Role of GLT-1 transporter activation in prevention of cannabinoid tolerance by the β-lactam antibiotic, ceftriaxone, in mice.

Recently, it has been indicated that beta lactam antibiotics offer neuroprotection by increasing glutamate transporter expression. Furthermore, these antibiotics have been shown to prevent the development of tolerance and dependence to opioids. Since cannabinoid tolerance is known to be similar to opioids, our purpose was to examine the effect of ceftriaxone on the development of tolerance to WIN 55,212-2, a cannabinoid agonist. The tail flick test, a rectal thermometer, and the ring test were used for evaluating the degree of tolerance to the analgesic, hypothermic, and cataleptic effects of WIN 55,212-2, respectively. Within one week, animals became completely tolerant to analgesic, hypothermic and cataleptic effects of WIN 55,212-2 (6mg/kg). Ceftriaxone, with its higher doses (100-200mg/kg), attenuated the development of tolerance to the analgesic and hypothermic effects of WIN 55,212-2, but had no effect on its cataleptic action. Dihydrokainic acid (10mg/kg), a GLT-1 transporter inhibitor, prevented this effect of ceftriaxone. Our results suggest that repeated treatment with ceftriaxone prevents the development of tolerance to the analgesic and hypothermic effects of cannabinoids, and GLT-1 activation appears to play a key role in this preventive effect of beta-lactam antibiotics.