aconitine and Attention-Deficit-Disorder-with-Hyperactivity

Nicotinic agonists have been shown in a variety of studies to improve cognitive function. Since nicotinic receptors are easily desensitized by agonists, it is not completely clear to what degree receptor desensitization or receptor activation are responsible for nicotinic agonist-induced cognitive improvement. In the current study, the effect of the neuronal nicotinic cholinergic α4β2 receptor antagonist dihydro-β-erythroidine (DHβE) and the α7 nicotinic receptor antagonist methyllycaconitine (MLA) on attentional function was determined. Adult female Sprague-Dawley rats were trained on the visual signal detection task. They were required to discriminate whether or not a light signal occurred on a trial and respond with a lever press on one side after a signal and the opposite side after the absence of a signal in order to receive a food pellet reinforcer. Acute administration of the α4β2 antagonist DHβE improved attentional function either alone or in reversing the attentional impairment caused by the NMDA glutamate antagonist dizocilpine (MK-801). Acute administration of MLA also significantly attenuated the dizocilpine-induced attentional impairment. In previous research we have shown that the α4β2 nicotinic desensitizing agent and partial agonist sazetidine-A also was effective in reversing dizocilpine-induced attentional impairments on the signal detection task and that low doses of the general nicotinic antagonist mecamylamine improved learning and memory. The current studies indicate that blockade of nicotinic receptors can effectively attenuate attentional impairments. Development of drugs that provide a net decrease in nicotinic receptor activity either through antagonism or desensitization could be worth exploring for beneficial effects for treating cognitive impairments.

Topics: Aconitine; alpha7 Nicotinic Acetylcholine Receptor; Animals; Attention; Attention Deficit Disorder with Hyperactivity; Dihydro-beta-Erythroidine; Dizocilpine Maleate; Female; Nicotine; Nicotinic Antagonists; Rats; Rats, Sprague-Dawley; Receptors, Nicotinic

The spontaneously hypertensive rat (SHR) is widely used as a model of attention-deficit/hyperactivity disorder (ADHD). Deficits in central nicotinic receptors (nAChRs) have been previously observed in SHRs, which is interesting since epidemiological studies have identified an association between smoking and ADHD symptoms in humans. Here, we examine whether nAChR deficits in SHRs compared with Wistar Kyoto rat (WKY) controls are nAChR subtype-specific and whether these deficits correlate with changes at the level of mRNA transcription in specific brain regions. Levels of binding sites (B(max) ) and dissociation constants (K(d)) for nAChRs were determined from saturation curves of high-affinity [³H]epibatidine- and [³H] Methyllycaconitine (MLA) binding to membranes from cortex, striatum, hippocampus and cerebellum. In additional brain regions, nAChRs were examined by autoradiography with [¹²⁵I]A-85380 and [¹²⁵I]α-bungarotoxin. Levels of mRNA encoding nAChR subunits were measured using quantitative real-time PCR (qPCR). We showed that the number of α4β2 nAChR binding sites is lower globally in the SHR brain compared with WKY in the absence of significant differences in mRNA levels, with the exception of lower α4 mRNA in cerebellum of SHR compared with WKY. Furthermore, nAChR deficits were subtype- specific because no strain difference was found in α7 nAChR binding or α7 mRNA levels. Our results suggest that the lower α4β2 nAChR number in SHR compared with WKY may be a consequence of dysfunctional post-transcriptional regulation of nAChRs.

Topics: Aconitine; Animals; Attention Deficit Disorder with Hyperactivity; Azetidines; Brain Chemistry; Bridged Bicyclo Compounds, Heterocyclic; Bungarotoxins; In Vitro Techniques; Kinetics; Male; Membranes; Nicotinic Agonists; Nicotinic Antagonists; Protein Processing, Post-Translational; Pyridines; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Receptors, Nicotinic; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Thermodynamics

alpha7-Nicotinic acetylcholine receptors (alpha7-nAChR) have been implicated in a range of cognitive deficits in schizophrenia. Therefore we examined alpha7-nAChR knockout (KO), heterozygote (HT) and wildtype (WT) littermate mice in the 5-CSR (a rodent model of sustained attention) and odour span (a novel mouse working memory paradigm) tasks, and related performance to nAChR density. Whilst there was no difference between groups in baseline 5-CSR task performance, alpha7-nAChR KO's exhibited significantly higher omission levels compared to WT mice on increasing the attentional load, with HT mice performing at an intermediate level. Furthermore, alpha7-nAChR KO mice were significantly impaired in the odour span task when compared to WT mice, in a pattern consistent with impaired attention. These behavioural deficits were associated with the loss of alpha7-nAChRs, as alpha4beta2-nAChR density was unaltered in these mice. Thus these studies intimate that the attentional impairment in alpha7-nAChR transgenic mice maybe core to other deficits in cognition.

Topics: Aconitine; Alkaloids; alpha7 Nicotinic Acetylcholine Receptor; Animals; Animals, Newborn; Attention Deficit Disorder with Hyperactivity; Azocines; Behavior, Animal; Choice Behavior; Cognition Disorders; Dose-Response Relationship, Drug; Mice; Mice, Knockout; Nicotinic Antagonists; Protein Binding; Quinolizines; Reaction Time; Receptors, Nicotinic; Tritium