Genetics & Neurochemistry of Fear and Anxiety
Karen L. Overall, MA, VMD, PhD, DACVB
Center for Neurobiology and Behavior, Psychiatry Department, School of Medicine, University of Pennsylvania
Philadelphia, PA, USA

Anxiety disorders are among the most common health concerns in human medicine [26], as they are for pet dogs. Furthermore, like humans, dogs with one anxiety-related diagnosis frequently have other anxiety-related diagnoses [1, 2], suggesting the existence of some putative genetic or neurochemical liability [3, 4]. Neuroanatomical studies of panic disorder are closely linked to those pertaining to fear and to peripheral responses. The extent to which learning and memory play roles in fear, anxiety, phobias, and OCD has been poorly studied because it is difficult to do so given the complexity of the neurochemical systems involved. What is known is that: (1) a functioning amygdala is required to learn fear, (2) a functioning forebrain is required to unlearn fear (i.e., to effect habituation), and (3) many human fears appear to be the result of the inability to inhibit a fear response. Accordingly, it has been hypothesized that fear is, in part, due to chronic amygdala over-reaction and, or failure of the amygdala to turn off after the threat has passed. The specific neuroanatomy of a fear response involves the locus ceruleus (LC), the principal norepinerphrinergic (noradrenergic) nucleus in the brain. Dysregulation of the LC appears to lead to panic and phobias in humans [5]. The LC directly supplies the limbic systems and may be responsible for many correlated "limbic" signs. Patients with true panic and phobic responses are more sensitive to pharmacologic stimulation and suppression of the LC than are controls [5-7]

Although there are few quantitative clinical studies on anxious dogs, those focusing on separation anxiety [1] and obsessive-compulsive disorder [OCD] [2] have shown that a high percentage of affected patients experience other, co-morbid anxiety disorders (~90% and 75%, respectively). In the case of separation anxiety, the co-morbid diagnosis is usually noise or thunderstorm phobia. While the data are few owing to the nature of retrospective studies, heightened noise reactivity or fear as a young dog may predispose the individual to the later development of separation anxiety [1]. If so, this strongly suggests that associations between various anxiety and mood conditions (e.g., depression and anxiety; panic and social phobias, etc.) may be the result of increased risk that is either the direct result of a shared underlying cause of the initial disorder, or the indirect result of neurochemical and, or molecular changes that occur because of the initial disorder. Specific examination of findings regarding separation anxiety, noise phobia, and OCD follow.

Separation anxiety and noise phobia: Separation anxiety occurs significantly more often as a solitary diagnosis than would be expected under random conditions, and noise phobias occur significantly less often as a solitary diagnosis under the same conditions. These findings support the concept that although they share non-specific signs, the diagnoses are separate entities. Furthermore, the finding that the observed frequency of a diagnosis of separation anxiety + thunderstorm phobia, and of separation anxiety + noise phobia was significantly is lower than expected were they independent, but that the observed frequency of a diagnosis of thunderstorm phobia + noise phobia, and of separation anxiety + noise phobia + thunderstorm phobia is significantly higher than expected, were the diagnoses independent, supports 2 important conclusions [1]. First, noise and thunderstorm phobia are different from each other and affect the frequency and intensity of related behaviors in co-morbid diagnoses differently. Second, the interaction of multiple pathological responses to noise likely either reflects an altered, dysfunctional, underlying neurochemical substrate, or is the result of one.

The conditional probability that a patient has separation anxiety, given that they have noise phobia is high (88%) and approximately the same as if they have thunderstorm phobia (87%). However, the probability that a patient has noise phobia is higher (74%) than the probability that they have thunderstorm phobia (61%), given that either have separation anxiety. These data, combined with the finding that the probability of having a noise phobia given a thunderstorm phobia is not equivalent to the converse (90% v. 76%), supports the hypothesis that neurochemical responses to noise are different from those to thunderstorms, if the behavioral phenotypes or endophenotypes are manifestations of repeated exposure and LTP. The property of unpredictability / uncertainty associated with thunderstorms may have a role in shaping the neurochemical and behavioral responses to anxiety provoking situations, suggesting future areas of exploration for understanding anxiety-related responses in dogs.

Obsessive-compulsive disorder (OCD): Although the underlying etiology of OCD is unclear for both dogs and humans, the symptomology and pathophysiology are striking. OCD is characterized by repetitive, ritualistic behaviors, in excess of any required for normal function, the execution of which interferes with normal, daily activities and functioning. Inherent in this description is a behavior that is exaggerated in form as well as duration. The behavior can be perceived by the human patient as abnormal and may be controlled to the extent that the behavior is performed only minimally, or not at all, in the presence of others. This is probably also true for domestic animals. Dogs who flank suck or tail chase may, after frequent reprimands and corrections, remove themselves view, then commit the behavior elsewhere. Upon approach, the behavior ceases, to be begun again when no one is watching or when the animal removes himself from view. This study supported the existence of this evasive behavior pattern. The presence of a cognitive component suggests that the problem is rooted at a higher level than the behavior, alone, may indicate (i.e., the Dobie is flank-sucking, but not because anything is 'wrong' with his flank). Such examples support that obsessions are a valid component of OCD. We evaluate obsessions in humans by asking them about ruminant, invasive thoughts. The verbal or written component of the response is a translation of the rumination--it is not identical to the ruminant thought, itself. It is inappropriate to apply a criteria to one species that has a divergent phylogeny that prohibits the use of that tool or criteria.

Not all dogs and cats fit a volitional pattern where they can at least temporarily stop their compulsive behaviors. As noted in this paper some patients exhibit continuous stereotypic and ritualistic behavior regardless of training, distraction, or canine, feline, or human companionship. This is an important point because clients and veterinarians may attribute the non-specific signs associated with OCD to boredom. Boredom is an oft invoked and seldom proven "cause" of OCD. In situations involving minimal stimulation and exercise, such as some laboratory and other confinement conditions, animals may spin or chase their tails because they are bored. 32-35 In such cases, increased stimulation through exposure to human or canine companions, toys, music, exercise, or rooms with views of activity should diminish or stop this behavior.

It is not necessary that the behavior be continuously witnessed for the animal to have OCD, but it is requisite that the offending behavior substantially interfere with normal functioning in the absence of physical restraint. If the desire to exhibit the behavior is present, despite restraint because of punishment, training, or physical incarceration, the condition is present. The key is that if such control is removed and the animal could commit the behavior he will commit the behavior. Ignoring this crucial point will result in under-diagnosis of OCD and under-estimation of its frequency in canine and feline populations.

Obsessive-compulsive disorder in humans frequently appears in adolescence, at the onset of social maturity, and continues through mid-life. Human patients are generally clustered into four major groups: washers, checkers, ruminators, and an indistinct group of primary obsessive slowness. In dogs and cats, OCD also appears during this indistinct period of social maturity (Range for dogs: 12-36 month, average ~18-24 months; Range for cats: 24-48 months, average ~30-36 months) left untreated, whether by behavioral or pharmacologic intervention, it worsens. Given the relatively early age at which this condition develops and the probability of profound deterioration when left untreated, young animals should be routinely screened for OCD and treated appropriately early. Dogs and cats from families having a history of OCD should be carefully watched for its appearance, albeit possibly a different form than that exhibited by their relatives.

One recent study focuses on the phenomenology of OCD and compared both cats and dogs [2]. Of 23 cats studied, 10 manifest their particular form of OCD after some physical trauma or social upheaval, and the OCD in these cases may have occurred with intercat aggression or elimination complaints. Siamese were ranked as the second most common breed in this study. While this does not differ substantially from their rank in the overall VHUP population (3rd), it is dramatically different from the breed rank in the Behavior Clinic population (22nd), suggesting that when a Siamese cat is seen in the Behavior Clinic it is like to be because of behaviors associated with OCD. Siamese cats were most often involved in ingestion of fabric, supporting other findings regarding increased prevalence of OCD in Oriental-breed cats [8], but there were too few members of each breed on which to base broad, feline breed-related conclusions. It's interesting that the one Bengal cat showed self-mutilation and urine marking. These are both anxiety related conditions and may have some association with the relatively recent domestication history of this breed. Most cats affected with OCD exhibit self-mutilation or excessive grooming. No cats were reported to hallucinate. However, "hallucinations" may have been associated with tail chasing. Most clients with these cats reported that the cats acted as if something was on or near the cat's tail and that the cat was either trying to chase this entity or escape it. Accordingly, hallucinations may not be adequately identified in this study.

Unlike cats, few dogs exhibited OCD following trauma or social / situational distress or upheaval. For 2 cases in which trauma was involved (patients 23 and 99), it consisted of abusive training--hanging by a choker collar. That 2% of this self-selected population of patients for whom clients were seeking treatment for OCD was subject to such abuse should give us all pause.

One pet store dog exhibited profound coprophagia, eating his own feces while also seeking out and eating the feces of others, suggesting that at some point coprophagia represented a nutritional strategy. Of the 103 dogs, few (~10%) had a putative neurological disorder, physical condition, or potentially painful disorder associated with their OCD, which could either be primary or secondary to the OCD. One dog had a diagnosis of "irritable bowel syndrome", a diagnosis which may be simply a non-specific sign of an anxiety-related condition. This finding supports the hypothesis that OCD in dogs is based in some primary neurochemcial / neurogenetic dysfunction, and that mechanisms driving OCD may differ between dogs and cats.

Obsessive-compulsive disorder affects at least 2% of the human population, and this is believed to be an under-estimate [9-11]. Some forms of obsessive-compulsive disorder has a familial genetic component [12-14]; however, most instances of human obsessive compulsive disorders appear to be sporadic. It is important to recognize that the development of specific breeds and the practice of inbreeding within those breeds suggests that the incidence of obsessive-compulsive disorders in dogs could be higher than that reported for human beings.

Based on client interviews and complaints, the breeds of dogs in which OCD appears to run in family lines may include at least Great Danes, German short-haired pointers, German shepherd dogs, bull terriers [15], Jack Russell terriers, Dalmatians, Bouvier de Flanders, salukis, Cairn terriers, basset hounds, and soft-coated Wheaton terriers. The tight correlations between canine breeds and form of OCD (German shepherds: tail chasing; Rottweilers, Dalmatians, Bulldogs: hallucinations) strongly supports a genetic basis, albeit, in part, as the result of genetic canalization associated with breed, for OCD.

As is true for humans, first degree relatives usually have a different manifestation of OCD than does the proband. These features support the above hypotheses of a neurochemical basis for OCD. That 50% of the dogs in this study for whom familial data were known had a relative affected with some form of OCD strongly suggests 2 important points: (1) Purebred dogs appear to have a high incidence of OCD, perhaps higher than that in the human population. (2) A larger number of canine family members are affected than appears true for humans. This frequency of familial occurrence strongly suggests a genetic component of OCD that should be further investigated.

Recent research strongly suggests that OCD in humans is the result of genetically controlled dysfunction of genes involving regulatory systems [16, 17]. Such complex regulatory functions that have a genetic, heritable basis have also been reported for dogs [18], and warrant further investigation in dogs and cats affected with OCD.

The roles played by arousal and reactivity cannot be ignored if we are to understand dogs with anxiety-related conditions like separation anxiety, noise phobia, and thunderstorm phobia. Some dogs respond either more quickly to a stimulus, or react more intensely to a given stimulus than other dogs. At some level this "hyper-reactivity" is probably truly pathological and represents yet another phenotypical manifestation of some neurochemical variation associated with anxiety. If so, the more frequently the dog reacts to the anxiety provoking stimulus, the worse and more rapid the response. At some point any exposure can the result in a full-blown, non-graduated anxious reaction in which true panic may be involved. Accordingly, anticipation and early treatment is critical for these individuals, again supporting the concept that behavioral phenotype and underlying neurochemical response are linked in a dynamic way. Early intervention can only be accomplished by understanding the spectrum of signs exhibited in related conditions.

References

1.  Overall KL, Dunham AE, Frank D: Frequency of nonspecific clinical signs in dogs with separation anxiety, thunderstorm phobia, and noise phobia, alone or in combination. J Am Vet Med Assoc 2001;219:467-473.

2.  Overall KL, Dunham AE: Clinical features and outcome in dogs and cats with obsessive-compulsive disorder: 126 cases (1989-2000). J Am Vet Med Assoc 2002;221:1445-1452.

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12. Pauls DL, Alsobrook JP, Goodman W, et al. A family study of obsessive compulsive disorder. Am J Psychiatry 1995;152:76-84.

13. Nestadt G, Samuels JF, Bienvenu OJ, et al. A family study of obsessive-compulsive disorder. Arch Gen Psychiatry 2000;57:358-363.

14. Grados MA, Riddle MA, Samuels JF, et al. The familial phenotype of obsessive compulsive disorder in relation to tick disorders: the Hopkins OCD family study. Biol Psychiatry 2001;50:559-565.

15. Moon-Fanelli AA, Dodman NH. Description and development of compulsive tail chasing in terriers and response to clomipramine treatment. J Amer Vet Med Assoc 1998;212:1252-1257.

16. Nestadt G, Lan T, Samuels JF, et al. Complex segregation analysis provides compelling evidence for a major gene underlying obsessive-compulsive disorder (OCD) and heterogeneity by gender. Am J Hum Genet 2000;67:1611-1616.

17. Greer JM, Capecchi MR. Hoxb8 is required for normal grooming behavior in mice. Neuron 2002;33:23-34.

18. Mignot E. A commentary on the neurobiology of the hypocretin / orexin systems. Neuropsychopharmacology 2001;25:S5-S15.

Speaker Information
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Karen L. Overall, MA, VMD, PhD, DACVB
Center for Neurobiology and Behavior, Psychiatry Department
School of Medicine, University of Pennsylvania
Philadelphia, PA, USA


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