ANXITANE^® tablets reduce fear of human beings in a laboratory model of anxiety-related behavior

Abstract

Anxiety and fear are common underlying factors in many canine behavior problems that impair the human–pet bond and often result in abandonment, relinquishment, or euthanasia. A combination of behavioral and pharmacological interventions is used to ameliorate the behavioral signs associated with anxiety-related behaviors in dogs, but there continues to be need for effective interventions. The current study examined the effects of the nutraceutical ANXITANE^® (l-Theanine) chewable tablets on fear of unfamiliar human beings. We first characterized dogs as anxious on the basis of the existence of a fear response to human beings in their home-pen. We then demonstrated that dogs characterized as anxious (N = 10) showed reduced interaction with an unknown human being as compared with normal controls (N = 7). The effect of an administration of ANXITANE^® tablets (N = 5) on these anxious Beagle dogs was compared with placebo (N = 5). Objective behavioral measures of anxiety were obtained using an open-field test, a human interaction test, and an actiwatch protocol that allowed monitoring of activity over 24-hours. The ANXITANE^® tablets-treated dogs showed greater human interaction and approach than the placebo control group, and no side effects related to treatment, including motor stimulant or sedative effects, were seen. The current study suggests that ANXITANE^® tablets are effective for reducing fearful behavior toward unfamiliar human beings in dogs and supports their use for treating anxiety-related behaviors.

Introduction

Fear and anxiety are underlying factors in many behavior problems for which animals are referred to veterinary behaviorists. Examples include separation anxiety, noise phobias (e.g., thunderstorms), housesoiling in response to an anxiogenic stimulus, and many forms of aggression (Denenberg et al., 2005). In addition to the physical damage that the pet may cause to the household, itself, or others, fear and anxiety also lead to physiological changes that may affect the pet's health, including stimulation of the hypothalamic-pituitary-adrenal axis and increased release of noradrenalin, adrenaline and, in chronic states of anxiety, prolactin (Clark et al., 1997, Hennessey et al., 1998, Hennessy et al., 2001, Dreschel and Granger, 2005, Frank et al., 2006, Pageat et al., 2007, Beata and Schwobthaler, 2009). Chronic stress, which can result from untreated or ongoing anxiety, can contribute to a wide range of medical conditions including gastrointestinal, dermatologic, and urinary tract disorders, as well as immunosuppression (Siebert and Landsberg, 2008). Thus, effective treatment of anxiety disorders is not only a necessity for the health and welfare of the pet, but also to improve the problem for the owner and ultimately restore the bond between owner and pet. This, in turn, can help reduce abandonment or euthanasia of the pet (Miller et al., 1996, Lue et al., 2008). In fact, behavior problems are the most common cause of canine relinquishment (Houpt and Reisner, 1996, Miller et al., 1996, Gorodetsky, 1997).

Both clomipramine (a tricyclic antidepressant) and fluoxetine (a serotonin reuptake inhibitor) are licensed in the United States for the treatment of separation anxiety in dogs as an adjunct to a program of behavior modification (Sherman and Mills, 2008). These drugs may take a month or longer to achieve their full therapeutic effect limiting their short-term utility, although clinical effects might begin to be seen in as early as 1 week (Frank et al., 2006, Simpson, 1997). Side effects may include gastrointestinal signs such as decreased appetite. At high doses, or when used in combination with other drugs that enhance serotonin transmission, the pet can develop a serious and potentially fatal condition known as serotonin syndrome, which includes signs of confusion, agitation, hyperthermia, tachycardia, nausea, diarrhea, muscle tremors, and coma. Therefore, these drugs should not be used concurrently with monoamine oxidase inhibitors, such as amitraz and selegiline, or with other antidepressants (Crowell-Davis and Murray, 2006). Although not licensed for the treatment of anxiety disorders in dogs, benzodiazepines are commonly used for their short-term or immediate effects, such as before veterinary visits or as adjunctive therapy in the treatment of separation anxiety or storm phobias (Herron et al., 2008, Sherman and Mills, 2008). However, the duration of effect, dose, and therapeutic efficacy is not well established in dogs and the potential side effects, including ataxia, sedation, paradoxical excitation, disinhibition (leading to an increased possibility of aggression), and a rebound effect on withdrawal (Plumb, 2005, pp. 238), often result in treatment discontinuation (Herron et al., 2008). Numerous natural products are also marketed for the treatment of anxiety in dogs; however, few, if any, of these products have any documented evidence of efficacy in veterinary behavior with the exceptions of DAP® (Ceva Animal Health, Manchester, MO), a pheromone product that has a calming effect on some dogs (Levine et al., 2007, Mills et al., 2006, Tod et al., 2005), and, alpha-casozepine, (Schering-Plough, Middlesex, UK), a bovine milk protein that did not differ in the reduction of EDED (evaluation of dog's emotional disorder) when compared with selegiline (Beata et al., 2007). The exceptions notwithstanding, it is clear that there is a limited availability of therapeutics for canine anxiety disorders and a there is continued need for novel safe and effective products.

ANXITANE^® tablets (Virbac Animal Health, Fort Worth, TX) are a nutraceutical containing 99.95% pure l-theanine (N-ethyl-l-glutamine), an amino acid found largely in green tea. l-theanine may increase concentrations of gamma aminobutyric acid, an inhibitory neurotransmitter, and increase brain serotonin and dopamine (Nathan et al., 2006). ANXITANE^® tablets are palatable and showed no side effects when given at 5 times the recommended dose (http://www.virbacvet.com/images/resources/other/anxitane_firstintention.pdf). In a preliminary study of 12 dogs with noise phobias, dogs treated with ANXITANE^® tablets plus behavior modification showed greater behavioral improvement than dogs treated with behavior modification alone. The differences, however, did not reach statistical significance (Berteselli and Michelazzi, 2007). In a nonplacebo controlled open-label clinical trial, there was a significant reduction in global anxiety scores, including a reduction in fear of people (in the street) after a 2-month treatment with ANXITANE^® tablets (Kern, 2005, pp. 191-196), suggesting ANXITANE^® tablets are effective for treating anxiety-related behaviors.

The primary objective of this study was to obtain data on the efficacy of ANXITANE^® tablets compared with placebo control on an anxiety-related behavior in a laboratory model; more specifically, the fear of unknown human beings. We used an open-field and a human-interaction test to objectively assess the effects of ANXITANE^® tablets on fear of human beings and behavioral activity (Siwak et al., 2001). To identify fearful dogs, we developed a novel assessment on the basis of the occurrence of a fear response to human beings in their home-pens and on interaction duration with an unknown human being in the human-interaction test. We previously reported that dogs that show a fear response to human beings in their home-pen also show reduced interactions with human beings in the human-interaction test (Landsberg et al., 2009). In the current study, we hypothesized that treatment with ANXITANE^® tablets would reduce the fear response to human beings, which would be evident by increased interaction with and approach to the human being in the human-interaction test.