Inhibition of histamine release by local and intracerebroventricular infusion of galanin in hypothalamus, hippocampus and prefrontal cortex of awake rat: A microdialysis study

Neuroscience Letters 534 (2013) 58–63

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Inhibition of histamine release by local and intracerebroventricular infusion of galanin in hypothalamus, hippocampus and prefrontal cortex of awake rat: A microdialysis study Shimako Yoshitake a , Soichiro Ijiri b , Jan Kehr a,c,∗ , Takashi Yoshitake a,d,∗ a

Department of Physiology and Pharmacology, Karolinska Institutet, Nanna Svartz väg 2, 171 77 Stockholm, Sweden School of Pharmaceutical Sciences, International University of Health and Welfare, Ootawara City, Tochigi, Japan c Pronexus Analytical AB, Grindstuvägen 44, 167 33 Bromma, Sweden d Kagoshima University, Graduate School of Medical and Dental Sciences, 8-35-1, Sakuragaoka, Kagoshima, Japan b

h i g h l i g h t s  Galanin decreases histamine release in the rat brain in vivo.  Different effects of local versus intracerebroventricular infusions of galanin.  Measurement of histamine in brain microdialysis samples.

a r t i c l e

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Article history: Received 17 July 2012 Received in revised form 17 November 2012 Accepted 3 December 2012 Keywords: Galanin Histamine Neuropeptides Microdialysis Fluorescence derivatization Rat

a b s t r a c t The neuropeptide galanin is co-localized with histamine in subpopulations of neurons in the tuberomammillary nucleus suggesting its involvement in modulating histaminergic neurotransmission. The purpose of the present study was to investigate, by use of microdialysis, the effects of local intraparenchymal (combined infusion and microdialysis probe), and intracerebroventricular (i.c.v.) infusions of galanin on extracellular levels of histamine in its major projecting areas, ventromedial hypothalamic nucleus ventrolateral part (VMHVL), CA3 area of ventral hippocampus (vHipp) and medial prefrontal cortex (mPFC) in separate groups (n = 5 rats/each) of freely moving rats. Galanin (0.5 nmol and 1.5 nmol) dose-dependently decreased the basal histamine levels in the VMHVL to 77.1% (i.c.v.) at 40 min and to 82.1% (intra-VMHVL infusion) already at 20 min, of the control group (32.6 ± 3.5 fmol/10 ␮l), whereas only 1.5 nmol i.c.v. galanin and not the local infusions deceased the histamine levels in the vHipp (8.4 ± 0.6 fmol/10 ␮l) to 82.8% and in mPFC (9.8 ± 0.9 fmol/10 ␮l) to 87.5%. It is concluded that central administration of galanin decreased the basal extracellular histamine levels in major histamine projecting areas, however, these effects were less prominent than those observed for 5-HT (Kehr et al., 2002 [12]) and ACh (Yoshitake et al., 2011 [38]) in the ventral hippocampus following i.c.v. and/or local galanin infusions. © 2013 Elsevier Ireland Ltd. All rights reserved.

1. Introduction The neuropeptide galanin [33] is widely distributed in the mammalian central nervous system including the rat brain [18,27–29] where it often coexists in the neurons expressing the classic neuro-

Abbreviations: ACh, acetylcholine; aCSF, artificial cerebrospinal fluid; vHipp, CA3 area of the ventral hippocampus; GalR, galanin receptor; i.c.v., intracerebroventricular; mPFC, medial prefrontal cortex; NA, noradrenaline; TMN, tuberomammillary nucleus; VMHVL, ventromedial hypothalamic nucleus ventrolateral part. ∗ Corresponding authors at: Department of Physiology and Pharmacology, Karolinska Institutet, Nanna Svartz väg 2, 171 77 Stockholm, Sweden. Tel.: +46 8 5248 7084; fax: +46 8 5248 7234. E-mail addresses: [email protected] (J. Kehr), [email protected] (T. Yoshitake). 0304-3940/$ – see front matter © 2013 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.neulet.2012.12.036

transmitters acetylcholine (ACh), serotonin (5-HT), noradrenaline (NA), GABA and histamine [14,18,19]. A body of evidence exists for the role of galanin in mediating, cognitive function, affective behaviour, addiction, epilepsy, pain, neuronal injury and neurodegeneration, food intake, sexual behaviour, as well as in modulation of peripheral actions, for review, see [9,10]. Using the microdialysis technique, we and others have demonstrated that intracerebroventricular (i.c.v.) or intracerebral infusions of galanin reduced the basal extracellular levels of ACh [16,23,38], 5-HT and NA [12,13,37,39] in the ventral hippocampus of awake rats and mice. These findings support a notion that galanin acts predominantly as an inhibitory neuropeptide via its three receptors, which all are coupled to Gi/o and inhibit adenylyl cyclase [3]. In addition, galanin receptor 2 (GalR2) also signals via Gq/11 to activate phospholipase C and protein kinase C [30]. Subsequently, a differential

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distribution of galanin receptors in the rat brain was demonstrated for GalR1 [6,22], GalR2 [22] and for GalR3 [31]. Besides numerous studies on galanin modulating ACh, 5-HT and NA neurotransmission, less attention was paid to investigation of possible interactions between galanin and other coexisting neurotransmitters including histamine. Galanin has been shown to be co-localized with histamine in subpopulations of neurons in the tuberomammillary nucleus (TMN), suggesting its involvement in modulating histaminergic neurotransmission [14,15,32]. Histamine together with its four receptor subtypes is implicated in mediating important physiological functions such as sleep–wakefulness, circadian rhythm, thermoregulation, food intake, as well as behavioural functions involving cortical arousal, cognitive function, affective behaviour, and nociception, for review, see [1,7,8]. Consequently, histamine and its receptors, have been implicated in the pathophysiology of neurological and psychiatric disorders including cognitive impairment associated with Alzheimer’s disease and Parkinson’s disease, ADHD, schizophrenia, sleep–wakefulness disorders including narcolepsy, eating disorders, neuroinflammation and pain, for review, see [8,24,34]. The purpose of the present study was to investigate, by use of microdialysis in freely moving rats, the effects of local, and i.c.v. infusion of galanin on extracellular histamine levels in major histamine projecting areas: ventromedial hypothalamic nucleus, CA3 area of ventral hippocampus (vHipp) and medial prefrontal cortex (mPFC).

2. Materials and methods 2.1. Animals Adult male Sprague-Dawley rats, weighing 230–330 g at the time of the experiment (Charles River Laboratories, Japan) were used in all studies. The rats (three animals/cage) were maintained at free access to food and water, on a 12-h light–dark cycle (light at 7:00 AM), room temperature 22 ± 2 ◦ C and humidity 50–55%. All animal experiments were approved by the local ethical committee following “Guidelines for Proper Conduct of Animal Experiments” (Science Council of Japan) and the directives of the “Principles of Laboratory Animal Care” (NIH publication No. 8023). All efforts were made to minimize animal suffering and the number of animals used for the study.

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2.3. Microdialysis surgery and sampling The microdialysis experiments were carried out on awake rats following the protocol described elsewhere [11,38]. Briefly, the animals were anaesthetized with isoflurane and placed into a stereotaxic frame (Narishige Co., Ltd, Tokyo, Japan) in a flat skull position with the incisor bar set to −3.2 mm, the body temperature of the rat was controlled by a rectal thermometer and maintained at +37 ◦ C using a CMA/150 temperature controller (CMA/Microdialysis, Stockholm, Sweden). After exposing the skull, a hole for a probe, for an i.c.v. cannula and two holes for the fixing screws were drilled using a fine trephine drill. Animals were implanted each with a guide cannula for a combined microdialysis/infusion probe (Eicom, Kyoto, Japan) or the separate groups combining the i.c.v. infusion with a microdialysis probe (Eicom) implanted into the ventromedial hypothalamic nucleus ventrolateral part (VMHVL), mPFC, and the vHipp at the following coordinates: VMHVL: AP −2.5 mm; L −0.7 mm; V −8.6 mm; vHipp: AP −4.3 mm; L −4.6 mm; V −5.8 mm, and mPFC: AP 3.2 mm; L −0.5 mm; V −1.4 mm; all coordinates were relative to bregma and the dura surface, according to the stereotaxic atlas of Paxinos and Watson [25]. The placement of the combined microdialysis/infusion probes in the respective areas is illustrated in Fig. 1 for (A) VMHVL, 0.5 mm membrane length, (B) vHipp, 1 mm membrane length and (C) mPFC, 3 mm membrane length. In experiments including i.c.v. infusions of galanin, a second guide cannula for the infusion needle (Eicom) was implanted into the lateral ventricle (AP −1.3 mm; L −1.8 mm; V −3.3 mm). The guide cannulae were fixed to the skull using two anchor screws and dental cement. Seven days after surgery, the microdialysis probe with the injection cannula (MI-A-I series: 0.22 mm o.d., 0.5 mm, 1 mm or 3.0 mm membrane length, molecular weight cut-off 50,000 Da) or microdialysis probe (A-I series: the same membrane lengths as for MI-A-I) and the i.c.v. infusion cannula (AMI series) were inserted into the respective guide cannulae in awake, freely moving rats. The dialysis probes were perfused with aCSF at a flow rate of 1.0 ␮l/min. Dialysates were collected every 20 min and the first four samples were used for estimation of basal extracellular histamine levels. Galanin (0.5 nmol/0.5 ␮l or 1.5 nmol/0.5 ␮l) or aCSF in control groups was infused via the respective injection cannulae of the combined microdialysis probes or via a separate i.c.v. cannula in the lateral ventricle at the flow rate of 0.5 ␮l/min. After finalizing the experiment, the animals were sacrificed by an overdose of isoflurane and dislocation of the neck. The brains were removed, frozen on dry ice and stored at −20 ◦ C for histological examination of the probe position and the infusion site.

2.2. Chemicals and solutions 2.4. Measurement of histamine Galanin (porcine) trifluoroacetate salt was purchased from Bachem, Bubendorf, Switzerland. Histamine dihydrochloride, o-phthalaldehyde (OPA), sodium 1-octanesulfonate, methanol (CHROMASOLV® Plus) and all other salts and chemicals were purchased from Sigma–Aldrich (St. Louis, MO, USA). The reagents were used without further purification. Deionized water, purified with a Barnstead EASYpure RF (Hansen Co., Hyogo, Japan) system, was used for preparation of all aqueous solutions. Galanin was dissolved in freshly made aCSF (NaCl 123.4 mM, NaHCO3 23.4 mM, KCl 2.4 mM, KH2 PO4 0.5 mM, CaCl2 ·2H2 O 1.1 mM, MgCl2 ·6H2 O 0.8 mM, Na2 SO4 0.5 mM and glucose 5.8 mM, pH 7.1), which also served as the control. The concentration of galanin was calculated as a free base and corrected for the purity (water content) of the each batch as declared in the corresponding information sheet provided by the supplier. For the microdialysis perfusions the aCSF solution contained 148 mM NaCl, 4 mM KCl, 0.8 mM MgCl2 ·6H2 O, 1.4 mM CaCl2 ·2H2 O, 1.2 mM Na2 HPO4 , 0.3 mM NaH2 PO4 , pH 7.2.

Concentrations of histamine in the microdialysis samples were measured by high-performance liquid chromatography (HPLC) with postcolumn OPA derivatization and fluorescence detection. Briefly, the HPLC system included three L-2130 isocratic pumps, each with an inbuilt degasser unit, a L-2300 temperature oven, a L-2200 Refrigerated Microsampler and a fluorescence detector L-2480, all purchased from Hitachi (Tokyo, Japan). The fluorescence detector was equipped with a 12-␮l flow cell and operated at an excitation wavelength of 340 nm and an emission wavelength of 450 nm. The chromatograms were recorded and integrated by use of the computerized data acquisition system EZChrom Elite (Hitachi). A HPLC column EICOMPAK SC-5ODS (3.0 mm, i.d. × 150 mm) and a precolumn PREPAKSET CA-ODS (3.0 mm, i.d. × 4 mm) were purchased from Eicom (Kyoto, Japan). The mobile phase (Pump A) was a mixture of 0.1 M NaH2 PO4 buffer and methanol (9:1, v/v) and containing sodium 1-octanesulfonate at a final concentration of 0.786 mM, the flow-rate was 500 ␮l/min. The

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Fig. 1. A schematic illustration of the placement of the microdialysis probe combined with the infusion cannula in (A) ventromedial hypothalamic nucleus ventrolateral part, (B) CA3 area of ventral hippocampus and (C) mPFC. The exact coordinates are listed in Section 2. The membrane lengths were for (A) 0.5 mm, (B) 1 mm and (C) and 3 mm. Adapted from Paxinos and Watson [25].

OPA solution (Pump B) was prepared by dissolving 16 mg OPA first in 5 ml of methanol, thereafter diluting the solution with deionized water up to 200 ml, the flow-rate was 100 ␮l/min. Potassium carbonate solution (0.5 M) was pumped by the Pump C at a flow-rate of 100 ␮l/min. At these conditions, the limit of detection (signal-tonoise ratio = 3) for histamine was 2 fmol/10 ␮l injected on-column. 2.5. Data presentation and statistical analysis The basal concentrations of histamine were calculated from the mean values of four fractions collected from each individual

animal during the pre-administration period (−60 to 0 min) and then expressed as a mean ± standard error of the mean (SEM) for each treated group. The mean histamine concentrations at time 0 min were taken as 100% and all values were recalculated to the percentage of these basal levels. Statistical analysis was performed using Prism 5 (GraphPad Software, San Diego, CA, USA) statistical software. Mean basal levels were compared by use of one-way analysis of variance (ANOVA) followed by Newman–Keuls multiple comparison test. Differences between the groups and treatments were evaluated by use of two-way repeated measures ANOVA followed by Bonferroni’s post-test. A

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Fig. 2. Effects of galanin infusion (A) into the lateral ventricle and (B) locally into the VHMVL on extracellular levels of histamine in the VHMVL. Both i.c.v. and local infusion of galanin into the VHMVL caused significant and dose-dependent decreases in basal histamine levels ( p < 0.001;  p < 0.01; +++ p < 0.001).

significance level of p < 0.05 was accepted as a statistically significant effect. 3. Results 3.1. Basal histamine levels The estimated mean extracellular concentrations (not corrected for in vitro probe recovery) of histamine at basal conditions for the four galanin-treated groups and two control groups were within the range of 31.5 ± 2.7 and 35.0 ± 2.3 fmol/10 ␮l in the VMHVL, 8.0 ± 0.5 and 8.8 ± 0.4 fmol/10 ␮l in vHipp and 9.8 ± 0.9 and 11.0 ± 1.0 fmol/10 ␮l in mPFC, respectively. There were no significant differences in basal histamine levels between the corresponding groups receiving either local or i.c.v. infusions. 3.2. Effects of galanin on histamine levels in the hypothalamus Infusion of galanin in the lateral ventricle, as well as in the vicinity of the probe implanted in the VMHVL caused significant and dose-dependent decreases in extracellular histamine levels, as shown in Fig. 2A and B, respectively. Galanin infused i.c.v. at a dose of 0.5 nmol and 1.5 nmol decreased the histamine levels to 86.6 ± 2.7% and 77.1 ± 4.7%, at 40 min (p < 0.001), respectively. These effects were significant both for the treatment [F2,12 = 9.28; p < 0.01] and the interaction time and the treatment [F24,144 = 4.11; p < 0.001]. Similarly, galanin infused locally into the VMHVL at a dose of 0.5 nmol and 1.5 nmol decreased the histamine levels to 87.6 ± 3.7% and 82.1 ± 2.7% already at 20 min (p < 0.001), respectively. These effects were significant both for the treatment [F2,12 = 6.26; p < 0.02] and the interaction time and the treatment [F24,144 = 3.14; p < 0.001]. All levels returned to the basal histamine values within 60–80 min post-infusion. 3.3. Effects of galanin on histamine levels in the ventral hippocampus and mPFC Infusion of galanin at a dose of 1.5 nmol into the lateral ventricle but not locally caused significant decreases in extracellular histamine levels both in the vHipp and mPFC, as shown in Fig. 3A and B, respectively. In the vHipp, the histamine levels decreased to 82.8 ± 2.8% at 20 min (p < 0.001) after i.c.v. infusion but only to 93.7 ± 0.9%, at 40 min following the local infusion. These effects

were significant both for the treatment [F1,8 = 5.41; p < 0.05] and the interaction time and the treatment [F12,96 = 4.42; p < 0.001]. Similarly, in the mPFC, i.c.v. galanin significantly decreased the histamine levels down to 87.5 ± 2.5% at 40 min (p < 0.001), whereas local infusion of galanin had no effect. The overall effects of galanin were significant both for the treatment [F1,8 = 5.91; p < 0.05] and the interaction time and the treatment [F12,96 = 2.55; p < 0.01]. Infusions of galanin i.c.v. or locally at a lower dose of 0.5 nmol had no significant effects on basal histamine levels in the vHipp or mPFC (data not shown).

4. Discussion The major finding of the present study is that galanin infused i.c.v. or intracerebrally in awake rats caused a dose-dependent decrease in basal extracellular histamine levels in the lateral part of the ventromedial hypothalamic nucleus, whereas only the higher dose of i.c.v. galanin but not the local galanin infusion significantly decreased the histamine levels in vHipp and in mPFC. To date, the only neurochemical study investigating the effects of galanin on histamine was performed in brain slices and synaptosomes from rat cerebral cortex, striatum, hippocampus and hypothalamus, measuring K+ -evoked release of preloaded [3 H]-histamine [2]. Thus, porcine galanin (0.3 ␮M) significantly inhibited histamine release induced by 25 mM K+ in slices and synaptosomes from hypothalamus and hippocampus, but not from cerebral cortex and striatum. In this respect, our data confirm the in vitro results of Arrang et al. [2] for the direct inhibitory action of galanin on histamine release in the rat hypothalamus. It was suggested that these effects of galanin are mediated directly by the inhibitory presynaptic galanin heteroreceptors [2]. Indeed, hypothalamic nuclei express mRNA for all three galanin receptors at high to moderate levels as shown for GalR1 [6,22], GalR2 [22] and for GalR3 receptors [20,31]. However, it should be noted that these in situ hybridization data demonstrate that galanin receptors are expressed by various populations of hypothalamic neurons rather than they are present on the histaminergic afferents to the hypothalamus. The same is likely valid for the distribution of galanin receptors in the hippocampus and frontal cortex. For example, in our previous study, we have shown that galanin plays a differential role in modulating cholinergic transmission in the ventral and dorsal hippocampus and provided further evidence that the effects of galanin are unlikely to be mediated via galanin autoreceptors on the cholinergic terminals

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Fig. 3. Effects of galanin i.c.v. and local infusions on histamine levels in (A) vHipp and (B) mPFC. Only galanin i.c.v. caused minor but significant ( p < 0.001;  p < 0.05) decreases in basal histamine levels in these two structures, whereas local galanin infusion was without effect.

but rather via indirect mechanisms involving hippocampo-septohippocampal loops, attenuation of the excitability of the principal cells, or modulation by galanin containing vasopressin terminals [38]. In line with these findings, it can be hypothesized that the present in vivo data showing that i.c.v. galanin causes temporal decreases in basal extracellular histamine levels in the VMHVL and also in the vHipp and mPFC most likely via direct inhibition of histaminergic neurons expressing galanin receptors in the TMN or indirectly, by decreasing excitability of other neurotransmitter feedback loops projecting to the TMN. The direct action of galanin on histaminergic neurons is also supported by earlier electrophysiological data in brain slices showing that galanin (0.1 ␮M) markedly reduced (by 65%) the firing rate of action potentials of the histaminergic neurons in the TMN [26]. In the rat brain, only some subpopulations of TMN histaminergic neurons are immunoreactive to galanin [14,17] and galanin is not co-localized with histamine in the human TMN [35]. Galanin hyperinnervation was observed in the brains of Alzheimer’s disease patients [21] and in corresponding transgenic mice models [4,5,21]. In this respect, abnormal galanin function may contribute to impaired cognitive performance via decreased cholinergic transmission as reported elsewhere [23] and also by decreasing histaminergic signalling in the PFC and hippocampus. In addition, galanin-induced decrease in histamine levels in the lateral part of the ventromedial hypothalamic nucleus provide a further support for a role of galanin in stimulating feeding behaviour, as it was shown that histamine suppresses feeding, whereas inhibition of histamine synthesis increases food intake (for review, see [1,7,8]). Taken together, the present findings show that central administration of galanin decreased the basal extracellular histamine levels in major histamine projecting areas: ventromedial hypothalamic nucleus, ventral hippocampus and medial prefrontal cortex of awake rats. However, these effects were less prominent than those observed for 5-HT [12] and ACh [38] in the ventral hippocampus and NA and cAMP [36] in the mPFC following i.c.v. and/or local galanin infusions.

Conflict of interest The authors have no conflict of interest to declare.

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