Differential Effects of Intrahippocampal Administration of Ceftriaxone on Morphine Dependence and Withdrawal Syndrome in Rats

Glutamate is a key factor in opiate addiction. Glial glutamate transporter-1 (GLT-1) plays a prominent role in glutamate homeostasis. Therefore, different regimens of ceftriaxone as a GLT-1 activator were prescribed to determine whether modulating GLT-1 prevents morphine dependence or withdrawal syndrome. Rats received 10 mg/kg morphine subcutaneously for ten consecutive days. Intrahippocampal ceftriaxone (0.5 mu L of 0.5 mM solution) was injected 30 min before morphine administration to assess its effect on dependence process. In the next experiment, after the animals became dependent, ceftriaxone was injected before or after the last morphine administration, and its effect on withdrawal symptoms was evaluated. The reversibility of developed dependence was evaluated in the conditions when morphine and ceftriaxone were administered simultaneously. Two hours after the last morphine injection, naloxone hydrochloride (1.5 mg/kg) was administered, and morphine withdrawal syndrome was recorded for 25 min. Ceftriaxone administration before each morphine injection caused a decrease in the occurrence of withdrawal symptoms. Single dose of ceftriaxone after or before the last dose of morphine did not change the withdrawal symptoms significantly. Ceftriaxone injection for 5 days after becoming dependent could decrease the occurrence of some withdrawal symptoms. Modulation of glutamate with ceftriaxone during morphine injection may be able to prevent dependence. However, a single dose of ceftriaxone after becoming dependent could not decrease withdrawal syndrome. More prolonged administration of ceftriaxone could alleviate the induced dependence.