Chinese researchers have reported that the different of L-type calcium channels in the hippocampus plays different roles in the withdrawal response of morphine-dependent rats. Led by Dr. SHEN fang from institute of Psychology of the Chinese Academy of Science (CAS), the researchers found the Cav1.2 siRNA, but not Cav1.3 shRNA, inhibited the acquirement of CPA and relieved somatic withdrawal symptoms.

The study was published in Progress in Neuro-Psychopharmacology and Biological Psychiatry on June 20.

Negative effects coming with opiate withdrawal are thought to play a critical role in causing craving and relapse. As one of the necessary brain regions encoding negative memory, the dorsal hippocampus (DH) was shown to modulate the aversive symptoms induced by morphine withdrawal in rats. And in vitro experiments have shown that the activation of opioid receptors induced abnormal Ca2+ homeostasis in the hippocampal neurons. L-type Ca2+ channels (LTCCs), as one of the primary sources of activity-dependent Ca2+ current into neurons, were associated with drug dependence and opiate withdrawal.

Previous results found that Cav1.2 and Cav1.3 showed the opposite protein expression in habitual cocaine-seeking behavior in the dorsal striatum. The above evidence suggests that determining the roles of Cav1.2 and Cav1.3 in the DH may be the key to understanding mechanisms of opiate withdrawal.

The conditioned place aversion (CPA) is a sensitive index to reflect the aversive state induced by withdrawal.

The current study used the naloxone-induced conditioned place aversion model in morphine-dependent rats to examine the distinctive roles of LTCCs subtypes.

The researchers injected the non-specific LTCCs antagonist verapamil into the DH of morphine-dependent rats before conditioning an environment with naloxone-precipitated withdrawal. The results showed that verapamil blocked the acquisition of CPA.

Furthermore, they measured the protein expression of Cav1.2 and Cav1.3 in morphine-dependent rats under different conditions. In morphine-dependent rats, conditioning with withdrawal increased Cav1.2 expression in the membrane, while only acute naloxone injection increased the membrane expression of Cav1.3.

Lastly, RNA interference (Cav1.2 siRNA or Cav1.3 shRNA) were applied to knock down the expression of subtypes and detected the effects on CPA and somatic withdrawal signs in morphine-dependent rats. Cav1.2 siRNA, but not Cav1.3 shRNA, inhibited the acquirement of CPA and relieved somatic withdrawal symptoms.

This study suggests this subtype may serve as a potential therapeutic target for the treatment of negative effects in opiate dependence.

LIU Chen Institute of Psychology
Chinese Academy of Sciences
Beijing 100101, China.
E-mail: liuc@psych.ac.cn