A Cavalier King Charles dog with shadow chasing: Clinical recovery and normalization of the dopamine transporter binding after clomipramine treatment

A Cavalier King Charles dog with shadow chasing: Clinical recovery and normalization of the dopamine transporter binding after clomipramine treatment

Journal of Veterinary Behavior (2010) 5, 345-349 CASE REPORT A Cavalier King Charles dog with shadow chasing: Clinical recovery and normalization of...

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Journal of Veterinary Behavior (2010) 5, 345-349

CASE REPORT

A Cavalier King Charles dog with shadow chasing: Clinical recovery and normalization of the dopamine transporter binding after clomipramine treatment Simon Vermeirea, Kurt Audenaertb, Andre Dobbeleira,c, Eva Vandermeulena, Tim Waelbersd, Kathelijne Peremansa a

Department of Veterinary Medical Imaging and Small Animal Orthopaedics, Faculty of Veterinary Medicine, Merelbeke, Belgium; b Department of Psychiatry and Medical Psychology, Faculty of Medical and Health Sciences, Ghent, Belgium; c Department of Nuclear Medicine, Faculty of Medical and Health Sciences, Ghent, Belgium; and d Department of Clinical Biology and Medicine of Small Animals, Faculty of Veterinary Medicine, Merelbeke, Belgium. KEYWORDS: canine obsessive compulsive behavior; in vivo neuro-imaging; clomipramine; dopamine; serotonin; 123 I-FP-CIT

Abstract A 30-month-old female Cavalier King Charles dog was presented with a history of worsening compulsive behavior (shadow chasing). In vivo brain imaging using single-photon emission computed tomography and the dopamine transporter (DAT)-specific radiopharmaceutical 123I-FP-CIT revealed a significantly higher DAT striatal-to-brain ratio. Treatment was started with the tricyclic antidepressant clomipramine 2.5 mg/kg PO, q. 12 hours. After 2 months of medication that resulted in clinical improvement, the DAT binding regained normal values. Ó 2010 Elsevier Inc. All rights reserved.

Introduction The expression of excessive, uncontrollable and repetitive motor behavior is a sign common to stereotypic behavior in animals and to obsessive compulsive disorder (OCD) in human beings. The neurocircuitry of OCD is primarily located in the orbitofrontal cortex and the cortico-striatal-thalamiccortical loops (Stein, 2002; Maia et al., 2008), but other brain areas such as the dorsolateral prefrontal cortex, the anterior cingulate cortex and the amygdala have been included more recently (Friedlander and Desrocher, 2006; Menzies et al., Address for reprint requests and correspondence: Simon Vermeire, Department of Veterinary Medical Imaging and Small Animal Orthopaedics, Faculty of Veterinary Medicine, Salisburylaan 133, 9820 Merelbeke, Belgium; Tel: 32-9-264-7634; Fax: 32-9-264-7793. E-mail: [email protected] 1558-7878/$ - see front matter Ó 2010 Elsevier Inc. All rights reserved. doi:10.1016/j.jveb.2010.07.001

2008). Both serotonergic and dopaminergic neurotransmitter pathways are known to be involved in OCD (Westenberg et al., 2007). Serotonergic involvement is mainly based on the successful pharmacological treatment of OCD with selective serotonin reuptake inhibitors (e.g., fluoxetine) or the induction of compulsive behavior after administration of serotonin (5-hydroxytryptamine [5-HT]) receptor agonists (Vandebroek and Odberg, 1997; Westenberg et al., 2007). Other clinical and preclinical studies additionally provide evidence that the dopaminergic neurotransmitter system (highly concentrated in the striatum) is involved in the pathophysiology of OCD in human beings and stereotypic behavior in animals (Rapoport and Wise, 1988; Kennes et al., 1988; Pitman, 1989; Denys et al., 2004b). Evaluating the dopaminergic system is possible by either (1) peripheral measurements (e.g., dopamine metabolite

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homovanillic acid in cerebrospinal fluid or blood), but the results are seldom straightforward because of the uncertain relationship between peripheral and central processes, or (2) central measurements using in vivo functional imaging modalities such as single-photon emission computed tomography (SPECT). SPECT is a nuclear imaging technique based on the intravenous injection of a gamma ray emitting isotope (mostly 99m Tc or 123I). Detectors on the gamma-SPECT camera rotate around the patient and register these gamma rays. Subsequently, a reconstruction of the acquired data allows crosssectional slice analysis as well as 3-dimensional view of the patient. Together with the radiopharmaceutical 123I-FP-CIT, which is the combination of (1) the radioactive isotope iodine 123 I required for imaging and (2) FP-CIT, a cocaine analogue binding at the dopamine transporter (DAT), SPECT imaging allows evaluating the DATavailability, a biomarker for the dopaminergic neurotransmission (Alvarez-Fischer et al., 2007).

Case description The present case report describes a drug-naive, 30-month-old, 10-kg intact female Cavalier King Charles dog. The problematic behavior was first noticed at 18 months of age, with sporadic fixating and chasing shadows. It was, however, exclusively noticed on one specific wall on which shadows were created by reflections of the sun. During this behavior, the dog did not respond, as she usually use did, to her name or obeyed to basic requests as ‘‘sit’’ or ‘‘down.’’ Repeated signals were necessary to engender compliance. Gradually, additional behaviors, such as excitement and agitation, accompanied by barking, excessive salivation and licking were noticed; these usually started after 2-3 minutes of fixation. The frequency of the behaviors also increased (to maximum of 4 hours a day), along with the level of excitement and agitation. Videotape analysis showed that the behavior also occurred during the absence of the owner. The 3 other dogs in the household did not show any signs of shadow chasing. No abnormalities were noticed on physical, neurological, laboratory, dermatologic, or ophthalmalogic examination. The CBARQ questionnaire (Canine Behavioral Assessment and Research Questionnaire; Hsu and Serpell, 2003) revealed no co-morbid aggression or anxiety. The results of the blood work revealed normal values. The definitive diagnosis of OCD in canines was made on the basis of finding repetitive, stereotypic motor behavior (i.e., shadow chasing) that occurred in a disproportional frequency and duration (Overall and Dunham, 2002; Irimajiri et al., 2009). This case study was approved by the local Ethical Committee of the Faculty of Veterinary Medicine, Ghent University. In this case study, a brain perfusion scan (with 99mTc-ECD), a serotonin 2A receptor scan (with 123I-R91150), and a DAT scan (with 123I-FP-CIT) were performed to check for brain abnormalities and possible involvement of the serotonergic or dopaminergic system. These 3 scans were performed under

general anesthesia (sedation: intravenous [iv] injection of medetomidine hydrochloride [Domitor; Pfizer] 1,000 mg/m2 body surface area 30 minutes before the scan; induction: iv propofol [Propovet; Abbott]; general anesthesia: isoflurane [Isoba; Schering-Plough] on oxygen), using a triple-head gammacamera (Triad, Trionix, Twinsburg, OH) equipped with lowenergy ultra-high resolution parallel hole collimators (8-mm spatial resolution). The dog was scanned weekly for a period of 3 weeks. Acquisition of the perfusion scan was started 30 minutes after 773 MBq 99mTc-ECD was injected iv and it lasted for 20 minutes. This scan is very valuable because it not only reflects the brain neuronal activity, but it can also rule out anatomical brain abnormalities (e.g., hydrocephalus) that may be implicated in OCD. Additionally, scans can be used as anatomical map to evaluate the 5-HT2A receptors scans. For evaluating the serotonergic neurotransmitter system, the SPECT tracer 123I-R91150 (with high affinity and selectivity for the 5-HT2A receptor, which is involved in impulsivity and anxiety) was injected (dose, 133 MBq) 90 minutes before the acquisition (30 minutes). Using a region-of-interest analysis, it was feasible to calculate the 5-HT2A receptor availability in the frontal, temporal, parietal, and occipital cortex, as well as in the subcortical region, a detailed description of which is found in the study by Peremans et al. (2003). Finally, evaluation of the dopaminergic neurotransmission was achieved by means of an iv injection of the highly selective DAT tracer 123I-FP-CIT (dose, 116 MBq), 3.5 hours before the acquisition (30 minutes). Values were compared with the previously calculated normal canine values based on the resolution-independent method of Dobbeleir et al. (Vermeire et al., 2010). In short, regions of interest were drawn over the left and right striatum (S) and over a third region, thus covering almost the whole brain. The calculations were done on the basis of the following formula (Dobbeleir et al., 2005): Striatal to brain uptake ratio

 cm3 in S  counts in S  counts in BG! 3 cm in BG 5 counts in BG cm3 in BG

With counts in background ðBGÞ 5 counts in brain ROI  counts in striatal ROIs and S 5 striatum. No brain perfusion or serotonin 2A receptor abnormalities were noticed. In contrast, the DAT scan revealed significantly higher DAT ratios in left (5 25.98; normal value: 15.39 6 2.38 [mean 6 SD]) and right (5 26.14; normal value: 15.23 6 2.23 [mean 6 SD]) striatum. Treatment was started with clomipramine, a tricyclic agent with both antidepressant and antiobsessional properties blocking the neuronal reuptake of serotonin and

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Shadow chasing: clinical recovery and normalization of the DAT binding

noradrenalin, known to be successful in treating canine compulsive behavior (Ananth, 1986; Rapoport et al., 1992; Hewson et al., 1998; Moon-Fanelli and Dodman, 1998; Seksel and Lindeman, 2001; Overall and Dunham, 2002). Starting dose was 2.5 mg/kg PO, q. 12 hours. A clinical improvement, based on a 10-point comparative rating scale of Rapoport, was noticed after 7 days of treatment (Rapoport et al., 1992). Shadow chasing disappeared almost completely after 3 weeks and, if performed, was easily stopped by calling the dog’s name. The same dose was administered for the following 2 months, with preservation of the clinical improvement. Gluttony (e.g., persistent searching and opening garbage pails) was noticed after 6 weeks of treatment as a single side effect. After 2 months of treatment, a post-therapeutic DAT scan was performed. The new DAT ratios were 10.82 and 12.49 for left and right striatum, respectively, both ratios located closely to or in the normal range. To minimize the gluttony, an attempt was made to reduce the dose of clomipramine without renewal of shadow chasing. A dose of 2.5 mg PO, q. 24 hours was daily alternated with a dose of 2.5 mg PO, q. 12 hours, with success. However, not giving the medication dose resulted in relapse of shadow chasing already after 2 days.

Discussion This case described significantly higher DAT ratios in a dog with shadow chasing. This alteration in the dopaminergic neurotransmitter system is in line with human and animal OCD studies. SPECT imaging studies on the DAT in patients with OCD mainly describe higher ratios, which is similar to our findings (van der Wee et al., 2004; Hesse et al., 2005). High DAT ratios reflect a high binding of the radiopharmaceutical 123I-FP-CIT to DATs. This is possibly because of a low amount of synaptic dopamine that resulted in a reduced occupancy of the DATs, thereby increasing the amount of available DAT on which 123I-FP-CIT can bind, which in turn resulted in an increased DAT ratio. Another interpretation is that higher DAT ratios reflect a compensatory higher DAT density because of increased firing and release of dopamine. This theory of an increased striatal dopaminergic drive is supported by multiple human imaging studies, focusing on the dopamine receptors. These studies indicated low levels of dopamine receptors D1 and D2 binding, secondary to a higher dopamine concentration at the level of the synaptic cleft (Denys et al., 2004a; Olver et al., 2009). This positive correlation between DAT ratios and dopamine concentrations was recently confirmed by a study of Alvarez-Fischer. They demonstrated a significant positive linear correlation between in vivo striatal 123I-FP-CIT ratio measured with SPECT, and post-mortem quantification of dopamine by chromatography of striatal tissue (Alvarez-Fischer et al., 2007). Increased dopaminergic drive is further supported by studies conducted on animal models with OCD (Szechtman

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et al., 1998; Pitman, 1989). These induced models of OCD primarily noticed that rodents treated with D2 and/or D3 dopamine receptor agonists resulted in exhibiting stereotyped behaviors, such as repetitive checking of particular places in open field. This repetitive checking may represent compulsive checking in human beings, which is the most common form of OCD (Rasmussen and Eisen, 1992). Attenuation of the druginduced stereotyped behavior was observed after clomipramine treatment (Szechtman et al., 1998). In this case report, suppression of the shadow chasing was observed after clomipramine treatment. Clomipramine is a tricyclic antidepressant that inhibits the reuptake of mainly serotonin and to a lesser extent of noradrenalin from the synaptic cleft. It is specifically known as drug of choice for canine separation anxiety (King et al., 2000a,b), but has already been used successfully in treatment of canine compulsive behavior such as repetitive tail-chasing, vocalization, and self-mutilation (Ananth, 1986; Hewson et al., 1998; Seksel and Lindeman, 2001; Overall and Dunham, 2002). Although the effect of clomipramine on the serotonergic system is straight forward – clomipramine is the most serotonin-selective tricyclic antidepressant (Boothe, 2001) and its major metabolite (desmethylclomipramine) mainly inhibits the reuptake of noradrenalin (Benfield et al., 1980) – the effect on the dopaminergic system is unclear (Kapur and Remington, 1996). Because of a close interplay between the serotonergic and dopaminergic system, it remains ambiguous whether the normalization of DAT availability after clomipramine treatment noticed in this dog, is a direct (desmethylclomipramine also slightly inhibits the dopamine reuptake; [Benfield et al., 1980]) or indirect effect on the dopaminergic system. This serotonin-dopamine interplay is far from being completely understood, partly because of the different influences (inhibiting or activating), depending on which receptor-type is activated. For instance, it is assumed that 5-HT1A, 5-HT1B, 5-HT2A, 5-HT3, and 5-HT4 receptors act to facilitate dopamine release, whereas the 5-HT2C receptor has an inhibitory effect on the dopamine release. Additional interactions with the noradrenergic system, the inhibitory gamma-amino-n-butyric acid, and the excitatory glutamatergic input could also be confounding factors (Blier, 2001; Di Matteo et al., 2008; Esposito et al., 2008). In our case, clinical improvement was already noticeable after 7 days of medication. Most reports describe clinical improvement within 3-8 weeks of drug (tricyclic antidepressants and selective serotonin reuptake inhibitors) administration. However, Irimajiri et al. (2009) noticed improvement after 2 weeks of administering fluoxetine for canine compulsive disorder (CCD); a study on human beings with panic attacks noticed improvement after 7-21 days (McTavish and Benfield, 1990). This relative long delay in therapeutic effect is thought to be because of the time necessary to desensitize the somatodendritic 1A autoreceptor, responsible for a negative feedback system on the serotonin release. Only when this has happened, increased levels of 5-HT will sustain at

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the level of the synapse and cause clinical improvement (Stahl, 2008). A reduction of postsynaptic receptors (a so-called downregulation), which is a time consuming process, could also be responsible for the delay in clinical effect (King et al., 2000a). A relapse of shadow chasing was noticed after discontinuation of the medication. This is in line with the literature, as well as the age of onset in our case which is mostly situated around the period of social maturity (Ananth, 1986; Hewson et al., 1998; Overall and Dunham, 2002). In general, tricyclic antidepressants are well tolerated and have minimal side effects in canine patients compared with human beings. Gastrointestinal signs (diarrhea, vomiting, colitis) are among the most common side effects, followed by sedation, anorexia, weight gain, epileptic seizures, cardiac effects (arrhythmias), and anecdotally described pancreatitis (Pouchelon et al., 2000; Reich et al., 2000; Seksel and Lindeman, 2001; Luescher, 2003; Kook et al., 2009).

Conclusion This is the first report demonstrating a significantly higher DAT binding in a dog with shadow chasing, emphasizing the role of dopamine in CCD. Furthermore, clinical improvement and normalization of the DAT level were achieved after treatment with the clomipramine. Whether clomipramine acts directly on the dopaminergic system or indirectly through other neurotransmitters (serotonin, noradrenalin, gammaamino-n-butyric acid, glutamate) remains unclear, and should be elucidated in future studies.

Acknowledgments This case was supported by a scientific grant of the Ghent University Special Research Fund (BOF/07/24 J/152).

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