Intra-Accumbens Injection of a Dopamine Aptamer Abates MK-801-Induced Cognitive Dysfunction in a Model of Schizophrenia

Abstract

Systemic administration of the noncompetitive NMDA-receptor antagonist, MK-801, has been proposed to model cognitive deficits similar to those seen in patients with schizophrenia. The present work investigated the ability of a dopamine-binding DNA aptamer to regulate these MK-801-induced cognitive deficits when injected into the nucleus accumbens. 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. Two control groups were also included that did not receive MK-801. Data revealed that injection of Tris buffer or the random oligonucleotide sequence into the nucleus accumbens prior to treatment with MK-801 did not reduce the MK-801-induced extinction deficit. Animals continued to press at a high rate over the entire course of the extinction session. Injection of the dopamine aptamer 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.

Amygdala Lesions Reduce Cataplexy in Orexin Knock-Out Mice

“…The next night, we gave mice 3g of milk chocolate (Hershey's, Hershey, PA) at dark onset and recorded sleep-wake behavior and wheel running over the next 12 hours (19:00-7:00). We chose to use chocolate because it is used as a reward in rodent operant studies (Holahan et al, 2011, King et al, 2011), and cataplexy in mice and dogs is increased by palatable foods (Siegel et al, 1986, Clark et al, 2009). …”

Aptamers as Promising Molecular Recognition Elements for Diagnostics and Therapeutics in the Central Nervous System

“…In this model, treatment with D1-or D2-like receptor antagonists reversed MK-801-associated behavior, thus it was concluded that perseveration may be a result of overactivity of DA in the nucleus accumbens [38]. The potential for a DAbinding DNA aptamer to offer an alternative to traditional D1-and D2-like receptor antagonists was therefore explored [30,39]. The authors postulated that the aptamer would bind excess DA and prevent the molecules from binding to DA receptors, thereby normalizing lever pressing behavior.…”

“…Number in parentheses = rats per group. Figure reproduced from Holahan et al, 2011, in accordance with the PLOS Creative Commons Attribution (CC BY) license[39].…”

Aptamer Recognition of Multiplexed Small-Molecule-Functionalized Substrates

“…the dopamine aptamer investigated here). 35,36,48,49 These difficulties have been attributed to the complexity in targeting molecules with low molecular mass and rotatable bonds. 59,60 Recent advances in solution-phase SELEX methods that obviate tethering targets have enabled identification of aptamers that recognize small-molecule, low-epitope targets.…”