Behavioural effects of glutamate receptor agonists in morphine-dependent rats

Glutamate receptors are implicated in the development and expression of drug dependence. Substantial experimental evidence suggests that antagonists acting at the N-methyl-D-aspartate (NMDA) subtype of glutamate receptors attenuate the severity of opioid withdrawal. However, it is less clear whether opioid withdrawal can be potentiated by agonists of glutamate receptors. The present study evaluated the behavioural effects of various agonists of glutamate receptors, as well as a nitric oxide (NO) donor, in morphine-dependent rats trained to discriminate 0.1 mg/kg of naloxone from saline. None of the following drugs produced appreciable levels of naloxone-like responding (substitution tests) or potentiated the discriminative stimulus effects of naloxone: NMDA (3-56 mg/kg), glycine (100-1000 mg/kg), glutamate (1000-3000 mg/kg), kainate (0.3-3 mg/kg), isosorbide dinitrate (30-300 mg/kg). Nevertheless, expression of some morphine withdrawal-like somatic and behavioural signs ('wet-dog'-like shaking, scream on touch, ptosis, tremor, chewing, weight loss) was facilitated by NMDA, glycine, and isosorbide dinitrate. These results suggest that, compared to somatic symptoms, subjective effects of opioid withdrawal (as reflected by discriminative stimulus effects) are not mimicked by direct activation of glutamate receptors.