Activation of adenosine₁ receptors induces antidepressant-like, anti-impulsive effects on differential reinforcement of low-rate 72-s behavior in rats.
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.
Abbott Laboratories, Neuroscience Development, GPRD, R48B, Bldg. AP04-1, 100 Abbott Park Road, Abbott Park, IL 60064-6075, USA. gerard.marek@abbott.com
Gerard J
GJ
Marek
D000241:Adenosine / Q000031:analogs & derivatives / Q000494:pharmacology; D058907:Adenosine A1 Receptor Agonists / Q000494:pharmacology; D058916:Adenosine A1 Receptor Antagonists / Q000494:pharmacology; D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology*; D017660:Autoreceptors / Q000378:metabolism; D001522:Behavior, Animal / Q000187:drug effects*; D018698:Glutamic Acid / Q000378:metabolism; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D043682:Receptor, Adenosine A1 / Q000378:metabolism*; D018094:Receptors, Metabotropic Glutamate / Q000378:metabolism; D012055:Reinforcement Schedule; D012054:Reinforcement, Psychology; D013569:Synapses / Q000378:metabolism; D009435:Synaptic Transmission / Q000187:drug effects*; D014970:Xanthines / Q000494:pharmacology
D058907:Adenosine A1 Receptor Agonists; D058916:Adenosine A1 Receptor Antagonists; D000928:Antidepressive Agents; D017660:Autoreceptors; D043682:Receptor, Adenosine A1; D018094:Receptors, Metabotropic Glutamate; D014970:Xanthines; C108822:metabotropic glutamate receptor 2; C027513:N(6)-cyclohexyladenosine; D018698:Glutamic Acid; C051360:1,3-dipropyl-8-cyclopentylxanthine; D000241:Adenosine