Galanin-acetyicholine interactions in rodent memory tasks and Alzheimer's disease Michael P. McDonald, PhD; Jacqueline N. Crawley, PhD Section on Behavioral Neuropharmacology, Experimental Therapeutics Branch, National Institute of Mental Health, Bethesda, Md.
Galanin is a 29-amino-acid neuropeptide that is widely distributed in the mammalian central nervous sysGalanin-immunoreactive cell bodies, fibres and terminals, and galanin binding sites, are located in the basal forebrain of rats, monkeys and humans. Galanin fibres hyperinnervate the surviving cholinergic cell bodies in patients with Alzheimer's disease (AD). In rats, galanin inhibits acetylcholine release and produces deficits in learning and memory. These findings suggest that overexpressed galanin may contribute to the cognitive impairments exhibited by patients with AD. This paper reviews the literature on galanin distribution and function in light of its putative role in the mnemonic deficits in patients with AD, the effects of galanin on tests of learning and memory, and preliminary experiments with galanin antagonists in animal models of AD.
tem.
Galanin distribution and function Galanin was discovered by Viktor Mutt et all in the porcine gastrointestinal tract. Its 29-amino-acid sequence is not homologous with any other known family of peptides. Galanin is localized peripherally in the pancreas, lungs and gastrointestinal tract in a variety of species.2 10 In the peripheral nervous system, galanin is located in the dorsal root ganglia," in the autonomic ganglia innervating the heart, kidney, liver, pancreas and spleen,12-29 and in the pituitary gland.3-37
Galanin is widely distributed in the central nervous system. In rats, galanin-immunoreactive cell bodies
located in the cingulate, medial prefrontal cortex, striatum, hypothalamus, superior colliculus, medial septum and nucleus of the diagonal band of Broca (MS/DBB), nucleus basalis magnocellularis (NBM), locus ceruleus, raphe nucleus, nucleus of the solitary are
tract, trigeminal nucleus and spinal cord.30'38-42
Galanin-positive cell bodies in humans and monkeys have been observed in the neocortex, hippocampus, anterior olfactory nucleus, nucleus basalis of Meynert, MS/DBB, substantia nigra, locus ceruleus, central grey, amygdala, bed nucleus of the stria terminalis, caudate and hypothalamus.4"0 Galanin coexists with a number of classic neurotransmitters in the central nervous system. For exam-
Correspondence to: Dr. Jacqueline N. Crawley, Section on Behavioral Neuropharmacology, Experimental Therapeutics Branch, National Institute of Mental Health, Building 10, Room 4D I I, Bethesda MD 20892; fax 301 480-1164;
[email protected] Medical subject headings: Acetylcholine; age factors; Alzheimer's disease; brain; disease models, animal; galanin; learning; memory; neuropeptides; rats J Psychiatry Neurosci 1997;22(5):303-17.
Submitted Jan. 15, 1997 Acccepted Aug. 20, 1997 i 1997 Canadian Medical Association. All rights reserved in Canada; material is in the public domain in the US.
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ple, galanin coexists with serotonin in the raphe nucleus, with norepinephrine in the locus ceruleus, with dopamine in nerve terminals of the median eminence and with y-aminobutyric acid (GABA) in the arcuate nucleus and median eminence.30'5'-55 Galanin also coexists with other peptides, such as with vasopressin in the hypothalamus of rats and humans47'51156,57 and in the bed nucleus of the stria terminalis and horizontal limb of the DBB of rats,58 and with growth hormone releasing factor in the cell bodies of the infundibular nucleus and median eminence in monkeys.59 In monkeys and rats, galanin coexists with acetylcholine (ACh) in the magnocellular cell bodies of the MS/DBB.39 48' In monkeys, but not in rats, apes or humans, galanin also coexists with ACh in the NBM.61'62 In humans, gorillas, gibbons and chimpanzees, galanin does not coexist with ACh in the basal forebrain, suggesting that this coexistence occurs on the evolutionary tree only before the level of apes.62 Using 'l25-galanin receptor autoradiography, galanin binding sites were described in the rat prefrontal, piriform, periamygdaloid, entorhinal and insular cortical areas, olfactory bulbs, amygdala, bed nucleus of the stria terminalis, ventral pallidum, subiculum, spinal cord, medial forebrain bundle, hypothalamus, thalamus, superior colliculus, central grey, peripeduncular area, substantia nigra, ventral tegmental area and hipAlthough galanin binding sites are lopocampus.3' cated throughout the hippocampal formation, the density is much greater in the ventral hippocampus than in the dorsal hippocampus.65 The distribution of galaninimmunoreactive binding sites in monkeys is largely similar to that in rats, with the exception of the lack of neocortical binding in rats.31't In monkeys, "25I-galanin binding sites are located in the neocortex, hippocampal formation, amygdala, hypothalamus, substantia nigra pars compacta, locus ceruleus, central grey, nucleus accumbens, NBM, lateral septum and olfactory tubercle.6*68 In humans, galanin binding sites are located in the neocortex, basal forebrain, hippocampus, amygdala, piriform cortex and hypothalamus.46s67,69,70 Several galanin receptor complementary DNA (cDNA) sequences have been cloned recently. A human galanin receptor cDNA, cloned from a Bowes melanoma cell line and named hGALRl, has been described by Habert-Ortoli et al.71 The 349-amino-acid receptor protein encoded by hGALR1 comprises 7 transmembrane domains and belongs to the G-protein coupled receptor family. It is expressed in the gastroin-
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testinal tract and fetal brain. Currently, 2 rat galanin receptors have been cloned from Rinl4B insulinoma cells. One is 92% homologous to the hGALR1 receptor.72-78 This subtype has been designated the rat GALR1 receptor (rGALR1) and is expressed in the spinal cord, small intestine, ventral hippocampus, amygdala, supraoptic nucleus, hypothalamus, thalamus, parabrachial nucleus and locus ceruleus. New galanin receptor cDNAs have been recently cloned from Rinl4B insulinoma cells and rat hypothalamus. The cDNA sequences are reported to be approximately 40% homologous to the hGALRl, with mRNA expressed in the CAl region of the ventral hippocampus, olfactory tract, parabrachial nucleus, hypothalamus, piriform cortex, lateral septum, bed nucleus of the stria terminalis, horizontal limb of the DBB, olfactory bulbs and nucleus accumbens.76'79'80 An rGALR2 receptor, cloned from rat hypothalamus, has recently been characterized.81'82 There is considerable pharmacological evidence suggesting the existence of multiple galanin receptor subtypes in the rat brain, which indicates that there may be subtypes in addition to GALR1 and GL.37,65,83-85
Consistent with its extensive distribution in the nervous system, galanin is involved in a wide range of physiological functions.8-8 In the periphery, galanin inhibits glucose-stimulated insulin secretion in murine pancreatic islet cells89"9 and in mice in vivo.92 Galanin inhibits ACh-induced contractions of the small intestine muscle in dogs.93 Galanin appears to promote the growth of malignant tumours in the lungs and pituitary gland94-97 but may inhibit the growth of colon tumours.98 In the dorsal root ganglia, galanin potentiates antinociception mediated by leu-enkephalin.9908 In the pituitary, galanin stimulates the release of growth hormone-releasing hormone (GH-RH) and prolactin in both rats41","113 and humans. 1""11116 In the rat median eminence, galanin is thought to mediate the release of growth hormone through the action of GH-RH.59 In the rat striatum, galanin increases basal and stimulated-ACh release in vivo,"71179 and exerts anticonvulsive action in picrotoxin-induced seizure syndrome.'20 Galanin injected into the medial preoptic nucleus stimulates sexual behaviour in male and female rats.'2" In the locus ceruleus, galanin inhibits norepinephrine release'23 and neuronal activity in tissue slices.'24"25 Injected into the hypothalamus or amygdala, galanin increases food intake in rats.-2""46 Converging evidence suggests that galanin acts in
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the basal forebrain to inhibit cholinergic function.137'38 Galanin inhibits potassium-evoked ACh release in ventral hippocampal slices of rats139 and monkeys.140
Galanin inhibits scopolamine-induced ACh release in vivo in rats that are awake, when injected intracerebroventricularly (icv)83'39'411" or into the MS/DBB1 Galanin blocks cholinergic slow excitatory postsynaptic potentials (EPSPs) in ventral hippocampal CAl pyramidal neurons in vitro.146 Inhibition of evoked ACh release and inhibition of EPSPs imply a presynaptic mechanism of action for galanin. Galanin also inhibits potassium-evoked accumulation of phosphoinositide, a second messenger associated with the Ml muscarinic receptor subtype, in ventral hippocampal slices of rats147"48 and monkeys.140 This suggests a postsynaptic mechanism for galanin as well. Taken as a whole, these studies suggest that galanin inhibits cholinergic function in the basal forebrain of rodents and primates. It is important to note, however, that neither galanin nor galanin analogs have been found to change basal ACh release in the septohippocampal pathway.83'139-l1 This suggests that the release of endogenous galanin may be limited to circumstances in which cholinergic activity is greater than normal.137'45'49
Relevance to Alzheimer's disease Advanced Alzheimer's disease (AD) is characterized by extensive degeneration and neuropathology in the basocortical and septohippocampal cholinergic pathways, the primary cholinergic inputs to the cortex and hippocampus, respectively.151157 In contrast, galanin immunoreactivity and galanin levels are significantly higher in the basal forebrain of patients with AD compared with age-matched control subjects.50'158-161 Galanin overexpression is observed as a dramatic increase in both the number and staining intensity of galanin-immunoreactive fibres and varicosities in the fibre network that innervates the surviving basal forebrain cholinergic perikarya in the NBMI51859 and vertical limb of the DBB50'161 in postmortem AD brains. Galanin levels are also significantly elevated in several cortical areas in the brains of patients with AD. Minami et al'62 reported significantly more galanin immunoreactivity in the frontal lobe of patients with AD than in age-matched control subjects, but no difference in the parietal, temporal or occipital lobes. Gabriel et al1,3 reported significantly elevated galanin levels in circumscribed regions of the frontal, tempo-
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ral and parietal cortices of postmortem AD brains, but not in the occipital cortex. Galanin receptor binding appears to differ in AD. Ikeda et all" examined binding sites in AD brains using 11-I-galanin autoradiography in hippocampal formation preparations in which choline acetyltransferase (ChAT) was reduced 60% compared with age-matched controls. A significant reduction in galanin binding was observed only in the deep layers of the parahippocampal gyrus. Leverenz et all65 also reported decreased receptor binding in AD brain
compared with controls, using guanosine triphosphate to induce dissociation of endogenous galanin from galanin binding sites before incubation in the labelled medium. In contrast to the findings of Ikeda et a1164 and Leverenz et al,165 Rodriguez-Puertas et a1166
observed a significant increase in galanin receptor binding in the parahippocampal gyrus. The difference may be due to the type of galanin used. Leverenz et a1165 used labelled porcine galanin, whereas Rodriguez-Puertas et al', used labelled human galanin. Ikeda et al1" did not specify the type of galanin used. Anatomically specific changes in galanin receptor number in AD were also observed in cortical areas. Ikeda et a1167 observed significantly fewer receptors in layers V and VI of the inferior temporal gyrus of patients with AD compared with controls, but no change in the medial occipital gyrus even though ChAT levels in both cortical areas were significantly reduced. Rodriguez-Puertas et a1166 and Leverenz et all65 reported no change in cortical galanin binding sites in patients with AD. Leverenz et a1165 also found no difference in receptor density in the basal forebrain or hippocampus. Thus, despite widespread galanin overexpression in the basal forebrain, hippocampus and cortex of patients with AD, changes in the number of receptors are limited to a few circumspect areas. The functional significance of anatomically distinct changes in galanin receptor density is not clear, but its elucidation may provide a better understanding of the role of galanin overexpression in the cognitive deficits observed in patients with AD. The mechanism that triggers galanin overexpression in AD is not known. One possible explanation is that galanin reduces cholinergic overactivity in the basal forebrain. As hypothesized by Hokfelt et al,149
when basal forebrain cholinergic cells die, the surviving cells may increase their firing rates to compensate. Increased galanin expression may be a modulatory re-
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sponse, triggered to attenuate the high levels of cholinergic activity.'49 This notion is supported by evidence from a study using in vivo microdialysis in rats, showing that, in neurons containing both ACh and galanin, the level of stimulation required to release a measurable amount of galanin was much higher than that needed to release ACh.'" Additional evidence from studies using rodents shows that basal ACh levels are unchanged by galanin administration, but that galanin inhibits stimulated ACh activity.139'40"45 Alternatively, Vogels et al'69 suggested that galanin overexpression may serve a neuroprotective function in response to cell death. They noted an inverse relation between galanin immunoreactivity in the vertical limb of the DBB and the presence of senile plaques and neurofibrillary tangles in the hippocampus of postmortem AD brains. In addition, ChanPalay"l8 reported an inverse correlation between galanin expression and cholinergic cell loss. A study done by Liu et all70 provides support for a neuroprotective function for galanin in rats. Galanin administered 5 minutes before traumatic brain injury (TBI) significantly alleviated some of the deficits in motor function normally observed after TBI. However, data from Mufson et al,'6"'17' who examined postmortem tissue from patients with AD or Down syndrome, contradict the notion that galanin overexpression is a response to neural degeneration. Galaninergic fibres hyperinnervate the cholinergic cell bodies of the vertical limb of the DBB, a nucleus that exhibits minimal degeneration in AD.161 In addition, galanin overexpression does not occur in the NBM of subjects with Down syndrome, all of whom eventually have ADlike neuropathology and show severe reductions in ChAT in the basal forebrain.'7' This suggests that hypertrophy and hyperinnervation of the basal forebrain galaninergic network are not in response to local cholinergic cell death alone. Thus, the mechanism responsible for galanin overexpression in AD remains unknown. The location of the cell bodies contributing the excessive galanin-immunoreactive fibres also has not been determined. The early discovery of cholinergic cell loss in postmortem AD brains led researchers to focus on the basal forebrain cholinergic pathways both as a potential cause of AD and a site for therapeutic action.'50'151'172-175 The degree of loss of cholinergic markers in cortical and hippocampal tissue and cerebrospinal fluid in AD is strongly correlated to the severity of be-
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havioural symptoms, as well as to the density of senile plaques and neurofibrillary tangles.'76-"80 However, to date, cholinergic replacement therapies have been disappointing.'8'-"' Disinhibition of other neurotransmitters that inhibit cholinergic activity, such as GABA, has been proposed as an alternative or adjunct therapy.'TM The finding that galanin is overexpressed in AD and inhibits ACh and impairs memory suggests that a galanin antagonist may be a useful adjunct to cholinergic therapeutics in alleviating the mnemonic deficits in patients with AD.
Animal models of Alzheimer's disease Aged animals
Rats exhibit a loss of galaninergic neurons as they older. Unger and Schmidt'89 found significantly less intense and fewer galanin-immunoreactive fibres in the NBM of rats 20 months old compared with rats 3 months old. A similar effect has been reported in the MS/DBB.'M"187 Aged rats (25-30 months old) had significantly fewer galanin-immunopositive cell bodies in the MS/DBB than did rats 3-4 months old. In contrast to the age-related decrease in galanin-labelled neurons, Krzywkowski et allm reported more galaninspecific binding sites in rats 26-27 months old compared with rats 3-4 months old or 14-15 months old. The increase in galanin binding was specific for paleocortical areas, the CAl field of the ventral hippocampus, ventral subiculum and dorsal dentate gyrus. No increase in binding was observed in the ventral dentate gyrus, the dorsal subiculum, the CA3 field of the hippocampus, the amygdala or the septal area. An extensive analysis of the effects of aging on galanin immunoreactivity was performed by de Bilbao et al.'89 They compared galanin immunostaining in rats of several different ages, from 1 to 30 months. Consistent with previous studies,11,187 they found significant reductions in galanin-positive cells in the MS/DBB of aged rats. However, they found that the age-related reduction in galanin immunoreactivity was evident at the earliest time point measured 29% less in rats 3-6 months old than in rats 1 month old. There were nearly 50% fewer galanin-positive cells in rats 9-12 months old than in those 1 month old; little further reduction was evident in rats up to 30 months old. The results of the study by de Bilbao et al'89 suggest grow
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that the reduction in galaninergic cells is not a phenomenon of old age in rats. Most of the galaninergic cell loss was evident in rats 3-6 months old, and little further decline was evident after 9-12 months of age long before the rats are considered aged. In contrast, no significant changes in galanin receptor density were apparent in rats 14-15 months old, but significant increases were observed in rats 26-27 months old.'" Because behavioural impairments are typically not observed in normal rats younger than 18 months, this temporal dissociation between cellular degeneration and synaptic plasticity may indicate that galanin receptor upregulation may play a role in age-related cognitive decline in normal rats. However, the plasticity observed in aged rats appears to be different from the mechanisms operating in AD notably, a widespread increase in galanin expression and a decrease in the number of receptors in specific loci. The usefulness of aged rats as an AD model, therefore, may be limited with respect to testing galaninergic interventions.
Rats with lesions Lesions of the basal forebrain cholinergic system are the most commonly used rodent models of AD. Chemical toxins or electrolytic lesions are typically used to destroy neurons in the brain areas of interest. Depending on the technique and neurotoxin used, the resulting lesion may be limited to cell bodies or may be extensive and include all tissue in the area, including support cells and fibres of passage.190191 The septohippocampal pathway is the primary cholinergic input to the hippocampus, and septohippocampal lesions induce changes in galanin expression and binding sites in rats. In one study, Melander et all'92 showed that transection of the fimbria/fornix, the fibre pathway projecting from the MS/DBB to the hippocampus, eliminated the strongly galaninimmunoreactive fibre populations in the strata radiatum and oriens of the ventral CA3 hippocampal region. Ibotenic acid lesions of the MS/DBB, however, eliminated faintly galanin-immunoreactive puncta within the granule and pyramidal cell layers of the ventral hippocampus. Others have also reported reduced hippocampal galanin and ChAT immunoreactivity after MS/DBB lesion'93 or fornix transection.'94 Only one study to date has examined changes in galanin binding sites after septohippocampal lesion. Fisone et al139 showed that transection of the Vol. 22, V611 = no S5, IL1997 "7EE-
fimbria/fornix caused a decrease in hippocampal galanin binding sites in adult rats. They found the same results with lesions of the MS/DBB, suggesting that these hippocampal receptors are presynaptic. In contrast to reductions in hippocampal galanin immunoreactivity and binding sites, galanin expression in the MS/DBB appears to be upregulated after septohippocampal lesion. Cortes et al'l95 reported increases in galanin messenger RNA (mRNA) and galanin immunoreactivity in the MS/DBB of rats after electrocoagulative lesions of the ventral hippocampus, but not after ibotenate lesions of the same area. Because ibotenic acid selectively kills cell bodies, whereas electrolytic lesions destroy neural processes as well as somata, Cortes et all95 suggested that axonal destruction was necessary for galanin mRNA overexpression. Agoston et all' reported that galanin mRNA expression in the MS/DBB was increased 4 days after transection of the fimbria/fornix, but there were no differences at 1, 7, or 21 days. They also found that tetrodotoxin administered into the vertical limb of the DBB, which blocks neuronal electrical activity in septohippocampal neurons, increased galanin mRNA expression over an identical time course. This suggests that blocking neuronal activity, and not direct axonal lesion, is sufficient for increased galanin mRNA expression.196 The results of Cortes et all95 are also consistent with an explanation of activity dependence. A recent study conducted by de Lacalle et al'97 examined galaninergic immunoreactivity in MS/DBB neurons after lesion of either the MS or DBB using ibotenic acid. They observed a moderate to intense increase in galanin density in the MS and DBB 2 weeks after lesion. Lesion-induced upregulation of galanin expression in the MS/DBB of the rat, therefore, appears to be significant. In contrast to the changes after lesions of the septohippocampal system, Wenk and Rdkaeus'93 showed that ibotenate lesions of the NBM did not affect galanin immunoreactivity in the neocortex, despite a large reduction in ChAT levels. Cortical galanin levels are
also unchanged after NBM lesions using 192IgG
saporin, a novel neurotoxin that is specific for cholinergic cells of the basal forebrain, even though ChAT activity is virtually eliminated in the NBM and neocortex.'98 Harrington et al'l showed that ChAT activity in the NBM was reduced by NBM lesions induced by ibotenic or quisqualic acids, but neither toxin changed galanin levels. However, Unger and Schmidt'85
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showed an increase in immunoreactivity in the galaninergic NBM fibre network 6 months after quisqualate lesion of the NBM in rats 3 months old, but no change 1 or 3 months after the lesion. The change was observed as an increase in peptide expression, most likely in axon terminals, and not morphological changes such as hypertrophy or hyperinnervation. Aged rats 18-20 months old in the same study showed a reduced galanin immunoreactive fibre network after NBM lesion, which was unchanged during the course of the study. In summary, studies of lesions show some similarities to and some differences from the changes in galanin observed in patients with AD. Galanin immunoreactivity in cholinergic target areas is diminished after lesions of the MS/DBB but unchanged after NBM lesions. This likely reflects the fact that, in rats, galanin coexists with ACh in the MS/DBB but not in the NBM.'93 These changes are dissimilar to the galanin overexpression observed in the hippocampus and neocortex of AD brains. In contrast to the changes in target areas, lesions of both the MS/DBB and the NBM result in increases in galanin intensity in the fibres surrounding the surviving cholinergic cells. This increase in expression is similar to that observed in AD. However, changes in MS/DBB occur in a matter of days to weeks, whereas in the NBM the increase is not observed for 6 months. These distinctive temporal dynamics suggest that different plastic processes may be operating in the 2 brain pathways. The results of the study by Unger and Schmidt'85 demonstrate that changes in galanin expression after basal forebrain lesions are also mediated by age, and this factor should be considered when studying galaninergic responses in rats. Further examination of these dissociations in galaninergic plasticity between cholinergic nuclei and between young and aged rats may provide useful information about mechanisms of galanin overexpression in patients with AD.
Galanin effects on learning and memory In rats, central administration of galanin impairs performance of a variety of tasks used to measure learning and memory 138,200-202 Choice accuracy on delayed nonmatching-to-position (DNMTP), a delayed conditional discrimination (DCD) task commonly used to assess memory in rodents, monkeys and humans, is impaired in a dose-dependent fashion after galanin
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administration.203204 After injection into the ventral hippocampus, galanin induces a delay-dependent memory deficit, i.e., animals exhibit unimpaired performance at short delays but more pronounced impairments with increasing delays (Fig. lB)204'205 This type of impairment may be analogous to that observed in the early stages of AD,20212 when cognitive impairments are primarily mnemonic and neuropathology is largely restricted to the hippocampal formation. 51'57 In contrast, after icv galanin administration, rats are impaired in a delay-independent fashion on the DNMTP task, i.e., they show significant decrements in performance at short and long delays (Fig. lA).203'205 This type of performance is indicative of nonmnemonic or mixed mnemonic and nonmnemonic impairments,213-215 similar to that observed in moderate to late AD, when cognitive deficits and neuropathology are more widespread. Galanin did not impair choice accuracy on DNMTP when injected into the prefrontal or entorhinal cortices, amygdala or NBM.204 When injected into the MS/DBB, galanin alone did not have an effect on DNMTP choice accuracy, but potentiated the impairment induced by a low dose of scopolamine.216 Injected into the MS/DBB, galanin impairs T-maze delayed-alternation, a DCD task commonly used to measure short-term working memory in rodents.217 In the T-maze delayed alternation task, icv galanin blocked the improvement by ACh of impaired performance resulting from combined lesions of the NBM and MS/DBB.218 Galanin impairs single-trial appetitive learning in a sunburst maze after icv injection.219 Injected icv, galanin impairs acquisition but not retention of the Morris water-maze task.220 However, in another study, Aspley and Fone221 failed to replicate the water-maze deficits using similar doses of galanin but different experimental procedures. Galanin injected icv impairs step-down passive avoidance learning in mice222223 when injected 15 minutes before training. However, the same dose did not impair performance when injected immediately after initial training, indicating that galanin may have affected a nonmnemonic process mediating this task. Galanin injected icv in mice does not alter spontaneous alternation. In summary, exogenous galanin administration reliably impairs performance of many different behavioural tasks used to infer memory function in rats. However, the role of endogenous galanin in memory processes is not clear. Galanin antagonists provide a
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pharmacological tool with which to investigate the role of endogenous galanin in learning and memory and in patients with AD.
Galanin antagonists A number of galanin receptor antagonists have been synthesized. Galanin (1-29) was modified by synthesizing the N-terminal fragment of galanin (1-13) with the C-terminal portion of another bioactive peptide or a Cterminal composed of amino acids not homologous with any known peptide.221226 The first galanin receptor antagonist reported was M15, composed of the N-terminal end of galanin and C-terminal end of substance P, galanin(1-13)-Pro-substance P(5-1 l)-NH2.142 Galanin analogs subsequently developed include M35 [galanin(1 -13)-bradykinin-(2-9)], C7 [galanin(1-13)-spantideNH2], M32 [galanin (1-13)-neuropeptide Y(25-36)], M38 [galanin(1-13)-(Ala-Leu)3-Ala-NH2], M40 [galanin(l13)-Pro2-(Ala-Leu)2-Ala-N H2],83 8908142227-232 and [Ala6, DTrp8l galanin(1-15)ol.233 M15 displaces 1211-galanin binding in the hippocampus,
locus ceruleus and spinal cord of rats,'42 and in
the hypothalamus of humans.234 M40 has been shown to displace radiolabelled galanin binding at galanin receptors in the ventral hippocampus, hypothalamus and spinal cord.83 M15, M35, M40 and C7 all bind with high affinity to the rat GALR1 receptor79 and M35, M40 and C7 show a high affinity for galanin re-
ceptors in the human hypothalamus.84
These peptidergic galanin analogs block the actions of galanin on several physiological measures. M15 blocks galanin-induced changes in intracellular freecalcium concentrations in rat insulinoma cell suspensions239 and inhibition by galanin of hypothermia induced by cholinomimetic drugs.236 M15 and M35 both block galanin-mediated inhibition of glucose-induced insulin secretion from pancreatic islet cells.8990227 Galanin-induced ACh release in the striatum is partially blocked by M3522' and completely blocked by M15."8237238 M15, M32 and C7 all significantly reduce galanin-induced cardiac vagal inhibition in anesthetized cats.2324 In the septohippocampal system, M40 blocks galanin-mediated inhibition of scopolamineinduced ACh release in vivo.83 M40 alone does not affect basal or stimulated ACh release in vivo. M40 and C7 block galanin-induced feeding in rats after injection into the paraventricular nucleus of the hypothalamus, lateral ventricle or amygdala.231,132239240 M15 Vol. 22, no no 5.5, l1997 1997
blocks galanin-induced feeding in goldfish.241 M15 increases sexual behaviour and blocks the inhibition by galanin of sexual behaviour.242 The galanin-induced facilitation of the nociceptive spinal flexor reflex is completely blocked by M32 and C7 and partially blocked by M38.'08 In the spinal cord, M40 displays a weak antagonism at high doses but potentiates the facilitative effects of galanin at low doses.108 Intraventricular administration of M35 produces a small but significant facilitation of acquisition of a Morris water-maze task, providing the first evidence that endogenous galanin may play a role in learning.243 Intraventricular or intrahippocampal injection of M40 completely blocks galanin-induced impairment of DNMTP (Fig. 1).205 M40, therefore, may provide a useful tool for studying the role of endogenous galanin in cholinergic functions and memory processing in rodent models of AD. The putative galanin antagonists may also act as agonists under certain circumstances in vitro.244 M35 has been shown to have mixed agonist/antagonist properties in rat Rin m 5F insulinoma cells. At low doses, M35 blocks the inhibition by galanin of forskolin stimulated cAMP (cyclic adenosine monophosphate) production, but at high doses M35 exhibits actions similar to galanin.249 M40 fails to block this effect at any dose but instead exhibits a weak agonism.83 M35 displays agonist properties on striatal ACh release.228 M15, M32, M35, M40 and C7 were all found to inhibit forskolin-stimulated cAMP in a manner similar to that of galanin, in the human Bowes melanoma cell line.246 The degree of agonist action was equivalent to that of porcine galanin, in LM(tk-) cells expressing either the human or rat GALR1 receptor.76 Available peptidergic galanin analogs, therefore, may be useful tools only in certain paradigms, particularly in vivo. To date, nonpeptidergic galanin receptor antagonists remain to be developed. Nonpeptidergic compounds, with longer half-lives in vivo and the ability to cross the blood-brain barrier, are needed to pursue critical functional studies on the role of endogenous galanin in physiology and behaviour.
Conclusion A great deal of progress has been made during the 14 years since the discovery of galanin. Several intriguing questions remain. The mechanism inducing the hyperinnervation of cholinergic cell bodies by galaninergic cells in AD remains unclear. Studies of aged and le-
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sioned animals may provide information about the nature and timing of galaninergic changes in septohippocampal and basocortical cholinergic systems. Elucidation of the basic mechanism of galanin overexpression in AD may help researchers better understand the relationship between cholinergic cell death, ACh release and galanin overexpression in AD. The importance of the pattern of changes in receptor density in aged and lesioned rats and in AD requires further replication to determine its importance. Significant questions also remain regarding the role of galanin overexpression in the mnemonic deficits in pa-
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tients with AD. Although the detrimental effects of galanin on rodent tests of learning and memory have been reliably demonstrated, behavioural studies using galanin antagonists are just beginning. The continuing development and characterization of galanin antagonists is important both as a research tool to assist in our understanding of the biological actions of galanin and as a potential treatment for the mnemonic impairments in patients with AD. Because of the limited effectiveness of cholinergic replacement therapies in patients with AD, alternative and adjunct treatments should be explored."84 Administration of galanin an-
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Fig 1: Effects of galanin and the galanin receptor antagonist M40 on choice accuracy during delayed nonmatching-toposition (DNMTP) performance. A) Unilateral intraventricular injections in 12 rats of 1.6 nmol galanin (Gal; solid circles), which caused impaired choice accuracy compared with saline vehicle (Sal; open circles). An equimolar dose of M40 (1.6 nmol/5.0 ,uL) administered 5 minutes before galanin partially blocked the impairment (triangles). M40, 8.0 nmol/5.0 ,uL, completely blocked the galanin-induced impairment (squares). Data are expressed as means and standard error bars. Asterisks indicate values significantly different from saline injections (p < 0.0001). B) DNMTP choice accuracy after bilateral intrahippocampal injections in 10 rats. Administration of galanin (Gal, 0.5 nmol/hemisphere; solid circles) induced a significant choice accuracy impairment at the 20-second delay compared with saline vehicle (Sal; open circles). M40 (2.0 nmol/hemisphere) blocked the galanin-induced impairment (squares). Data are expressed as means and standard error bars. Asterisks indicate values significantly different from saline injections (p < 0.05). Source: McDonald MP, Crawley JN. Galanin receptor antagonist M40 blocks galanin-induced choice accuracy deficits on a delayed-nonmatching-to-position task. Behav Neurosci 1996; 110: 1025-32. Reprinted with the permission of the American Psychological Association. Material is in the public domain.
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Galanin-acetyicholine interactions tagonists, either alone or combined with cholinergic agonists or acetylcholinesterase inhibitors, may provide a novel approach for ameliorating the mnemonic impairments of AD.
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