Cotinine, a neuroactive metabolite of nicotine: potential for treating disorders of impaired cognition.
ABSTRACT The pharmacological effects of the tobacco-derived alkaloid nicotine have been widely studied in humans and animals for decades. However, relatively little attention has been given to the potential actions of its major metabolite, cotinine. After nicotine consumption the duration of cotinine's presence in blood and brain greatly exceeds that of nicotine. Therefore, cotinine could mediate the more protracted pharmacological effects of nicotine. The studies described in this report were thus designed to further investigate certain neuropharmacological actions of cotinine. Behavioral tests (e.g., delayed matching-to-sample) were conducted in aged rhesus monkeys to assess the effects of cotinine on working memory and attention. In rats a prepulse inhibition (PPI) procedure was used to assess the effects of the compound on auditory gating - a method for predicting the potential antipsychotic properties of drugs. Cotinine exhibited significant effectiveness in these tasks. The drug was also cytoprotective in differentiated PC-12 cells with a potency equivalent to that of nicotine. The effects of chronic cotinine treatment on the expression of nicotinic and muscarinic acetylcholine receptors in rat brain were measured by [125I]epibatidine, [125I]alpha-bungarotoxin ([125I]BTX), [3H]pirenzepine ([3H]PRZ), and [3H]AFDX-384 ([3H]AFX) autoradiography. Unlike nicotine, cotinine failed to upregulate the expression of brain nicotinic receptors. Based on its relative safety in man, cotinine should prove useful in the treatment of diseases of impaired cognition and behavior without exhibiting the toxicity usually attributed to nicotine.
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ABSTRACT: To better understand the effects of weak as well as strong agonists at the human α7 nicotinic acetylcholine receptor (human α7 nAChR), the abilities of several classic nAChR agonists to both activate and inhibit (desensitize) the human α7 nAChR expressed in Xenopus oocytes were quantified and compared. Activation was measured during 0.2–20 s agonist application, as required to elicit a peak response. Inhibition was measured as the reduction in the agonist response to 200 μM ACh in the presence of inhibitor during a 5–20 min incubation. Acetylcholine (ACh), (−)-nicotine, (+)-nicotine, and 1,1-dimethyl-4-phenylpiperazinium (DMPP) were 62- to 130-fold more potent as inhibitors than as activators, with excellent correlation between the IC50 and EC50 values (r2=0.924). Agonist concentrations that elicited only 0.6–1.2% nAChR activation were sufficient to inhibit the response to ACh by 50%. Thus, even a very weak agonist could appear to be a potent and effective inhibitor through receptor desensitization. (−)-Lobeline, in contrast, acted as an antagonist at the human α7 nAChR, eliciting no detectable agonist-like response at concentrations up to 1 mM, but inhibiting the response to ACh with an IC50 value of 8.5 μM. (−)-Cotinine and the novel ligand ABT-089 [2-methyl-3-(2-(S)-pyrrolidinylmethoxy)pyridine] acted as weak agonists at the human α7 nAChR (1 and 1.5% response at 1 mM, respectively) and inhibited the response to ACh with IC50 values of 175 and 48 μM, respectively. These effects could be explained by receptor desensitization, at least in part.Neuropharmacology. 01/1998;
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ABSTRACT: Alzheimer's disease is a complex disorder affecting multiple neurotransmitters. In particular, the degenerative progression is associated with loss within the cholinergic systems. It should be anticipated that both muscarinic and nicotinic mechanisms are affected as cholinergic neurons are lost. This review focuses on the basic roles of neuronal nicotinic receptors, some subtypes of which decrease during Alzheimer's disease. Nicotinic acetylcholine receptors belong to a superfamily of ligand-gated ion channels that play key roles in synaptic transmission throughout the central nervous system. Neuronal nicotinic receptors, however, are not a single entity, but rather there are many different subtypes constructed from a variety of nicotinic subunit combinations. This structural diversity and the presynaptic, axonal, and postsynaptic locations of nicotinic receptors contribute to the varied roles these receptors play in the central nervous system. Presynaptic and preterminal nicotinic receptors enhance neurotransmitter release, and postsynaptic nicotinic receptors mediate a small minority of fast excitatory transmission. In addition, some nicotinic receptor subtypes have roles in synaptic plasticity and development. Nicotinic receptors are distributed to influence many neurotransmitter systems at more than one location, and the broad, but sparse, cholinergic innervation throughout the brain ensures that nicotinic acetylcholine receptors are important modulators of neuronal excitability.Biological Psychiatry 03/2001; 49(3):166-74. · 9.25 Impact Factor
Article: Cognitive effects of nicotine.[show abstract] [hide abstract]
ABSTRACT: Nicotine and other nicotinic agonists have been found to improve performance on attention and memory tasks. Clinical studies using nicotine skin patches have demonstrated the efficacy of nicotine in treating cognitive impairments associated with Alzheimer's disease, schizophrenia, and attention-deficit/hyperactivity disorder. Experimental animal studies have demonstrated the persistence of nicotine-induced working memory improvement with chronic exposure, in addition to the efficacy of a variety of nicotinic agonists. Mechanistic studies have found that alpha7 and alpha4beta2 nicotinic receptors in the hippocampus are critical for nicotinic involvement in cognitive function. Clinical and experimental animal studies provide mutually supporting information for the development of novel nicotinic therapies for cognitive dysfunction.Biological Psychiatry 03/2001; 49(3):258-67. · 9.25 Impact Factor