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Órgano Oficial del Instituto Nacional de Psiquiatría Ramón de la Fuente Muñiz

2003, Number 3

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Salud Mental 2003; 26 (3)

La participación de los receptores de acetilcolina nicotínicos en trastornos del Sistema Nervioso Central

López-Valdés HE, García-Colunga J

Language: Spanish
References: 72
Page: 66-72
PDF size: 385.81 Kb.


ABSTRACT

Nicotinic acetylcholine receptors (nAChRs) are cationic channels opened after binding of the neurotransmitter acetylcholine (ACh). These receptors are membrane proteins composed of five subunits and are the key for the cholinergic nicotinic transmission in the neuromuscular junction as well as in different areas of the peripheral and central nervous system (PNS and CNS respectively), where they are widely distributed. Muscle and PNS nAChRs are located postsynaptically, mediating excitatory responses. In the CNS the nAChRs are preferentially located in presynaptic neurons, modulating the release of neurotransmitters such as dopamine, serotonin, γ-aminobutiric acid, noradrenaline, ACh and glutamate. Up to this day, 17 different genes encoding nAChR subunits have been identified. The subunits that form fetal skeletal muscle nAChRs are α1, Β1, γ and δ. The γ subunit is changed by ε subunit in adult muscle nAChRs. In the nervous system the α2-α10 and Β2-Β4 nAChR subunits have been identified, being α4 and Β2 the predominant subunits in the brain. In the CNS, different combinations of subunits produce multiple nAChR subtypes, showing different functional properties. Each nAChR subtype may present different regional, cellular and subcelluar distribution, which may help to explain the involvement of nAChRs in different physiological and pathological processes: muscle contraction, memory, attention, learning, the Alzheimer´s and Parkinson´s diseases, schizophrenia, anxiety and depression.
Alzheimer´s disease is a neurodegenerative condition that mainly affects persons older than sixty-five years. It is characterized by a progressive cognitive impairment, including loss of memory. On the other hand, Parkinson´s disease produces degeneration of dopaminergic neurons in the substantia nigra and a motor dysfunction (muscular rigidity, tremor and bradykinesia). Patients with Parkinson´s disease frequently present also cognitive dysfunctions or dementia. In patients with Alzheimer´s and Parkinson´s diseases have been identified a decrease of both, cholinergic projections and quantity of nAChRs.
The use of nicotine and nAChR agonists has beneficial effects in patients with these diseases. Furthermore, the treatment with nicotine increases the memory capacity and prevents the neurotoxin-induced loss of neurons. It has been suggested that the activation of nAChRs formed by ⓮⎶, the predominant nAChR subtype in the CNS, participate in learning and memory, and that their participation is very important in the beneficial effects observed in patients with Alzheimer´s and probably in Parkinson´s diseases. It is also known that in schizophrenia the decrease in the α7 nAChR expression is closely related with alteration in the filtering of auditive signal mechanisms. In normal subjects, an initial auditive stimulus evokes an excitatory response that activates inhibitory mechanisms. These latter mechanisms decrease the excitatory response with a subsequent stimulus. In patients with schizophrenia subsequent auditive stimulus do not decrease the excitatory responses. This alteration is temporary alleviated by the administration of nicotine or while smoking. Although the roles of nAChRs in anxiety and depression have not been well studied, it is known that in animal models of anxiety and depression nicotine and some nAChRs agonists as ABT-418, present similar effects as those of anxiolitics and antidepressants. Moreover, application of nicotine patches to nonsmoking patients produces antidepressant effects. Furthermore, diverse antidepressant substances interact with neuronal nAChRs, remaining unknown their functional roles.
The possible clinical uses of substances that interact with nAChRs have arisen high interest, due to the possibility of interfering in diverse mental processes.
In addition to the pathologies analyzed here, there is evidence that nAChRs participate in the Gilles de la Tourette´s syndrome, in nocturnal frontal lobe epilepsy and in the attention deficit/hyperactivity disorder.
Finally, it is necessary to continue with the identification of nAChRs that participate in a determined physiological or pathological function, which might be useful for designing selective substances that interact with only one subtype of receptor, and thus use the selective nicotinic modulation with secure therapeutical purposes


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