Hydroxyzine prevents isolation-induced vocalization in guinea pig pups: comparison with chlorpheniramine and immepip
Introduction
Guinea pigs mainly rely on vocal communication to maintain their social group structure (King, 1956). Infant guinea pigs exhibit high rates of vocalization when transiently separated from their mother in an unfamiliar environment (Pettijohn, 1979, Hennessy and Ritchey, 1987). These separation-induced distress calls are mainly audible sounds. Introduction of the mother has been shown to quieten the isolated pup and to suppress the hypothalamo–pituitary–adrenal and sympathetic activation concomitant to this separation (Hennessy and Ritchey, 1987, Hennessy et al., 1989). Moreover, the calls can be reduced by drugs used to treat affective disorders (Molewijk et al., 1996). Most mammals exhibit separation-induced vocalization and the potential application of this phenomenon in laboratory animals as a model of affective disorder has been recognized for at least two decades (Katz, 1981). Whilst separation-induced vocalization in rat pups has indeed been used as a model for screening anxiolytic drugs for over a decade (Gardner, 1985, Insel and Winslow, 1991, Miczek et al., 1995), this paradigm in guinea pig pups was originally studied in relation to development of social bonding (Herman and Panksepp, 1978, Panksepp, 1998). However, recently, interest has been increasing in using separation-induced vocalization in guinea pigs as an animal model to screen drugs that possess potential anxiolytic and/or antidepressant activity (Molewijk et al., 1996, Rupniak et al., 2000, Steinberg et al., 2001). A preference for using this species over the rat is based on several arguments, such as similarities between guinea pig and human receptors, e.g., 5-HT1D or NK1, and importantly, the fact that in contrast to rat or mice pups, guinea pig pups are relatively mature at birth. Therefore, physiological/pharmacological studies in pups of this species may be more confidently extrapolated to adults (Ibuka, 1984, Molewijk et al., 1996).
Brain histaminergic systems are known to regulate important integrative nervous system functions, like food intake, fluid balance, temperature regulation and arousal (Brown et al., 2001). Moreover, several studies support a regulatory role for brain histaminergic systems in stress, particularly in the neuroendocrine regulation of stress hormones (Knigge and Warberg, 1991), which has implications for anxiety or even depression (see Brown et al., 2001, Ito, 2000 for review). Postsynaptic H1 and presynaptic H3 receptors are believed to play a key role in this regulation (Soe-Jensen et al., 1993, Yanai et al., 1995, Westerink et al., 2002). Thus, histaminergic neurotransmission via H1 and/or H3 receptors is theoretically an obvious target mechanism to modulate transient maternal-separation-induced HPA axis activation and distress calls in guinea pig pups.
To our knowledge, there are no published findings on the consequence of brain histaminergic modulation on transient maternal-separation-induced vocalization in guinea pig pups. Thus, the present study was aimed at exploring the effect of selected H1 and H3 ligands in this paradigm. The following histamine ligands were evaluated: hydroxyzine (ATARAX), an H1 antagonist, which has been widely used for its tranquilizing and anxiolytic activity in premedication for surgery and anxiety disorders (Argyropoulos et al., 2000, Bandelow et al., 2002, Khalid-Khan et al., 2002); chlorpheniramine, a prototypical selective H1 antagonist (Nicholson et al., 1991) and immepip, a brain-penetrating and selective H3 agonist (Jansen et al., 1998, Lamberty et al., 2003). In addition, imipramine, fluoxetine and chlordiazepoxide, which are all reported to be active in this paradigm (Rupniak et al., 2000, Steinberg et al., 2001), were included, to validate the testing conditions.
Section snippets
Animal housing
Dunkin Hartley guinea pig dams with a litter of at least three pups aged approximately 24 h old, were purchased from Harlan. On arrival, each guinea pig dam with litter was assigned to an open-topped plastic cage (38×54×29 cm high) with solid floor. Wood shavings were provided as bedding material and sterile shredded paper was provided for nesting. Standard guinea pig diet and tap water were freely available. Guinea pigs remained in their maternal groups throughout the study.
Procedure
All vocalization
Results
As shown in Fig. 1, hydroxyzine, 4.3 to 14.3 mg/kg (corresponding to 10−5, 1.8 and 3.2×10−5 mol/kg) dose-dependently decreased the duration of vocalization [ANOVA, F(3,20)=6.21, P<0.005]; the dose of 14.3 mg/kg was found to be significantly different from control animals (Dunnett test, P<0.01). In contrast, neither chlorpheniramine, 2 to 16 mg/kg, nor immepip, 5 to 20 mg/kg, had any significant effect on maternal-separation-induced vocalization in pups [ANOVA, F(4,37)=0.69, P>0.05 and F
Discussion
The present study was conducted to investigate a possible role of the histaminergic system in separation-induced vocalization in guinea pig pups by determining the effects of drugs acting at histamine receptors. The main finding was that hydroxyzine dose-dependently suppressed vocalization but neither chlorpheniramine nor immepip was active. These contrasting effects appear to suggest that additional nonhistaminergic actions may be involved in the observed activity of hydroxyzine.
The positive
Acknowledgements
The authors are grateful to Mrs. Julie Connell for setting up the experimental procedure and to Mrs. Sabine Feraille for her technical assistance.
References (45)
- et al.
The psychobiology of anxiolytic drugs: Part 2. Pharmacological treatments of anxiety
Pharmacol. Ther.
(2000) - et al.
The physiology of brain histamine
Prog. Neurobiol.
(2001) Distress vocalization in rat pups. A simple screening method for anxiolytic drugs
J. Pharmacol. Methods
(1985)- et al.
The elevated T-maze as an experimental model of anxiety
Neurosci. Biobehav. Rev.
(1998) - et al.
The influence of maternal separation on plasma concentrations of ACTH, epinephrine, and norepinephrine in guinea pig pups
Physiol. Behav.
(1989) - et al.
Effects of a novel potential antidepressant on the behavior and cortisol levels of isolated guinea pig pups
Pharmacol. Biochem. Behav.
(2001) - et al.
Effects of morphine and naloxone on separation distress and approach attachment: evidence for opiate mediation of social affect
Pharmacol. Biochem. Behav.
(1978) Ontogenesis of circadian sleep–wakefulness rhythms and developmental changes of sleep in the altricial rat and in the precocial guinea pig
Behav. Brain Res.
(1984)- et al.
Species-related pharmacological heterogeneity of histamine H (3) receptors
Eur. J. Pharmacol.
(2001) The role of brain histamine in acute and chronic stresses
Biomed. Pharmacother.
(2000)
In vivo modulation of rat hypothalamic histamine release by the histamine H3 receptor ligands, immepip and clobenpropit. Effects of intrahypothalamic and peripheral application
Eur. J. Pharmacol.
Dorsal periaqueductal gray-induced aversion as a stimulation of panic anxiety: elements of face and predictive validity
Psychiatry Res.
Animal models and human depressive disorders
Neurosci. Biobehav. Rev.
H3 agonist immepip markedly reduces cortical histamine release, but weakly promotes sleep in the rat
Pharmacol. Res.
Pharmacological blockade or genetic deletion of substance P (NK1) receptors attenuates neonatal vocalisation in guinea-pigs and mice
Neuropharmacology
Cetirizine: actions on neurotransmitter receptors
J. Allergy Clin. Immunol.
Auto-inhibition of brain histamine release mediated by a novel class (H3) of histamine receptor
Nature
World Federation of Societies of Biological Psychiatry (WFSBP) guidelines for the pharmacological treatment of anxiety, obsessive–compulsive and posttraumatic stress disorders
World J. Biol. Psychiatry
5-HT receptors and anxiolytic drugs
5-HT2 receptor antagonism in dysthymic disorder: a double-blind placebo-controlled study with ritanserin
Acta Psychiatr. Scand.
Do animal models of anxiety predict anxiolytic-like effects of antidepressants?
Psychopharmacology
4-(2-Chloro-4-methoxy-5-methylphenyl)-N-[(1s)-2-cyclopropyl(3-fluoro-4-methylphenyl)ethyl]5-methyl-N-(2-propynyl)-1,3-thiazol-2-amine hydrochloride (SSR125543A), a potent and selective corticotrophin-releasing factor (1) receptor antagonist: II. Characterization in rodent models of stress-related disorders
J. Pharmacol. Exp. Ther.
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Pharmacological and methodological aspects of the separation-induced vocalization test in guinea pig pups; A systematic review and meta-analysis
2015, European Journal of PharmacologyCitation Excerpt :In the guinea pig pup vocalization test, hydroxyzine reduced total duration of calls, whereas the prototypic H1 receptor antagonist chlorpheniramine was inactive. The authors pointed out that additional non-histaminergic effects are probably involved in the tranquilizing action of hydroxyzine (Lamberty and Gower, 2004). The two histamine H3 receptor agonists tested, showed mixed results (Yokoyama et al., 2009; Lamberty and Gower, 2004).
Neuroendocrine Regulation of Anxiety: Beyond the Hypothalamic-Pituitary-Adrenal Axis
2016, Journal of NeuroendocrinologyAnxiety
2015, CONTINUUM Lifelong Learning in Neurology
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AJG is presently Consultant Pharmacologist, Holly Lodge, Gislingham, Suffolk, IP238JS, England.