Effects of Drugs of Abuse on the Blood-Brain Barrier: A Brief Overview

Abstract

The use of psychostimulants and alcohol disrupts blood-brain barrier (BBB) integrity, resulting in alterations to cellular function, and contributes to neurotoxicity. The BBB is the critical boundary of the central nervous system (CNS) where it maintains intracellular homeostasis and facilitates communication with the peripheral circulation. The BBB is regulated by tight junction (TJ) proteins that closely interact with endothelial cells (EC). The complex TJ protein network consists of transmembrane proteins, including claudins, occludins, and junction adhesion molecules (JAM), as well as cytoskeleton connected scaffolding proteins, zonula occludentes (ZO-1, 2, and 3). The use of psychostimulants and alcohol is known to affect the CNS and is implicated in various neurological disorders through neurotoxicity that partly results from increased BBB permeability. The present mini review primarily focuses on BBB structure and permeability. Moreover, we assess TJ protein and cytoskeletal changes induced by cocaine, methamphetamine, morphine, heroin, nicotine, and alcohol. These changes promote glial activation, enzyme potentiation, and BBB remodeling, which affect neuroinflammatory pathways. Although the effect of drugs of abuse on BBB integrity and the underlying mechanisms are well studied, the present review enhances the understanding of the underlying mechanisms through which substance abuse disorders cause BBB dysfunction.

Transcriptional alterations in opioid use disorder reveal an interplay between neuroinflammation and synaptic remodeling

“…Surprisingly, we discovered that all of the predicted upstream regulators that were inhibited have key roles in the regulation of the vasculature, including KLF2 (20), NRAS (21), and PTEN (22) (Figure 2d). These findings suggest that vascular integrity may be compromised in DLPFC of OUD subjects, in line with growing evidence that the blood brain barrier (BBB) is eroded as consequence of repeated opioid use (23,24).…”

Think Big, Start Small: How Nanomedicine Could Alleviate the Burden of Rare CNS Diseases

“…A relevant illustration of this latter point would be the use of cationic nanoparticles which have long been demonstrated to disrupt the BBB, hence inducing neurotoxicity; consequently, the effect on the BBB integrity should be automatically assessed when dealing with this type of nanoformulation [21]. The same goes for certain classes of agents, such as psychostimulants or alcohol, which are known to alter the BBB integrity, resulting in neuroinflammation and subsequent toxicity [22]. Above all, drug development for CNS disorders is confronted with an additional major hurdle, regarding how to get therapies past the BBB.…”

Posterior Reversible Encephalopathy Syndrome (PRES) in a Patient with Opioid Use Disorder

“…Clinical and radiographic syndromes that overlap with PRES have been described in overdoses of drugs of abuse like benzodiazepines, amphetamines, and opiates. Drugs of abuse increase blood-brain barrier permeability, which, in turn, increases the influx of peripheral toxins into the brain [11,12]. Protein disruption at tight junctions, neuroinflammation, oxidative stress, and production of reactive oxygen species have all been postulated as fundamental mechanisms through which drugs alter the blood-brain barrier structure and integrity.…”

“…Heroin's effects indirectly involve its metabolites (morphine and 6-MAM) that act as substrates in P-glycoprotein membrane regulation. Pglycoprotein inhibition at the blood-brain barrier acutely disrupts the blood-brain barrier permeability and selectivity in the nucleus accumbens [11,12]. Cases of toxic leukoencephalopathy have been reported in patients with illicit heroin vapor inhalation [13][14][15][16].…”