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Behavioural Brain Research 124 (2001) 137– 143 www.elsevier.com/locate/bbr Histamine reduces firing and bursting of anterior and intralaminar thalamic neurons and activates striatal cells in anesthetized rats Nora Sittig, Helga Davidowa * Johannes-Mueller-Institute of Physiology, Charité, Faculty of Medicine, Humboldt Uni6ersity Berlin, Tucholskystr. 2, D-10117 Berlin, Germany Received 3 June 2000; accepted 4 July 2000 Abstract Histamine is known to play a role in the regulation of waking behavior as well as in processes of memory and reinforcement. The striatum and thalamic nuclei as the intralaminar complex and the anterior group can be involved in these functions. Little is known about the action of histamine on neurons of these brain structures. Single unit activity was extracellularly recorded in rats anesthetized with urethane. Firing of anterior and intralaminar thalamic neurons that responded to iontophoretically administered histamine was predominantly reduced (Wilcoxon test (Wt), P B 0.05, n = 49 and 63, respectively), whereas striatal neurons were mainly activated by the drug (Wt, PB 0.05, n=29). Thalamic neurons also significantly reduced the number of burst discharges and the proportion of spikes involved in bursts. The histaminergic effects could be blocked by H1 or H2 receptor antagonists. In conclusion, histamine may control waking behavior also via nonspecific thalamic nuclei and basal ganglia circuits. Through modulation of the transmission in the anterior thalamus it may exert an influence on learning and emotional processes. © 2001 Elsevier Science B.V. All rights reserved. Keywords: Single unit activity; Burst discharges; Caudate-putamen; Iontophoresis; Histamine receptor antagonists 1. Introduction The histaminergic system of the brain originating from the tuberomammillar hypothalamic nucleus [47] is known to be involved in the regulation of sleep and wakefulness, processes of learning and memory, locomotion and reward [3,12,24,42,45,50]. The knowledge of sedative effects of antihistaminergic substances therapeutically used has on the one hand induced attempts to evolve drugs not crossing the blood – brain barrier, on the other hand it has activated the study of brain functions of histamine. Also the action of antihistamines as psychotropic drugs points to the involvement of histamine in a variety of functions. Neurons of the tuberomammillary nucleus are spontaneously active [43]. In freely moving rats they release histamine especially in the dark period, starting a gradual increase in the second half of the light period [22]. * Corresponding author. Tel.: + 49-30-28026620; fax: +49-3028026669. E-mail address: [email protected] (H. Davidowa). This circadian rhythm suggests an involvement of histamine in normal regulation of sleep and waking periods. Furthermore, the hypothalamic suprachiasmatic nucleus known as circadian pacemaker is densely innervated by histaminergic fibers, and its neurons are predominantly activated by histamine acting on H1 receptors [37]. On the other hand, tuberomammillar neurons are innervated from the brainstem and several structures of the limbic system [30]. Thus, the release of histamine may be modulated in connection with limbic functions. There are a lot of data speaking in favor of the importance of histamine for arousal [17,18,24,34]. Concerning learning and memory there are differing reports. It has been shown that histamine facilitates long term potentiation in the hippocampus [1,44] and improves learning and memory [33,42]. On the other hand, there are results that underline an inhibitory function of histamine in the control of reinforcement and mnemonic processes [12,50]. Due to their connections, thalamic neurons can be involved in processes of arousal as well as of memory 0166-4328/01/$ - see front matter © 2001 Elsevier Science B.V. All rights reserved. PII: S 0 1 6 6 - 4 3 2 8 ( 0 1 ) 0 0 2 2 3 - 6 138 N. Sittig, H. Da6idowa / Beha6ioural Brain Research 124 (2001) 137–143 and reward. The group of anterior nuclei consisting of the anteromedial, anterodorsal and anteroventral nucleus represents the hypothalamic relay to the cortex [40]. The laterodorsal nucleus is associated to these nuclei because of connectional and functional similarities. These nuclei project to cingulate areas of the cerebral cortex and get a feedback through the hippocampal formation [40]. These circuits are found to play a role in learning and emotion [46]. The intralaminar thalamic system is involved in the regulation of waking behavior and accompanying changes in cortical synchronization/desynchronization [9,38]. There are very few studies on the effects of histamine on thalamic neurons [10] except on the lateral geniculate nucleus [21]. There is evidence of a histaminergic innervation of thalamic nuclei [29,47], but the existence of the H1 and H2 receptor subtypes of histamine could not be clearly shown in all nuclei of the rat thalamus [28,45] in contrast to the occurrence of H3 receptors [32]. Therefore, we wanted to know how far H1 and H2 receptor antagonists can block histaminergic effects in the thalamus. Since the firing mode of thalamic neurons may vary between regular firing during wakefulness and the formation of bursts during sleep [21,38,39], we analyzed the discharge pattern. The occurrence of groups of action potentials (bursts) after a long period of hyperpolarization can depend on activation of low-threshold calcium channels [13,20]. In depolarized neurons, normal high-threshold bursts of action potentials may develop. Furthermore, since intralaminar neurons do not only innervate cortical areas, but also the basal ganglia [6,16], especially the caudate-putamen being important for motor and cognitive functions [2], we were interested in knowing direct in-vivo effects of histamine on the striatum. 2. Materials and methods Adult male Wistar rats (250–400 g) were anesthetized with urethane (1.2 g/kg i.p., supplemental doses as required). Rectal temperature was maintained at 37–38°C. The experiments were carried out as described earlier [4,5] in accordance with international standards of animal welfare and approved by the regional Berlin animal ethics committee (G 0251/95). The head of the rat was fixed in a stereotaxic device. Four holes were drilled into the bone overlying the thalamus and the striatum. Single unit activity was extracellularly recorded by means of a glass microelectrode filled with a solution of trypan blue that was used to mark the recording positions. The action potentials were amplified, monitored and discriminated using con- ventional methods. A multibarrel electrode affixed to the recording electrode was used for the iontophoretic ejection of the following drugs: histamine dihydrochloride, the H1 receptor antagonist mepyramine maleate and the H2 receptor antagonist cimetidine, in several cases also dimaprit dihydrochloride, H2 receptor agonist, and (R)-(− )-a-methylhistamine dihydrobromide, H3 receptor agonist. All drugs (0.1 M, pH 4.5) were ejected with positive currents from 5 to 90 nA. One barrel was filled with sodium chloride (165 mM) for balance and current control. Retaining currents (5 nA) of opposite polarity were applied between the ejection periods. At the end of the experiment, the animals were given a lethal dose of urethane and decapitated. The brains were fixed with a solution of 10% paraformaldehyde. The marked recording positions were histologically determined in frontal frozen sections by means of the stereotaxic atlas [31]. The discharge rate of a neuron was determined for periods of 100 s duration before (control), and during ejection (early response), and in two periods after termination of the administration of drugs (late response and recovery). Neurons that changed their discharge rate by more than 25% (or at least by 0.5 impulses per s when firing at a rate below 1 spike per s) during at least one response period were regarded as being responsive to the applied drug. The prevailing direction of changes in all neurons of one population was proved with the Wilcoxon paired rank sum test (Wt). All neurons irrespective of their responsiveness were included in this test. Differences were considered to be statistically significant at PB 0.05 (two-tailed). In some of the neurons that were responsive to histamine we tried to prevent this effect by coadministration of histamine with one of the histamine receptor antagonists. A reduction of the effect of histamine by more than 25% (or by more than 70% for neurons with a discharge rate below 1 impulse per s) was judged as antagonization. The medians as well as the mean9 standard deviation (S.D.) of the discharge rates during the different conditions were calculated from the data of neuronal populations. Furthermore, the discharge pattern of thalamic neurons was analyzed [4] by determining the number of bursts in each 100 s period (Spike 2 software, burst analysis program (Cambridge Electronic Design, UK)). A sequence of spikes with an interspike interval 54 ms was regarded as burst as recommended in the literature [20]. Also the number of spikes within a burst and the percentage of spikes involved in bursts was determined. Additionally, the silent period prior to a burst was measured. Bursts occurring after a silent period \100 ms possibly starting with a low-threshold Ca++ spike were named LTS, in contrast to bursts with possibly high-threshold spikes (HTS). N. Sittig, H. Da6idowa / Beha6ioural Brain Research 124 (2001) 137–143 139 rons were mainly activated by histamine (Wt, PB0.01, n=29). It caused in 14 cells (46.7%) a change in the firing frequency by more than 25%, 12 increased; two decreased (means and medians in Table 1). Also very slowly discharging striatal neurons (less than 1 spike per s) responded to histamine. 3.2. Effects of histamine receptor antagonists and agonists Fig. 1. Discharge rate (spikes per 3 s) of a centrolateral neuron. Abscissa: time (bar at the bottom: 5 min). Bars: duration of administration of the drugs; numbers: current in nA. The neuron was inhibited by histamine (Hist). This effect was not blocked by the H1 receptor antagonist Mepyramine (Mep), but with the H2 receptor antagonist cimetidine (Cim) applied with a higher current. 3. Results 3.1. Effects of histamine on firing rate Discharge rates of 141 histologically verified neurons were recorded. They were located in the anterior thalamus (anterodorsal, -ventral, -medial and laterodorsal, n= 49) and intralaminar thalamic nuclear complex (centromedial, centrolateral, paracentral and parafascicular nuclei, n=63) as well as in the striatum (n =29). The neuronal firing rate was predominantly reduced by histamine in thalamic neurons (anterior: Wt, P B0.01, n = 49; intralaminar: Wt, P B0.02, n =63). A change in the discharge rate by more than 25% was observed in 27 anterior cells (55.1%), 17 decreased and eight increased firing, two cells showed a biphasic response. Similarly, about two thirds of responsive intralaminar neurons reduced firing (n = 23) (Fig. 1), one third increased it (n=12), one cell responded in a biphasic manner. Means and medians of firing of the neuronal populations are given in Table 1. It is to mention that the values do not provide the maximal response, since they were determined for given periods. Striatal neu- Histamine receptor antagonists were applied to 27 thalamic neurons that were responsive to histamine. In 19 neurons (70%) the effects of histamine could be reduced or prevented by coadministration with mepyramine or cimetidine. The H1 receptor antagonist mepyramine reduced the inhibitory effect of histamine in eight of 16 neurons tested, cimetidine was effective in six of 11 neurons. In one neuron, both antagonists could prevent the action of histamine. Fig. 1 shows an inhibition of a centrolateral thalamic neuron by histamine and the antagonizing effect of cimetidine. The activating effect of histamine could be reduced or prevented by mepyramine in six of seven cells, cimetedine was not effective in one cell tested. Fig. 2 shows the means of neuronal firing rates demonstrating the antagonizing effect. Blocking effects of the H1 as well as the H2 receptor antagonist could be seen in both anterior as well as intralaminar neurons. The involvement of H2 receptors in the mediation of histaminergic effects could also be shown by use of the H2 receptor agonist dimaprit that activated three and inhibited two of 15 cells in the anterior thalamus. In the intralaminar complex, five of 25 cells were activated and one cell inhibited. Out of the neurons activated by dimaprit, four were inhibited by histamine. Effects of dimaprit were especially observed in the centromedial nucleus. In few cells tested, the H3 receptor agonist was also effective, the drug activated two and inhibited two of seven neurons. In the striatum, the H1 receptor antagonist blocked the activation induced by histamine in three out of five neurons tested. In two neurons, cimetidine also had an antagonistic effect. The suppressive effect of histamine on one neuron could be blocked by the H1 receptor antagonist. Only one of 12 neurons tested was activated by the H2 receptor agonist. Table 1 Discharge rates observed in neuronal populations of the anterior and intralaminar thalamus and the striatum Spontaneous Histamine Late response Recovery Anterior neurons (n= 49) Intralaminar neurons (n = 63) Striatal neurons (n = 29) Mean9S.D. Median Mean 9S.D. Median Mean9 S.D. Median 3.85 94.16 3.559 4.09 3.329 3.79 3.859 3.9 3.03 2.24 2.04 3.12 1.63 9 1.2 1.40 91.2 1.43 9 1.4 1.64 9 1.3 1.44 0.98 1.05 1.22 3.20 93.8 3.64 9 4.1 3.77 9 4.0 3.30 93.6 1.8 2.3 2.3 2.6 140 N. Sittig, H. Da6idowa / Beha6ioural Brain Research 124 (2001) 137–143 Fig. 3. Bursts (sequences of potentials with an interspike interval B 4 ms) and spikes of two intralaminar thalamic neurons during different conditions. Abscissa: time (bar: 100 s). The periods of drug administration are marked. Each vertical line represents a burst or a spike. Top: Bursts with a silent period less than 100 ms prior to the first spike in the burst (named HTS); LTS: bursts with a silent period longer than 100 ms prior to the first spike. The time course in the change differed between bursts and firing. Especially neuron B showed a prolonged reduction of bursts. Fig. 2. Means of the discharge rates of histamine-responsive thalamic neuronal populations during different conditions showing the blocking effects of histamine receptor antagonists. (A) Effect of the H1 receptor antagonist on the inhibitory action of histamine, (B) effect of the H2 receptor antagonist on the inhibitory action of histamine, (C) effect of mepyramine on histamine-activated neurons. Numbers: 1 spontaneous activity, 2 firing rate during administration of the drugs, 3 late response, 4 recovery. * significant change compared with 1, Wt, P B0.05. for both nuclear groups (Wt, PB 0.005). The number of spikes within a burst did not significantly alter. Since the reduction in firing is caused especially by a reduction in bursting, the fraction of spikes involved in bursts also was predominantly diminished (Wt, PB 0.005) by histamine. The mean changed from 58.1 to 51% spikes involved in bursts in anterior neurons and from 47.5 to 35.5% in intralaminar cells. Thus, there is a significant change to more regular spiking in response to histamine. 3.3. Effects of histamine on bursting of thalamic neurons Burst discharges as shown in Figs. 3 and 4 were observed in 40 of the 49 anterior and 46 of the 63 intralaminar thalamic neurons. Comparable to the change in the discharge rate, the number of burst discharges was significantly decreased (Wt, P B 0.001, n = 40, means 64.3 bursts per 100 s control to 54.3 during and 50.3 after histamine in the late response phase for anterior neurons; Wt, P B 0.005, n= 46; mean 32.4 bursts per 100 s control to 27.8 during and 23.8 after histamine for intralaminar neurons). Although changes in the number of burst discharges positively correlated with changes in the firing rate, they can be different in the time course as seen in Figs. 3 and 4. Anterior and intralaminar neurons express especially bursts after a long silent period that could possibly follow low-threshold spikes (LTS). The reduction of this type of bursts was shown to be significant Fig. 4. Bursts and impulses of an anteroventral (A) and a laterodorsal (B) neuron. Denotations as in Fig. 3. Neuron A formed HTS in a variable manner. Histamine induced a pronounced reduction of LTS. N. Sittig, H. Da6idowa / Beha6ioural Brain Research 124 (2001) 137–143 4. Discussion The predominating effect of histamine on thalamic neurons consisted in a suppression of the firing rate, accompanied by a reduction of bursts that were possibly induced by low-threshold Ca++ spikes. The inhibition of firing could be caused by a direct postsynaptic hyperpolarization or by a reduction of endogenous depolarizing events. An involvement of activated GABAergic interneurons can be neglected, since in the rat only very few interneurons have been observed in the thalamic nuclei studied in this work [27]. On the other hand, the reduction of low-threshold bursts and the change to more regular occurring spikes not involved in bursts has been shown to be the result of depolarizing effects that inactivate low-threshold Ca++ channels [13,20,21]. Thus, it could be assumed that more than one transduction mechanisms are involved. This is also supported by the observation of several activating effects. Generally, the action of histamine is mediated by three receptor subtypes that use various signal transduction mechanisms [11,36]. It seems that H1 as well as H2 receptors can mediate both suppression and activation of neuronal firing [21,34,35]. H3 receptors function as presynaptic autoreceptors and suppress the release of histamine [36]. As heteroreceptors they can also depress the release of other transmitters [11]. Due to the observed effects of histamine receptor antagonists and agonists, it is to assume that H1, H2 and H3 receptors participate in mediating the action of histamine in both thalamic nuclear groups studied. In the lateral geniculate nucleus of the thalamus, slow depolarization induced by histamine and associated with a decrease in a potassium current could be blocked by H1 receptor antagonists [21]. A further activating component associated with an increase in membrane conductance and brought about by stimulation of a hyperpolarization-activated cationic current could be blocked by the H2 receptor antagonist [21]. In our investigations on thalamic neurons, the effects of histamine could also partly be blocked by the H1 receptor antagonist, partly by the H2 receptor antagonist. The predominant reduction in firing was in most neurons a consequence of the reduction in bursting. Generally, the main effect of histamine seems to consist in the change from rhythmic firing to more tonic firing of thalamic cells mentioned to be important for induction of the waking state [38] and for a faithful transmission of information [21]. On the other hand, high-frequency groups of action potentials are shown to be more efficient in releasing transmitters and thus relaying signals across the synapse than single spikes [19]. Thus, bursts by themselves may transmit signals better than single spikes. 141 The modulating effect of histamine on anterior thalamic nuclei that connect limbic structures involved in processes of learning, memory and reward [46] shows that activation of the histaminergic system exerts its role not only through direct action on the hippocampus, but also the thalamic relay. The reduction in firing especially in the form of bursts by intralaminar thalamic neurons and activation of striatal neurons in response to histamine support the view of the involvement of the drug in regulation of waking behavior through thalamo-basal-ganglia circuits. Although it has been shown that individual nuclei of the intralaminar complex regulate functionally segregated basal-ganglia-thalamo-cortical circuits, the intralaminar neurons can modify the level of the entire basal ganglia system by way of a common input [9], for instance histamine as shown with our results. Several brain structures seem to be involved in the regulatory processes of histamine in sleep and wakefulness. Cortical neurons are reported to be innervated by the histaminergic fibers [41]. They seem to be activated by histamine [34], although also depressant effects were described [10,35]. Histamine influences sleep-generating mechanisms of the preoptic/anterior hypothalamus [18]. Furthermore, histamine may influence the cortex by activation of cholinergic neurons of the nucleus basalis Meynert [14], but also of neurons of the mesopontine tegmentum that by itself exerts regulatory effects on thalamo-cortical circuits [17]. In the striatum, only 25% of the varicosities of histaminergic axons seem to form synaptic contacts of the asymmetric type [41]. In acutely dissociated striatal cells, histamine was reported to evoke a net inward current accompanied by a decrease in the membrane conductance [25]. Munakata and Akaike [25] concluded from the study that histamine reduced potassium currents in possibly cholinergic interneurons by means of H1 and H2 receptors. It is known that striatal cholinergic interneurons receive especially an input from the parafascicular thalamic nucleus [16]. Although these interneurons represent only about 2% of the neuronal population [16], they are possibly easy to detect by a recording electrode due to their large size and the higher spontaneous activity in comparison to projection neurons. In anesthetized animals they have a tonic firing frequency between 2 and 10 spikes per s [49]. Since we also observed effects of histamine in very slowly firing cells, and projection cells form about 95% of the population, we would assume that histamine is also able to affect projection neurons. Naturally, indirect effects mediated by different interneurons located in the near vicinity have to be taken into account. Due to the action of histamine on cholinergic neurons, interactions with acetylcholine have to be considered. Acetylcholine has been shown to interact with other transmitter systems [5,7,15] and to stabilize the potentials of striatal cells [15]. 142 N. Sittig, H. Da6idowa / Beha6ioural Brain Research 124 (2001) 137–143 Furthermore, interactions of histamine with the dopaminergic system can be involved [26]. In the rat striatum, the synthesis of dopamine can be inhibited by H3 receptor activation [23]. The dopamine level seems to be reduced by histamine also via the H1 receptor [8]. Thus, the modulatory action of dopamine on striatal neurons [7,15] may be changed also by histamine. Striatal projection neurons are often silent in anesthetized rats [5,48]. Due to the existence of various potassium conductances their membrane polarization can spontaneously vary between two states [48]. Since histamine mainly activates striatal neurons, it might promote the transition to the more depolarized ‘up’ state [48]. Thus, histamine has to be included into the transmitter systems modulating the activity of the neostriatum [2,7]. Acknowledgements The authors would like to thank Ursula Seider and Roland Schneider for expert technical assistance. 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