The α7 nicotinic acetylcholine receptor (nAChR) allosteric modulator UCI-40083 differentially increases dopamine (DA) and norepinephrine (NE) release in adolescent rat brain

CARBONI, EZIO;IBBA M;CADEDDU R;HOGENKAMP D;JOHNSTONE T;GEE KW

2011-01-01

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Abstract

The selective α7 nAChR positive allosteric modulator UCI-40083 (N-(4-chlorophenyl)-α-[[(4-chlorophenyl)amino]methylene]-3-methyl-5-isoxazolacet-amide), has been shown to evoke robust positive modulation of agonist-induced currents at α7 nAChRs. In order to evaluate its pharmacological potential in cognition disorders such as the attention deficit with hyperactivity disorder (ADHD), we assessed the effect of systemic UCI-40083 administration on DA and NE release in the medial prefrontal cortex (PFC) of adolescent spontaneous hypertensive (SHR) and Sprague Dawley (SD) rats, by using a microdialysis technique in freely moving animals. We also assessed the effect on DA and NE release in the nucleus accumbens (NAcc) shell to gain insight into potential motivational properties of UCI-40083. Our results show that UCI-40083 (1 mg/kg i.p.) increases NE and DA in the PFC of both SD and SHR rats. This effect yielded an optimum dose as the effect of 3 mg/kg was not significantly different (NE) or was lower (DA) when compared to 1 mg/kg in both strains. In addition, our results show that UCI-40083 significantly increased DA and NE output in the NAcc shell of both SD and SHR rats. The stimulant effect on DA and NE levels in the PFC was blocked by the selective α7 nAChR antagonist methyllycaconitine (MLA) at 3 mg/kg i.p. In summary our results suggest that UCI-40083 has the potential of modulating catecholamine transmission in the PFC and in the NAcc shell and thus may possess cognitive and motivational properties, features that are shown also by stimulant drugs currently used in ADHD therapy such as amphetamine and methylphenidate. (NIH grant MH080246)