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Updated: Mar 7, 2026
A General Method for Evaluating Deep Brain Stimulation Effects on Intravenous Methamphetamine Self-Administration
Published on: January 22, 2016
Extended-access methamphetamine self-administration elicits neuroinflammatory response along with blood-brain barrier
Joana Gonçalves1, Ricardo A Leitão1, Alejandro Higuera-Matas2
1Institute for Biomedical Imaging and Life Sciences (IBILI), Faculty of Medicine, University of Coimbra, Coimbra, Portugal; Institute of Pharmacology and Experimental Therapeutics, Faculty of Medicine, University of Coimbra, Coimbra, Portugal; CNC.IBILI, University of Coimbra, Coimbra, Portugal.
Abstract:
Methamphetamine (METH) is a highly addictive psychostimulant drug that can lead to neurological and psychiatric abnormalities. Several studies have explored the central impact of METH use, but the mechanism(s) underlying blood-brain barrier (BBB) dysfunction and associated neuroinflammatory processes after chronic METH consumption are still unclear. Important findings in the field are mainly based on in vitro approaches and animal studies using an acute METH paradigm, and not much is known about the neurovascular alterations under a chronic drug use. Thus, the present study aimed to fill this crucial gap by exploring the effect of METH-self administration on BBB function and neuroinflammatory responses. Herein, we observed an increase of BBB permeability characterized by Evans blue and albumin extravasation in the rat hippocampus and striatum triggered by extended-access METH self-administration followed by forced abstinence. Also, there was a clear structural alteration of blood vessels showed by the down-regulation of collagen IV staining, which is an important protein of the endothelial basement membrane, together with a decrease of intercellular junction protein levels, namely claudin-5, occludin and vascular endothelial-cadherin. Additionally, we observed an up-regulation of vascular cell and intercellular adhesion molecule, concomitant with the presence of T cell antigen CD4 and tissue macrophage marker CD169 in the brain parenchyma. Rats trained to self-administer METH also presented a neuroinflammatory profile characterized by microglial activation, astrogliosis and increased pro-inflammatory mediators, namely tumor necrosis factor-alpha, interleukine-1 beta, and matrix metalloproteinase-9. Overall, our data provide new insights into METH abuse consequences, with a special focus on neurovascular dysfunction and neuroinflammatory response, which may help to find novel approaches to prevent or diminish brain dysfunction triggered by this overwhelming illicit drug.
Insights
Chronic methamphetamine (METH) use damages the blood-brain barrier (BBB) and causes neuroinflammation. This study reveals structural blood vessel changes and immune cell infiltration in the brain following METH self-administration in rats.
Area of Science:
- Neuroscience
- Pharmacology
- Toxicology
Background:
- Methamphetamine (METH) is a psychostimulant causing addiction and neurological issues.
- Mechanisms of blood-brain barrier (BBB) dysfunction and neuroinflammation from chronic METH use are not well understood.
- Existing research often uses acute METH models, limiting knowledge of chronic use effects.
Purpose of the Study:
- To investigate the impact of chronic METH self-administration on BBB integrity and neuroinflammatory responses in rats.
- To elucidate the neurovascular alterations associated with prolonged METH exposure and subsequent abstinence.
Main Methods:
- Extended-access METH self-administration followed by forced abstinence in a rat model.
- Assessment of BBB permeability using Evans blue and albumin extravasation.
- Analysis of blood vessel structural proteins (collagen IV, claudin-5, occludin, VE-cadherin).
- Evaluation of immune cell markers (CD4, CD169) and neuroinflammatory markers (microglia, astrocytes, TNF-α, IL-1β, MMP-9).
Main Results:
- Chronic METH use significantly increased BBB permeability in the hippocampus and striatum.
- Structural damage to blood vessels was observed, including down-regulation of collagen IV and tight junction proteins.
- Increased expression of adhesion molecules and infiltration of T cells and macrophages into the brain parenchyma.
- Evidence of neuroinflammation, including microglial activation, astrogliosis, and elevated pro-inflammatory cytokines and MMP-9.
Conclusions:
- Chronic METH self-administration leads to significant BBB disruption and neurovascular damage.
- These changes are associated with substantial neuroinflammatory responses in the brain.
- Findings highlight potential therapeutic targets for mitigating METH-induced brain dysfunction.
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