Figure 5. Pharmacological targets.

Observations of stress-induced effects on the glutamate synapse have suggested several unique forms of pharmacological interventions for stress related disorders such as mood and anxiety disorders¹⁷⁹. Drugs that modify glutamate release (a), such as lamotrigine and rilzuole, have been shown to have antidepressant-like actions in rodent models and in clinical trials^171,227,228. In addition, negative and positive allosteric modulators of group II mGluRs that also modulate presynaptic glutamate release (not shown), have been shown to have antidepressant-like actions in rodent models¹⁸⁶. Drugs targeting NMDA receptors (b), especially NMDA antagonists (ketamine, RO 25-6981, and CP101,606) have demonstrated rapid and robust antidepressant-like effects in both rodent models and clinical trials^187,188. Positive and negative allosteric modulators of the mGlu 5 receptor (c) have been shown to possess antidepressant and anxiolytic properties in preclinical studies¹⁸⁶ Drugs targeting AMPA receptors (d), especially agents that potentiate the activation of AMPA receptors, have both nootropic (cognition-enhancing) properties and antidepressant-like effects in rodent models¹⁹². Various agents that regulate glucocorticoid signalling have effects on memory and possess mood and anxiety modifying properties²²⁹ (e). Drugs such as riluzole and ceftriaxone that indirectly facilitate glutamate transport into glia (f), possess both neuroprotective and antidepressant-like effects^171,184,185. Considering endocannabinoids are reduced in the PFC and hippocampus in animal models of depression, and CB1 receptor stimulation in the PFC and hippocampus is anxiolytic and antidepressant, targeted pharmacological augmentation of endocannabinoid signalling (g) has recently been proposed as a promising therapeutic strategy for the treatment of mood and anxiety disorders²³⁰.