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Presynaptic nicotinic ACh receptors
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S. Wonnacott – Presynaptic nACh receptors
Presynaptic nicotinic ACh receptors Susan Wonnacott Nicotinic ACh (nACh) receptors in the CNS are composed of a diverse array of subunits and have a range of pharmacological properties. However, despite the fact that they are ligand-gated cation channels, their physiological functions have not been determined.This has led to increased interest in presynaptic nACh receptors that act to modulate the release of transmitter from presynaptic terminals. Trends Neurosci. (1997) 20, 92–98
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Susan Wonnacott is at the School of Biology and Biochemistry, University of Bath, Bath, UK BA2 7AY.
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O FAR, ten nicotinic ACh (nACh)-receptor subunits (a2–a8; b2–b4) have been found to be expressed in vertebrate neurones. These subunits share homology with muscle nACh-receptor subunits (and with the a9 subunit, which is present in certain endocrine cells and sensory end organs), and most have been shown to contribute to the formation of functional nACh receptors in heterologous expression systems1,2. In view of this diversity, it is striking that there is scant evidence for nicotinic synaptic transmission in the brain: given that nACh receptors are ligand-gated cation channels and subserve a pivotal role in mediating neuromuscular and ganglionic transmission, an analogous role in fast excitatory transmission in the CNS has been anticipated. The difficulty in demonstrating such a function, together with recognition of the high Ca2+ permeability of neuronal nACh receptors, has recently kindled the notion that nACh receptors might have a more modulatory role in the brain3. The wellestablished ability of nicotine to elicit transmitter release, commonly by acting at presynaptic nACh receptors, is consistent with such a modulatory activity. Indeed, it has been suggested2 that ‘presynaptic nACh receptors might be the exclusive or predominant role of nACh receptors in the CNS’. However, the occurrence of nACh receptors on somatodendritic regions of neurones is clear4. For example, electrophysiological recordings have shown that exogenously applied nicotinic agonists can excite cells directly4–6, and in vivo microdialysis has demonstrated that systemically administered nicotine exerts its effects on the ascending dopamine pathways predominantly in the cell-body areas 7. Somatodendritic nACh receptors are consistent with the evidence for local cholinergic inputs (as distinct from synaptic contacts) in several cases4. Nevertheless, the modulation of transmitter release (and synaptic transmission?) directly through nACh receptors on nerve terminals is more evident than the relatively low abundance of neuronal nACh receptors might predict, reinforcing the proposition that this is a significant function of nACh receptors in the brain. Although dopamine release has received the greatest attention, the release of most of the classical neurotransmitters has been shown to be influenced by nicotine acting at the level of the nerve terminal8: recent examples include the release of noradrenaline9, ACh (Ref. 10), glutamate11 and GABA (Ref. 6) from diverse preparations. This review will focus on the properties, mechanisms and implications of presynaptic nACh receptors in the mammalian brain. TINS Vol. 20, No. 2, 1997
Presynaptic and preterminal nACh receptors Presynaptic receptors can be defined as receptors at or near the nerve terminal that can positively or negatively modulate transmitter release directly, or influence the probability of an action potential resulting in exocytosis. The concept of preterminal nACh receptors (Fig. 1) was raised by Wessler12 to describe axonal receptors that modulate ACh release from motor-nerve terminals. Preterminal nACh receptors have also been defined on GABA-containing neurones in the rat interpeduncular nucleus (IPN; Ref. 13) and chick lateral spiriform nucleus14, using whole-cell patch-clamp recording to show that nicotinic agonists increase the frequency of postsynaptic currents in a tetrodotoxin (TTX)-sensitive manner. By contrast, presynaptic nACh receptors have been proposed to elicit neurotransmitter release through a TTX-insensitive mechanism8. By this criterion, presynaptic nACh receptors have been identified using electrophysiological recordings, for example, in the chick IPN (Ref. 11) and lateral geniculate nucleus15. Recent studies of striatal synaptosomes16,17 (defined as presynaptic elements) have challenged this simple distinction, by reporting a partial block by TTX of nicotine-elicited 86Rb or [3H]dopamine release. TTX-sensitive and insensitive mechanisms might reflect the relative proximity of nACh receptors to the synapse and the exocytotic machinery. Thus, TTXsensitivity alone does not necessarily distinguish preterminal nACh receptors from those presumed to reside on terminal boutons. Ultrastructural studies will be required to resolve this issue: in the case of muscarinic binding sites on rat sympathetic neurones18, of the 10% or so of labelling associated with nerve endings, less than 40% corresponded to synaptic areas, compared with 60% of specific binding located on non-synaptic surfaces of nerve terminals and preterminal axon segments. TTX-insensitivity of nicotinic agonist-elicited responses has been taken to define presynaptic nACh receptors in neurochemical studies of more integrated preparations, such as brain slices19,20 and cultured neurones21. Where synaptosome studies show little or no TTX sensitivity (for example, nicotine-elicited noradrenaline release from hippocampal synaptosomes9), corresponding experiments on slice preparations20,22 have reported substantial inhibition by TTX, equivalent to a total block of nACh receptor-mediated (mecamylamine-sensitive) noradrenaline release. A similar picture is seen with nicotine-elicited dopamine release from striatal preparations17. Does this mean that presynaptic nACh receptors are vastly outnumbered by
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S. Wonnacott – Presynaptic nACh receptors
preterminal nACh receptors and nACh receptors acting via local interneurones? Or might the preparation of synaptosomes disrupt mechanisms operative in intact systems, leading to a false picture of TTX-insensitivity? The latter view is particularly pertinent to systems where varicosities and en passant terminals are abundant, such as catecholamine projections. Thus TTXinsensitivity as a definition of presynaptic nACh receptors might underestimate the number of nACh receptors located near synapses.
Somatodendritic
Presynaptic Preterminal
Heterogeneity of presynaptic nACh receptors Given the diversity of nicotinic subunits expressed in neurones, one might reasonably enquire which subunit combinations constitute presynaptic nACh receptors, and if presynaptic nACh receptors show heterogeneity in different brain pathways or transmitter systems. The identification of subunits comprising native nACh receptors has been attempted by comparison with the characteristics of heterologously expressed combinations of subunits. However, this approach generally gives imperfect correlations2, perhaps reflecting altered post-translational modification of nACh receptors in non-neuronal cells, or a more complex subunit composition of native nACh receptors than the pairwise combinations of subunits typically studied in expression systems. Indeed, there is now evidence that the a5 subunit associates with a3 or a4 subunits in chick brain and ganglia23,24, and that the synaptic nACh receptors in chick ciliary ganglion neurones is composed of a3, a5 and b4 subunits25. Similar complexity might be anticipated in mammalian brain. The impossibility of direct electrophysiological recordings from presynaptic nACh receptors at the present time, the paucity of definitive pharmacological tools to discriminate different nACh-receptor subtypes, and the incomplete pharmacological characterization of presynaptic nACh receptors, in most cases, makes assessment of their subunit composition even more problematical. Other strategies that might help to resolve this issue include immunogold electron microscopy with subunit-specific antibodies and in vivo antisense deletion experiments to knock out selected subunits.
Presynaptic nACh receptors on striatal dopamine terminals Presynaptic nACh receptors regulating dopamine release have been studied extensively, using neurochemical techniques. In superfused synaptosome preparations from striatum, nicotine is a potent agonist, acting with a sub-micromolar EC50 to elicit [3H]dopamine release9,26,27. Cytisine is reported to be a partial agonist in the rat20,28 (but not in the mouse26). These features encourage the notion of a presynaptic nACh receptor composed of a4 and b2 subunits9: this subunit combination has the highest sensitivity to nicotine of any heterologously expressed nACh receptor (for example, EC50 = 0.3 mM for rat a4 and b2 subunits expressed in Xenopus oocytes29), and cytisine has low efficacy at this nACh receptor composed of rat subunits30 (but this is not the case for chick subunits31). Indeed, cytisine is essentially ineffective at the rat b2-containing nACh receptors expressed in Xenopus oocytes30, such that its substantial, albeit partial, agonism in striatal preparations implies a contribution from the b4 subunit9,26. The role of the b4 subunit is incompatible with subunit expression patterns in rat (see below) and mouse32, but alternative or additional subunits might confer the observed properties. Lesion studies33,34 support the presence
Preterminal nACh receptor Presynaptic nACh receptors
Fig. 1. Putative locations of neuronal nicotinic ACh (nACh) receptors.
of [3H]nicotine binding sites (which have been correlated with a4 and b2 subunits on the basis of microsequencing35 and immunoprecipitation36 data) on dopamine-containing terminals. On the other hand, antagonism by neuronal bungarotoxin (nBgt) has been documented26,37 and interpreted in favour of nACh receptors containing the a3 subunit. Interpretation of subunit expression at the transcriptional level is also fraught with limitations. Subunit mRNAs are expressed in the cell-body regions, typically at some distance from the projection areas; the subcellular destinations of different subunits cannot be discerned readily; numerous subunits are detected in various amounts; and there is not necessarily a quantitative relationship between subunit mRNA, subunit protein, assembled pentamer and functional surface nACh receptors. Moreover, low levels of expression are difficult to resolve from the background. With these caveats in mind, one can, nevertheless, examine documented expression patterns (Fig. 2). Notably in the substantia nigra, a4 and b2 mRNAs predominate, with lower levels of a3 expressed38. No b4 mRNA has been detected39 but significant expression of a5 (Ref. 40) and b3 (Ref. 41) has been reported. While these data are compatible with a4b2 combinations, they would also support more complex subunit compositions. The occurrence of more than one nACh-receptor subtype on dopamine terminals is a further possibility43.
Presynaptic nACh receptor on hippocampal noradrenaline terminals A recent study by Clarke and Reuben9 compared the nicotinic stimulation of [3H]dopamine release from striatal synaptosomes and [3H]noradrenaline release from hippocampal synaptosomes. The latter preparation was 40-fold less sensitive to nicotine (EC50 = 6.5 mM; Fig. 2) and 30-fold less sensitive to the competitive antagonists dihydro-b-erythroidine and methyllycaconitine. Moreover, cytisine was as efficacious as nicotine in eliciting [3H]noradrenaline release. This comparative TINS Vol. 20, No. 2, 1997
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A
C SN MS
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Substantia nigra β2 +++ α2 – β3 +++ α3 ++ β4 – α4 +++ α5 +++ α7 ?
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Fig. 2. Examples of pathways bearing presynaptic nicotinic ACh (nACh) receptors in the rat brain. (A) The dopamine-containing nigro– striatal pathway; (B) innervation of the hippocampus by noradrenaline-containing neurones; and (C) innervation of the hippocampus by AChcontaining neurones from the medial septum: transmitter release from each of these projection areas has been studied by superfusion of synaptosomes, yielding quantitative dose–response relationships for agonists. A and B redrawn from Ref. 9, C redrawn from Ref. 10. (D) Presynaptic nACh receptors in the habenulo–interpeduncular pathway have been characterized using electrophysiological techniques in the rat 5 and chick11. Although the innervation of the IPN is partly from ACh-containing neurones, the transmitter modulated by presynaptic nACh receptors in the rat is not known. In the chick it appears to be glutamate. The boxes list the nACh-receptor subunit mRNAs expressed in the regions containing the cell bodies in the rat, according to in situ hybridization. Data from Refs 38–42. Abbreviations: –, no signal above background; (+), very weak; +, detectable; ++, moderate; +++, strong; ++++, very strong; ?, no information (presumably no distinct signal or it would have been noted); DA, dopamine; IPN, interpeduncular nucleus; LC, locus coeruleus; MH, medial habenula; MS, medial septum; NA, noradrenaline; SN, substantia nigra.
study, using essentially identical protocols in the same laboratory, suggests strongly that the presynaptic nACh receptors acting in these two pathways are pharmacologically distinct, which very probably reflects different nACh receptor-subunit compositions. Qualitatively similar pharmacological differences have been seen in a comparison of striatal and hippocampal slice preparations20,22, although the presynaptic locus of the nACh-receptor functions monitored in such preparations is less clear-cut. The rat hippocampus derives its noradrenergic innervation from the locus coeruleus, which expresses a different complement of nACh-receptor subunits than the substantia nigra (Fig. 2). In particular, a3 mRNA is very abundant with little a4 mRNA expressed38. Comparison with nACh receptors expressed in heterologous systems44,45 has led to the tentative proposition that a3 and b4 subunits might constitute the presynaptic nACh receptor modulating [3H]noradrenaline release in the hippocampus, although the correlation is not perfect9.
Presynaptic nicotinic autoreceptors regulating ACh release in the hippocampus Nicotinic agonists stimulate the release of [3H]ACh from hippocampal slices19 and synaptosomes10. This 94
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response could be blocked by dihydro-b-erythroidine, (+)-tubocurarine and mecamylamine, but not by a-bungarotoxin (aBgt) or low concentrations of methyllycaconitine. The ‘bell-shaped’ agonist dose–response curves and EC50 of 1 mM for nicotine (Fig. 2) resemble the profile exhibited by the a4b2 subunit combination expressed in Xenopus oocytes29 and in a mammalian cell line46. This subunit composition is consistent with the loss of high-affinity [3H]nicotine binding sites from the hippocampus as cholinergic inputs degenerate in Alzheimer’s disease47, but the ability of cytisine to elicit maximum responses10 does not fit with the small responses to this agonist of a4b2 nACh receptors in Xenopus oocytes30. The cholinergic innervation of the hippocampus arises from cell bodies in the medial septum, which expresses yet another complement of nACh-receptor subunits (Fig. 2). a4 and b2 transcripts predominate, with only very weak signals for a3 or b4. However, this is one of the few areas in the rat brain reported to express the a2 subunit38, whose contribution to native nACh receptors has not been established.
Presynaptic nACh receptors in the IPN In contrast to the preceding neurochemical studies, nACh receptors in the habenular–interpeduncular
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system (Fig. 2) have been characterized using electrophysiological approaches, in 500 mM slices from adult rat5, and in co-cultures from embryonic chicken11. In the rat preparation, nicotinic agonists decreased the afferent volley recorded in the IPN following stimulation of the fasciculus retroflexus (the tract that connects the medial habenula to the IPN). This is consistent with the activation of presynaptic nACh receptors on axon terminals of the fasciculus retroflexus. Nicotine was the most potent agonist examined: cytisine, ACh, carbachol and dimethyl phenyl piperazine (DMPP) were 5–20 times less potent. Hexamethonium and mecamylamine were potent blockers, (+)-tubocurarine and dihydro-b-erythroidine were less effective (although these competitive antagonists were tested against a single, rather high agonist concentration) and nBgt and aBgt were without effect. Habenular lesions to destroy the fasciculus retroflexus have resulted in a sustained decrease (35%) in [3H]nicotine binding and a transient decrease in [125I]aBgt binding in the IPN (Ref. 48), consistent with the presence of nACh receptors on afferent axons or terminals. Most nAChreceptor subunits (except a2 and possibly a5; see Fig. 2) are reported to be expressed in the rat medial habenula. In the co-cultures of chick medial habenula and IPN explants11, glutamate was inferred to be the transmitter. Low concentrations of nicotine (EC50 = 170 nM) enhanced synaptic transmission elicited by lowfrequency (0.1 Hz) extracellular stimulation of the medial habenula tissue, and increased the frequency of spontaneous excitatory postsynaptic potentials (in the presence of TTX). This study is notable for two unusual features: first, the nicotinic response was inhibited by aBgt, albeit with a rather high IC50 of 70 nM (possibly reflecting accessibility problems or insufficient preincubation for maximum blockade). Sensitivity to aBgt implicates the a7 subunit (or a8 in chick), and antisense knockdown experiments confirmed the involvement of a7 in this response. The second novel observation was that despite apparently complete antisense deletion of a7 expression, the nicotinic synaptic enhancement persisted (but was now aBgt-insensitive). Compensatory changes in subunit synthesis, assembly or targeting are proposed11. The sensitivity to nanomolar concentrations of nicotine shown by the aBgt-sensitive responses argues that this is not a typical a7-type nACh receptor, which requires 100-fold higher nicotine concentrations for activation49. The persistence of the nicotinic modulation after a7 deletion encourages the view that a7 is co-assembled with other nicotinic subunits. This study provides the first substantial report of an aBgt-sensitive presynaptic nicotinic response in the CNS. In a preliminary account, a7 has since been implicated in the presynaptic modulation of glutamate transmission in rat optic-bulb neurones50. It is important to note, however, that these preparations displaying a7-type presynaptic nicotinic modulation were derived from embryonic brain; synapses were presumably established over the few days in culture. Given the suggested involvement of a7 in pathfinding and synapse formation3 (see below), the participation of this subunit in the presynaptic response might reflect the immature status of the tissues, with inherent plasticity in nACh-receptor complement or composition. Therefore, caution is warranted before extrapolating these observations to the mature synapse. The immunocytochemical localization
of the a7 subunit at the cellular level in the rat CNS has revealed immunostaining of somata and dendrites, whereas axonal and terminal labelling was not observed51. The only report of nicotinic modulation of excitatory transmission (mediated by non-NMDA glutamate receptors) in the adult rat brain found it to be insensitive to aBgt (Ref. 52), but see the note added in proof. Taken together with the data from other transmitter systems, it seems unlikely that the a7 subunit plays a major role in presynaptic nACh receptors in the adult rat brain. Clearly the few examples of presynaptic nACh receptor discussed here (Fig. 2) display a range of pharmacological properties, with differences in agonist sensitivity and efficacy, and susceptibility to blockade by various antagonists. At the present time, the subunit composition has not been established for any presynaptic nACh receptor. The heterogeneity of mRNA expression is compatible with multiple types of nACh receptor. A question common in biology today is ‘why have this potential for such diversity?’2. An early suggestion53 was that presynaptic nACh receptors might be composed of distinct subunits (a3) from their somatodendritic counterparts (a4) for the purposes of targeting to terminal regions. This is not supported by the apparent heterogeneity between presynaptic nACh receptors in different systems, although presently unknown determinants might control the spatial segregation of nACh-receptor subtypes in the plasma membrane2. There could be other explanations for the observed variation between presynaptic nACh receptors, including alternative splicing (a4; Ref. 53), posttranslational modification, or regulation through phosphorylation, as well as possible developmentally regulated changes in expression. Moreover, nACh receptors will not operate in isolation to modulate transmitter release, and the local complement of other receptors, second messengers, etc., and the extracellular milieu will influence the impact of nicotinic stimulation on the release process. Hence, different presynaptic nACh-receptor subtypes might be finely tuned with respect to agonist sensitivity, channel open time and desensitization to best suit the needs of the synapse where they are located.
Mechanism of action of presynaptic nACh receptors Nicotinic ACh receptors positively modulate transmitter release. This is consistent with their operation as ligand-gated cation channels. Unlike metabotropic presynaptic receptors that only influence stimulated release, nACh receptors can elicit Ca2+-dependent transmitter release under resting conditions11,54. This is explained readily by nACh-receptor activation resulting in Na+ influx and consequent depolarization, sufficient to activate local voltage-sensitive Ca2+ channels (VSCC). An alternative possibility, suggested by the high Ca2+ permeability of neuronal nACh receptors55, is that nACh-receptor activation might lead to sufficient Ca2+ influx via the nicotinic channel itself to promote exocytosis independently of VSCC. However, synaptosome studies54,56 have demonstrated a requirement for external Na+ for nACh receptor-stimulated transmitter release to proceed. The reports of rather variable TTX sensitivity already alluded to also support the participation of voltage-sensitive Na+ channels in nACh receptor-stimulated transmitter release in some TINS Vol. 20, No. 2, 1997
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instances. (At motor-nerve terminals, the inability of prejunctional nACh receptors to influence spontaneous release has been attributed to the absence of voltage-sensitive Na+ channels from the terminals12.) The Cd2+-sensitivity of nACh receptor-stimulated transmitter release implicates VSCC, and the involvement of N-type channels has been inferred57,58. This is consistent with other reports that VSCC account for the bulk of the Ca2+ influx arising from nACh-receptor activation in neurones59 and chromaffin cells60. Nevertheless, the local Ca2+ signal that results from influx through the nicotinic channel might be of some consequence for hitherto unrecognized functions. Moreover, this Ca2+ influx through nACh receptors will be more significant under resting or hyperpolarizing conditions, when VSCC will not be operative55.
Physiological significance of presynaptic nACh receptors A great many peripheral nerve endings, both sensory and motor, possess a variety of receptors, including nACh receptors, that in many instances seem to have no physiological relevance. That is to say, there is no evidence of how they might come into contact physiologically with their endogenous agonist. Why are they there? Perhaps because they do no harm, so that they have survived evolutionarily. Perhaps the local source of agonist, classical or novel, has not been discovered. In the CNS, physiological redundancy of presynaptic nACh receptors is harder to determine: most brain regions where such nACh receptors occur receive cholinergic innervation4, although evidence of axo–axonic synapses is generally lacking.
Nicotinic autoreceptors Nicotinic ACh receptors on ACh-containing terminals present the most straightforward concept of physiological presynaptic modulation, since they are likely to serve a feedback regulatory influence on ACh release where the source of agonist is not in doubt. This phenomenon has been examined in some detail at motor-nerve terminals12,61: although this article focuses on presynaptic nACh receptors in the CNS, it might be instructive to consider this example for comparison. Evidence in favour of presynaptic autofacilitation of synaptic transmission at the neuromuscular junction comes from the ability of neuromuscular blocking drugs, notably (+)-tubocurarine, to produce ‘tetanic fade’ in response to sustained nerve stimulation. Bowman and colleagues61 have postulated that prejunctional nACh receptors, when stimulated by released ACh, facilitate the mobilization of a reserve store of ACh, so that availability for release matches demand. Blockade of the receptors prevents the mobilization, and a decline in the magnitude of consecutive responses to a train of stimuli results. This observation, obtained in the absence of acetylcholinesterase (AChE) inhibitors, favours the location of prejunctional nACh receptors close to the terminals, because the receptors are activated by transmitter ACh before it is hydrolysed by AChE. Direct evidence for autofacilitation is provided by the measurement of ACh release, following synthesis from [3H]choline12,62. Such experiments might not be exactly comparable with the electrophysiological approach because of the inclusion of a choline-uptake blocker (hemicholinium-3), but in general terms the results are in accord. Sensitivity to hexamethonium, but not to a-neuro96
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toxins, indicates that the prejunctional nACh receptor is distinct from the postsynaptic muscle nACh receptor, reflecting synthesis of neuronal nACh-receptor subunits in the motor-nerve cell bodies in the spinal cord. The propensity to desensitize faster and in response to lower agonist concentrations than the muscle nACh receptor supports this distinction12 (but see Ref. 63). In addition, a distinct population of prejunctional inhibitory nicotinic autoreceptors has been inferred from the observation that nicotinic antagonists can enhance quantal release from motor-nerve terminals63–65. However, their activation by released ACh [implicit in the opposing action of (+)-tubocurarine] is only evident when AChE is inhibited. Thus, these nACh receptors have dubious physiological significance, as they would not ordinarily be exposed to released ACh, possibly reflecting a more distant, preterminal localization. In contrast to (+)-tubocurarineinduced decreases in ACh release (for example, facilitatory nACh receptors), which are Ca2+-independent and only occur at high-frequency stimulation, enhancement of quantal release by (+)-tubocurarine is Ca2+-dependent and observed at low-frequency stimulation63. These nACh receptors probably mediate nerve-terminal depolarization in a predictable manner (see above), but they can result in inhibition under conditions that cause excessive depolarization and block of nerve conduction. Thus, inhibition of elicited ACh release can result. The character of the putative nACh-receptor subtype responsible is controversial63,64. The anatomical and chemical complexity of the brain does not lend itself to comparable analyses of nicotinic autoregulation of ACh release at central synapses. Nevertheless, there is accumulating evidence for the phenomenon in cortex and hippocampus, from superfused slices19 and synaptosome preparations10,66 loaded with [3H]choline (see Fig. 2C). The nicotinic stimulation of endogenous ACh release in cortex has been reported, from synaptosomes in vitro67 and using in vivo microdialysis with nicotine administered locally68. These studies provide only limited evidence for physiologically relevant nicotinic autoregulation, as exogenous agonists were employed: the effect of released ACh has not been examined. Positive feedback mechanisms have been regarded with suspicion by physiologists, because of the potential for selfgenerating escalation. Rapid desensitization shown by the presynaptic nACh receptor10 would provide a safeguard against this happening. Despite the lack of proof of their physiological value, the pharmacological potential of such presynaptic nACh receptors as therapeutic targets for enhancing ACh release in Alzheimer’s disease has been highlighted68. In this connection, it is interesting that lesion of the cholinergic inputs to the hippocampus with AF64A resulted in an apparent increased sensitivity of nicotineelicited [3H]ACh release from hippocampal slices69. Quirion et al.68 noted that in the presence of a muscarinic antagonist, nicotine resulted in ‘tremendous releases of cortical ACh’, measured by in vivo microdialysis; the effect was more than anticipated from the net sum of muscarinic and nicotinic contributions. These observations hint at the possibility that nicotinic modulation might assume particular importance under adverse conditions of perturbed neurotransmission.
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Nicotinic heteroreceptors
Alternative theories of presynaptic nACh-receptor function
There is a larger body of evidence for presynaptic nACh receptors capable of modulating the release of neurotransmitters other than ACh in the brain8. This is especially true for the terminal fields of the ascending dopamine pathways. Even if axo–axonic synapses from ACh-containing nerves are absent, local cholinergic innervation might release sufficient ACh in the vicinity to survive hydrolysis by AChE and reach neighbouring terminals. Thus, presynaptic nACh receptors would participate in ‘volume transmission’ (as opposed to ‘wiring transmission’)70, recently alluded to as the ‘soup theory of the brain’71. One example where ACh acting in a paracrine manner has been considered is with respect to the physiological activation of preterminal nACh receptors on GABAcontaining interneurones in the IPN (Ref. 13). In this scenario, it is noteworthy that presynaptic nACh receptors in many systems are activated by low agonist concentrations (see above; Fig. 2), and they might be at least 10-fold more sensitive to agonist than their postsynaptic counterparts11,13. Not all presynaptic nACh receptors show such high sensitivity to agonist, for example, those nACh receptors that modulate noradrenaline release from hippocampus9,20. But, accepting that there might be sufficient ACh to reach presynaptic nACh receptors, what would be the consequences? Exogenous agonists typically increase basal neurotransmitter release: in in vitro neurochemical preparations, nicotinic agonists are ineffective in the presence of KCl depolarization19,54, which serves to maintain the membrane potential at a more positive level. The majority of electrophysiological studies has looked at spontaneous release11,13–15. In other examples, single5, brief52 or low-frequency stimulation11 has been employed. The inward rectification that is characteristic of neuronal nACh receptors implies that they will gate progressively less current as the membrane is depolarized, becoming essentially silent when the membrane potential reaches about –40 mV (Refs 55,72). Thus, their influence might be anticipated to be greatest under hyperpolarized or resting conditions, diminishing with increasing depolarization. This view is consistent with in vivo data: using in vivo microdialysis in a study of the mesolimbic pathway7, nicotine was equally effective in releasing dopamine whether applied to the terminal regions via the dialysis probe in the nucleus accumbens, or applied to the dopamine cell body area, via a canula inserted into the ventral tegmentum. This might be interpreted as presynaptic and somatodendritic nACh receptors in the pathway having similar capacities to provoke dopamine release. However, the dopamine release elicited by a systemically administered dose of nicotine was completely blocked by mecamylamine administered to the ventral tegmentum and not at all when mecamylamine was delivered to the terminal field. Thus, it appears that when somatodendritic nACh receptors are activated, leading to firing of the cells, terminal nACh receptors might have no additional effect. A further property of presynaptic nACh receptors that must be heeded in the context of ‘volume transmission’ is their propensity to desensitize2, such that in the sustained presence of nanomolar concentrations of agonist (too low to activate the nACh receptors) they are rendered insensitive to a subsequent challenge dose73,74.
Perhaps we are misguided in assuming that enhancement of neurotransmitter release is the sole physiological purpose of presynaptic nACh receptors. This happens to be what we measure but might not be physiologically pertinent. At motor-nerve terminals, the mobilization of ACh stores in order to sustain (rather than promote) release has been proposed as the physiological role of prejunctional nACh receptors61,65. Other observations (mentioned above) suggest that nACh receptors might provide a safety mechanism, having maximum impact on neurotransmitter release only when normal synaptic transmission is impaired. Plasticity of nACh-receptor subunit composition11 might contribute to such responses. Alternatively, nACh receptors might serve as a signalling mechanism for informing or modulating other aspects of nerve-terminal function. A hint of such a role comes from the emerging evidence for nACh receptors on growth cones, where they participate in the regulation of neurite outgrowth and pathfinding (for a recent review, see Ref. 3). These nACh receptors respond to ACh release by the growth cones. It is postulated that when ACh release increases on contact with a postsynaptic target, the growth cone nACh receptors might halt growth and foster synapse formation and stabilization. These developmentally important nACh receptors appear to be a7-like, and their high Ca2+ permeability suggests that this might be their principal signalling mechanism. The Ca2+dependent activation of second-messenger cascades3 and signalling pathways75 following nicotinic stimulation has been noted in cultured cells. As growth cones can be considered to be the precursors of presynaptic terminals, perhaps presynaptic nACh receptors might retain an analogous function at the mature synapse, having a role in maintaining or stabilizing the structure. This is pure speculation, and the data from developing systems3 only implicate a7-type nACh receptors in having a feedback (reporting) role, presumably at ACh-containing neurones. Nevertheless, this provides an alternative scenario for presynaptic nACh-receptor function, and we should perhaps be open to the possibility of this or other, as yet uncomprehended, functions for presynaptic nACh receptors.
Note added in proof The application of high-resolution techniques has disclosed presynaptic nicotinic modulation in the rat hippocampus. John Dani and colleagues76 have reported that sub-micromolar concentrations of nicotine enhance glutamate-mediated neurotransmission in cultures of hippocampal neurones from postnatal rats. This effect was TTX-insensitive and blocked by the a7-selective antagonists aBgt or methyllycaconitine, favouring the participation of presynaptic a7-like nACh receptors. Similar observations were made in hippocampal slices from young rats, indicating that this phenomenon is not limited to early developmental ages. In slices, the application of nicotine also elicited an increase in intracellular Ca2+ in terminal boutons; this occurred in the presence of Cd2+, consistent with entry of Ca2+ through a7 nACh-receptor channels. It is postulated that such nicotinic elevation of presynaptic Ca2+ could increase the probability of transmitter release in response to a subsequent action TINS Vol. 20, No. 2, 1997
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Acknowledgements I am grateful to Paul Whiteaker and Bill Bowman for helpful discussions, and to Paul Clarke for his critical appraisal of this manuscript and for providing the data for Fig. 2A and 2B. Work in the author’s laboratory is supported by grants from BBSRC, MRC, Wellcome Trust and BAT Co. Ltd.
potential: ‘thus properly timed nACh-receptor activity could ensure that important events emerge out of the noise of synaptic probabilities’.
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Selected references
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1 Sargent, P.B. (1993) Annu. Rev. Neurosci. 16, 403–443 2 McGehee, D.S. and Role, L.W. (1995) Annu. Rev. Physiol. 57, 521–546 3 Role, L.W. and Berg, D.K. (1996) Neuron 16, 1077–1085 4 Clarke, P.B.S. (1993) in Progress in Brain Research (Vol. 98) (Cuello, A.C., ed.), pp. 77–83, Elsevier 5 Mulle, C. et al. (1991) J. Neurosci. 11, 2588–2597 6 Yang, X., Criswell, H.E. and Breese, G.R. (1996) J. Pharmacol. Exp. Ther. 276, 482–489 7 Nisell, M., Nomikos, G.G. and Svensson, T.H. (1994) Synapse 16, 36–44 8 Wonnacott, S. et al. (1990) in Ciba Foundation Symposium 152: The Biology of Nicotine Dependence (Marsh, J., ed.), pp. 87–101, John Wiley & Sons 9 Clarke, P.B.S. and Reuben, M. (1996) Br. J. Pharmacol. 117, 595–606 10 Wilkie, G.I. et al. (1996) Neurochem. Res. 21, 1147–1154 11 McGehee, D.S. et al. (1995) Science 269, 1692–1696 12 Wessler, I. (1992) Int. Rev. Neurobiol. 34, 283–384 13 Lena, C., Changeux, J-P. and Mulle, C. (1993) J. Neurosci. 13, 2680–2688 14 McMahon, L.L., Yoon, K-W. and Chiappinelli, V.A. (1994) Neuroscience 59, 689–698 15 McMahon, L.L., Yoon, K-W. and Chiappinelli, V.A. (1994) J. Neurophysiol. 71, 826–829 16 Marks, M.J., Bullock, A.E. and Collins, A.C. (1995) J. Pharmacol. Exp. Ther. 274, 833–841 17 Marshall, D. et al. Neuropharmacology (in press) 18 Ramcharan, E.J. and Matthews, M.R. (1996) Neuroscience 71, 797–832 19 Araujo, D.M. et al. (1988) J. Neurochem. 51, 292–299 20 Sacaan, A.I., Dunlop, J.L. and Lloyd, G.K. (1995) J. Pharmacol. Exp. Ther. 274, 224–230 21 Dolezal, V., Schobert, A. and Hertting, G. (1995) Neurochem. Res. 20, 261–267 22 Sacaan, A.I. et al. (1996) J. Pharmacol. Exp. Ther. 276, 509–515 23 Conroy, W.G., Vernallis, A.B. and Berg, D.K. (1992) Neuron 9, 679–691 24 Ramirez-Latorre, J. et al. (1996) Nature 380, 347–351 25 Vernallis, A.B., Conroy, W.G. and Berg, D.K. (1993) Neuron 10, 451–461 26 Grady, S. et al. (1992) J. Neurochem. 59, 848–856 27 Whiteaker, P. et al. (1995) Br. J. Pharmacol. 116, 2097–2105 28 El-Bizri, H. and Clarke, P.B.S. (1994) Br. J. Pharmacol. 111, 406–413 29 Vibat, C.R.T. et al. (1995) Cell. Mol. Neurobiol. 15, 411–425 30 Papke, R.L. and Heinemann, S. (1994) Mol. Pharmacol. 45, 142–149 31 Peng, X. et al. (1994) Mol. Pharmacol. 46, 523–530 32 Marks, M.J. et al. (1992) J. Neurosci. 12, 2765–2784 33 Schwartz, R.D., Lehman, J. and Kellar, K.J. (1984) J. Neurochem. 42, 1495–1498
40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65
66 67 68 69 70 71 72 73 74 75 76
Clarke, P.B.S. and Pert, A. (1985) Brain Res. 348, 355–358 Whiting, P. et al. (1987) FEBS Lett. 219, 459–463 Flores, C.M. et al. (1992) Mol. Pharmacol. 41, 31–37 Schulz, D.W. and Zigmond, R.E. (1989) Neurosci. Lett. 98, 310–316 Wada, E. et al. (1989) J. Comp. Neurol. 284, 314–335 Dineley-Miller, K. and Patrick, J. (1992) Mol. Brain Res. 16, 339–344 Wada, E. et al. (1990) Brain Res. 526, 45–53 Deneris, E.S. et al. (1989) J. Biol. Chem. 264, 6268–6272 Seguela, P. et al. (1993) J. Neurosci. 13, 596–604 Wonnacott, S. et al. (1995) in Effects of Nicotine on Biological Systems II (Clarke, P.B.S. et al., eds), pp. 87–94, Birkhauser-Verlag Cachelin, A.B. and Rust, G. (1994) Mol. Pharmacol. 46, 1168–1174 Wong, E.T. et al. (1995) Mol. Brain Res. 28, 101–109 Thomas, P. et al. (1993) J. Neurochem. 60, 2308–2311 Araujo, D.M. et al. (1988) J. Neurochem. 50, 1914–1923 Clarke, P.B.S. et al. (1986) J. Comp. Neurol. 251, 407–413 Amar, M. et al. (1993) FEBS Lett. 327, 284–288 Rocha, E.S. et al. (1995) Soc. Neurosci. Abstr. 21, 526.9 Dominguez del Toro, E. et al. (1994) J. Comp. Neurol. 349, 325–342 Vidal, C. and Changeux, J-P. (1993) Neuroscience 56, 23–32 Goldman, D. et al. (1987) Cell 48, 965–973 Soliakov, L., Gallagher, T. and Wonnacott, S. (1995) Neuropharmacology 34, 1535–1541 Mulle, C. et al. (1992) Neuron 8, 135–143 Hillard, C.J. (1992) Neuropharmacology 31, 909–914 Vizi, E.S. et al. (1995) Ann. New York Acad. Sci. 757, 84–99 Soliakov, L. and Wonnacott, S. (1996) J. Neurochem. 67, 163–170 Rathouz, M.M. and Berg, D.K. (1994) J. Neurosci. 14, 6935–6945 Zhou, Z. and Heher, E. (1993) Pflügers Arch. 425, 511–517 Bowman, W.C. et al. (1988) Trends Pharmacol. Sci. 9, 16–20 Vizi, E.S. and Somogyi, G.T. (1989) Br. J. Pharmacol. 97, 65–70 Tian, L. et al. (1994) J. Physiol. 476, 517–529 Domet, M.A., Webb, C.E. and Wilson, D.F. (1995) Neurosci. Lett. 199, 49–52 Bowman W.C. (1996) in Neuromuscular Transmission (Fundamentals of Anaesthesia and Acute Medicine) (Booij, L.H.D., ed.), pp. 1–27, BMJ Publishing Group Rowell, P.P. and Winkler, D.L. (1984) J. Neurochem. 43, 1593–1598 Ochoa, E.L.M. and O’Shea, S.M. (1994) Cell. Mol. Neurobiol. 14, 315–340 Quirion, R., Richard, J. and Wilson, A. (1994) Synapse 17, 92–100 Thorne, B. and Potter, P.E. (1995) Brain Res. Bull. 38, 121–127 Agnati, L.F. et al. (1995) Neuroscience 69, 711–726 Sivilotti, L. and Colquhoun, D. (1995) Science 269, 1681–1682 Couturier, S. et al. (1990) J. Biol. Chem. 265, 17560–17567 Grady, S.R., Marks, M.J. and Collins, A.C. (1994) J. Neurochem. 62, 1390–1398 Rowell, P.P. and Hillebrand, J.A. (1994) J. Neurochem. 63, 561–569 Lev, S. et al. (1995) Nature 376, 737–745 Gray, R. et al. (1996) Nature 383, 713–716
Books Received Review copies of the following books have been received. Books that have been reviewed in Trends in Neurosciences are not included. The appearance of a book in the list does not preclude the possibility of it being reviewed in the future. S.D. Cook (ed.) Handbook of Multiple Sclerosis Marcel Dekker, 1996. $175.00 (xiv + 620 pages) ISBN 0 8247 9726 4
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G.D. Jackson and J.S. Duncan MRI Neuroanatomy Churchill Livingstone, 1996. £85.00 (xiii + 303 pages) ISBN 0 443 04543 7
C.F. Ferris and T. Grisso (eds) Understanding Aggressive Behaviour in Children New York Academy of Sciences, 1996. $125.00 (ix + 426 pages) ISBN 1 57331 012 3 (HB) 1 57331 013 1(PB)
K.A. Neve and R.L. Neve (eds) The Dopamine Receptors Humana Press, 1996. $119.50 (xi + 553 pages) ISBN 0 896 03433 X
P.W. Halligan and J.C. Marshall (eds) Method in Madness: Case Studies in Cognitive Neuropsychiatry Psychology Press, 1996. £29.95 (x + 310 pages) ISBN 0 86377 441 5
L. Packer, M. Hiramatsu and T. Yoshikawa (eds) Free Radicals in Brain Physiology and Disorders Academic Press, 1996. $95.00 (xxx + 474 pages) ISBN 0 12 543445 6
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M.E.A. Reith (ed.) Neurotransmitter Transporters: Structure, Function, and Regulation Humana Press, 1996. $125.00 (x + 405 pages) ISBN 0 896 03372 4 R.W. Thatcher, G. Reid Lyon, J. Rumsey and N. Krasnegor (eds) Developmental Neuroimaging: Mapping the Development of Brain Behavior Academic Press, 1996. $120.00 (xv + 312 pages) ISBN 0 12 686070 X M.J. Tovée An Introduction to the Visual System Cambridge University Press, 1996. £12.95 (PB) £35.00 (HB) (xiv + 202 pages) ISBN 0 521 48339 5 (PB) 0 521 48290 9 (HB) W. Wasco and R.E. Tanzi (eds) Molecular Mechanisms of Dementia Humana Press, 1996. $99.50 (xi + 312 pages) ISBN 0 89603 371 6
S. Wonnacott – Presynaptic nACh receptors
Presynaptic nicotinic ACh receptors Susan Wonnacott Nicotinic ACh (nACh) receptors in the CNS are composed of a diverse array of subunits and have a range of pharmacological properties. However, despite the fact that they are ligand-gated cation channels, their physiological functions have not been determined.This has led to increased interest in presynaptic nACh receptors that act to modulate the release of transmitter from presynaptic terminals. Trends Neurosci. (1997) 20, 92–98
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Susan Wonnacott is at the School of Biology and Biochemistry, University of Bath, Bath, UK BA2 7AY.
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O FAR, ten nicotinic ACh (nACh)-receptor subunits (a2–a8; b2–b4) have been found to be expressed in vertebrate neurones. These subunits share homology with muscle nACh-receptor subunits (and with the a9 subunit, which is present in certain endocrine cells and sensory end organs), and most have been shown to contribute to the formation of functional nACh receptors in heterologous expression systems1,2. In view of this diversity, it is striking that there is scant evidence for nicotinic synaptic transmission in the brain: given that nACh receptors are ligand-gated cation channels and subserve a pivotal role in mediating neuromuscular and ganglionic transmission, an analogous role in fast excitatory transmission in the CNS has been anticipated. The difficulty in demonstrating such a function, together with recognition of the high Ca2+ permeability of neuronal nACh receptors, has recently kindled the notion that nACh receptors might have a more modulatory role in the brain3. The wellestablished ability of nicotine to elicit transmitter release, commonly by acting at presynaptic nACh receptors, is consistent with such a modulatory activity. Indeed, it has been suggested2 that ‘presynaptic nACh receptors might be the exclusive or predominant role of nACh receptors in the CNS’. However, the occurrence of nACh receptors on somatodendritic regions of neurones is clear4. For example, electrophysiological recordings have shown that exogenously applied nicotinic agonists can excite cells directly4–6, and in vivo microdialysis has demonstrated that systemically administered nicotine exerts its effects on the ascending dopamine pathways predominantly in the cell-body areas 7. Somatodendritic nACh receptors are consistent with the evidence for local cholinergic inputs (as distinct from synaptic contacts) in several cases4. Nevertheless, the modulation of transmitter release (and synaptic transmission?) directly through nACh receptors on nerve terminals is more evident than the relatively low abundance of neuronal nACh receptors might predict, reinforcing the proposition that this is a significant function of nACh receptors in the brain. Although dopamine release has received the greatest attention, the release of most of the classical neurotransmitters has been shown to be influenced by nicotine acting at the level of the nerve terminal8: recent examples include the release of noradrenaline9, ACh (Ref. 10), glutamate11 and GABA (Ref. 6) from diverse preparations. This review will focus on the properties, mechanisms and implications of presynaptic nACh receptors in the mammalian brain. TINS Vol. 20, No. 2, 1997
Presynaptic and preterminal nACh receptors Presynaptic receptors can be defined as receptors at or near the nerve terminal that can positively or negatively modulate transmitter release directly, or influence the probability of an action potential resulting in exocytosis. The concept of preterminal nACh receptors (Fig. 1) was raised by Wessler12 to describe axonal receptors that modulate ACh release from motor-nerve terminals. Preterminal nACh receptors have also been defined on GABA-containing neurones in the rat interpeduncular nucleus (IPN; Ref. 13) and chick lateral spiriform nucleus14, using whole-cell patch-clamp recording to show that nicotinic agonists increase the frequency of postsynaptic currents in a tetrodotoxin (TTX)-sensitive manner. By contrast, presynaptic nACh receptors have been proposed to elicit neurotransmitter release through a TTX-insensitive mechanism8. By this criterion, presynaptic nACh receptors have been identified using electrophysiological recordings, for example, in the chick IPN (Ref. 11) and lateral geniculate nucleus15. Recent studies of striatal synaptosomes16,17 (defined as presynaptic elements) have challenged this simple distinction, by reporting a partial block by TTX of nicotine-elicited 86Rb or [3H]dopamine release. TTX-sensitive and insensitive mechanisms might reflect the relative proximity of nACh receptors to the synapse and the exocytotic machinery. Thus, TTXsensitivity alone does not necessarily distinguish preterminal nACh receptors from those presumed to reside on terminal boutons. Ultrastructural studies will be required to resolve this issue: in the case of muscarinic binding sites on rat sympathetic neurones18, of the 10% or so of labelling associated with nerve endings, less than 40% corresponded to synaptic areas, compared with 60% of specific binding located on non-synaptic surfaces of nerve terminals and preterminal axon segments. TTX-insensitivity of nicotinic agonist-elicited responses has been taken to define presynaptic nACh receptors in neurochemical studies of more integrated preparations, such as brain slices19,20 and cultured neurones21. Where synaptosome studies show little or no TTX sensitivity (for example, nicotine-elicited noradrenaline release from hippocampal synaptosomes9), corresponding experiments on slice preparations20,22 have reported substantial inhibition by TTX, equivalent to a total block of nACh receptor-mediated (mecamylamine-sensitive) noradrenaline release. A similar picture is seen with nicotine-elicited dopamine release from striatal preparations17. Does this mean that presynaptic nACh receptors are vastly outnumbered by
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preterminal nACh receptors and nACh receptors acting via local interneurones? Or might the preparation of synaptosomes disrupt mechanisms operative in intact systems, leading to a false picture of TTX-insensitivity? The latter view is particularly pertinent to systems where varicosities and en passant terminals are abundant, such as catecholamine projections. Thus TTXinsensitivity as a definition of presynaptic nACh receptors might underestimate the number of nACh receptors located near synapses.
Somatodendritic
Presynaptic Preterminal
Heterogeneity of presynaptic nACh receptors Given the diversity of nicotinic subunits expressed in neurones, one might reasonably enquire which subunit combinations constitute presynaptic nACh receptors, and if presynaptic nACh receptors show heterogeneity in different brain pathways or transmitter systems. The identification of subunits comprising native nACh receptors has been attempted by comparison with the characteristics of heterologously expressed combinations of subunits. However, this approach generally gives imperfect correlations2, perhaps reflecting altered post-translational modification of nACh receptors in non-neuronal cells, or a more complex subunit composition of native nACh receptors than the pairwise combinations of subunits typically studied in expression systems. Indeed, there is now evidence that the a5 subunit associates with a3 or a4 subunits in chick brain and ganglia23,24, and that the synaptic nACh receptors in chick ciliary ganglion neurones is composed of a3, a5 and b4 subunits25. Similar complexity might be anticipated in mammalian brain. The impossibility of direct electrophysiological recordings from presynaptic nACh receptors at the present time, the paucity of definitive pharmacological tools to discriminate different nACh-receptor subtypes, and the incomplete pharmacological characterization of presynaptic nACh receptors, in most cases, makes assessment of their subunit composition even more problematical. Other strategies that might help to resolve this issue include immunogold electron microscopy with subunit-specific antibodies and in vivo antisense deletion experiments to knock out selected subunits.
Presynaptic nACh receptors on striatal dopamine terminals Presynaptic nACh receptors regulating dopamine release have been studied extensively, using neurochemical techniques. In superfused synaptosome preparations from striatum, nicotine is a potent agonist, acting with a sub-micromolar EC50 to elicit [3H]dopamine release9,26,27. Cytisine is reported to be a partial agonist in the rat20,28 (but not in the mouse26). These features encourage the notion of a presynaptic nACh receptor composed of a4 and b2 subunits9: this subunit combination has the highest sensitivity to nicotine of any heterologously expressed nACh receptor (for example, EC50 = 0.3 mM for rat a4 and b2 subunits expressed in Xenopus oocytes29), and cytisine has low efficacy at this nACh receptor composed of rat subunits30 (but this is not the case for chick subunits31). Indeed, cytisine is essentially ineffective at the rat b2-containing nACh receptors expressed in Xenopus oocytes30, such that its substantial, albeit partial, agonism in striatal preparations implies a contribution from the b4 subunit9,26. The role of the b4 subunit is incompatible with subunit expression patterns in rat (see below) and mouse32, but alternative or additional subunits might confer the observed properties. Lesion studies33,34 support the presence
Preterminal nACh receptor Presynaptic nACh receptors
Fig. 1. Putative locations of neuronal nicotinic ACh (nACh) receptors.
of [3H]nicotine binding sites (which have been correlated with a4 and b2 subunits on the basis of microsequencing35 and immunoprecipitation36 data) on dopamine-containing terminals. On the other hand, antagonism by neuronal bungarotoxin (nBgt) has been documented26,37 and interpreted in favour of nACh receptors containing the a3 subunit. Interpretation of subunit expression at the transcriptional level is also fraught with limitations. Subunit mRNAs are expressed in the cell-body regions, typically at some distance from the projection areas; the subcellular destinations of different subunits cannot be discerned readily; numerous subunits are detected in various amounts; and there is not necessarily a quantitative relationship between subunit mRNA, subunit protein, assembled pentamer and functional surface nACh receptors. Moreover, low levels of expression are difficult to resolve from the background. With these caveats in mind, one can, nevertheless, examine documented expression patterns (Fig. 2). Notably in the substantia nigra, a4 and b2 mRNAs predominate, with lower levels of a3 expressed38. No b4 mRNA has been detected39 but significant expression of a5 (Ref. 40) and b3 (Ref. 41) has been reported. While these data are compatible with a4b2 combinations, they would also support more complex subunit compositions. The occurrence of more than one nACh-receptor subtype on dopamine terminals is a further possibility43.
Presynaptic nACh receptor on hippocampal noradrenaline terminals A recent study by Clarke and Reuben9 compared the nicotinic stimulation of [3H]dopamine release from striatal synaptosomes and [3H]noradrenaline release from hippocampal synaptosomes. The latter preparation was 40-fold less sensitive to nicotine (EC50 = 6.5 mM; Fig. 2) and 30-fold less sensitive to the competitive antagonists dihydro-b-erythroidine and methyllycaconitine. Moreover, cytisine was as efficacious as nicotine in eliciting [3H]noradrenaline release. This comparative TINS Vol. 20, No. 2, 1997
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A
C SN MS
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EC50 = 0.16 µM
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Substantia nigra β2 +++ α2 – β3 +++ α3 ++ β4 – α4 +++ α5 +++ α7 ?
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Medial habenula β2 ++ α2 – β3 +++ α3 +++ β4 ++++ α4 +++ α5 ? α7 +
–9 –8 –7 –6 –5 –4 –3 Log [nicotine] (M)
Fig. 2. Examples of pathways bearing presynaptic nicotinic ACh (nACh) receptors in the rat brain. (A) The dopamine-containing nigro– striatal pathway; (B) innervation of the hippocampus by noradrenaline-containing neurones; and (C) innervation of the hippocampus by AChcontaining neurones from the medial septum: transmitter release from each of these projection areas has been studied by superfusion of synaptosomes, yielding quantitative dose–response relationships for agonists. A and B redrawn from Ref. 9, C redrawn from Ref. 10. (D) Presynaptic nACh receptors in the habenulo–interpeduncular pathway have been characterized using electrophysiological techniques in the rat 5 and chick11. Although the innervation of the IPN is partly from ACh-containing neurones, the transmitter modulated by presynaptic nACh receptors in the rat is not known. In the chick it appears to be glutamate. The boxes list the nACh-receptor subunit mRNAs expressed in the regions containing the cell bodies in the rat, according to in situ hybridization. Data from Refs 38–42. Abbreviations: –, no signal above background; (+), very weak; +, detectable; ++, moderate; +++, strong; ++++, very strong; ?, no information (presumably no distinct signal or it would have been noted); DA, dopamine; IPN, interpeduncular nucleus; LC, locus coeruleus; MH, medial habenula; MS, medial septum; NA, noradrenaline; SN, substantia nigra.
study, using essentially identical protocols in the same laboratory, suggests strongly that the presynaptic nACh receptors acting in these two pathways are pharmacologically distinct, which very probably reflects different nACh receptor-subunit compositions. Qualitatively similar pharmacological differences have been seen in a comparison of striatal and hippocampal slice preparations20,22, although the presynaptic locus of the nACh-receptor functions monitored in such preparations is less clear-cut. The rat hippocampus derives its noradrenergic innervation from the locus coeruleus, which expresses a different complement of nACh-receptor subunits than the substantia nigra (Fig. 2). In particular, a3 mRNA is very abundant with little a4 mRNA expressed38. Comparison with nACh receptors expressed in heterologous systems44,45 has led to the tentative proposition that a3 and b4 subunits might constitute the presynaptic nACh receptor modulating [3H]noradrenaline release in the hippocampus, although the correlation is not perfect9.
Presynaptic nicotinic autoreceptors regulating ACh release in the hippocampus Nicotinic agonists stimulate the release of [3H]ACh from hippocampal slices19 and synaptosomes10. This 94
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response could be blocked by dihydro-b-erythroidine, (+)-tubocurarine and mecamylamine, but not by a-bungarotoxin (aBgt) or low concentrations of methyllycaconitine. The ‘bell-shaped’ agonist dose–response curves and EC50 of 1 mM for nicotine (Fig. 2) resemble the profile exhibited by the a4b2 subunit combination expressed in Xenopus oocytes29 and in a mammalian cell line46. This subunit composition is consistent with the loss of high-affinity [3H]nicotine binding sites from the hippocampus as cholinergic inputs degenerate in Alzheimer’s disease47, but the ability of cytisine to elicit maximum responses10 does not fit with the small responses to this agonist of a4b2 nACh receptors in Xenopus oocytes30. The cholinergic innervation of the hippocampus arises from cell bodies in the medial septum, which expresses yet another complement of nACh-receptor subunits (Fig. 2). a4 and b2 transcripts predominate, with only very weak signals for a3 or b4. However, this is one of the few areas in the rat brain reported to express the a2 subunit38, whose contribution to native nACh receptors has not been established.
Presynaptic nACh receptors in the IPN In contrast to the preceding neurochemical studies, nACh receptors in the habenular–interpeduncular
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system (Fig. 2) have been characterized using electrophysiological approaches, in 500 mM slices from adult rat5, and in co-cultures from embryonic chicken11. In the rat preparation, nicotinic agonists decreased the afferent volley recorded in the IPN following stimulation of the fasciculus retroflexus (the tract that connects the medial habenula to the IPN). This is consistent with the activation of presynaptic nACh receptors on axon terminals of the fasciculus retroflexus. Nicotine was the most potent agonist examined: cytisine, ACh, carbachol and dimethyl phenyl piperazine (DMPP) were 5–20 times less potent. Hexamethonium and mecamylamine were potent blockers, (+)-tubocurarine and dihydro-b-erythroidine were less effective (although these competitive antagonists were tested against a single, rather high agonist concentration) and nBgt and aBgt were without effect. Habenular lesions to destroy the fasciculus retroflexus have resulted in a sustained decrease (35%) in [3H]nicotine binding and a transient decrease in [125I]aBgt binding in the IPN (Ref. 48), consistent with the presence of nACh receptors on afferent axons or terminals. Most nAChreceptor subunits (except a2 and possibly a5; see Fig. 2) are reported to be expressed in the rat medial habenula. In the co-cultures of chick medial habenula and IPN explants11, glutamate was inferred to be the transmitter. Low concentrations of nicotine (EC50 = 170 nM) enhanced synaptic transmission elicited by lowfrequency (0.1 Hz) extracellular stimulation of the medial habenula tissue, and increased the frequency of spontaneous excitatory postsynaptic potentials (in the presence of TTX). This study is notable for two unusual features: first, the nicotinic response was inhibited by aBgt, albeit with a rather high IC50 of 70 nM (possibly reflecting accessibility problems or insufficient preincubation for maximum blockade). Sensitivity to aBgt implicates the a7 subunit (or a8 in chick), and antisense knockdown experiments confirmed the involvement of a7 in this response. The second novel observation was that despite apparently complete antisense deletion of a7 expression, the nicotinic synaptic enhancement persisted (but was now aBgt-insensitive). Compensatory changes in subunit synthesis, assembly or targeting are proposed11. The sensitivity to nanomolar concentrations of nicotine shown by the aBgt-sensitive responses argues that this is not a typical a7-type nACh receptor, which requires 100-fold higher nicotine concentrations for activation49. The persistence of the nicotinic modulation after a7 deletion encourages the view that a7 is co-assembled with other nicotinic subunits. This study provides the first substantial report of an aBgt-sensitive presynaptic nicotinic response in the CNS. In a preliminary account, a7 has since been implicated in the presynaptic modulation of glutamate transmission in rat optic-bulb neurones50. It is important to note, however, that these preparations displaying a7-type presynaptic nicotinic modulation were derived from embryonic brain; synapses were presumably established over the few days in culture. Given the suggested involvement of a7 in pathfinding and synapse formation3 (see below), the participation of this subunit in the presynaptic response might reflect the immature status of the tissues, with inherent plasticity in nACh-receptor complement or composition. Therefore, caution is warranted before extrapolating these observations to the mature synapse. The immunocytochemical localization
of the a7 subunit at the cellular level in the rat CNS has revealed immunostaining of somata and dendrites, whereas axonal and terminal labelling was not observed51. The only report of nicotinic modulation of excitatory transmission (mediated by non-NMDA glutamate receptors) in the adult rat brain found it to be insensitive to aBgt (Ref. 52), but see the note added in proof. Taken together with the data from other transmitter systems, it seems unlikely that the a7 subunit plays a major role in presynaptic nACh receptors in the adult rat brain. Clearly the few examples of presynaptic nACh receptor discussed here (Fig. 2) display a range of pharmacological properties, with differences in agonist sensitivity and efficacy, and susceptibility to blockade by various antagonists. At the present time, the subunit composition has not been established for any presynaptic nACh receptor. The heterogeneity of mRNA expression is compatible with multiple types of nACh receptor. A question common in biology today is ‘why have this potential for such diversity?’2. An early suggestion53 was that presynaptic nACh receptors might be composed of distinct subunits (a3) from their somatodendritic counterparts (a4) for the purposes of targeting to terminal regions. This is not supported by the apparent heterogeneity between presynaptic nACh receptors in different systems, although presently unknown determinants might control the spatial segregation of nACh-receptor subtypes in the plasma membrane2. There could be other explanations for the observed variation between presynaptic nACh receptors, including alternative splicing (a4; Ref. 53), posttranslational modification, or regulation through phosphorylation, as well as possible developmentally regulated changes in expression. Moreover, nACh receptors will not operate in isolation to modulate transmitter release, and the local complement of other receptors, second messengers, etc., and the extracellular milieu will influence the impact of nicotinic stimulation on the release process. Hence, different presynaptic nACh-receptor subtypes might be finely tuned with respect to agonist sensitivity, channel open time and desensitization to best suit the needs of the synapse where they are located.
Mechanism of action of presynaptic nACh receptors Nicotinic ACh receptors positively modulate transmitter release. This is consistent with their operation as ligand-gated cation channels. Unlike metabotropic presynaptic receptors that only influence stimulated release, nACh receptors can elicit Ca2+-dependent transmitter release under resting conditions11,54. This is explained readily by nACh-receptor activation resulting in Na+ influx and consequent depolarization, sufficient to activate local voltage-sensitive Ca2+ channels (VSCC). An alternative possibility, suggested by the high Ca2+ permeability of neuronal nACh receptors55, is that nACh-receptor activation might lead to sufficient Ca2+ influx via the nicotinic channel itself to promote exocytosis independently of VSCC. However, synaptosome studies54,56 have demonstrated a requirement for external Na+ for nACh receptor-stimulated transmitter release to proceed. The reports of rather variable TTX sensitivity already alluded to also support the participation of voltage-sensitive Na+ channels in nACh receptor-stimulated transmitter release in some TINS Vol. 20, No. 2, 1997
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instances. (At motor-nerve terminals, the inability of prejunctional nACh receptors to influence spontaneous release has been attributed to the absence of voltage-sensitive Na+ channels from the terminals12.) The Cd2+-sensitivity of nACh receptor-stimulated transmitter release implicates VSCC, and the involvement of N-type channels has been inferred57,58. This is consistent with other reports that VSCC account for the bulk of the Ca2+ influx arising from nACh-receptor activation in neurones59 and chromaffin cells60. Nevertheless, the local Ca2+ signal that results from influx through the nicotinic channel might be of some consequence for hitherto unrecognized functions. Moreover, this Ca2+ influx through nACh receptors will be more significant under resting or hyperpolarizing conditions, when VSCC will not be operative55.
Physiological significance of presynaptic nACh receptors A great many peripheral nerve endings, both sensory and motor, possess a variety of receptors, including nACh receptors, that in many instances seem to have no physiological relevance. That is to say, there is no evidence of how they might come into contact physiologically with their endogenous agonist. Why are they there? Perhaps because they do no harm, so that they have survived evolutionarily. Perhaps the local source of agonist, classical or novel, has not been discovered. In the CNS, physiological redundancy of presynaptic nACh receptors is harder to determine: most brain regions where such nACh receptors occur receive cholinergic innervation4, although evidence of axo–axonic synapses is generally lacking.
Nicotinic autoreceptors Nicotinic ACh receptors on ACh-containing terminals present the most straightforward concept of physiological presynaptic modulation, since they are likely to serve a feedback regulatory influence on ACh release where the source of agonist is not in doubt. This phenomenon has been examined in some detail at motor-nerve terminals12,61: although this article focuses on presynaptic nACh receptors in the CNS, it might be instructive to consider this example for comparison. Evidence in favour of presynaptic autofacilitation of synaptic transmission at the neuromuscular junction comes from the ability of neuromuscular blocking drugs, notably (+)-tubocurarine, to produce ‘tetanic fade’ in response to sustained nerve stimulation. Bowman and colleagues61 have postulated that prejunctional nACh receptors, when stimulated by released ACh, facilitate the mobilization of a reserve store of ACh, so that availability for release matches demand. Blockade of the receptors prevents the mobilization, and a decline in the magnitude of consecutive responses to a train of stimuli results. This observation, obtained in the absence of acetylcholinesterase (AChE) inhibitors, favours the location of prejunctional nACh receptors close to the terminals, because the receptors are activated by transmitter ACh before it is hydrolysed by AChE. Direct evidence for autofacilitation is provided by the measurement of ACh release, following synthesis from [3H]choline12,62. Such experiments might not be exactly comparable with the electrophysiological approach because of the inclusion of a choline-uptake blocker (hemicholinium-3), but in general terms the results are in accord. Sensitivity to hexamethonium, but not to a-neuro96
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toxins, indicates that the prejunctional nACh receptor is distinct from the postsynaptic muscle nACh receptor, reflecting synthesis of neuronal nACh-receptor subunits in the motor-nerve cell bodies in the spinal cord. The propensity to desensitize faster and in response to lower agonist concentrations than the muscle nACh receptor supports this distinction12 (but see Ref. 63). In addition, a distinct population of prejunctional inhibitory nicotinic autoreceptors has been inferred from the observation that nicotinic antagonists can enhance quantal release from motor-nerve terminals63–65. However, their activation by released ACh [implicit in the opposing action of (+)-tubocurarine] is only evident when AChE is inhibited. Thus, these nACh receptors have dubious physiological significance, as they would not ordinarily be exposed to released ACh, possibly reflecting a more distant, preterminal localization. In contrast to (+)-tubocurarineinduced decreases in ACh release (for example, facilitatory nACh receptors), which are Ca2+-independent and only occur at high-frequency stimulation, enhancement of quantal release by (+)-tubocurarine is Ca2+-dependent and observed at low-frequency stimulation63. These nACh receptors probably mediate nerve-terminal depolarization in a predictable manner (see above), but they can result in inhibition under conditions that cause excessive depolarization and block of nerve conduction. Thus, inhibition of elicited ACh release can result. The character of the putative nACh-receptor subtype responsible is controversial63,64. The anatomical and chemical complexity of the brain does not lend itself to comparable analyses of nicotinic autoregulation of ACh release at central synapses. Nevertheless, there is accumulating evidence for the phenomenon in cortex and hippocampus, from superfused slices19 and synaptosome preparations10,66 loaded with [3H]choline (see Fig. 2C). The nicotinic stimulation of endogenous ACh release in cortex has been reported, from synaptosomes in vitro67 and using in vivo microdialysis with nicotine administered locally68. These studies provide only limited evidence for physiologically relevant nicotinic autoregulation, as exogenous agonists were employed: the effect of released ACh has not been examined. Positive feedback mechanisms have been regarded with suspicion by physiologists, because of the potential for selfgenerating escalation. Rapid desensitization shown by the presynaptic nACh receptor10 would provide a safeguard against this happening. Despite the lack of proof of their physiological value, the pharmacological potential of such presynaptic nACh receptors as therapeutic targets for enhancing ACh release in Alzheimer’s disease has been highlighted68. In this connection, it is interesting that lesion of the cholinergic inputs to the hippocampus with AF64A resulted in an apparent increased sensitivity of nicotineelicited [3H]ACh release from hippocampal slices69. Quirion et al.68 noted that in the presence of a muscarinic antagonist, nicotine resulted in ‘tremendous releases of cortical ACh’, measured by in vivo microdialysis; the effect was more than anticipated from the net sum of muscarinic and nicotinic contributions. These observations hint at the possibility that nicotinic modulation might assume particular importance under adverse conditions of perturbed neurotransmission.
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Nicotinic heteroreceptors
Alternative theories of presynaptic nACh-receptor function
There is a larger body of evidence for presynaptic nACh receptors capable of modulating the release of neurotransmitters other than ACh in the brain8. This is especially true for the terminal fields of the ascending dopamine pathways. Even if axo–axonic synapses from ACh-containing nerves are absent, local cholinergic innervation might release sufficient ACh in the vicinity to survive hydrolysis by AChE and reach neighbouring terminals. Thus, presynaptic nACh receptors would participate in ‘volume transmission’ (as opposed to ‘wiring transmission’)70, recently alluded to as the ‘soup theory of the brain’71. One example where ACh acting in a paracrine manner has been considered is with respect to the physiological activation of preterminal nACh receptors on GABAcontaining interneurones in the IPN (Ref. 13). In this scenario, it is noteworthy that presynaptic nACh receptors in many systems are activated by low agonist concentrations (see above; Fig. 2), and they might be at least 10-fold more sensitive to agonist than their postsynaptic counterparts11,13. Not all presynaptic nACh receptors show such high sensitivity to agonist, for example, those nACh receptors that modulate noradrenaline release from hippocampus9,20. But, accepting that there might be sufficient ACh to reach presynaptic nACh receptors, what would be the consequences? Exogenous agonists typically increase basal neurotransmitter release: in in vitro neurochemical preparations, nicotinic agonists are ineffective in the presence of KCl depolarization19,54, which serves to maintain the membrane potential at a more positive level. The majority of electrophysiological studies has looked at spontaneous release11,13–15. In other examples, single5, brief52 or low-frequency stimulation11 has been employed. The inward rectification that is characteristic of neuronal nACh receptors implies that they will gate progressively less current as the membrane is depolarized, becoming essentially silent when the membrane potential reaches about –40 mV (Refs 55,72). Thus, their influence might be anticipated to be greatest under hyperpolarized or resting conditions, diminishing with increasing depolarization. This view is consistent with in vivo data: using in vivo microdialysis in a study of the mesolimbic pathway7, nicotine was equally effective in releasing dopamine whether applied to the terminal regions via the dialysis probe in the nucleus accumbens, or applied to the dopamine cell body area, via a canula inserted into the ventral tegmentum. This might be interpreted as presynaptic and somatodendritic nACh receptors in the pathway having similar capacities to provoke dopamine release. However, the dopamine release elicited by a systemically administered dose of nicotine was completely blocked by mecamylamine administered to the ventral tegmentum and not at all when mecamylamine was delivered to the terminal field. Thus, it appears that when somatodendritic nACh receptors are activated, leading to firing of the cells, terminal nACh receptors might have no additional effect. A further property of presynaptic nACh receptors that must be heeded in the context of ‘volume transmission’ is their propensity to desensitize2, such that in the sustained presence of nanomolar concentrations of agonist (too low to activate the nACh receptors) they are rendered insensitive to a subsequent challenge dose73,74.
Perhaps we are misguided in assuming that enhancement of neurotransmitter release is the sole physiological purpose of presynaptic nACh receptors. This happens to be what we measure but might not be physiologically pertinent. At motor-nerve terminals, the mobilization of ACh stores in order to sustain (rather than promote) release has been proposed as the physiological role of prejunctional nACh receptors61,65. Other observations (mentioned above) suggest that nACh receptors might provide a safety mechanism, having maximum impact on neurotransmitter release only when normal synaptic transmission is impaired. Plasticity of nACh-receptor subunit composition11 might contribute to such responses. Alternatively, nACh receptors might serve as a signalling mechanism for informing or modulating other aspects of nerve-terminal function. A hint of such a role comes from the emerging evidence for nACh receptors on growth cones, where they participate in the regulation of neurite outgrowth and pathfinding (for a recent review, see Ref. 3). These nACh receptors respond to ACh release by the growth cones. It is postulated that when ACh release increases on contact with a postsynaptic target, the growth cone nACh receptors might halt growth and foster synapse formation and stabilization. These developmentally important nACh receptors appear to be a7-like, and their high Ca2+ permeability suggests that this might be their principal signalling mechanism. The Ca2+dependent activation of second-messenger cascades3 and signalling pathways75 following nicotinic stimulation has been noted in cultured cells. As growth cones can be considered to be the precursors of presynaptic terminals, perhaps presynaptic nACh receptors might retain an analogous function at the mature synapse, having a role in maintaining or stabilizing the structure. This is pure speculation, and the data from developing systems3 only implicate a7-type nACh receptors in having a feedback (reporting) role, presumably at ACh-containing neurones. Nevertheless, this provides an alternative scenario for presynaptic nACh-receptor function, and we should perhaps be open to the possibility of this or other, as yet uncomprehended, functions for presynaptic nACh receptors.
Note added in proof The application of high-resolution techniques has disclosed presynaptic nicotinic modulation in the rat hippocampus. John Dani and colleagues76 have reported that sub-micromolar concentrations of nicotine enhance glutamate-mediated neurotransmission in cultures of hippocampal neurones from postnatal rats. This effect was TTX-insensitive and blocked by the a7-selective antagonists aBgt or methyllycaconitine, favouring the participation of presynaptic a7-like nACh receptors. Similar observations were made in hippocampal slices from young rats, indicating that this phenomenon is not limited to early developmental ages. In slices, the application of nicotine also elicited an increase in intracellular Ca2+ in terminal boutons; this occurred in the presence of Cd2+, consistent with entry of Ca2+ through a7 nACh-receptor channels. It is postulated that such nicotinic elevation of presynaptic Ca2+ could increase the probability of transmitter release in response to a subsequent action TINS Vol. 20, No. 2, 1997
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Acknowledgements I am grateful to Paul Whiteaker and Bill Bowman for helpful discussions, and to Paul Clarke for his critical appraisal of this manuscript and for providing the data for Fig. 2A and 2B. Work in the author’s laboratory is supported by grants from BBSRC, MRC, Wellcome Trust and BAT Co. Ltd.
potential: ‘thus properly timed nACh-receptor activity could ensure that important events emerge out of the noise of synaptic probabilities’.
34 35 36 37
Selected references
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Books Received Review copies of the following books have been received. Books that have been reviewed in Trends in Neurosciences are not included. The appearance of a book in the list does not preclude the possibility of it being reviewed in the future. S.D. Cook (ed.) Handbook of Multiple Sclerosis Marcel Dekker, 1996. $175.00 (xiv + 620 pages) ISBN 0 8247 9726 4
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G.D. Jackson and J.S. Duncan MRI Neuroanatomy Churchill Livingstone, 1996. £85.00 (xiii + 303 pages) ISBN 0 443 04543 7
C.F. Ferris and T. Grisso (eds) Understanding Aggressive Behaviour in Children New York Academy of Sciences, 1996. $125.00 (ix + 426 pages) ISBN 1 57331 012 3 (HB) 1 57331 013 1(PB)
K.A. Neve and R.L. Neve (eds) The Dopamine Receptors Humana Press, 1996. $119.50 (xi + 553 pages) ISBN 0 896 03433 X
P.W. Halligan and J.C. Marshall (eds) Method in Madness: Case Studies in Cognitive Neuropsychiatry Psychology Press, 1996. £29.95 (x + 310 pages) ISBN 0 86377 441 5
L. Packer, M. Hiramatsu and T. Yoshikawa (eds) Free Radicals in Brain Physiology and Disorders Academic Press, 1996. $95.00 (xxx + 474 pages) ISBN 0 12 543445 6
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M.E.A. Reith (ed.) Neurotransmitter Transporters: Structure, Function, and Regulation Humana Press, 1996. $125.00 (x + 405 pages) ISBN 0 896 03372 4 R.W. Thatcher, G. Reid Lyon, J. Rumsey and N. Krasnegor (eds) Developmental Neuroimaging: Mapping the Development of Brain Behavior Academic Press, 1996. $120.00 (xv + 312 pages) ISBN 0 12 686070 X M.J. Tovée An Introduction to the Visual System Cambridge University Press, 1996. £12.95 (PB) £35.00 (HB) (xiv + 202 pages) ISBN 0 521 48339 5 (PB) 0 521 48290 9 (HB) W. Wasco and R.E. Tanzi (eds) Molecular Mechanisms of Dementia Humana Press, 1996. $99.50 (xi + 312 pages) ISBN 0 89603 371 6