Nicotine-stimulated release of [3H]norepinephrine is reduced in the hippocampus of an animal model of attention-defidt/hyperactivity disorder, the spontaneously hypertensive rat

摘要

Attenuon-deficit/hyperactivity disorder (ADHD) is a heterogeneous, developmental disorder, and is one of the most common child-psychiatric disorders. It is also a risk factor for early smoking and adult nicotine dependence. Nicotine has been shown to improve symptoms associated with ADHD, including problems with attention, working memory and response inhibition. Norepinephrine, a neurotransmitter involved in attention, is highly implicated in ADHD, and often targeted in the treatment thereof. In the present study we investigated nicotine's effect on release of norepinephrine in the hippocampus of a validated rat model of ADHD, the spontaneously hypertensive rat (SHR), as well as in two control strains: Wistar-Kyoto rats (WKY) and Sprague-Dawley rats (SD). Hippocampal slices obtained from male SHR, WKY and SD (postnatal day 31-33) were pre-incubated with radioactively labelled norepinephrine ([3H]NE) and perfused with buffer. The slices were stimulated by exposure to different concentrations of nicotine (1,10, 100 or 1000 M) for 1 min at 2 intervals (SI and S2, separated by 20 min). Following a 10 min wash, slices were stimulated with 25 mM potassium. Since glutamate and GABA receptor function differ in SHR and WKY, we investigated the possible involvement of AMPA and GABAA receptors in nicotine (100 nM)-stimulated release of hippocampal [3H]NE in each of the strains by blocking these receptors with CNQX (AMPA receptor antagonist, 10 M) or bicuculline (GABAA receptor antagonist, 30 nM) respectively. Nicotine-stimulated release (SI) of [3H]NE from SHR hippocampal slices was less than that of WKY and SD, at 100 |aM and 1000 M nicotine, suggesting reduced density and/or function of nicotinic receptors in SHR hippocampus. Nicotine-stimulated release of [3H]NE in response to S2 was reduced compared to SI in all strains, indicating desensitization of receptors involved in stimulation of [3H1NE bv nicotine. Potassium-stimulated release of [3HlNE following the nicotine stimulations (SI and S2) was elevated in SHR hippocampal slices compared to that of WKY and SD, agreeing with the hypothesis that SHR have reduced negative feedback inhibition by ot2-adrenoceptors on varicosities of locus coeruleus-norepinephrine neurons. Blocking AMPA receptors with CNQX had no effect on nicotine-stimulated release of [3H]NE in any of the strains. In WKY, nicotine-stimulated release of [3H]NE was reduced by the GABAa receptor antagonist, bicuculline. We conclude that reduced nicotinic receptor activity, and reduced involvement of GABAA receptors in nicotine receptor activity, may be part of ADHD neuropathology.