Working memory span capacity improved by a D2 but not D1 receptor family agonist

Abstract

Patients with schizophrenia exhibit poor working memory (WM). Although several subcomponents of WM can be measured, evidence suggests the primary subcomponent affected in schizophrenia is span capacity (WMC). Indeed, the NIMH-funded MATRICS initiative recommended assaying the WMC when assessing the efficacy of a putative therapeutic for FDA approval. Although dopamine D1 receptor agonists improve delay-dependent memory in animals, evidence for improvements in WMC due to dopamine D1 receptor activation is limited. In contrast, the dopamine D2-family agonist bromocriptine improves WMC in humans. The radial arm maze (RAM) can be used to assess WMC, although complications due to ceiling effects or strategy confounds have limited its use. We describe a 12-arm RAM protocol designed to assess whether the dopamine D1-family agonist SKF 38393 (0, 1, 3, and 10 mg/kg) or bromocriptine (0, 1, 3, and 10 mg/kg) could improve WMC in C57BL/6N mice (n=12) in cross-over designs. WMC increased and strategy usage decreased with training. The dopamine D1 agonist SKF 38393 had no effect on WMC or long-term memory. Bromocriptine decreased WMC errors, without affecting long-term memory, consistent with human studies. These data confirm that WMC can be measured in mice and reveal drug effects that are consistent with reported effects in humans. Future research is warranted to identify the subtype of the D2-family of receptors responsible for the observed improvement in WMC. Finally, this RAM procedure may prove useful in developing animal models of deficient WMC to further assess putative treatments for the cognitive deficits in schizophrenia.

The effect of CA1 dopaminergic system in harmaline-induced amnesia

“…In agreement with the present results there are evidence showing that SCH23390 (Rezayof et al, 2007;, SKF38393 (Zarrindast et al, 2012), and sulpiride (Hale and Crowe, 2003) impaired learning and memory. Nevertheless, some investigators indicted that SCH23390 (Nasehi et al, 2010), SKF38393 (Tarantino et al, 2011), sulpiride (Rezayof et al, 2007;Nasehi et al, 2010), and quinpirole (Rezayof et al, 2007), had no effect on learning and memory. The controversial results may be due to methods, route of injection and/or the doses of drugs used.…”

Further evidence for ClockΔ19 mice as a model for bipolar disorder mania using cross-species tests of exploration and sensorimotor gating

“…Hence, tasks such as the Iowa Gambling Task [72] could be used to determine putative changes in ‘mood state’ in these mice resulting from environmental challenges [3]. Hence, future studies will determine the neurocognitive performance of the Clock △19 mutant mice, such as attention in a continuous performance test [73, 74], spatial working memory [75, 76], and decision-making under risk conditions in an Iowa Gambling Task [49, 50]. Such studies will be vital in the future given the correlation between cognition and a subject’s functional capabilities [77, 78].…”

Developing treatments for cognitive deficits in schizophrenia: The challenge of translation

“…Of course, pharmacological validation has yet to be determined between the human and rodent RAMs. Improvements in performance can be seen however in healthy rats using nicotine and nicotinic agonists (Levin et al, 1990, Levin, 2002, Levin et al, 2009), as well as dopamine D 2 family agonists (Tarantino et al, 2011). Although there is limited evidence for nicotine improving traditional measures of working memory in humans, the same D 2 family agonist improved human spatial working memory span capacity in subjects with poor span capacity (Mehta et al, 2001, Gibbs and D'esposito, 2006).…”