90 Intra-accumbens injection of a dopamine aptamer abates MK-801-induced cognitive dysfunction in a model of Schizophrenia

Abstract

Aptamers are short, single-stranded sequences of DNA or RNA, which exhibit conformationally unique three-dimensional structures. Aptamer binding to target molecular substrates (from small molecules to proteins) demonstrates a high degree of affinity and specificity, in an analogous fashion to antigen-antibody binding. Aptamers offer several advantages over antibodies, including highly reproducible synthesis and ease of modification. Though the characteristics of aptamers and their applicability within the central nervous system show great potential, research in this area is limited. In the present work, the ability of a dopamine-binding DNA aptamer to regulate MK-801-induced cognitive deficits when injected into the nucleus accumbens was investigated. Systemic administration of the non-competitive NMDA-receptor antagonist, MK-801, has been proposed to model cognitive deficits similar to those seen in patients with schizophrenia. Rats were trained to bar press for chocolate pellet rewards then randomly assigned to receive an intra-accumbens injection of a DNA aptamer (200 nM; n = 7), tris buffer (n=6) or a randomized DNA oligonucleotide (n = 7). Animals were then treated systemically with MK-801 (0.1 mg/kg) and tested for their ability to extinguish their bar-pressing response. Injection of 200nM dose of the dopamine apt- amer reversed this MK-801-induced elevation in lever pressing to levels as seen in rats not treated with MK- 801. Tests for activity showed that the aptamer did not impair locomotor activity. Results demonstrate the in vivo utility of DNA aptamers as tools to investigate neurobiological processes in preclinical animal models of mental health disease.