Activation of adenosine1 (A1) receptors suppresses head shakes induced by a serotonergic hallucinogen in rats

Abstract Modulation of glutamatergic neurotransmission by metabotropic glutamate2/3 (mGlu2/3) receptor agonists effectively treats seemingly diverse neuropsychiatric illness such as generalized anxiety disorder and schizophrenia. Activation of adenosine A 1 heteroceptors, like mGlu2 autoreceptors, decreases glutamate release in the medial prefrontal cortex (mPFC) and other limbic brain regions. Previously, we have reported electrophysiological, neurochemical and behavioral evidence for interactions between the 5-hydroxytryptamine 2A (5-HT 2A ) and mGlu2/3 receptors in the mPFC. The present studies were designed to investigate the effects in rats of adenosine A 1 receptor activation/blockade on a behavior modulated by 5-HT 2A receptor activation/blockade in the mPFC: head shakes induced in the rat by phenethylamine hallucinogens. An adenosine A 1 receptor agonist, N 6 -cyclohexyladenosine (CHA) suppressed head shakes induced by activation of 5-HT 2A receptors with the phenethylamine hallucinogen (±)-2,5-dimethoxy-4-iodoamphetamine hydrochloride (DOI). An adenosine A1 receptor antagonist, 8-cyclopentyl-1,3-dipropylxanthine (DPCPX), enhanced DOI-induced head shakes and blocked the suppressant action of an adenosine A 1 receptor agonist on DOI-induced head shakes. Thus, the pattern of activity for an agonist and antagonist at the adenosine A1 receptor with respect to modulating DOI-induced head shakes is similar to the pattern observed with mGlu2/3 receptor agonists and antagonists. These novel observations with an adenosine A 1 receptor agonist suggest that this pharmacological action could contribute to antipsychotic effects in addition to thymoleptic effects.