The Effects of Psychostimulant Drugs on Blood Brain Barrier Function and Neuroinflammation

Abstract

The blood brain barrier (BBB) is a highly dynamic interface between the central nervous system (CNS) and periphery. The BBB is comprised of a number of components and is part of the larger neuro(glio)vascular unit. Current literature suggests that psychostimulant drugs of abuse alter the function of the BBB which likely contributes to the neurotoxicities associated with these drugs. In both preclinical and clinical studies, psychostimulants including methamphetamine, MDMA, cocaine, and nicotine, produce BBB dysfunction through alterations in tight junction protein expression and conformation, increased glial activation, increased enzyme activation related to BBB cytoskeleton remodeling, and induction of neuroinflammatory pathways. These detrimental changes lead to increased permeability of the BBB and subsequent vulnerability of the brain to peripheral toxins. In fact, abuse of these psychostimulants, notably methamphetamine and cocaine, has been shown to increase the invasion of peripheral bacteria and viruses into the brain. Much work in this field has focused on the co-morbidity of psychostimulant abuse and human immunodeficiency virus (HIV) infection. As psychostimulants alter BBB permeability, it is likely that this BBB dysfunction results in increased penetration of the HIV virus into the brain thus increasing the risk of and severity of neuro AIDS. This review will provide an overview of the specific changes in components within the BBB associated with psychostimulant abuse as well as the implications of these changes in exacerbating the neuropathology associated with psychostimulant drugs and HIV co-morbidity.

Blood-Brain Barrier Disruption Is Initiated During Primary HIV Infection and Not Rapidly Altered by Antiretroviral Therapy

“…One participant, in the low baseline group, had a known diagnosis of diabetes mellitus type 2. Abuse of substances such as cocaine has been shown to at least transiently increase BBB permeability [49]; thus, misreporting of ongoing drug use or long-term effects of previous drug use cannot be discounted as confounding factors. Furthermore, given the observational nature of this study, cART regimens were heterogeneous, which may result in distinct effects on the BBB.…”

Drugs of abuse and blood-brain barrier endothelial dysfunction: A focus on the role of oxidative stress

“…53 Following a series of initial demonstrations of mammalian BBB disruption by amphetamines, 54,55 it is now widely established that METH abuse/addiction directly impairs various structural and functional facets of BBB resulting in loss of barrier integrity. 17,56 Both acute/binge and long-term (chronic) paradigms of METH administration promotes a region-specific BBB disruption in a concentration and time-dependent manner. 57,58 For example, acute high dose of METH (40 mg/kg) in mice, reflecting a binge intoxication model, was shown to elicit a rapid and transient BBB disruption primarily in the hippocampus within 3-h post-injection that is associated with severe hyperthermia and seizures.…”

Effects of HIV-1 Tat and Methamphetamine on Blood-Brain Barrier Integrity and FunctionIn Vitro

“…Furthermore, many of the studies used methamphetamine concentrations that are in excess of the plasma concentrations found in typical drug abuse (55). The use of extremely high concentrations may result in direct neurotoxic stress which, in turn, could lead to BBB breakdown (56,57). Our studies used 10 M, which is within the range of plasma concentrations measured from methamphetamine abusers (0.1 to 11.1 M) (58), and we demonstrated a lack of toxicity at this concentration using the LIVE/DEAD assay.…”