Histamine

Rüdiger U. Hasenöhrl and Joseph P. Huston Abstract

Histamine is an important but largely neglected modulator in the central nervous system. Histaminergic neurons are located exclusively in the posterior hypothalamus, the tuberomammillary nucleus (TM), from where they project to almost all brain regions, with ventral areas (hypothalamus, basal forebrain, amygdala) receiving a particularly strong innervation. Here we summarize behavioural data based on TM-lesions as well as on electrophysiological, neurochemical and pharmacological studies related to histamine agonists and antagonists. The outcome of these studies provides evidence that the brain histamine system is a) involved in neural plasticity and functional recovery following unilateral damage of the brain and b) may subserve inhibitory functions in the control of reward and learning processes.

Introduction

In recent years, evidence has accrued from neurochemical, electrophysiological and pharmacological studies that histamine functions as a central neurotransmitter and/or neuromodulator.43'106'120 The characteristic distribution of histamine and the presence of specific histamine receptive sites in the brain121 underlined such a possibility and incited further investigation to unravel the role of this biogenic amine in brain function (see ref. 14 for review). Much attention has been focused on the effects of histamine or its agonists and antagonists on various (electro)physiological parameters and behaviours.41'51'150 The existence of a histaminergic neuronal system was, however, disputed until immunocytochemical studies revealed the existence of histaminergic neurons in the brain,98'128'145 which allowed a more precise anatomical and neurochemical analysis of this neuronal system beyond the pharmacological approach. This chapter will start with a short description of some of the properties of the neuronal histamine system, its receptors and its chemoarchitecture in the brain; then we present a summary of experiments, which investigated a possible involvement of the TM histamine system in neural plasticity, reinforcement and memory functions.

The Histaminergic Neuron System

The presence of histamine can be demonstrated in two major pools—in neurons as well as in mast cells, which, however, are relatively scarce in the brain.35,12 Histamine is synthesized in a single step from L-histidine by the enzyme histidine decarboxylase (HDC). Up to now, no high-affinity uptake system for histamine has been reported and termination of its action in brain appears to require catabolism to telemethylhistamine, which is further metabolised by MAO. 2 Inhibition of histamine synthesis can be achieved by alpha-fluoromethylhistidine, an irreversible inhibitor of HDC,70 which is frequently used as a research tool with which to investigate the functional role of neuronal histamine.94

Histaminergic neurons are exclusively located in the posterior hypothalamus, specifically in the tuberomammillary (TM) nucleus (Fig. 1). Fibres arising from the TM constitute two ascending pathways: one laterally, via the medial forebrain bundle, and the other periventricularly.

From Messengers to Molecules: Memories Are Made of These, edited by Gernot Riedel and Bettina Platt. ©2004 Eurekah.com and Kluwer Academic / Plenum Publishers.

Figure 1. Left: A series ofschematic drawings of frontal sections through the posterior part of the hypothalamus of the rat, illustrating the topographical localization of subgroups E1-E5 of histaminergic neurons. (Modified after ref. 142). Right: Schematic diagram of histaminergic pathways in the rat brain. (Modified after ref. 120)

Figure 1. Left: A series ofschematic drawings of frontal sections through the posterior part of the hypothalamus of the rat, illustrating the topographical localization of subgroups E1-E5 of histaminergic neurons. (Modified after ref. 142). Right: Schematic diagram of histaminergic pathways in the rat brain. (Modified after ref. 120)

These two pathways combine in the diagonal band of Broca to project to many telencephalic areas. The projections from the TM to the various brain regions are bilateral with ipsilateral predominance and, curiously, no differences have been reported so far in the projection sites of the cell bodies of the respective subgroups, E1 to E5.58 In most brain areas histamine is released from varicosities, mostly at non-synaptic sites, indicating modulatory functions similar to those found for other biogenic amines.142

The diverse actions of the histaminergic neuronal system appear to be mediated by at least three classes of receptors, namely H1, H2 and H3, which differ in pharmacology, localization and the intracellular response they mediate.50,75,121 The H1 receptor was initially defined in functional assays and by the design of potent antagonists, the so-called 'antihistamines'. The widespread distribution of H1 receptive sites in areas involved in arousal, such as thalamus, cortex and cholinergic cell groups in tegmentum and basal forebrain, possibly accounts for the sedative properties of most H1 antagonistic compounds. High densities of H1 receptors are also found in hypothalamus, septum, nucleus accumbens and in several hippocampal areas.11,97 It is interesting to note that several drugs used in the treatment of psychiatric disorders, such as tricyclic antidepressants and neuroleptics, also have significant Hi receptor blocking ability.50 The finding that most of the peripheral actions of histamine cannot be blocked by classical antihistamines led to the proposal of an additional class of histamine receptors.6 This second subtype was validated pharmacologically by Black and co-workers9 and designated the H2 receptor. Like the histamine Hi receptor, the H2 type has a widespread distribution in brain and spinal cord with high densities in basal ganglia, hippocampus and amygdala; unlike the Hi receptors, H2 receptive sites are present in low density in septal areas, hypothalamic and tha-lamic nuclei.103 Furthermore, Hi and H2 receptors show partial overlap in several brain regions, including hippocampus, nucleus coeruleus, ventral tegmental area and substantia nigra, where the receptors can interact in a synergistic manner. A third histamine receptor subtype, H3, has received much interest in recent years, as this receptor was initially detected as an autoreceptor mediating feedback inhibition of histamine synthesis and release.4,5 High concentrations of H3 receptors are found in neostriatum, nucleus accumbens and in cingulate/ infralimbic cortices,104 whereas its density is relatively low in hypothalamus, which contains most of the histaminergic axons and perikarya in the brain. This distribution pattern suggests that the majority of H3 receptors are not autoreceptors. Actually, H3-receptors can also function as heteroreceptors, modulating the activity of other monoaminergic,118 glutamatergic12 and peptidergic systems.81 Recently, a fourth histamine receptor has been cloned and characterised.91 This H4 receptor is primarily found on intestinal tissue and immune active cells and, thus, differs markedly from the H3 receptor, whose expression seems to be restricted to brain.77,78

In spite of many different suggestions mainly derived from observations of responses to locally applied histamine or related compounds, only few physiological roles of the histaminergic neuronal system are relatively well documented.14,45,56 Recent research emphasis has been placed on the possible role of neuronal histamine in the control of the waking state86,122 and circadian rhythmicity,15,139 in autonomic37 and neuroendocrine processes,68 in the regulation of seizure susceptibility,60,154,155 in motivated behaviours like feeding and drinking,72,89,138 in affective processes such as fear/anxiety,59,114 in neuropsychiatric disorders,28,90,107 in learning and memory processes96,102 and in the control of reward or reinforcement.49,108 Furthermore, histamine was found to promote survival of developing hippocampal tissue23 and to alleviate neuronal damage subsequent to experimental brain lesion,1,32 and may, therefore, be important for processes related to neurogenesis and neuronal functional recovery.

The Role of the Tuberomammillary Nucleus Projection System in Neural Plasticity and Functional Recovery

Swanson135 was one of the first to report who reported extrahypothalamic projections of the TM. Specific crossed and uncrossed projections from the TM to the caudate putamen were then described by Watanabe et al145 with immunohistochemical methods and by Steinbusch et al129 with retrograde tracing by fluorescent dyes. We confirmed these findings by using the horseradish peroxidase (HRP) tracing technique, and extended them by showing neuroplastic changes in tuberomammillary-striatal projections in relation to recovery from behavioural asymmetries induced by hemivibrissotomy 47 and unilateral 6-hydroxydopamine (6-OHDA) lesion of the substantia nigra (SN). Hemivibrissotomy, which stands for the removal of the tactile hairs (vibrissae) on one side of the rat's snout, induces a transient asymmetry in the side of the face used to scan the wall while traversing the edge of an open field (i.e., 'thigmotactic scanning'; see Fig. 2A) from which rats recover over time.55 Time-related to these behavioural changes we found an increase in 'strength' (i.e., in structure and/or activity) in the uncrossed and crossed projections from the TM to the caudate nucleus. Rats examined four to twenty days after unilateral clipping of vibrissae had more HRP-labelled cells in the crossed and uncrossed projections from the TM nuclei to the caudate nucleus on the side of intact vibrissae (i.e., to the hemisphere deprived of vibrissal sensory input) compared to projections to the caudate nucleus on the side of vibrissae removal (Fig. 2B). The neuronal asymmetries in the

Figure 2. A) Duration (mean±SEM, in seconds) of thigmotactic scanning with the vibrissae-intact side (continuous line) and the vibrissae-clipped side (broken line) through a 5-min test session. Rats tested between 1 h and 3 days after hemivibrissotomy exhibited a strong asymmetry in scanning during the first minute of testing, as they scanned more with the vibrissae-intact side (left). This behavioural asymmetry was absent in rats tested 6 days, or later, after clipping the vibrissae (right). B) Corresponding neuronal changes in the tuberomammillary-striatal projections 1-3 days (left) and 4-20 days after hemivibrissotomy (right) in comparison with the findings in the nigro-striatal projections. (Data from ref. 55 and 147)

Figure 2. A) Duration (mean±SEM, in seconds) of thigmotactic scanning with the vibrissae-intact side (continuous line) and the vibrissae-clipped side (broken line) through a 5-min test session. Rats tested between 1 h and 3 days after hemivibrissotomy exhibited a strong asymmetry in scanning during the first minute of testing, as they scanned more with the vibrissae-intact side (left). This behavioural asymmetry was absent in rats tested 6 days, or later, after clipping the vibrissae (right). B) Corresponding neuronal changes in the tuberomammillary-striatal projections 1-3 days (left) and 4-20 days after hemivibrissotomy (right) in comparison with the findings in the nigro-striatal projections. (Data from ref. 55 and 147)

TM-striatal projections were in the same direction as the asymmetries previously found in nigro-striatal projections after hemivibrissotomy.131,132 However, unlike in the nigro-striatal pathway, apparent neuronal asymmetries in the tuberomammillary-striatal projections were only evident during the period when the rats had recovered from the behavioural asymmetry. Given the coincidence of changes in striatal afferents from the SN and from the TM, both being correlated in time with recovery from behavioural asymmetries after hemivibrissotomy, it is conceivable that an interaction between histamine and dopamine (DA) could play a role in the control of compensatory processes and recovery of function. In line with this suggestion, nigrostriatal DA denervation was found to induce a marked up-regulation of ^-receptors in the striatum, which was reduced by dopamine D1 receptor stimulation.112 Furthermore, partial destruction of the TM resulted in increased DA and serotonin levels in neostriatum,79 corroborating the notion that histamine has an inhibitory impact on striatal monoamine activity under physiological conditions.117 Taken together, these data provided first evidence for a role of the tuberomammillary-striatal system in behavioural plasticity subsequent to unilateral removal of the vibrissae, in concert with the nigro-striatal system.

Based on these anatomical findings we were interested in a behavioural correlate of a lesion in the TM region. Therefore, we investigated the influence of a unilateral direct current (DC) lesion in the TM region on thigmotactic scanning behaviour. Destruction of the TM region was found to produce more thigmotactic wall scanning behaviour with the vibrissae contralateral to the lesion; the histamine precursor histidine reversed the effects of the TM lesion, suggesting that histamine is involved in this effect.148 In contrast, a unilateral 6-OHDA lesion of the SN produced more wall scanning behaviour with the vibrissae ipsilateral to the lesion.130 The finding that lesions in the SN and TM have opposite effects on scanning behaviour suggests that the projections (perhaps to the striatum) could represent a reciprocally acting regulatory system in terms of sensorimotor processes, possibly involving DA and histamine. In accordance with the idea of a reciprocal relationship between the TM system (histaminergic) and the SN (dopaminergic) is the finding that functional recovery from a unilateral 6-OHDA lesion of the SN was associated with an enhancement of the nigro-striatal projections,87 whereas in rats that failed to recover from the nigral lesion, an enhancement of the TM-striatal projections (based on the extent of HRP-labelling in TM and SN after HRP injection into the caudate-putamen region) was observed.88 These findings suggest that the increase in HRP-labelling seen in the tuberomammillary-caudate projections indicates an enhancement of histaminergic activity, which, in turn may be related to the lack of recovery from a unilateral SN lesion, and to the increase in asymmetry that develops over time in such animals.

The Role of the Histaminergic Neuronal System in the Control of Reinforcement

A number of pharmacological studies have examined the role of histamine in reinforcement processes. For example, the self-administration of histamine and histamine-blocking compounds has been evaluated.7,113 The injection of histamine and histamine antagonists was also studied in combination with rewa rding brain stimulation22,110,140,146 and in drug-discrimination tests.36 Their effects were assessed on operant behaviour8,84,136 and in conditioned place preference tasks, either alone82,134 or in combination with stimulants80 and opioids.66,133 The results of these experiments provided evidence that histamine agonists may have aversive properties, whereas histamine antagonists, particularly those blocking the H1-receptor, can exert reinforcing as well as reward potentiating effects.

The TM nucleus itself has largely been neglected in the search for the neural mechanisms underlying reinforcement. Some studies, in which the hypothalamic region was mapped for reinforcing properties of electrical stimulation reported negative or ambivalent stimulation effects in the posterior hypothalamus, the region where the TM is located.93 Given the evidence for a role of the TM projections in neural plasticity and functional recovery and the proposed reciprocal relation between histaminergic and dopaminergic mechanisms (see above), a series of experiments was performed to examine the possible involvement of the TM in the brain's reinforcement system. In the first experiment, the effects of an electrolytic lesion in the rostroventral part of the TM (E2-region) on lateral hypothalamic self-stimulation were as-sessed.143 From the second day post-lesion, the response rate gradually increased in TM-lesioned animals and peaked on day thirteen in the ipsilateral hemisphere only. Although there was no further increase over subsequent days, response rates remained elevated during the following seven weekly tests (Fig. 3A). Since electrolytic lesions lead to general tissue damage, it was not possible to pinpoint with certainty that the TM neurons were responsible for the observed

Figure 3. Lateral hypothalamic self-stimulation ipsi- (left) and contralateral (right) to the side of a unilateral electrolytic (A) or ibotenic acid lesion (B) in the region of the tuberomammillary nucleus. Rats were implanted bilaterally with stimulating electrodes in the lateral hypothalamus and unilaterally with one lesion electrode/injection cannula in the TM area. Following three days of baseline testing, one half of the animals were given an electrolytic or excitotoxic TM lesion. Response rates are expressed as mean (±SEM) percentage of corresponding baseline values. (Data from refs. 143 and 144)

Figure 3. Lateral hypothalamic self-stimulation ipsi- (left) and contralateral (right) to the side of a unilateral electrolytic (A) or ibotenic acid lesion (B) in the region of the tuberomammillary nucleus. Rats were implanted bilaterally with stimulating electrodes in the lateral hypothalamus and unilaterally with one lesion electrode/injection cannula in the TM area. Following three days of baseline testing, one half of the animals were given an electrolytic or excitotoxic TM lesion. Response rates are expressed as mean (±SEM) percentage of corresponding baseline values. (Data from refs. 143 and 144)

'disinhibition' of reinforcement in this experiment. Thus, another study was performed to determine, whether the observed increase in response rate was due to the destruction of intrin sic TM neurons or to the destruction of passing fibres.144 Therefore, lateral hypothalamic self-stimulation was examined following a unilateral TM-lesion with ibotenic acid, which destroys cell bodies but can spare fibres of passage.16,119 Figure 3B shows increasing response rates obtained from the hemisphere ipsilateral to the excitotoxic TM lesion. As in the previous experiment, there were no changes in rate when the animals stimulated themselves in the lateral hypothalamus contralateral to the lesion, and therefore, an interpretation of the rate increase in terms of an unspecific enhancement of general arousal can be ruled out.76 Since the response curves revealed in both studies were very similar, it can be concluded that the destruction of TM-intrinsic neurons was critical for the effects, rather than the denervation of remote structures induced by damaged fibres of passage. Furthermore, it is important to note that in both experiments facilitation of self-stimulation only occurred after destruction of the E2- but not of the El-subgroup of the TM. This dissociation can be considered as the first indication for a functional specificity of a cell population within the TM, which until now has been defined on anatomical grounds only.

To establish whether the observed effects following TM lesions involve a histaminergic component, pharmacological studies were performed to investigate the effects of different his-tamine-receptor blocking drugs in the nucleus accumbens (NAcc) and the nucleus basalis of the ventral pallidum.108,157 Both structures are known to play an important role in reinforcement-related processes53,71 receive specific histaminergic input99,129 and contain all three histamine receptor subtypes.121 In order to assess the effects of histamine receptor blockade on reinforcement, the administration of the histamine antagonists was either combined with lat-eral-hypothalamic self-stimulation, or their effects were examined with the corral version of the conditioned place preference paradigm.46 In the NAcc, the administration of the H1-blocking drug chlorpheniramine produced a lateralised increase of hypothalamic self-stimulation and was effective in inducing a conditioned corral preference, indicative of a positively reinforcing action. Furthermore, the effects of chlorpheniramine were found to be restricted to the caudal part of the NAcc, since injection of the H1-antagonist into the rostral NAcc did not affect the behaviour in either paradigm.157 In the ventral pallidum, chlorpheniramine as well as the H2-antagonist ranitidine were tested for possible reinforcing effects by the use of the corral method.108 The results are summarized in (Fig. 4): A single intrabasalis injection of chlorpheniramine increased the sojourn time in the corral previously paired with the drug treatment in a dose-dependant manner, indicative of a reinforcing action of the ^-antagonist. In contrast, the H2-antagonist ranitidine did not significantly influence the preference behaviour within the entire dose range tested.

Taken together, the outcome of this series of lesion studies and pharmacological experiments suggest that the TM and its histaminergic projections (specifically the histaminergic efferents to basal forebrain) exert inhibitory effects on reinforcement under normal conditions. Reducing histaminergic activity either by a partial destruction of TM-intrinsic histamine neurons or by inhibiting histaminergic transmission at H1-receptive sites apparently results in a disinhibition of reinforcement. The described inhibitory function of the TM in the control of intracranial self-stimulation and the effects of histaminergic agonists and antagonists on various measures of reinforcement stand in sharp contrast to the effects of DA on reinforcement. It is widely accepted that DA agonists facilitate and DA antagonists inhibit brain stimulation reward.151 Thus, DA seems to influence the brain's reinforcement system in a way, which is again reciprocal to histamine. The brain's reinforcement mechanism or mechanisms can be considered as being activated in a tonic fashion by DA and histamine, with the further promoting, and the latter diminishing reinforcement, i.e., the effectiveness of a reinforcing stimulus to increase the probability of recurrence of a preceding operant behavior, as also evidenced by changes in the organism's degree of 'preference for' that stimulation or for place cues that have been associated with such reinforcing stimulation.

Figure 4. Mean (+SEM) time in seconds spent in the treatment corral during test for conditioned corral preference. The corral apparatus was a circular open field, which could be divided into 4 quadrants (corrals) of equal size, identical floor and wall texture, and identical colour. Spatial orientation inside the apparatus was provided by external cues located in the surroundings. During the conditioning session, the animals received a single injection of different doses of (A) the H1-antagonist chlorpheniramine, (B) the H2-antagonist ranitidine, or vehicle (SAL; 0.5 |ll) into the ventral pallidum, after which they were confined for 15 min to one quadrant of the apparatus (treatment corral). During test for conditioned corral preference, the undrugged animals were again placed into the corral for 15 min and the time spent in each quadrant was scored (open corral). *p<0.05, significantly different from vehicle controls; Mann-Whitney U-test, two-tailed. (Data from ref. 108)

Figure 4. Mean (+SEM) time in seconds spent in the treatment corral during test for conditioned corral preference. The corral apparatus was a circular open field, which could be divided into 4 quadrants (corrals) of equal size, identical floor and wall texture, and identical colour. Spatial orientation inside the apparatus was provided by external cues located in the surroundings. During the conditioning session, the animals received a single injection of different doses of (A) the H1-antagonist chlorpheniramine, (B) the H2-antagonist ranitidine, or vehicle (SAL; 0.5 |ll) into the ventral pallidum, after which they were confined for 15 min to one quadrant of the apparatus (treatment corral). During test for conditioned corral preference, the undrugged animals were again placed into the corral for 15 min and the time spent in each quadrant was scored (open corral). *p<0.05, significantly different from vehicle controls; Mann-Whitney U-test, two-tailed. (Data from ref. 108)

The Role of the Histaminergic Neuronal System in the Control of Learning and Mnemonic Processes

The role of the histaminergic system in learning and memory has been generally investigated pharmacologically, with contradictory results.95,101 For example, histamine was reported to improve inhibitory and active avoidance conditioning,24,65 whereas administration of H1-antagonists disrupted learning in an active avoidance task.61,64 Both histamine and acetylcholine reversed the impairing effects of H1 receptor antagonist injection,61 suggesting an interaction between the central histaminergic and cholinergic system in learning. Thioperamide, a histamine ^-antagonist, was found to improve the retention performance of adult105 and senescence-accelerated mice,85 whereas H3-agonists such as imetit or (R)-alpha-methylhistamine produced learning disruption.10 Furthermore, histamine was reported to improve memory retrieval in old and hippocampus-lesioned rats.62,63 On the contrary, histamine has been shown to reduce active avoidance responding, an effect mediated via the H1-receptive site,137 and long-term depletion of neuronal histamine by alpha-fluoromethylhistidine proved to be effective in facilitating active avoidance3 and radial maze learning (ref. 113, but see ref. 20). Microinjection of histamine into the dentate area and subiculum complex was reported to adversely affect active avoidance conditioning via histamine Hi-receptive sites.3 Furthermore, the H3-receptor agonist (R)-alpha-methylhistamine was found to improve navigation performance in the Morris water maze task.111,124

The reasons for these discrepant findings require clarification; however, the main problem with the reliability of the data may lie in the effectiveness/specificity of the histaminergic drugs tested, rather than, for example, in the use of different learning tasks, modes of injection and variation in the time of injection in relation to the learning trials, etc. Moreover, the exact functions of the histamine receptor subtypes remain to be determined. For example, mutant mice lacking the H1-receptor showed reduced aggressive and exploratory behaviours but no apparent change in learning capacities.152,153 Furthermore, although functionally characterized as an inhibitory autoreceptor, the histamine H3-receptor is not restricted to presynaptic elements of the histaminergic neurons, but can also function as a heteroreceptor modulating the activity of several other transmitter system.115,116

Lesion Studies

Our strategy in investigating the role of the histaminergic neuronal system in learning and mnemonic processes was guided by a theory of reinforcement,54 which proposes that reinforc-ers 'strengthen' behaviour by preventing memory traces from fading out and therefore leading to learning (consolidation). Based on this theory, one aim of the present studies was to examine possible effects of lesions in the TM region on learning and memory processes in adult rats. Given the parallelism between reinforcing and memory-promoting effects of manipulations of the brain, it was hypothesized that lesion of the TM region could have a facilitatory effect on learning and mnemonic processing in addition to its facilitatory effect on reinforcement processes. Furthermore, it was asked whether TM lesions might exert a beneficial action on the performance of aged rats, which are considered an animal model for learning and memory disturbances related to aging and nervous system disorders like Alzheimer's disease.33

In the first series of experiments,30,67 adult and aged rats with a bilateral electrolytic lesion in the TM region were tested along with sham-lesioned controls in a set of learning tasks, which differed in terms of complexity and reward contingencies (habituation of exploratory activity, inhibitory avoidance retention, discrimination learning). An improvement was found in every test applied, indicating that TM lesions can generally enhance learning and memory capacities independent of the special demands of a given task. Moreover, age-related learning deficits were strongly diminished by the lesion (Fig. 5A-C). The fact that habituation learning was improved is important. For one, this test of memory, as assessed by behavioural habituation, does not involve application of conventional reinforcers, such as food or escape from or avoidance of aversive stimulation, and secondly, the TM histaminergic system is thought to play a role in stress, perception of pain, and thermoregulation,51,95 which are important factors in aversive conditioning, but not for habituation. This makes an interpretation of the performance enhancement following TM lesion simply in terms of an interaction between the lesion and physiological processes induced by a punishing/aversive stimulus, unlikely. Based on these initial findings, the objectives of a follow-up study were two- to determine whether the facilitation of learning and memory was due to the destruction of intrinsic TM neurons, adult and aged rats with bilateral ibotenic acid lesions of the TM region were tested along with vehicle-injected controls in the Morris water maze, in which old rats display marked performance deficits.47 In addition, the number of histamine cells was determined at the site of the neurotoxic lesion by immunohistochemistry using specific antibodies against the amine.128 The main finding of this study was that adult and aged rats with neurotoxic lesions of the TM showed accelerated navigation performance in the course of place learning in the maze and an improved ability to locate the platform site during a spatial probe trial (Fig. 6). Inspection of the site of the ibotenic acid microinjection in the TM region revealed a marked decrease of

Figure 5. The effects of a bilateral DC lesion in the TM region on performance of adult (3-month-old) and aged (31-month-old) rats in different learning tasks. (A) Habituation paradigm: Mean (+SEM) number of rearing (left) and mean (+SEM) distance travelled in the open field (right) during test for habituation learning. Habituation was measured in an open field by recording the number of rearing and square crossings during 5 min of free exploration in one baseline and one test session with a baseline-test interval of 7 days (aged rats had to be disqualified from this task because baseline activity was too low to determine possible effects of the TM lesion on habituation). (B) Step-through task: Median (with interquartile range) step-through latency revealed in the retention test. Immediately after the rat had entered the dark compartment in the third familiarization trial, a foot shock was applied (training). Retention of the step-through response was measured 24 hours after shock administration with a 300 s cut-off. (C) T-maze discrimination: During one baseline trial, the rats were trained to swim to the end of the left or right arm of the maze in order to escape. After a training-test interval of 7 days, the animals were retrained on the same task to the same criterion. The figure depicts the number of trials required to reach the criterion of 5 successive correct choices in the T-maze during the retention test. Trials to criterion during retention test are expressed as mean (+SEM) percentage of corresponding baseline values (= 100%, dashed line). *p<0.05 vs. sham-lesioned controls, indicative of enhanced learning (Data from refs. 30 and 67)

Figure 6. The effects of a bilateral ibotenic acid lesion in the TM-region on the navigation performance of (A) adult (3-month-old) and (B) aged (28 to 31-month-old) rats in the Morris water maze. Left: Mean (±SEM) path length to find the hidden platform in the place version of the maze. Right: Mean (+SEM) distance to target during a spatial probe trial without platform. *p<0.05 vs. vehicle-injected controls. (Data from ref. 30)

Figure 6. The effects of a bilateral ibotenic acid lesion in the TM-region on the navigation performance of (A) adult (3-month-old) and (B) aged (28 to 31-month-old) rats in the Morris water maze. Left: Mean (±SEM) path length to find the hidden platform in the place version of the maze. Right: Mean (+SEM) distance to target during a spatial probe trial without platform. *p<0.05 vs. vehicle-injected controls. (Data from ref. 30)

Figure 7. Effects of ibotenic acid injections into the E2-subregion of the TM on histamine-positive neurons of the TM. (A) Schematic drawings of frontal sections through the posterior hypothalamus illustrating the location of subgroups of histaminergic neurons (E1-E5) in the TM region (Modified after ref. 142). The dotted area indicates the extent of a representative lesion induced by ibotenic acid, based on cresyl violet staining. Box indicates the location from where the photomicrographs were taken. (B) and (C): Photomicrographs of coronal sections showing histamine immunoreactive neurons and fibres in the E2-subgroup of the TM two weeks after injection of (B) vehicle or (C) ibotenic acid; magn. x 200. (from ref. 30.)

Figure 7. Effects of ibotenic acid injections into the E2-subregion of the TM on histamine-positive neurons of the TM. (A) Schematic drawings of frontal sections through the posterior hypothalamus illustrating the location of subgroups of histaminergic neurons (E1-E5) in the TM region (Modified after ref. 142). The dotted area indicates the extent of a representative lesion induced by ibotenic acid, based on cresyl violet staining. Box indicates the location from where the photomicrographs were taken. (B) and (C): Photomicrographs of coronal sections showing histamine immunoreactive neurons and fibres in the E2-subgroup of the TM two weeks after injection of (B) vehicle or (C) ibotenic acid; magn. x 200. (from ref. 30.)

histamine-staining neurons mainly in the rostral part of the TM (Fig. 7), suggesting that the facilitatory effects on maze navigation observed after TM lesion might be related to reduced histaminergic activity produced by a partial destruction of TM-intrinsic histaminergic cells. It is important to note that the facilitatory effects on learning and memory parameters produced by irreversible TM lesions could be mimicked by a transient inactivation of this brain region with the short-acting local anaesthetic lidocaine.31 This suggests, that the beneficial effects on reinforcement and memory observed after permanent TM lesion were not a function of long-term compensatory processes of the brain, but, instead, a direct result of an inhibition of (his-taminergic) TM activity induced by the lesion.

Pharmacological Approach

Congruent with the outcome of the lesion studies are the results from our pharmacological experiments dealing with the effects of histamine antagonists on different aspects of learning, which are also suggestive for an inhibitory action of the biogenic amine. Thus, we found that the histamine Hi receptor antagonist chlorpheniramine, but not the H2 antagonist ranitidine, can exert memory-promoting effects when administered into nucleus accumbens or ventral pallidum.49,109 The peripheral injection of chlorpheniramine improved appetitive learning in goldfish125 and the compound ameliorated learning deficits in behaviourally impaired old rats

Figure 8. Effect of intra-accumbens histamine and chlorpheniramine injection on the performance of the uphill avoidance task, which involves punishment of a high-probability turning response on a tilted plat-form.127 Immediately after the learning trial, that is, after a shock was administered upon performing the response, different doses of chlorpheniramine and histamine were injected unilaterally into caudal or rostral NAcc. Retention is expressed as median latency (s) to step-up, measured 24 h after shock administration with a 180 s cut-off. Numbers at the bottom of the histograms indicate 25./75. percentiles. Controls included vehicle-injected (VEH; 0.5 |ll) rats and a group administered 10 ng chlorpheniramine 5 h after training (DEL). *p<0.05 vs. vehicle controls, indicative of enhanced learning. Note: The failure of the delayed posttrial injection of the antagonist to influence learning indicates that the compound influenced learning by modulating early memory storage processes, rather than by acting on performance variables during retrieval of the task or by influencing memory consolidation going on 5 h after learning or later. (from ref. 49)

Figure 8. Effect of intra-accumbens histamine and chlorpheniramine injection on the performance of the uphill avoidance task, which involves punishment of a high-probability turning response on a tilted plat-form.127 Immediately after the learning trial, that is, after a shock was administered upon performing the response, different doses of chlorpheniramine and histamine were injected unilaterally into caudal or rostral NAcc. Retention is expressed as median latency (s) to step-up, measured 24 h after shock administration with a 180 s cut-off. Numbers at the bottom of the histograms indicate 25./75. percentiles. Controls included vehicle-injected (VEH; 0.5 |ll) rats and a group administered 10 ng chlorpheniramine 5 h after training (DEL). *p<0.05 vs. vehicle controls, indicative of enhanced learning. Note: The failure of the delayed posttrial injection of the antagonist to influence learning indicates that the compound influenced learning by modulating early memory storage processes, rather than by acting on performance variables during retrieval of the task or by influencing memory consolidation going on 5 h after learning or later. (from ref. 49)

when administered systemically29 or into the ventricles.48 Furthermore, neurochemical experiments with in vivo microdialysis in anaesthetized rats revealed that peripheral administration of chlorpheniramine can produce increases in extracellular levels of acetylcholine in the cortex and dopamine in nucleus accumbens,25,26 confirming that the memory enhancing and reinforcing effects of Hi antagonists involve dopaminergic134 and cholinergic mechanisms.124 However, histaminergic antagonists, particularly those acting at H1 receptors, have been seriously questioned with regard to their selectivity, since they can bind also to receptors other than histaminergic ones.73,92, 23 Hence, we compared the H1 antagonist chlorpheniramine with histamine in their effects on learning following injection into different subregions of the NAcc. With respect to the proposed inhibitory function of histamine in reward-related processes (see above), we expected that accumbal injection of the biogenic amine should produce a behavioural profile distinct from or even opposite to that obtained after intra-NAcc administration of the H1 receptor antagonist; that is, histamine injection should be non-rewarding or even interfere negatively with reward and memory processes.49 However, incongruent with this premise intraaccumbens injection of both chlorpheniramine as well as histamine produced a conditioned place preference and facilitated negative reinforcement learning when administered post-

trial (Fig. 8). These effects were evident only when drug infusion was performed into the caudal-shell but not into the rostral subregion of the NAcc, providing further evidence for behavioural relevance of the known histaminergic innervation of this brain region with a functional subdivision on its rostrocaudal axis.157 Interestingly, it was shown that locally administered histamine can increase DA levels in the NAcc, whereby the histamine-induced DA release could be blocked by peripheral administration of the Hi-antagonist pyrilamine, which itself was found to decrease DA levels after local intraacumbens injection.34 These findings suggest that histamine and Hi antagonists could be operative via quite different neurochemical mechanisms within the NAcc, which, however, can produce a quite similar behavioural profile. Thus, it seems that the promnestic and reinforcing effects of chlorpheniramine involve pharmacodynamic aspects beyond its antagonistic activity at Hi-receptive sites. Furthermore, these data imply that the behavioural changes observed after manipulations of the TM-histamine system may not necessarily be related to disturbances specific to histaminergic neurotransmission.

Tuberomammillary Modulation of Hippocampal Signal Transfer

The hippocampus is thought to play an important role in memory formation27 and in reward-related processes.156 The hippocampus receives histaminergic fibres through both a ventral and a dorsal route57 and contains all three histamine receptor subtypes.5,39 Furthermore, a number of electrophysiological studies have demonstrated that TM histamine projections are involved in the subcortical modulation of neuronal excitability and synaptic plasticity in the hippocampal circuitry.13,41,44 Given the evidence for an inhibitory role of the TM in reinforcement and mnemonic processes and the functional link between TM and hippocampus, we149 gauged whether activation of the TM could modulate evoked field potentials in the dentate gyrus, frequently used to study electrophysiological correlates of learning.17,38 Therefore, paired-pulses of electrical stimulation were delivered to the perforant path (PP) and evoked field potentials (fEPSPs) were recorded in the dentate gyrus (DG) in freely moving rats. Before activating the PP, the TM was triggered by electrical stimulation when the rat explored an unfamiliar environment [Type I, 'theta' behaviour, including walking, sniffing and rearing according to Vanderwolf141] or when the animals showed Type II, 'non-theta' behaviour, including grooming, awake immobility and slow-wave sleep. The results indicate that activation of the histaminergic TM nucleus in the freely moving rat differentially affected the efficacy of afferent transmission to the hippocampus, depending on the behavioural state of the animal. Prestimulation of the TM was found to modulate neuronal transmission in the PP during learning-related exploratory behavior, but not during 'non-theta' related behaviours, including awake immobility (Fig. 9). During exploration both the conditioning as well as the test response of the dentate fEPSPs decreased with increasing TM train stimulation intensities, whereas the population-spikes were unchanged. Similar excitability changes in the PP-dentate area were previously observed following glutamate microinjections into the TM in vivo (unpublished results) and in hippocampal slices exposed to high concentrations of histamine.4 ,42 Taken together, these results indicate that the TM and the hippocampus may comprise a common system involved in the inhibition of the brain's reinforcement system and suggest that the TM projection system exerts its inhibitory action on associative functioning by interfering negatively with the signal transfer across the PP-granule cell synapses of the dentate gyrus. Congruent with this hypothesis, it was recently found that histamine and certain H2 antagonists can inhibit high frequency oscillations ('ripples') in hippocampus CA1 subfield,69 that are known to be associated with processes related to memory formation and certain behavioural states such as slow wave sleep;21 application of histamine H1 receptor antagonists had the opposite effect and facilitated the occurrence of ripples. Furthermore, behavioural studies revealed that a lesion of the hippocampus can amplify rewarding hypothalamic stimulation156 and microinjection of histamine into the dentate area was reported to adversely affect active avoidance conditioning.3

Figure 9. Normalized fEPSP slopes recorded in the dentate area evoked by paired-pulse stimulation (ISI= 30 ms) of the perforant path 50 ms following train stimulation in the TM with three different current intensities (0= no train, baseline) during exploration and awake immobility. The values given are mean (±SEM) percentage of the respective baseline condition (=100%). Black bars: Response on the conditioning (first) pulse (RC). White bars: Response on the test (second) pulse (RT). The Wilcoxon test for related samples performed on raw data was used to test for within group differences; *p<0.05 vs. conditioning pulse (RC0); tp< 0.05 vs. test pulse (RT0). (from ref. 149)

Figure 9. Normalized fEPSP slopes recorded in the dentate area evoked by paired-pulse stimulation (ISI= 30 ms) of the perforant path 50 ms following train stimulation in the TM with three different current intensities (0= no train, baseline) during exploration and awake immobility. The values given are mean (±SEM) percentage of the respective baseline condition (=100%). Black bars: Response on the conditioning (first) pulse (RC). White bars: Response on the test (second) pulse (RT). The Wilcoxon test for related samples performed on raw data was used to test for within group differences; *p<0.05 vs. conditioning pulse (RC0); tp< 0.05 vs. test pulse (RT0). (from ref. 149)

Conclusions

Results from this laboratory suggest that TM histamine projections are involved in behavioural asymmetries and in subsequent behavioural recovery after hemivibrissotomy and unilateral 6-OHDA lesions of the substantia nigra. Furthermore, our findings indicate that the histaminergic neuronal system (histamine fibres arising from E2-subgroup) may function as an inhibitory neurochemical substrate in the control of reinforcement and mnemonic processes. Both amplification of rewarding hypothalamic stimulation as well as facilitation of mnemonic processes were demonstrated following destruction of the TM. On the other hand, electrical or chemical stimulation of the TM was found to negatively interfere with the signal transfer in the hippocampus during learning-related behaviours. Moreover, administration of the histamine Hj-receptor antagonist chlorpheniramine, but not the H2-receptor antagonist ranitidine, was found to exert reinforcing effects and to promote learning in projection areas of the TM known to be crucial for reward and memory, namely, the ventral pallidum and the NAcc. However, the finding that histamine itself can have beneficial effects on learning and reward-related functions do not implicitly support this view and suggest that the behavioural effects observed after destruction of the TM might involve neurochemical processes other than a lesion-induced downregulation of histaminergic activity. Possible mechanisms that might account for the behavioural effects could involve TM-lesion produced alterations in diverse neurochemical systems that are colocalized and functionally linked to histamine such as GABA, glutamate, adenosine and certain neuropeptides.2,74,126 Thus, it remains to be determined which endogenous processes are related to the inhibitory control ofTM neurons, thereby affecting processes of learning and memory. This can only be achieved through knowledge of the distinct and opposite modulatory actions that the TM-histamine system might exert by activating different receptor subtypes on different neuronal systems involved in reinforcement and learning processes.

Nevertheless, our results are the first to focus on an inhibitory element in the neural system underlying the reinforcement process ('stamping-in'). Up to now, such an inhibitory substrate has been largely ignored or neglected in the attempt to characterize the neural basis of the reinforcement system.52 Furthermore, we found that lesions of the TM or blockade of certain histamine receptors generally induced changes in behavioural parameters, which were opposite to those known to occur after destruction or pharmacological manipulations of the substantia nigra.19,55 Such an antagonism was evident for turning and thigmotactic scanning, lateral-hypothalamic self-stimulation, place conditioning and mnemonic functioning. The evidence that the TM, the substantia nigra, and their transmitters DA and histamine can act in a reciprocal fashion with regard to the behaviours investigated so far, may be indicative of a functional link between the tuberomammillary-striatal and the nigrostriatal system.

Finally, another aspect should be pointed out. The lesions in the TM region and the application of the Hj-blocking drug chlorpheniramine not only improved learning in adult rats but also ameliorated performance deficits of aged rats, which are proposed to be an animal model for Alzheimer's disease.33 This finding is interesting in the light of recent studies, showing increased levels of histamine in aged rats83 as well as in Alzheimer's disease patients with mental deterioration (ref. 18; but see ref. 100). Based on these findings, histamine antagonists, particularly those acting at the H1-receptive site, or H3-agonists could be considered in terms of their possible therapeutic and/or protective role in Alzheimer patients, and also in patients suffering from other neuropathies, such as Parkinson's disease.

Acknowledgments

This work was supported by grants from the German National Science Foundation to J.PH. and R.U.H. The experiments were carried out in accordance with the German Law on the Protection of Animals and were approved by the state authority.

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