Combined α2 and D2/3 receptor blockade enhances cortical glutamatergic transmission and reverses cognitive impairment in the rat
The α2 adrenoceptor antagonist idazoxan enhances antipsychotic efficacy of classical dopamine D2 antagonists in treatment-resistant schizophrenia. The mechanisms are not fully understood, but we have previously shown that the combination of idazoxan with the D2/3 receptor antagonist raclopride, similarly to clozapine but not classical antipsychotic drugs, augments dopamine efflux in the prefrontal cortex, and also generates an enhanced suppression of the conditioned avoidance response. We have now investigated the effects of clozapine, raclopride, idazoxan and the combination of raclopride and idazoxan on (i) electrically evoked excitatory post-synaptic potentials and currents in pyramidal cells of the rat medial prefrontal cortex, using intracellular electrophysiological recording in vitro, (ii) the impaired cognitive function induced by the selective N-methyl-D-aspartate (NMDA) receptor antagonist MK-801, using the 8-arm radial maze test, (iii) the in-vivo D2, α2A and α2C receptor occupancies of these pharmacological treatments, using ex-vivo autoradiography. Whereas neither idazoxan nor raclopride alone had any effect, the combination exerted the same facilitation of glutamatergic transmission in rat prefrontal pyramidal neurons as clozapine, and this effect was found to be mediated by dopamine acting at D1 receptors. Similarly to clozapine, the combination of idazoxan and raclopride also completely reversed the working-memory impairment in rats induced by MK-801. Moreover, these effects of the two treatment regimes were obtained at similar occupancies at D2, α2A and α2C receptors respectively. Our results provide novel neurobiological and behavioural support for a pro-cognitive effect of adjunctive use of idazoxan with antipsychotic drugs that lack appreciable α2 adrenoceptor-blocking properties, and define presynaptic α2 adrenoceptors as major targets in antipsychotic drug development.(Received October 17 2004)
(Reviewed November 24 2004)
(Revised December 6 2004)
(Accepted December 12 2004)
Key Words: α2 adrenoceptors; cognition; dopamine; glutamate; schizophrenia.
c1 Department of Physiology and Pharmacology, Section for Neuropsychopharmacology, Karolinska Institutet, S-171 77 Stockholm, Sweden. Tel.: +46 8 524 879 21 Fax: +46 8 308 424 E-mail: Torgny.Svensson@fyfa.ki.se