intriguingly, cocaine exposure of primary neurons in the presence of the neurotoxin-HIV envelope protein gp 120, resulted in increased enhancement of neuronal beading as compared with exposure of neurons to either agent alone. Conclusion: Taken together these findings imply that cocaine in co-operation with HIV protein exacerbates neuronal damage in the brains of HIV-infected cocaine abusers.

Fig. 1, 10 μM of cocaine caused dendritic varicosity throughout the dendritic arbors within 120 min of treatment, an effect that was not observed with 1 μM cocaine. 2. Cocaine regulated Arc expression in hippocampal neurons

Since neuronal plasticity is exemplified by the expression of the Arc gene, we next sought to explore the expression of Arc Western blot analysis in parallel with the dendritic varicosity. Interestingly, exposure of neurons to 10 μM of cocaine, that resulted in enhanced dendritic varicosity, correspondingly demonstrated decreased Arc expression (Fig. 2).

Rat primary neurons exposed to different concentrations of cocaine were monitored for cocaine-mediated Arc expression. Exposure of neurons to 10 μM of cocaine resulted in decreased Arc expression while exposure of cell to 1μM cocaine resulted in increased Arc expression. The figure is a representative image of three independent experiments

Gp120 and cocaine caused enhanced dendritic varicosity formation: Drugs of abuse are known to accelerate the progress of HIV[1,12]. We next sought to explore the effect of both cocaine and the HIV protein gp120 on dendritic varicosity. Rat primary neurons co-treated with gp120 and cocaine were examined for somatodendritic microtubule-associated protein MAP2 using staining by immunofluoresence. Control group revealed neurons with round somata and an intricately branched dendritic arbor with smooth dendrites.

Fig. 1: Cocaine exposure resulted in formation of dendritic varicosity in primary hippocampus neurons. Rat hippocampal neurons exposed to 10 μM but not 1µM cocaine developed dendritic varicosities. The image shown is a representative picture of three independent experiments. Images were captured on a time-lapse confocal microscope. Arrows indicate the sites of dendritic varicosity formation

Fig. 2: Cocaine regulated Arc expression in hippocampal neurons

Fig. 3: Gp120 and cocaine caused enhanced dendritic varicosity formation. (a) MAP2 immunofluorescence of primary hippocampal neurons exposed to cocaine, gp120 and cocaine plus gp120 demonstrated increased dendritic varicosity formation in the presence of both cocaine and gp120 as compared with neurons exposed to either agent alone. Arrows indicate the sites of dendritic varicosity formation. (b) Quantification of percentage of cells with dendritic varicosities. All the data are presented as mean±SD of four individual experiments. *p<0.05; **p<0.01 vs control group

Exposure of neurons to either cocaine (10 μM) or gp120 (200 ng mL-1) alone for 120 min demonstrated the appearance of dendritic varicosity along the length of the dendrite. This effect was further enhanced in neurons exposed to both cocaine as well as gp120, with increased dendritic varicosity formation as shown in Fig. 3.


While there is ample evidence suggesting that drugs of abuse such as cocaine can co-operate with HIV-1 to induce neurotoxicity[3], the mechanisms involved in this process remain elusive. The present study demonstrated that cocaine exposure of hippocampal neurons resulted in increased neuronal beading. Further findings determined that the mechanisms underlying the cocaine exposure-mediated impairment of neuronal dendrites in primary hippocampal neurons involved down-regulation of the expression of the neuronal plasticity gene Arc. Additionally, exposure of neurons to HIV-1 envelope protein gp120 resulted in enhanced loss of dendrites of neurons exposed to cocaine.

Acute dendritic swelling and spine loss are pathological hallmarks of brain injury and spine loss is associated with focal dendritic swelling[13]. In present study, we demonstrated that cocaine exposure damaged neuronal dendrites in cell culture, a finding that was consistent with the previous study demonstrating that in locus coeruleus neurons, cocaine treatment decreased both the number of cell initiating neuritis as well as the length of neuritis[14]. Although there are conflicting reports indicating that acute cocaine exposure increased spine density and synaptic plasticity of the dopaminergic neurons in the ventral tegmental area in vivo[15], the cellular mechanism(s) underlying the effects of cocaine on neuronal plasticity remain unclear. In our study, it was interesting to note that the spine loss occurred over short intervals following treatment with 10 μM of cocaine, but not with 1 μM of cocaine. These findings likely suggest dose-dependent differential effects of cocaine on neuronal plasticity. Long-lasting changes in synaptic efficacy are accompanied by the expression of immediate early genes, including the activity-regulated cytoskeleton-associated gene Arc, also known as Arg3.1[16]. In the present study, we observed that different concentrations of cocaine exerted distinct effects on Arc expression, with1 μM of cocaine increasing Arc expression, while 10 μM of cocaine exhibiting the opposite effects. Based upon the effects of cocaine on the neuronal dendrites, down-regulation of Arc expression may contribute to the damage of neuronal dendrites. Up-regulation of Arc expression following exposure of cells to 1uM cocaine (this concentration was identical to the physiological concentration)[17] was consistent with the previous reports demonstrating cocaine-mediated up-regulation of Arc expression primarily in striatum, prefrontal cortex and the hippocampus[18].

Neurologic impairment in patients with HAND correlates well with injury to dendrites and synapses[7]. Despite significant progress in understanding the molecular mechanisms underlying HIV-1 infection and drug abuse-induced neurotoxicity, very few studies have directly examined the impact of HIV-1 infection on dendrites and whether such alterations may contribute to HIV-1-associated neurologic dysfunction.


Present study demonstrated enhanced neuronal beading in the presence of cocaine and HIV proteins as compared with neurons exposed to either agent alone thus shedding light on the exacerbated toxicity mediated by drugs of abuse such as cocaine in the presence of HIV-infection. A better understanding of how HIV-1 and drugs of abuse together can affect the molecular and cellular mechanisms of dendrite damage, can lead to development of new therapeutic approaches targeting preservation of dendrites.


This study was supported by grants RR016443, MH-068212, DA020392, DA023397 and DA024442 from the National Institutes of Health (SB).

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