Neuronal nicotinic receptors in synaptic functions in humans and rats: physiological and clinical relevance
Introduction
Tobacco smoking represents one of the major concerns in public health worldwide [55], [63]. In France, for instance, 12% of all deaths are attributed to tobacco smoking [41], and in the United States, more than 400 000 people die every year from tobacco smoking [24]. This represents 20% of all deaths occurring in a year in the United States, a country that spends over 50 billion dollars treating patients with pathological conditions related to tobacco smoking. It is estimated that the incidence of lung carcinoma in the entire world could be reduced by more than 20% if tobacco smoking was eradicated [72]. Even more alarming is the fact that in developing countries the prevalence of smoking is as high as 40–50% and that very little effort is made in those countries to reduce cigarette smoking [16], [18].
Although there are more than 4000 compounds present in tobacco, nicotine is believed to be the psychoactive substance accountable for the abuse of cigarette smoking and smokeless tobacco [22], [39]. Nicotine is considered as an addictive drug because it provides positive reinforcement that leads to high self-administration rates, and, when withheld after chronic use, it causes negative reinforcement manifested as withdrawal symptoms [24]. In smoking cessation programs, nicotine replacement therapy reduces the severity of the withdrawal symptoms, allowing the patients to focus on psychosocial aspects of tobacco abstinence. Although numerous reports highlight the long-term effectiveness and health benefits of nicotine replacement therapy combined with education and cognitive/behavioral therapy, the average abstinence rate of patients participating in smoking cessation programs is still considerably low, ranging from 15 to 20% in 1 year [25], [76], [79]. Undoubtedly, understanding the molecular basis underlying the psychological, behavioral, and physical components of nicotine addiction will be a crucial step for designing a more effective treatment plan.
It should also be noted that nicotine, in addition to being an addictive drug, has many effects in the central nervous system (CNS) that are of therapeutic significance [53]. Reportedly, nicotine and nicotinic agonists have analgesic properties [28], [57], [62], and improve several aspects of cognitive function including attention, learning and memory [50]. The effects of nicotine are mediated by the interaction of the alkaloid with a number of nicotinic receptors (nAChRs), each of which has a specific pattern of distribution in the brain. To date, eight agonist-binding, subunits and three ‘structural’ subunits have been cloned from the brain of various animal species. Most of the α subunits have to be combined with a β subunit to give rise to a functional nAChR. However, three α subunits (α7, α8, and α9) are capable of forming homomeric functional nAChRs when expressed in heterologous systems [32], [51]. Undoubtedly, the large diversity of nAChRs makes it difficult to assess the molecular basis of nicotine’s actions in the CNS [19].
Two subtypes of functional nAChR, i.e. those composed of the α7 subunits (which bind α-bungarotoxin (α-BGT)) and those bearing the α4β2 subunits (which bind nicotine with high affinity), have been shown to be expressed by neurons harvested from the hippocampus of 16–18-day-old rat fetuses and cultured for up to 45 days [2]. These two nAChR subtypes can be easily identified on the basis of their pharmacological and kinetic properties. Whereas activation of α7 nAChRs gives rise to fast-desensitizing responses that are sensitive to blockade to nanomolar concentrations of α-BGT, methyllycaconitine (MLA), and α-conotoxin-ImI, activation of α4β2 nAChRs gives rise to slowly desensitizing responses that are sensitive to blockade by dihydro-β-erythroidine (DHβE) [2], [9], [69]. Also, α7-containing nAChR channels have a short open time (∼100 μs at 80 mV) and large conductance (>60 pS), whereas α4β2 nAChR channels have much longer open times and lower conductances [13], [59].
In different areas of the brain of primates and non-primate species, α4β2- and α7-like nAChRs have been shown to mediate synaptic transmission [4], [29], [74], [89] and to control synaptic transmission mediated by the major inhibitory and excitatory neurotransmitters, GABA and glutamate, respectively [1], [5], [7], [12], [36], [47], [48], [52], [54], [58], [73], [75], [86]. If similar physiological functions could be mediated by these nAChRs in the human CNS, then inferences could be made regarding the involvement of these receptors in the fine tuning of brain activity, which has been shown to depend on complex mechanisms of synaptic integration [45]. Clearly, with the ever increasing body of evidence of species-related differences in the pharmacological profile and function of many receptors [26], [33], [60], [65], understanding the involvement of the human neuronal nAChRs [42], [70], [83] on the effects of nicotine and cigarette smoking and, perhaps, even more significantly, on a number of physiological processes and pathological conditions requires the demonstration of nAChR function directly in human brain.
The present paper describes most of our recent findings regarding the involvement of α4β2-and α7-like nAChRs on the control of the activity of interneurons in the human cerebral cortex [8] and in the rat hippocampus [7]. Also, it discusses the relevance of the finding that choline, a metabolite of ACh hydrolysis, by acting as a selective, full agonist of α7 nAChRs, can play a major role in fine tuning the activity of neuronal circuitries in the human and the rat brain. Understanding the physiological significance of the neuronal nAChRs will certainly aid in the dissection of the molecular basis of the many CNS effects of nicotine, and will lay the groundwork for the development of more efficacious smoking cessation programs and better treatments for neuropathological conditions in which nAChR function is known to be altered.
Section snippets
Rat hippocampal and human cortical slices
Slices of 250 μm thickness were obtained from the hippocampus of 15–30-day-old Sprague–Dawley rats or from cortical samples obtained from patients undergoing surgery for intractable seizures. Slices were stored in artificial cerebrospinal fluid (ACSF), which was bubbled with 95% O2 and 5% CO2 and had the following composition (in mM): NaCl, 125; NaHCO3, 25; KCl, 2.5; NaH2PO4, 1.25; CaCl2, 2, MgCl2, 1; and glucose, 25. Interneurons in the slices were visualized by means of infrared-assisted
Functional nAChRs in CA1 interneurons in rat hippocampal slices
Recent studies from our laboratory and from others have provided evidence that, in the absence of TTX and under current-clamp conditions, rapid application of choline (≥300 μM) to interneurons in the CA1 stratum radiatum of rat hippocampal slices triggers short-lasting bursts of action potentials [7], [30]. In the presence of TTX and under voltage-clamp conditions, choline evokes in these interneurons rapidly decaying nicotinic currents (Fig. 1). These responses, being blocked by prolonged
Neuronal nAChRs in interneurons of various species, including humans, and their involvement in inhibitory and disinhibitory mechanisms in the CNS
In the CNS, signals are relayed by either pyramidal or granular neurons, the two together constituting the principal class of neurons in the brain. Interneurons belong to a minor group of neurons that have a widespread distribution in the CNS. Most interneurons are GABAergic in nature; they are diverse in their anatomical location and morphological appearance and exert a powerful influence on the principal neurons. In general, GABAergic interneurons affect the excitability of the CNS, and are
Acknowledgements
The technical assistance of Barbara Marrow and Benjamin Cumming is gratefully acknowledged. Also, the authors would like to thank Mabel Zelle for her helpful comments in the manuscript. This study was support by United States Public Health Service Grants NS25296 and ES05730 (for E.X. Albuquerque), PRONEX (from Brazil, for E.X. Albuquerque), and Fogarty fellowship TW05389 (for A.Mike).
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