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

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 A1 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-hydroxytryptamine2A (5-HT2A) and mGlu2/3 receptors in the mPFC. The present studies were designed to investigate the effects in rats of adenosine A1 receptor activation/blockade on a behavior modulated by 5-HT2A receptor activation/blockade in the mPFC: head shakes induced in the rat by phenethylamine hallucinogens. An adenosine A1 receptor agonist, N6-cyclohexyladenosine (CHA) suppressed head shakes induced by activation of 5-HT2A 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 A1 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 A1 receptor agonist suggest that this pharmacological action could contribute to antipsychotic effects in addition to thymoleptic effects.