The authors of a new study in Biological Psychiatry¹ explore pharmacological（药理学的） strategies for reducing cocaine² self-administration in animals that may have implications for treating cocaine dependence³ in humans. Glutamate is the primary excitatory（兴奋的，刺激的） neurotransmitter（神经传递素） in the brain, which has been implicated⁴ in drug addiction⁵. Metabotropic glutamate（谷氨酸盐） receptors (mGluRs) represent a family of G-protein coupled receptors that modulate⁶ glutamate transmission. Glutamate is an important neurotransmitter involved in learning and memory. Today, these receptors are considered to be promising⁷ targets for drug discovery, with therapeutic⁸ potential to treat various neurological and psychiatric disorders⁹（精神疾病） , including drug addiction.

Scientists from The Scripps Research Institute examined whether dysregulation（调节异常） of mGluRs function is a factor in escalating¹⁰ cocaine self-administration in rats. Rats with a history of daily short (1 hour) or long (6 hours) access to cocaine were tested for differences in cocaine consumption after receiving treatment with LY379268, an mGluR2/3 agonist, and MTEP, an mGluR5 antagonist¹¹.

They found that the capacity of LY379268 and MTEP to diminish cocaine use changed into opposite directions during development to addiction. LY379268 became more effective, whereas MTEP lost its effect in cocaine dependent rats (long-access). These behavioral changes were paired with distinct changes in the function of mGlu2/3 and mGlu5 receptors.

Dr. Yue Hao, corresponding author of this study, explains their findings: "We provide novel evidence that during the transition from 'casual' cocaine use to addiction, dysregulation develops in both mGlu2/3 and mGlu5 function as reflected by enhanced mGlu2/3 activity and decreased mGlu5 expression." These data suggest that changes in the function of mGlu2 and mGlu5 receptors may play a role in the transition to cocaine addiction.

According to the authors, these new findings identify mGlu2/3 receptors as a particularly promising treatment target for severely¹² cocaine-addicted individuals.

In contrast, the treatment target potential of mGlu5 receptors may be limited to early stages of cocaine abuse.

"This type of study highlights an aspect of the complexity¹³ that may be associated with the pharmacotherapy（药物疗法） of treating cocaine dependence. All types of cocaine use may not be alike," comments Dr. John Krystal, Editor of Biological Psychiatry. "Cocaine exposure to different extents may produce different adaptations in the brain systems. The different profile of the effects of mGluR2/3 agonists and mGluR5 antagonists¹⁴（敌手，对抗剂） is interesting and it should stimulate¹⁵ further research."