As previously mentioned in this chapter, aggressive behaviour is considered normal as long as it fits within the canine ethogram. However, distinguishing different types of aggression remains susceptible to subjective behavioural analysis. The challenge also remains to differentiate impulsive aggression from aggression originating from an anxiety disorder. In that respect, functional brain imaging was carried out to evaluate the 5-HT_2A receptor as an objective biomarker for differentiating impulsive-aggressive dogs from dogs with anxiety disorders. In the following study, a dual goal was aimed at. First, increasing the knowledge in canine behavioural problems will safeguard the human-dog bond which is under pressure in case of aggressive behaviour. Aggression, but also anxiety leading to aggressive behaviour, results in a low quality of life and expands the previously mentioned welfare issues to a safety issue as well. A second goal was to further investigate the value of behaviourally disordered dogs as a model for human behavioural disorders. Previous SPECT research already pointed out the value of this canine model in diagnostic and therapeutic aspects of impulsive-aggressive, anxiety-disordered and compulsive-disordered dogs (Peremans et al. 2003, 2005; Vermeire et al. 2009a, b, 2010, 2012).

Sixty-six dogs were included and divided in three equally sized groups, i.e. 22 dogs with impulsive-aggressive behaviour (18 M (7 neutered), 4 F (all intact); mean age 2.73 years; range 12–84 m; breeds included are 3 Rottweilers, 3 Belgian shepherds, 2 Berger de Beauce, 2 golden retrievers, 2 Great Danes, 2 Labrador retrievers, 2 Dobermans, 1 Caucasian shepherd, 1 Jack Russell, 1 bull mastiff, 1 pit bull, 1 mongrel and 1 English bulldog), 22 dogs with severe anxiety (18 M (10 neutered), 4 F (2 neutered); mean age 3.67 years; range 14–86 m; breeds included are 4 mongrels, 3 golden retrievers, 3 Border collies, 2 German shepherds, 1 Staffordshire bull terrier, 1 Dutch Decoy Dog, 1 Berger de Beauce, 1 Bernese mountain dog, 1 Bleu de Gascogne, 1 Bordeaux dog, 1 boxer, 1 English bulldog, 1 miniature pinscher and 1 Shar Pei), and 22 normally behaving dogs (14 M (3 neutered), 8 F (all intact); mean age 3.17 years; range 12–84 m; breeds included are 4 German shepherds, 4 mongrels, 3 Border collies, 3 Belgian shepherds, 2 Boerboels, 2 Dutch Decoy Dogs, 1 dachshund, 1 French bulldog, 1 Rottweiler and 1 Labrador retriever). As in the previous study, ECVBM specialists selected the patients and categorised them based on behavioural analysis and a validated canine behavioural questionnaire CBARQ (Hsu and Serpell 2003). Possible neurological or physical illnesses were excluded (Haug 2008; Sherman and Mills 2008).

Age correction was performed for previously mentioned reasons. The comparison of the 5-HT_2A receptor binding revealed significant changes in both impulsive-aggressive and anxious behaving dogs in the frontal, temporal and occipital cortices (both hemispheres). Those changes were in opposing directions, with increased 5-HT_2A receptor binding for the impulsive-aggressive dogs and decreased 5-HT_2A receptor binding for the anxiety-disordered dogs, compared to the normal group. Brain perfusion changes were again excluded as the cause of the altered serotonin 2A receptor binding indices as no correlations were found between perfusion and radioligand data. The receiver operating characteristic (ROC) analysis of the data determined that the cut-off values for the frontal cortex had the highest statistical power to differentiate the separate groups (Fig. 26.6), a not surprising observation as the (pre)frontal cortex has been extensively identified as the key regulating region in behaviour (Fuster 1997). This region also contains the highest density of 5-HT_2A receptors of the brain in the human and canine species (Busatto et al. 1997; Peremans et al. 2002b), strengthening the role of the frontal cortex in behaviour. It is essential to realise that the proposed cut-off value is not rigid and a higher or lower cut-off value can be chosen depending on whether priority is given to risk assessment or to animal welfare issues. In case of risk assessment, one would prefer a high sensitivity (to avoid impulsive-aggressive animals ending in families); however, this would be at the expense of the specificity (more nonaggressive animals being labelled as impulsive aggressive). In case of animal welfare, one would prioritise a lower sensitivity with a higher specificity to avoid unnecessary euthanasia (Vermeire et al. 2011).

Variations in the 5-HT_2A receptor gene have been suggested to play a role in anxiety and impulsive traits in man and could in theory affect radioligand binding due to conformational or functional alterations (Bjork et al. 2002; Giegling et al. 2006; Nomura et al. 2006; Unschuld et al. 2007). However, no variants in the HTR_2A gene were detected in aggressive golden retrievers, making a genetic modification as the cause of alterations found in the impulsive-aggressive dogs less likely (van den Bergh et al. 2008). No comparative studies have been performed in the anxiety-disordered dog up till now.

A correct differentiation of the underlying 5-HT_2A receptor imbalance is important in view of psychopharmacological and behavioural treatment choice (Moresco et al. 2007; Peremans et al. 2008; Vermeire et al. 2010; Zanardi et al. 2001). Hereby, the 5-HT_2A receptor neuroimaging and semiquantification is a more objective means to differentiate behaviour according to its biological underpinnings, in addition to the more subjective behavioural analysis.

SSRIs are currently used to manage impulse control disorders and/or aggression in man and dogs (Dodman et al. 1996; Fuller 1996). In a pilot SPECT study the effect of a single dose of citalopram on the canine serotonin reuptake transporters (SERT) was evaluated with the radioligand [¹²³I]-labelled 2 h-carboxymethoxy-3 h-(4-iodophenyl)tropane (¹²³I β-CIT), a nonselective competitive antagonist of norepinephrine, dopamine and serotonin transporters (Peremans et al. 2006) (Fig. 26.7a, b). A decreased binding was observed compared to the blank scan, providing proof that the SSRI, citalopram, binds to the canine serotonin reuptake transporters.

Nine impulsive-aggressive dogs were then treated daily with SSRIs (citalopram, 1 mg/kg) and were re-examined at 6 weeks of treatment (no behaviour therapy was allowed in this period). Both perfusion and 5-HT_2A receptor radioligand binding were evaluated, and behavioural changes were assessed before and after treatment.

After treatment, a significant decreased binding of the 5-HT_2A radioligand was evident in the frontotemporal and to a lesser extent in the occipital area without alterations in regional perfusion (Peremans et al. 2005). These findings show also resemblance with the results of a 5-HT_2A receptor PET study in depressed patients, where decreased binding of ¹⁸F-setoperone was found in the cortex of young patients with depression, treated for 6 weeks with paroxetine (Meyer et al. 2001). An increased synaptic serotonin concentration due to chronic blockade of the SERT seems the most logical explication for the observed decreased radioligand binding, the decrease being invoked by either compensatory downregulation of the receptors or competition of endogenous serotonin with the radioligand. The extent of clinical behavioural recovery paralleled the extent of reduction of 5-HT_2A binding index. The possibility has been raised that even though downregulation of the receptors may not be a therapeutic effect in itself, the decreased numbers of 5-HT_2A receptor may reduce the agonistic impact on these receptors (Meyer et al. 2001). More, it is well known in human depression that a lag period exists between initiation of SSRI treatment and the onset of their antidepressive effect. Initial agonistic activation of the 5-HT_2A receptor by blocking the SERT has been pointed at as one of the culprits for this phenomenon. In this regard, augmentation with a 5-HT_2A-receptor antagonist has been proposed as a potential alternative treatment strategy (Nemeroff 2005).

This study represents a nice example of the potency of functional imaging to evaluate receptor alterations after drug interventions in the canine brain and the therapeutic impact of psychopharmaca.