Sigma1 (σ1) receptor antagonists represent a new strategy against cocaine addiction and toxicity

Abstract

Cocaine is a highly addictive substance abused worldwide. Its mechanism of action involves initially inhibition of neuronal monoamine transporters in precise brain structures and primarily the dopamine reuptake system located on mesolimbic neurons. Cocaine rapidly increases the dopaminergic neurotransmission and triggers adaptive changes in numerous neuronal circuits underlying reinforcement, reward, sensitization and the high addictive potential of cocaine. Current therapeutic strategies focus on counteracting the cocaine effects directly on the dopamine transporter, through post-synaptic D1, D2 or D3 receptors or through the glutamatergic, serotoninergic, opioid or corticotropin-releasing hormone systems. However, cocaine administration also results in the activation of numerous particular targets. Among them, the sigma1 (σ1) receptor is involved in several acute or chronic effects of cocaine. The present review will first bring concise overviews of the present strategies followed to alleviate cocaine addiction and animal models developed to analyze the pharmacology of cocaine addiction. Evidence involving activation of the σ1 receptor in the different aspects of cocaine abuse, will then be detailed, following acute, repeated, or overdose administration. The therapeutic potentials and neuropharmacological perspectives opened by the use of selective σ1 receptor antagonists in cocaine addiction will finally be discussed. © 2002 Elsevier Science Ltd. All rights reserved.