This chapter summarizes what we know about compulsive behavioral disorders in several animal species. Animals can develop repetitive behaviors in a range of circumstances, generally associated with anxiety or stress. It is increasingly apparent that these behaviors recapitulate core features of obsessive-compulsive disorder. They are clearly partially genetic; for example, specific breeds of dog are susceptible to specific compulsive behavioral disorders. Understanding such OCD-like behaviors provides a potentially fruitful avenue towards understanding OCD in humans. This chapter reviews this literature, emphasizing the points of parallelism between repetitive behavior syndromes in animals and human disease. Recent advances in our understanding of the biology of these spontaneously occurring animal models, especially in dogs, have great potential to elucidate the pathophysiology of OCD.

Dogs naturally suffer the same complex diseases as humans, including mental illness. The dog is uniquely suited as a model organism to explore the genetics of neuropsychiatric disorders. Historical breed demo-graphics have enriched purebred populations for founder effect mutations with tractable architectures, making genotypic analyses advantageous. Over a pet's lifetime, owners observe the animal's stress tolerance, arousal, and anxiety, and can inform on rich behavioral profiles for phenotypic analyses. Here we leverage these strengths in a search for inherited factors that exacerbate canine compulsive disorder (CCD), the dog counterpart to human obsesssive compulsive disorder (OCD). Our rationale is that identifying pathways that predispose to disease severity will expand therapeutic options, and ultimately bring relief to those patients suffering the most. We have performed a GWAS of purebred Doberman pinschers that compares severely affected cases to moderately affected cases (24: 70). This GWAS identified two statistically sig-nificant risk loci, on CFA34 and CFA11, and a third with suggestive evidence on CFA16. The locus on CFA34 includes a cluster of 5-HT3 receptor genes (HTR3C, HTR3D, and HTR3E) that implicate a serotonergic pathway that is routinely targeted by anti-OCD medications. The locus on CFA11 is syntenic with human CTXN3-SLC12A2 (5q35.1), an inherited risk factor for schiz-ophrenia. The third locus harbors teneurin-3 (TENM3), a modulator of the hypothalamic-pituitary-adrenal (HPA) axis, with effects on stress tolerance and stress-related behavior. We dis-cuss candidate genes and putative functional variants in light of pharmacological responsiveness, psychiatric comorbidity, and the potential for gene-by-environment interactions in the genetic etiology of OCD and CCD.

Autism spectrum disorders (ASD) are neurodevelopmental disorders characterized by defects in communication and social interactions, as well as stereotypic behaviors. Symptoms typically worsen with anxiety and stress. ASD occur in early childhood, often present with regression and have a prevalence of 1 out of 68 children. The lack of distinct pathogenesis or any objective biomarkers or reliable animal models hampers our understanding and treatment of ASD. Neurotensin (NT) and corticotropin-releasing hormone (CRH) are secreted under stress in various tissues, and have proinflammatory actions. We had previously shown that NT augments the ability of CRH to increase mast cell (MC)-dependent skin vascular permeability in rodents. CRH also induced NT receptor gene and protein expression in MCs, which have been implicated in ASD. Here we report that serum of ASD children (4-10 years old) has significantly higher NT and CRH levels as compared with normotypic controls. Moreover, there is a statistically significant correlation between the number of children with gastrointestinal symptoms and high serum NT levels. In Bull Terriers that exhibit a behavioral phenotype similar to the clinical presentation of ASD, NT and CRH levels are also significantly elevated, as compared with unaffected dogs of the same breed. Further investigation of serum NT and CRH, as well as characterization of this putative canine breed could provide useful insights into the pathogenesis, diagnosis and treatment of ASD.

Background: Obsessive-compulsive disorder (OCD) is a common debilitating psychiatric illness that typically improves but does not remit with first-line medication and behavioral treatments. Serotonergic agents including selective serotonin reuptake inhibitors and clomipramine have provided the mainstay of OCD medication management for decades. Combined dopamine/serotonergic agents such as atypical antipsychotics are presently the only OCD-augmenting strategies proven effective via randomized controlled trials. Despite increasing evidence for a pathogenic role of glutamate in OCD, no controlled trials of glutamatergic augmenting agents have been reported.Methods: An intent-to-treat sample included 44 subjects receiving standard treatment at the McLean/Massachusetts General Hospital Intensive Residential Treatment (IRT) program, 22 of whom also received memantine augmentation. Admission, monthly and discharge measures of OCD, depression, and psychosocial functioning were collected by raters blinded to augmentation status. Matched controls were selected based on sex, initial OCD severity, psychosocial functioning, and timing of admission. The Clinical Global Improvement Scale captured global clinical change.Results: Mean (SD) Yale-Brown Obsessive Compulsive Scale score decreases were 7.2 (6.4) among the cases and 4.6 (5.9) among the matched controls, reflecting mean clinical improvement among the cases (27.0% decrease) but not the controls (16.5% decrease). Mean (SD) depression severity score decreases were 5.8 (9.5) among the cases and 4.7 (9.9) among the controls. Initial intrusive obsessions were significantly more severe among marked responders compared with limited response or nonresponse cases (4.4 vs 2.9; t = 2.15; P = 0.048).Conclusions: This study provides preliminary supportive evidence for the effectiveness of memantine as a glutamatergic augmenting agent in severe OCD. Future randomized double-blind placebo-controlled trials are warranted.

Obsessive Compulsive Disorder (OCD) is currently treated with behavioral modification and psychotropic medications, with varying degrees of success. The most popular drugs for the treatment of OCD are the selective serotonin reuptake inhibitors (SSRIs). Another drug, the N-methyl-D-aspartate antagonist memantine, has recently been tested in the treatment of OCD. The present study investigates the effect of fluoxetine and memantine alone and in combination in a mouse model of compulsive behavior. In this model, compulsive scratching is induced by a subcutaneous injection of serotonin or a serotonin releasing agent, compound 48-80, in the back of the neck. The effects of the memantine and fluoxetine combination were found to synergistic, specifically as defined by an isobologram. The results of the present investigation suggest the potential of a more effective management of the symptoms of OCD.

An SAR study of psilocybin and psilocin derivatives reveals that 1-methylpsilocin is a selective agonist at the h5-HT2C receptor. The corresponding phosphate derivative, 1-methylpsilocybin, shows efficacy in an animal model for obsessive–compulsive disorder, as does 4-fluoro-N,N-dimethyltryptamine. These results suggest a new area for development of novel 5-HT2C agonists with applications for drug discovery.

AbstractFor Abstract see ChemInform Abstract in Full Text.

OBJECTIVE:To evaluate the efficacy of oral dextromethorphan in dogs with a repetitive behavior problem (self-licking, self-chewing, and self-biting associated with chronic allergic dermatitis).ANIMALS:Fourteen dogs with chronic allergic dermatitis were enrolled in the study. Twelve dogs completed the study.PROCEDURE:The dogs were treated for 2 weeks each with dextromethorphan (2 mg/kg BID) and placebo in a randomized, double blind, crossover designed study. A dermatology score, including an assessment of affected areas of the integument and the level of self-directed behavior, was generated before and following each 2-week phase of the study. Owners were required to record daily the amount of time they spent with their dog and the amount of time that the dog was observed to be engaged in any of the specified self-directed behaviors.RESULTS:The percent of the observed time that the dogs were reported to be involved in self-directed behaviors was significantly less during the 2-week active drug treatment phase. The pruritus score component of the dermatology score also was significantly less during the active treatment phase. In addition, a dermatologist-rated global assessment was more favorable in 11 of 12 dogs following the active treatment phase.CONCLUSIONS:Dextromethorphan significantly reduces the percentage of time that allergic dogs spend self-licking, self-chewing, and self-biting.CLINICAL RELEVANCE:Dextromethorphan may be a useful adjunct in the management of self-directed behaviors associated with allergic dermatitis and possibly in other repetitive behaviors as well.

The effects of drugs that either stimulate or inhibit central opioid, dopamine, norepinephrine, and serotonin neurotransmitter systems were examined in horses demonstrating signs of equine self-mutilation syndrome (ESMS), a condition similar to Tourette’s syndrome in humans. Eight flankbiting horses with ESMS were recruited for the study. A series of drugs selected for their activity on the aforementioned neurotransmitter systems were administered to the horses in a saline-controlled behavioral study. Specific behaviors associated with the syndrome were videotaped for 4 hours following administration of drug or saline. Behaviors recorded hourly during each phase of the study were compared with those of a composite saline control baseline to determine whether there were significant differences among the treatments. Acepromazine, a dopamine blocker, produced a significant reduction in the primary ESMS behaviors of self-mutilative attempts and hemiballismus. Detomidine, an α -2 antagonist, also produced a significant (P < .05) reduction in these behaviors, as did the

We aimed to evaluate the antihyperalgesic efficacy of a combination of hydromorphone (HM) and bupivacaine (BP) delivered via controlled release from a biodegradable cylindrical rod. In vivo studies were performed using a rat model of thermal hyperalgesia induced by chronic constriction injury (CCI) of the sciatic nerve with loose ligatures. Poly(lactic-co-glycolic acid) (PLGA) rods (10 mm length, 1 mm diameter) loaded with HM (5 mg per rod), BP (5 mg per rod) or no drug (placebo) were implanted subcutaneously, in single or dual pairs, adjacent to the constriction injury, immediately after nerve ligation. We evaluated the efficacy of two dose levels for each drug, alone or in combination, in attenuating thermal hyperesthesia over a period of 12 days according to a prevention protocol. Plasma levels of drugs released from the rods and also released in an in vitro simulation were evaluated. In vitro studies demonstrated that drug release is maintained for at least 10 days. HM (5 mg) alone and BP (5 mg) alone did not attenuate hyperalgesia. Their combination provided a significant increase in the paw withdrawal latency as compared to single agents or placebo. When the dose in each group was doubled, implanting four rods, significant attenuation of hyperalgesia was observed. Analyses of rods retrieved after termination of experiments (after 12 days) revealed 30% residual HM and 70% residual BP content. Prolonged delivery of HM and BP alone or in combination via locally applied PLGA rods may offer a feasible alternative to provide long-lasting analgesia.

The objective of this study is to develop an improved dose form for the longer-term delivery of a combined local—systemic system for pain management in an emergency situation. The amelioration of pain associated with injury (automobile accidents, industrial accidents, battlefield scenario, and so on), when treated with potent narcotic analgesics, may be associated with sedation and possible side effects, such as dizziness and nausea. Thus, functional activity may be reduced for as long as pain relief is necessary. Nevertheless, the opiate analgesics have an important role that cannot always be filled by local anesthetics (LAs). However, when pain is severe and long-lasting, it may be desirable to couple a narcotic with a LA. The side effects may be minimized, and long-lasting relief may be achieved, by controlled-release implants for delivery of either or both types of agent. Such anesthetic formulations may be implanted at the wound site, for local delivery of drug. Analgesic formulations may likewise be implanted at alternative, nontraumatized sites, for systemic delivery of drug. By use of a biodegradable excipient, poly(d,l-lactide-co-glycolide) (PLGA), the implants need not be removed, and drug delivery can be adjusted to address targeted deliveries from several days to approx 2 wk, using one long-acting dose form.

OBJECTIVETo evaluate the effect of high- and low-protein diets with or without tryptophan supplementation on behavior of dogs with dominance aggression, territorial aggression, and hyperactivity.DESIGNProspective crossover study.ANIMALS11 dogs with dominance aggression, 11 dogs with territorial aggression, and 11 dogs with hyperactivity.PROCEDUREIn each group, 4 diets were fed for 1 weeks each in random order with a transition period of not < 3 days between each diet. Two diets had low protein content (approximately 18%), and 2 diets had high protein content (approximately 30%). Two of the diets (1 low-protein and 1 high-protein) were supplemented with tryptophan. Owners scored their dog's behavior daily by use of customized behavioral score sheets. Mean weekly values of 5 behavioral measures and serum concentrations of serotonin and tryptophan were determined at the end of each dietary period.RESULTSFor dominance aggression, behavioral scores were highest in dogs fed unsupplemented high-protein rations. For territorial aggression, [corrected] tryptophan-supplemented low-protein diets were associated with significantly lower behavioral scores than low-protein diets without tryptophan supplements.CONCLUSIONS AND CLINICAL RELEVANCEFor dogs with dominance aggression, the addition of tryptophan to high-protein diets or change to a low-protein diet may reduce aggression. For dogs with territorial aggression, tryptophan supplementation of a low-protein diet may be helpful in reducing aggression.

S336 INTRODUCTION: Implantable delivery systems consisting of biodegradable materials are an alternative to injectable formulations or electronic pumps when chronic opioid or local anesthetic administration is necessary to treat pain [1,2] We present pilot pharmacological and efficacy results in the rat of a novel implantable biodegradable delivery system for hydromorphone(HM):poly(lactide-co-glycolide) (PLGA) matrix. MATERIAL AND METHODS: All procedures were approved by the Tufts Animal Research Committee. Male Sprague-Dawley rats (200-250 g) were implanted subcutaneously with PLGA matrices (rods) prepared to contain five doses of HM (0.5, 1.25, 3.13, 15, 30 mg) or placebo rods (PLGA only). An osmotic mini-pump (25 mg over 10 days) was used as a positive delivery control. Tail flick latency testing was used to determine percentage of maximal analgesic response (%MPR). Blood samples (0.3 ml) were collected prior to implantation, one hour later and every two days thereafter until the end of the study. Serum HM concentrations were determined by HPLC with EC detection. RESULTS: Release of hydromorphone at a steady rate release coupled with significant antinociception as compared to control was observed in the 15, 25 and 30 mg groups as compared to control up to 4 days (Fig). No local toxicity at the implantation site was observed. The decline of analgesia reflects the development of tolerance to the opioid, which is known to develop faster in pain models as compared to actual pain in patients. In summary our data suggest that the PLGA-HMh system may be a safe and cost-effective alternative to computerized or repeated or microprocessor controlled parenteral or enteral opioid administration when prolonged analgesia is required. Grant support by US Department of Defense DAMD17-96-C-6043 & the Saltonstall Fund.