Activation of Adenosine1 Receptors Induces Antidepressant-Like Anti-Impulsive Effects on Differential Reinforcement of Low-Rate 72-s Behavior in Rats

摘要

Stress and psychiatric illness have been associated with a dysregulation of glutamatergic neurotransmission. Recently, positive allosteric modulators (PAMs) of the metabotropic glutamate 2 (mGlu2) receptor have been found to exert antidepressant-like activity in rats performing under a differential reinforcement of low rate (DRL) 72-s schedule. An autoreceptor role at glutamatergic synapses is the most salient physiological role played by the mGlu2 receptor. Adenosine A1 receptors play a heteroreceptor role at many of the same forebrain synapses where mGlu2 autoreceptors are found. Agonists and/or PAMs of mGlu2 receptors act similarly to adenosine A1 receptor agonists with respect to a wide range of electrophysiological, biochemical, and behavioral responses mediated by limbic circuitry thought to play a role in the pathophysiology of neuropsychiatric disease and to mediate therapeutic drug effects. Therefore, the role of adenosine A1 receptor activation on rat DRL 72-s behavior was explored to provide preclinical evidence consistent or inconsistent with potential antidepressant effects. The adenosine A1 receptor agonist N⁶-cyclohexyladenosine (CHA) increased the reinforcement rate, decreased the response rate, and induced a rightward shift in inter-response time distributions in a dose-dependent fashion similar to most known antidepressant drugs. The adenosine A1 receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine (DPCPX) blocked these antidepressant-like effects. These novel observations with CHA and DPCPX suggest that activation of adenosine A1 receptors could contribute to antidepressant effects, in addition to previous preclinical reports of anxiolytic and antipsychotic effects. By implication, targeting a dysregulated glutamatergic system may be an important principle in discovering novel antidepressant agents that may also possess anti-impulsive activity.