The effects of psychotomimetic and putative cognitive-enhancing drugs on the performance of a n-back working memory task in rats

Working memory impairment is a core symptom of schizophrenia, but no existing treatment remediates this deficit. Inconsistent conceptualizations and few reliable translational measures are major hindrances to understanding the neurobiology of this aspect of cognition. Using comparable task designs may help bridge clinical and preclinical research efforts. A novel rodent procedure was designed to translate the n-back working memory task used in schizophrenic patients. Rats were trained in five-lever operant chambers to recall either the last (one-back) or penultimate (two-back) lever from random sequences of lever presentations of variable lengths. Psychotomimetic doses of amphetamine, dizocilpine maleate (MK801), and (+/-)-2,5-dimethoxy-4-iodoamphetamine hydrochloride (DOI) were tested for disruption of accuracy, and cognitive-enhancing doses of amphetamine, nicotine, and (+/-)-1-phenyl-2,3,4,5-tetrahydro-(1H)-3-benzazepine-7,8-diol hydrochloride (SKF38393 hydrochloride) were examined for improvements in performance. High doses of amphetamine (0.8 and 1.6 mg/kg) significantly reduced accuracy while increasing total trials; 0.1 mg/kg MK801 and 2.0 mg/kg DOI also reduced accuracy, but the latter concurrently impaired responding. At the lowest dose (0.2 mg/kg), amphetamine increased total trials and rewards without affecting accuracy; 1.0 mg/kg nicotine reduced accuracy without affecting total trials, whereas 10.0 mg/kg SKF38393 had the opposite effect. Although the possibility for mediating behaviors may exist, the rodent n-back task provides a clinically relevant model of working memory. Amphetamine and MK801 produced selective impairments without disrupting responding. The cognitive enhancers did not improve working memory, but low doses of amphetamine improved response efficiency. This novel procedure may be useful for examining cognitive deficits and their potential reversal in animal models of schizophrenia.