4 - Animal models for studying obsessive-compulsive and related disorders

Abstract

Obsessive–compulsive and related disorders comprise neuropsychiatric syndromes that involve intrusive thoughts, preoccupations, or sensory phenomena, and behaviors that are persistent, repetitive, stereotyped, and ritualistic. As is the case for anxiety disorders, obsessive–compulsive and related disorders represent a spectrum of conditions. Disorders within the obsessive–compulsive spectrum are proposed to vary with respect to at least three continuous cognitive-behavioral dimensional measures. These dimensions are called the compulsivity-impulsivity dimension, the cognitive-motoric dimension, and the obsessional-delusional dimension. (Compulsivity and impulsivity have more recently been suggested to represent two orthogonal dimensions.) Obsessive–compulsive disorder (OCD), the prototypical syndrome within the obsessive–compulsive dimension, is a heterogeneous condition divisible into subtypes that could have at least partially distinct etiologies. Some of the proposed OCD subtypes include juvenile-onset and adult-onset OCD, and symptom subtypes that involve primarily themes of contamination/washing, doubts/checking, ritual/superstition, sexual/aggressive/religious, and hoarding/symmetry. OCD symptoms can also be considered as motivated primarily to prevent harm (harm avoidant) or motivated by persistent feelings of doubt, perceptions of irregularities in the environment, or that one’s actions are not being completed in the correct manner (incompleteness). A large body of evidence concurs that OCD symptoms involve aberrant functioning of cortico-basal ganglia-thalamocortical circuits as well as heightened performance monitoring or error sensitivity mediated by the anterior cingulate cortex. Neuroanatomical models of OCD involving these circuits square well with endophenotypes that have been identified for OCD, which have to do with deficits in the ability to withhold a prepotent response, in behavioral and cognitive flexibility, in implicit learning, and enhanced electrophysiologic error- and conflict-related brain activity. These models are also completely consistent with stereotaxic brain surgeries that are known to alleviate OCD symptoms. The endophenotypes just mentioned (with the exception of error and conflict processing) all have rodent homologs, making it possible to study their underlying neurobiology in detail, in rodent models. Obsessions in OCD symptoms are continuous with “normal” thought patterns, essentially differing only in their intensity, frequency, and duration, as well as in the distress that they cause. Compulsions are often directed toward objectives of cleaning, ordering, protection of loved ones and of one’s “territory,” the performance of ritual, or collecting and hoarding. Obsessive–compulsive symptoms, therefore, might be considered as dysregulated versions of innate, adaptive behavioral patterns. A number of candidate genes have been associated with OCD, including several involved in monoaminergic, glutamatergic, GABAergic, and cholinergic neurotransmission. Two genes have been associated with trichotillomania as well as with pathologic grooming in mice; interestingly, both are implicated in striatal synaptogenesis. Animal models of OCD include signal attenuation (compulsive lever-pressing), schedule-induced hyperactivity and polydipsia, infection-based models, quinpirole-induced compulsive checking, 8-OH-DPAT-induced perseverative choice, m-chlorophenylpiperazine-induced directional persistence, neonatal clomipramine treatment, mice genetically selected for enhanced nest-building behavior, and a number of genetic models involving some of the candidate genes mentioned above. Naturally occurring stereotypies in the deer mice, bank voles, parrots, dogs, pigs, and nonhuman primates are also extremely useful models for OCD. A detailed understanding of the neurobiology of normal processes such as motivation, displacement behavior, ritual and habit formation, and innate species-specific behavioral patterns should also clarify the pathologic mechanisms that underlie OCD symptoms.