dizocilpine-maleate and methyllycaconitine

Recurrent relapse is a major problem in treating opiate addiction. Pavlovian conditioning plays a role in recurrent relapse whereby exposure to cues learned during drug intake can precipitate relapse to drug taking. α7 nicotinic acetylcholine receptors (nAChRs) have been implicated in attentional aspects of cognition and mechanisms of learning and memory. In this study we have investigated the role of α7 nAChRs in morphine-conditioned place preference (morphine-CPP). CPP provides a model of associative learning that is pertinent to associative aspects of drug dependence. The α7 nAChR antagonist methyllycaconitine (MLA; 4 mg/kg s.c.) had no effect on the acquisition, maintenance, reconsolidation or extinction of morphine-CPP but selectively attenuated morphine-primed reinstatement of CPP, in both mice and rats. Reinstatement of morphine-CPP in mice was accompanied by a selective increase in [

Topics: Aconitine; alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; alpha7 Nicotinic Acetylcholine Receptor; Analgesics, Opioid; Animals; Conditioning, Classical; Dizocilpine Maleate; Excitatory Amino Acid Agonists; Excitatory Amino Acid Antagonists; Extinction, Psychological; Hippocampus; Mice; Morphine; Nicotinic Antagonists; Opioid-Related Disorders; Rats; Receptors, AMPA; Receptors, N-Methyl-D-Aspartate; Recurrence; Tritium

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

Nicotine has been demonstrated to enhance the subsequent use of illicit drugs in animals and humans. We previously demonstrated in female, Holtzman rats that one low dose of nicotine will potentiate locomotor activity and dopamine (DA) efflux in response to a subsequent low dose of d-amphetamine (AMPH) given 1-4 h later. In the present study, we show this also occurs in male rats and characterize the receptors required for the rapid sensitizing effect of nicotine on AMPH-stimulated locomotor behavior and AMPH-induced DA efflux. Pretreatment of male, Holtzman rats with a low dose (0.1 mg/kg, i.p.) of nicotine 2-4 h before a challenge with AMPH (0.32 mg/kg, i.p.) enhanced locomotor behavior as compared to saline pretreatment. Dihydro-β-erythroidine (DHβE), a relatively selective antagonist at β2 subunit-containing (β2∗) nicotinic acetylcholine receptors (nAChR), but not methyllycaconitine (MLA), a relatively selective antagonist at α7 nAChRs, blocked the sensitizing effect of nicotine on AMPH-stimulated locomotor activity. Pretreatment with varenicline, a partial agonist selective for β2∗ nAChRs, blocked the sensitizing effect of nicotine on AMPH-stimulated locomotor behavior. Nicotine pretreatment sensitized AMPH-induced DA overflow in slices from ventral (nucleus accumbens, NAc), but not dorsal striatum as compared to saline-pretreated rats. Nicotine sensitization of the DA overflow was blocked by DHβE. Pretreatment with the glutamate N-methyl-D-aspartate (NMDA) receptor antagonist (+)-MK-801 (0.1 mg/kg, s.c.) 30 min before nicotine blocked sensitization of both locomotion and DA overflow in response to AMPH challenge. These results demonstrate that activation of the β2∗ nAChRs and NMDA receptors are required for the rapid sensitizing effect of nicotine on AMPH actions. This article is part of a Special Issue entitled 'Trends in neuropharmacology: in memory of Erminio Costa'.

Topics: Aconitine; Amphetamine; Animals; Behavior, Animal; Benzazepines; Central Nervous System Stimulants; Dizocilpine Maleate; Dopamine; Excitatory Amino Acid Antagonists; Female; Male; Nicotine; Nicotinic Agonists; Nicotinic Antagonists; Quinoxalines; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate; Receptors, Nicotinic; Varenicline

Application of choline (5 and 10 mM) to electrically stimulated (1 Hz) rat hippocampal slices evoked epileptoid activity manifested by generation of extra population spikes. Application of methyllycaconitine (10 nM), a specific agonist for α7-subunit of nicotinic acetylcholine receptors, did not prevent generation of extra population spikes. In contrast, pretreatment of slices with Mg(2+) (5 mM) or blockade of NMDA-type glutamate receptors with MK-801 (100 μM) prevented generation of the extra population spikes. It was hypothesized that elevation of choline concentration during cerebral pathology can promote activation of NMDA-receptors and provoke epileptoid activity not related to activation of α7-subunit of nicotinic acetylcholine receptor.

Topics: Aconitine; Action Potentials; Animals; CA1 Region, Hippocampal; Choline; Dizocilpine Maleate; Epilepsy; Excitatory Amino Acid Antagonists; In Vitro Techniques; Nicotinic Antagonists; Pyramidal Tracts; Rats; Rats, Wistar; Receptors, N-Methyl-D-Aspartate; Receptors, Nicotinic

Previous studies have shown that alterations in acetylcholine (ACh) receptor subtypes might contribute to cognitive impairment observed in schizophrenia and that choline acetyltransferase activity in the parietal cortex is negatively correlated with the severity of such cognitive impairment. However, clinical data suggest that the acetylcholinesterase (AChE) inhibitors galantamine and donepezil have different effects on negative and cognitive symptoms in schizophrenia. Prepulse inhibition (PPI) deficits--sensory information-processing deficits observed in schizophrenia--may be useful models for studying the efficacy of AChE inhibitors as cognitive enhancers.. The present study examined the effects of galantamine and donepezil on PPI deficits induced by an environmental factor and drugs.. In the isolation-rearing model, 3-week-old male ddY mice were housed either in groups of five or six per cage or isolated in cages of the same size for more than 6 weeks. In the drug-induced model, apomorphine 1 mg/kg and MK-801 0.2 mg/kg were administered to 9- to 10-week-old male ddY mice.. In isolation-reared mice, galantamine attenuated PPI deficits, while donepezil did not. Galantamine and donepezil both attenuated PPI deficits induced by apomorphine, but not by MK-801. The galantamine-induced improvements in PPI deficits were not prevented by the nicotinic ACh receptor antagonists mecamylamine and methyllycaconitine.. These observations suggest that galantamine and donepezil have different effects on the environmentally induced PPI deficits and that these observations may be relevant to the different effects of these drugs observed clinically in schizophrenia.

Topics: Aconitine; Acoustic Stimulation; alpha7 Nicotinic Acetylcholine Receptor; Analysis of Variance; Animals; Animals, Outbred Strains; Apomorphine; Behavior, Animal; Cholinesterase Inhibitors; Dizocilpine Maleate; Donepezil; Dose-Response Relationship, Drug; Galantamine; Indans; Male; Mecamylamine; Mice; Neural Inhibition; Nicotinic Antagonists; Piperidines; Receptors, Nicotinic; Reflex, Startle; Risperidone; Social Isolation

Responses of the human alpha 7 nicotinic acetylcholine receptor (alpha 7 nAChR) expressed in Xenopus laevis oocytes were quantified in the presence of barium (10 mM) to prevent secondary activation of Ca(2+)-dependent Cl- currents and atropine (2 microM) to block endogenous muscarinic receptors. Acetylcholine (ACh) elicited responses with EC50 values of 177 +/- 32 microM to 272 +/- 26 microM in different experiments. Responses to ACh (200 microM) were blocked by the nAChR antagonists alpha-bungarotoxin (IC50 = 0.54 +/- 0.04 nM), methyllycaconitine (IC50 = 0.64 +/- 0.08 nM) and mecamylamine (IC50 = 1.8 +/- 02 microM). Additionally, MK-801, a non-competitive blocker of N-methyl-D-aspartate (NMDA) sensitive glutamate receptor channels, inhibited the human alpha 7 nAChR. This effect was not stereoselective; the IC50 for (+)-MK-801 was 15 +/- 3 microM while that for (-)-MK-801 was 14 +/- 3 microM. The inhibition by MK-801, in contrast to methyllycaconitine, was dependent upon cell potential, consistent with a mechanism involving channel blockade. The inhibition by MK-801 reversed slowly (time constant approximately 20 min) compared to that by methyllycaconitine (100% recovery within 10 min). However, MK-801 did not appear to be trapped in the channel because the recovery from inhibition showed little dependence upon stimulation rate or cell potential. Thus, MK-801 acted as a non-stereoselective alpha 7 nAChR inhibitor that was only about 8-fold less potent than the nAChR antagonist mecamylamine and probably acted through channel blockade.

Topics: Aconitine; Animals; Bungarotoxins; Dizocilpine Maleate; Evaluation Studies as Topic; Excitatory Amino Acid Antagonists; Humans; Mecamylamine; Oocytes; Patch-Clamp Techniques; Receptors, N-Methyl-D-Aspartate; Receptors, Nicotinic; Xenopus laevis