close
Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2021 Jan 22:14:589897.
doi: 10.3389/fnins.2020.589897. eCollection 2020.

Single Low Dose of Cocaine-Structural Brain Injury Without Metabolic and Behavioral Changes

Camilla Nicolucci  1 , Mariana Lapo Pais  2   3   4 , A C Santos  3   4   5 , Fabiana M Ribeiro  6 , Pedro M C C Encarnação  6 , Ana L M Silva  6   7 , I F Castro  7 , Pedro M M Correia  6   7 , João F C A Veloso  6 , Julie Reis  4 , Marina Z Lopes  8 , Maria F Botelho  3   4 , Frederico C Pereira  4   5   9 , Denise G Priolli  1
Affiliations

Single Low Dose of Cocaine-Structural Brain Injury Without Metabolic and Behavioral Changes

Camilla Nicolucci et al. Front Neurosci. .

Abstract

Chronic cocaine use has been shown to lead to neurotoxicity in rodents and humans, being associated with high morbidity and mortality rates. However, recreational use, which may lead to addictive behavior, is often neglected. This occurs, in part, due to the belief that exposure to low doses of cocaine comes with no brain damage risk. Cocaine addicts have shown glucose metabolism changes related to dopamine brain activity and reduced volume of striatal gray matter. This work aims to evaluate the morphological brain changes underlying metabolic and locomotor behavioral outcome, in response to a single low dose of cocaine in a pre-clinical study. In this context, a Balb-c mouse model has been chosen, and animals were injected with a single dose of cocaine (0.5 mg/kg). Control animals were injected with saline. A behavioral test, positron emission tomography (PET) imaging, and anatomopathological studies were conducted with this low dose of cocaine, to study functional, metabolic, and morphological brain changes, respectively. Animals exposed to this cocaine dose showed similar open field activity and brain metabolic activity as compared with controls. However, histological analysis showed alterations in the prefrontal cortex and hippocampus of mice exposed to cocaine. For the first time, it has been demonstrated that a single low dose of cocaine, which can cause no locomotor behavioral and brain metabolic changes, can induce structural damage. These brain changes must always be considered regardless of the dosage used. It is essential to alert the population even against the consumption of low doses of cocaine.

Keywords: behavior; brain damage; cocaine; histological change; metabolic imaging.

PubMed Disclaimer

Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
General experimental design. A total of 18 animals were used, randomly divided into two groups: mice non-exposed (n = 8) or mice exposed (n = 10) to a single low dose of cocaine. Mice were submitted to a behavioral study. Five animals from each group were subsequently studied by PET imaging analysis. To histological analysis, six randomized mice brain samples were collected.
Figure 2
Figure 2
Open field behavior study. Mice non-exposed (saline injection, n = 8) and mice exposed (cocaine injection, n = 10) had similar behavioral parameters (two-way repeated-measures ANOVA followed by Sidak's multiple comparison tests): (A) total distance (m); (B) mean speed (m/s); (C) maximum speed (m/s); (D) periphery distance (m); (E) periphery time (s); (F) latency to enter the center (s); (G) entries in center; (H) distance in center (m); and (I) time in center (s). Data represent mean ± standard error of the mean.
Figure 3
Figure 3
PET imaging study. Changes in metabolic activity in animals non-exposed (controls) and exposed to a single dose of cocaine (0.5 mg/kg). The atlas-derived volumes of interest (VOIs) of the main areas commonly affected by cocaine are shown superimposed on transverse, coronal, and sagittal image slices of mice brain from both representative 18F-FDG PET studies and CT derived from Digimouse 3D atlas. VOIs: prefrontal cortex (PFC, blue), striatum (St, red), hippocampus (HC, green), thalamus (TH, yellow), and amygdala (AMY, pink).
Figure 4
Figure 4
Bar graph of the statistical analysis of standardized uptake value (SUV) in animals non-exposed and exposed to a single low dose of cocaine. (A) SUV analysis of the following brain regions: striatum (ST), olfactory bulb (OB), prefrontal cortex (PFC), hippocampus (HC), amygdala (AMY), cerebellum (Cb), and hypothalamus (HT). (B) Metabolic all-brain analysis. Note the absence of metabolic changes. Data represent mean ± standard error of the mean.
Figure 5
Figure 5
Microphotographs of PFC, HC and Cb. Cb (A–D) of saline (A,B), and cocaine (C,D) animals. ML, molecular layer; G, granular layers; WM, white matter. Cocaine did not trigger any histopathological changes. HC (E–J) of saline (E–G), and cocaine (H–J) groups. CA1 region (F,I) dentate gyrus (G,J). SO, oriens layer; SP, pyramidal layer; SR, radiatum layer; SLM, lacunosum-moleculare layer; OML, outer molecular layer; IML, inner molecular layer; G, granule cell layer. Animals exposed to cocaine show hippocampal histopathological changes in the pyramidal cell layer and granule cell layer in the CA1 region and dentate gyrus, respectively, with neuronal loss (G,H). PFC (K–R) of saline (K–M) and cocaine (N–R) groups. Animals depthwise to cocaine present histological changes, including ischemic necrosis (P,Q). Observe (arrow) the clear halo around oligodendrocyte nuclei (O,R). These features demonstrate irreversible hypoxic lesions and the presence of granule-adipose cells (O,P). HandE: (A,C,E,H,K,N,Q), 40×; (F,G,I,J,L,M,P,R), 100×; (B,D,O), 400×. (S) The difference between cell numbers in PFC (p = 0.008) and HC (t-test, n = 6, p = 0.05). Data represent mean ± standard deviation of the mean. PFC, prefrontal cortex; HC, hippocampus; Cb, cerebellum. *Significant.
See this image and copyright information in PMC

References

    1. Alavi A., Reivich M. (2002). Guest editorial: the conception of FDG-PET imaging. Semin. Nucl. Med. 32, 2–5. 10.1053/snuc.2002.29269 - DOI - PubMed
    1. Barr J. L., Brailoiu G. C., Abood M. E., Rawls S. M., Unterwald E. M., Brailoiu E. (2020). Acute cocaine administration alters permeability of blood-brain barrier in freely-moving rats- Evidence using miniaturized fluorescence microscopy. Drug Alcohol Depend. 206:107637. 10.1016/j.drugalcdep.2019.107637 - DOI - PMC - PubMed
    1. Baumann M. H., Partilla J. S., Lehner K. R., Thorndike E. B., Hoffman A. F., Holy M., et al. (2013). Powerful cocaine-like actions of 3,4-methylenedioxypyrovalerone (MDPV), a principal constituent of psychoactive bath salts products. Neuropsychopharmacology 38, 552–562. 10.1038/npp.2012.204 - DOI - PMC - PubMed
    1. Benuck M., Lajtha A., Reith M. E. (1987). Pharmacokinetics of systemically administered cocaine and locomotor stimulation in mice. J. Pharmacol. Exp. Ther. 243, 144–149. - PubMed
    1. Browndyke J. N., Tucker K. A., Woods S. P., Beauvais J., Cohen R. A., Gottschalk P. C. H., et al. (2004). Examining the effect of cerebral perfusion abnormality magnitude on cognitive performance in recently abstinent chronic cocaine abusers. J. Neuroimaging 14, 162–169. 10.1111/j.1552-6569.2004.tb00234.x - DOI - PubMed

LinkOut - more resources