Table 1.
Summary of similarities and differences between the mechanisms of neurotoxicity of major drugs of abuse.
| Drug | Receptor Involved in Mediating Neurotoxicity | Neurotransmitter System Disrupted | Effect on Viral Proteins/HIV Replication | Mechanism of Neurotoxicity | Interaction with ART |
|---|---|---|---|---|---|
| Opioids | MOR: Mu (μ) opioid receptor KOR: Kappa (κ) opioid receptor DOR: Delta (δ) opioid receptor |
Dopaminergic system | Potentiates viral replication through: Increased expression of galectin 1 Inhibition of interferon Increased expression of CCR5 |
Disrupt the integrity of BBB Oxidative stress Neuroinflammation through cytokine secretion |
Compete with antiretrovirals for cytochrome P450 enzymes (CYP3A4, CYP2D6, CYP2C19, CYP2C9, and CYP2D67) |
| Cannabinoids | CB1 receptor CB2 receptor NMDA receptor |
Endocannabinoid system Glutamatergic system |
Gp120 increases the expression of FAAH, the enzyme that metabolizes the neuroprotective endocannabinoid, anandamide | Apoptosis Neuroinflammation |
Compete with antiretrovirals for cytochrome P450 enzymes (CYP3A4 and CYP2C19) |
| Cocaine | Dopamine (Serotonin) (Norepinephrine) |
Dopaminergic system | The combination of GP120 and cocaine increases the production of ROS and iNOS expression Cocaine augments Tat-mediated mitochondrial depolarization and production of ROS |
Oxidative stress Epigenetic modifications Apoptosis |
Compete with antiretrovirals for cytochrome P450 enzymes (CYP3A4 and CYP3A5) |
| Methamphetamine | Dopamine Serotonin Norepinephrine NMDA receptor |
Dopaminergic system Glutamatergic system |
Methamphetamine and Tat synergistically decrease dopamine reserves by binding to VMAT and DAT | Disrupt the integrity of BBB Impairing glial signaling Excitotoxicity |
Compete with antiretrovirals for cytochrome P450 enzymes (CYP2D6 and CYP3A4) |
| Ethanol | NMDA receptor GABA receptor |
Glutamatergic system GABAergic system |
Stimulates HIV transcription through TNF secretion The combination of ethanol and Tat increases cytokine production |
Apoptosis Ethanol exerts direct neurotoxicity |
Compete with antiretrovirals for cytochrome P450 enzymes (CYP2E1 and CYP3A4) |