OCD-like Behavior Research Articles

Increased Metabotropic Glutamate Receptor 5 Signaling Underlies Obsessive-Compulsive Disorder-like Behavioral and Striatal Circuit Abnormalities in Mice

BackgroundDevelopment of treatments for obsessive-compulsive disorder (OCD) is hampered by a lack of mechanistic understanding about this prevalent neuropsychiatric condition. Although circuit changes such as elevated frontostriatal activity are linked to OCD, the underlying molecular signaling that drives OCD-related behaviors remains largely unknown. Here, we examine the significance of type 5 metabotropic glutamate receptors (mGluR5s) for behavioral and circuit abnormalities relevant to OCD. MethodsSapap3 knockout (KO) mice treated acutely with an mGluR5 antagonist were evaluated for OCD-relevant phenotypes of self-grooming, anxiety-like behaviors, and increased striatal activity. The role of mGluR5 in the striatal circuit abnormalities of Sapap3 KO mice was further explored using two-photon calcium imaging to monitor striatal output from the direct and indirect pathways. A contribution of constitutive signaling to increased striatal mGluR5 activity in Sapap3 KO mice was investigated using pharmacologic and biochemical approaches. Finally, sufficiency of mGluR5 to drive OCD-like behavior in wild-type mice was tested by potentiating mGluR5 with a positive allosteric modulator. ResultsExcessive mGluR5 signaling underlies OCD-like behaviors and striatal circuit abnormalities in Sapap3 KO mice. Accordingly, enhancing mGluR5 activity acutely recapitulates these behavioral phenotypes in wild-type mice. In Sapap3 KO mice, elevated mGluR5 signaling is associated with constitutively active receptors and increased and imbalanced striatal output that is acutely corrected by antagonizing striatal mGluR5. ConclusionsThese findings demonstrate a causal role for increased mGluR5 signaling in driving striatal output abnormalities and behaviors with relevance to OCD and show the tractability of acute mGluR5 inhibition to remedy circuit and behavioral abnormalities.

Cortico-Striato-Thalamo-Cortical Circuitry, Working Memory, and Obsessive-Compulsive Disorder.

Cortico-Striato-Thalamo-Cortical Circuitry, Working Memory, and Obsessive-Compulsive Disorder.

OCD is associated with an altered association between sensorimotor gating and cortical and subcortical 5-HT1b receptor binding

Obsessive-compulsive disorder (OCD) is characterized by impaired sensorimotor gating, as measured using prepulse inhibition (PPI). This effect may be related to abnormalities in the serotonin (5-HT) system. 5-HT1B agonists can impair PPI, produce OCD-like behaviors in animals, and exacerbate OCD symptoms in humans. We measured 5-HT1B receptor availability using 11C-P943 positron emission tomography (PET) in unmedicated, non-depressed OCD patients (n=12) and matched healthy controls (HC; n=12). Usable PPI data were obtained from 20 of these subjects (10 from each group). There were no significant main effects of OCD diagnosis on 5-HT1B receptor availability (11C-P943 BPND); however, the relationship between PPI and 11C-P943 BPND differed dramatically and significantly between groups. 5-HT1B receptor availability in the basal ganglia and thalamus correlated positively with PPI in controls; these correlations were lost or even reversed in the OCD group. In cortical regions there were no significant correlations with PPI in controls, but widespread positive correlations in OCD patients. Positive correlations between 5-HT1B receptor availability and PPI were consistent across diagnostic groups only in two structures, the orbitofrontal cortex and the amygdala. Differential associations of 5-HT1B receptor availability with PPI in patients suggest functionally important alterations in the serotonergic regulation of cortical/subcortical balance in OCD.

Involvement of nitric oxide in anticompulsive-like effect of agmatine on marble-burying behaviour in mice

In view of the reports that nitric oxide modulates the neurotransmitters implicated in obsessive–compulsive disorder (OCD), patients with OCD exhibit higher plasma nitrate levels, and drugs useful in OCD influence nitric oxide. Agmatine is a polyamine and widely distributed in mammalian brain which interacts with nitrergic systems. Hence, the present study was carried out to understand the involvement of nitrergic systems in the anticompulsive-like effect of agmatine. We used marble-burying behaviour (MBB) of mice as the animal model of OCD, and nitric oxide levels in hippocampus (HC) and cortex homogenate were measured. Results revealed that, agmatine (20 and 40mg/kg, i.p) significantly inhibited the MBB. Intraperitoneal administration of nitric oxide enhancers viz. nitric oxide precursor – l-arginine (l-ARG) (400mg/kg and 800mg/kg) increased MBB as well as brain nitrites levels, whereas treatment with NG-nitro-l-arginine methyl ester (l-NAME) neuronal nitric oxide synthase inhibitor (30mg/kg and 50mg/kg, i.p.) and 7-nitroindazole (7-NI) (20mg/kg and 40mg/kg) attenuated MBB and nitrites levels in brain. Further, in combination studies, the anticompulsive-like effect of agmatine (20mg/kg, ip) was exacerbated by prior administration of l-ARG (400mg/kg) and conversely l-NAME (15mg/kg) or 7-NI (10.0mg/kg) attenuated OCD-like behaviour with HC and cortex changes in the levels of NO. None of the above treatment had any significant influence on locomotor activity. In conclusion, Agmatine is effective in ameliorating the compulsive-like behaviour in mice which appears to be related to nitric oxide in brain.

Developmental emergence of an obsessive-compulsive phenotype and binge behavior in rats.

Obsessive-compulsive disorder (OCD) gradually emerges and reaches clinical significance during early adulthood. Whether a predisposition for OCD manifests as binge eating disorder earlier during adolescence is proposed. To further characterize how OCD-like behaviors increase across maturation and to determine whether an OCD-like predisposition increases the likelihood of binge eating during adolescence. Male and female Sprague-Dawley rats were injected with the tricyclic antidepressant clomipramine (CMI, 15 mg/kg) or saline vehicle twice daily between postnatal days 9-15. Both groups were tested for perseverative (spontaneous alternation) and anxiety-like (elevated plus maze; marble burying) behaviors during juvenility (day 28), adolescence (day 60), and adulthood (day 90). Both motivations to eat sucrose pellets and binge eating on fat were investigated. Sex- and age-dependent increases in anxiety-like and perseverative behavior were observed in CMI subjects. Differences in consummatory behaviors emerged during late adolescence, while no significant differences in alternation or anxiety-like behaviors were detected between CMI and vehicle animals until adulthood. Adolescent CMI females consumed more sucrose pellets in 30 min relative to vehicle females, whereas adolescent CMI males consumed approximately half as much as vehicle males. Sucrose consumption did not differ between groups in adulthood. Adolescent CMI rats demonstrated more fat bingeing than vehicles, independent of sex. OCD-like behaviors are emerging during adolescence, but sucrose consumption and fat bingeing in CMI-treated animals significantly precedes the appearance of anxiety and perseveration. This OCD-like phenotype emerges fully during adulthood, suggesting that eating may likely serve as a coping strategy in these animals.

Preliminary Randomized Trial of Function-Based Cognitive-Behavioral Therapy to Treat Obsessive Compulsive Behavior in Children With Autism Spectrum Disorder

Individuals with high functioning autism spectrum disorder (ASD) frequently experience obsessions and/or compulsions that are similar to those specified in Diagnostic and Statistical Manual of Mental Disorders (5th ed.; DSM-5) criteria for obsessive-compulsive disorder (OCD). However, little research exists on effective interventions for OCD-like behaviors (referred to as OCBs) in ASD. In a preliminary randomized controlled trial (RCT; N = 14), a manualized function-based cognitive-behavior therapy (Fb-CBT) consisting of traditional CBT components (psychoeducation and mapping, cognitive-behavioral skills training, exposure, and response prevention) as well as function-based behavioral assessment and intervention significantly decreased OCBs in 8- to 12-year-old children with ASD at post-treatment and 5-month follow-up. This multi-component treatment shows considerable promise, and a larger RCT is needed to further validate and expand these findings.

Behavioral in-effectiveness of high frequency electromagnetic field in mice

The present investigation was carried out with an objective to study the influence of high frequency electromagnetic field (HF-EMF) on anxiety, obsessive compulsive disorder (OCD) and depression-like behavior. For exposure to HF-EMF, non-magnetic material was used to fabricate the housing. Mice were exposed to HF-EMF (2.45GHz), 60min/day for 7 or 30 or 60 or 90 or 120days. The exposure was carried out by switching-on inbuilt class-I BLUETOOTH device that operates on 2.45GHz frequency in file transfer mode at a peak density of 100mW. Mice were subjected to the assessment of anxiety, OCD and depression-like behavior for 7 or 30 or 60 or 90 or 120days of exposure. The anxiety-like behavior was assessed by elevated plus maze, open field test and social interaction test. OCD-like behavior was assessed by marble burying behavior, whereas depression-like behavior was assessed by forced swim test and tail suspension test. The present experiment demonstrates that up to 120days of exposure to HF-EMF does not produce anxiety, OCD and depression-like behavior in mice.

Experimental evidence for involvement of nitric oxide in low frequency magnetic field induced obsessive compulsive disorder-like behavior

It is well documented that extremely low frequency magnetic field (ELF MF) produced effects on the function of nervous system in humans and laboratory animals. Dopaminergic and serotonergic pathways have been implicated in obsessive compulsive disorder (OCD). Recently involvement of nitric oxide (NO) in OCD-like behavior is suggested. Hence, the present study was carried out to understand the involvement of dopamine, serotonin and NO in ELF MF induced OCD-like behavior. Swiss albino mice were exposed to ELF MF (50Hz, 10G) for 8h/day for 7, 30, 60, 90 and 120days by subjecting them to Helmholtz coils. OCD-like behavior was assessed in terms of marble burying behavior (MBB) test. Results revealed that ELF MF induced time dependant MBB, on 7th, 30th, 60th, 90th, and 120th exposure day.Further, levels of dopamine, serotonin and NO after 120days of ELF MF exposure were determined in the regions of the brain. The neurohumoral studies revealed that exposure to ELF MF increased NO levels in cortex, hippocampus and hypothalamus, and levels of dopamine and serotonin remain unaffected. As OCD-like behavior after ELF MF exposure was associated with higher levels of NO with no significant change in serotonin and dopamine. The effect of such exposure was studied in groups concurrently treated with NO modulators, NO precursor, l-ARG (400mg/kg) or NOS inhibitor, l-NAME (15.0mg/kg) or 7-NI (10.0mg/kg). These treatments revealed that NO precursor exacerbated and NOS inhibitors attenuated ELF MF induced OCD-like behavior with corresponding changes in the levels of NO.

Obsessive–compulsive-like behaviors in house mice are attenuated by a probiotic (Lactobacillus rhamnosus GG)

Two experiments examined probiotic pretreatment (Lactobacillus rhamnosus GG) on obsessive-compulsive disorder (OCD)-like behavior induction by RU 24969 in BALB/cJ house mice. In the first experiment, two groups were defined by their daily pretreatment by oral gavage of either (a) L. rhamnosus (1×10⁹ CFU/day) or (b) the saline vehicle. Both a 2- and 4-week probiotic pretreatment attenuated OCD-like behavior induction (increased perseverative open-field locomotion, stereotypic turning, and marble burying) relative to saline pretreatment. Experiment 2 re-examined the 2-week probiotic pretreatment while also comparing it to a 4-week fluoxetine pretreatment. Again, groups were defined by daily pretreatment of either (a) L. rhamnosus for 2 weeks, (b) the saline vehicle for 2 weeks, or (c) fluoxetine (10 mg/kg) for 4 weeks. Pretreatment by either L. rhamnosus or fluoxetine blocked the induction of OCD-like behavior compared with saline pretreatment. Thus the 2-week probiotic pretreatment was again effective. Although side effects of fluoxetine or L. rhamnosus on androgen-dependent behaviors could not be demonstrated, L. rhamnosus treatment appeared comparable to fluoxetine treatment in attenuating mouse OCD-like behaviors.

Histidine Decarboxylase Deficiency Causes Tourette Syndrome: Parallel Findings in Humans and Mice

Tourette syndrome (TS) is characterized by tics, sensorimotor gating deficiencies, and abnormalities of cortico-basal ganglia circuits. A mutation in histidine decarboxylase (Hdc), the key enzyme for the biosynthesis of histamine (HA), has been implicated as a rare genetic cause. Hdc knockout mice exhibited potentiated tic-like stereotypies, recapitulating core phenomenology of TS; these were mitigated by the dopamine (DA) D2 antagonist haloperidol, a proven pharmacotherapy, and by HA infusion into the brain. Prepulse inhibition was impaired in both mice and humans carrying Hdc mutations. HA infusion reduced striatal DA levels; in Hdc knockout mice, striatal DA was increased and the DA-regulated immediate early gene Fos was upregulated. DA D2/D3 receptor binding was altered both in mice and in humans carrying the Hdc mutation. These data confirm histidine decarboxylase deficiency as a rare cause of TS and identify HA-DA interactions in the basal ganglia as an important locus of pathology.

Circuit-Selective Striatal Synaptic Dysfunction in the Sapap3 Knockout Mouse Model of Obsessive-Compulsive Disorder

Synapse-associated protein 90/postsynaptic density protein 95-associated protein 3 (SAPAP3) is an excitatory postsynaptic protein implicated in the pathogenesis of obsessive-compulsive behaviors. In mice, genetic deletion of Sapap3 causes obsessive-compulsive disorder (OCD)-like behaviors that are rescued by striatal expression of Sapap3, demonstrating the importance of striatal neurotransmission for the OCD-like behaviors. In the striatum, there are two main excitatory synaptic circuits, corticostriatal and thalamostriatal. Neurotransmission defects in either or both of these circuits could potentially contribute to the OCD-like behaviors of Sapap3 knockout (KO) mice. Previously, we reported that Sapap3 deletion reduces corticostriatal alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid-type glutamate receptor-mediated synaptic transmission. Whole-cell electrophysiological recording techniques in acute brain slices were used to measure synaptic transmission in the corticostriatal and thalamostriatal circuits of Sapap3 KO mice and littermate control animals. Transgenic fluorescent reporters identified striatopallidal and striatonigral projection neurons. SAPAP isoforms at corticostriatal and thalamostriatal synapses were detected using immunostaining techniques. In contrast to corticostriatal synapses, thalamostriatal synaptic activity is unaffected by Sapap3 deletion. At the molecular level, we find that another SAPAP family member, SAPAP4, is present at thalamostriatal, but not corticostriatal, synapses. This finding provides a molecular rationale for the functional divergence we observe between thalamic and cortical striatal circuits in Sapap3 KO mice. These findings define the circuit-level neurotransmission defects in a genetic mouse model for OCD-related behaviors, focusing attention on the corticostriatal circuit for mediating the behavioral abnormalities. Our results also provide the first evidence that SAPAP isoforms may be localized to synapses according to circuit-selective principles.

Effects of chronic fluoxetine treatment on serotonin 1B receptor-induced deficits in delayed alternation

Obsessive-compulsive disorder (OCD) patients show overactivation of the orbitofrontal cortex and deficits in cognitive tasks that require proper orbitofrontal functioning including delayed alternation tests of spatial working memory. We recently showed that OCD-like behavior is induced in mice by activating orbitofrontal serotonin 1B receptors (5-HT1Bs). However, the role of 5-HT1Bs in delayed alternation remains unclear. We examined the effects of 5-HT1B receptor activation on delayed alternation task (DAT) performance. We also assessed the ability of an effective OCD treatment, fluoxetine, to prevent 5-HT1B-induced deficits in DAT performance. Mice were tested on the DAT after acute treatment with saline, 3 or 6mg/kg RU24969 (5-HT1B/1A agonist), 0.3 or 3mg/kg 8-OH-DPAT (5-HT1A agonist), or co-injection with 3mg/kg RU24969 and 5mg/kg GR127935 (5-HT1B/1D antagonist). Separate mice were pretreated chronically (28days) with 10mg/kg fluoxetine and then tested on the DAT after acute treatment with 3mg/kg RU24969, 0.3mg/kg 8-OH-DPAT, or saline. Both doses of RU24969 decreased accuracy and increased latency on the DAT, and GR127935 blocked RU24969-induced effects on accuracy. The 0.3mg/kg 8-OH-DPAT did not affect the DAT performance, whereas 3mg/kg increased omissions on the DAT. Finally, RU24969-induced DAT deficits were absent in fluoxetine-pretreated mice. We show that 5-HT1B receptor activation disrupts DAT performance in mice, and chronic fluoxetine pretreatment blocks these 5-HT1B-induced deficits. Our findings suggest that 5-HT1B receptors play an important role in modulating orbitofrontal-dependent delayed alternation. Moreover, 5-HT1B-induced DAT deficits may provide a mouse model for DAT deficits in OCD.

Effects of the active constituents of Crocus Sativus L., crocins, in an animal model of obsessive–compulsive disorder

Crocins are among the active components of the plant Crocus Sativus L. C. Sativus L. and its constituents were effective in different models of psychiatric disorders including anxiety and depression. Obsessive–compulsive disorder (OCD) is a common psychiatric disorder defined by the presence of obsessive thoughts and repetitive compulsive actions. The non selective serotonin (5-HT) receptor agonist mCPP is known to induce OCD-like behavior (excessive self-grooming) in rodents and exacerbate symptoms in patients with OCD. The present study investigated whether or not crocins were able to counteract excessive self-grooming induced by mCPP (0.6mg/kg, i.p.) in rats. Crocins (30 and 50mg/kg, i.p.) attenuated mCPP-induced excessive self-grooming. The present results also indicate that these effects of crocins on an animal model of OCD cannot be attributed to changes in locomotor activity. Our findings suggest that the active constituents of C. Sativus L. crocins might play a role in compulsive behavior and support a functional interaction between crocins and the serotonergic system.

Avoidance of swallowing saliva: A symptom related to aberrant basal ganglia functions?

We report two patients with avoidance of swallowing saliva despite intact swallowing functions. One, with mild, de novo Parkinson's disease, had a fear that his saliva was contaminated and would harm him. The other, with a history of CNS germinoma in remission for 3 years following chemotherapy, expectorated because his saliva was distasteful and disgusting. He had a lesion involving the left pallidum. Both appeared obsessed with the idea of saliva contamination and both expectorated compulsively, presenting obsessive–compulsive disorder (OCD) symptoms. OCD-like behavior may be induced in association with pathological conditions in which aberrant basal ganglia functions are present.

Essential Role for Orbitofrontal Serotonin 1B Receptors in Obsessive-Compulsive Disorder-Like Behavior and Serotonin Reuptake Inhibitor Response in Mice

Perseveration and sensorimotor gating deficits are core features of obsessive-compulsive disorder (OCD). Serotonin 1B receptor (5-HT1BR) agonists exacerbate OCD symptoms in patients and induce perseveration and sensorimotor gating deficits in mice. Serotonin reuptake inhibitors (SRIs), but not noradrenaline reuptake inhibitors (NRIs), reduce OCD symptoms following 4 to 8 weeks of treatment. Using mice, we compared the effects of chronic SRI versus NRI treatment on 5-HT1BR-induced OCD-like behavior and 5-HT1BR sensitivity in orbitofrontal-subcortical OCD circuits. Furthermore, we localized the 5-HT1BR population that mediates OCD-like behavior. Mice chronically received the SRI clomipramine or the NRI desipramine and were examined for 5-HT1BR-induced OCD-like behavior or 5-HT1BR binding and G-protein coupling in caudate putamen, nucleus accumbens, and orbitofrontal cortex. Separate mice were tested for OCD- or depression-like behavior following 4, 14, 21, 28, or 56 days of SRI treatment. Finally, OCD-like behavior was assessed following intra-orbitofrontal 5-HT1BR agonist infusion or intra-orbitofrontal 5-HT1BR antagonist infusion coupled with systemic 5-HT1BR agonist treatment. Effective, but not ineffective, OCD treatments reduced OCD-like behavior in mice with a time course that parallels the delayed therapeutic onset in OCD patients and downregulated 5-HT1BR expression in the orbitofrontal cortex. Intra-orbitofrontal 5-HT1BR agonist infusion induced OCD-like behavior, and intra-orbitofrontal 5-HT1BR antagonist infusion blocked OCD-like effects of systemic 5-HT1BR agonist treatment. These results indicate that orbitofrontal 5-HT1BRs are necessary and sufficient to induce OCD-like behavior in mice and that SRI pharmacotherapy reduces OCD-like behavior by desensitizing orbitofrontal 5-HT1BRs. Our findings suggest an essential role for orbitofrontal 5-HT1BRs in OCD pathophysiology and treatment.

Dysfunction of glutamate neurotransmission and OCD-like behavior in GLT1 conditional knock out mouse

Dysfunction of glutamate neurotransmission and OCD-like behavior in GLT1 conditional knock out mouse

Activity modulation of the globus pallidus and the nucleus entopeduncularis affects compulsive checking in rats

Deep brain stimulation at high frequencies (HFS) is currently studied in the treatment of therapy-refractory obsessive–compulsive disorder (OCD). The diversity of targeted brain areas and the discrepancy in demonstrating beneficial effects, highlight the need for better mapping of brain regions in which HFS may yield anti-compulsive effects. This goal may be achieved by investigating the effects of HFS in appropriate animal models of OCD. The present study tested the effect of bilateral HFS or pharmacological inactivation (as induced by intracerebral administration of the GABA-agonist muscimol) of both the Globus pallidus (GP; rodent equivalent to human GP externus) and the Nucleus entopeduncularis (EP; rodent equivalent to human GP internus) on checking behaviour in the quinpirole rat model of OCD. We demonstrate that HFS of the GP does not and HFS of the EP only partially reduces OCD-like behaviour in rats. In contrast, pharmacological inactivation of both GP and EP significantly reduces OCD-like behaviour in the model. These data contrast previously derived data on the effectiveness of HFS of the subthalamic nucleus, nucleus accumbens, GP and EP in the same and other rat models of OCD. We conclude that (i) although GP and EP play an important role in the pathophysiology of OCD, these areas may not represent first choice target structures for HFS, (ii) the effectiveness of HFS may depend on different subtypes of OCD, represented in different animal models, and (iii) differential net mechanisms may subserve the effectiveness of HFS and pharmacological inactivation.

Repetitive Behaviours in Patients with Gilles de la Tourette Syndrome: Tics, Compulsions, or Both?

BackgroundRepetitive behaviours (RB) in patients with Gilles de la Tourette syndrome (GTS) are frequent. However, a controversy persists whether they are manifestations of obssessive-compulsive disorder (OCD) or correspond to complex tics.Methods166 consecutive patients with GTS aged 15–68 years were recruited and submitted to extensive neurological, psychiatric and psychological evaluations. RB were evaluated by the YBOCS symptom checklist and Mini International Neuropsychiatric Interview (M.I.N.I), and classified on the basis of a semi-directive psychiatric interview as compulsions or tics.ResultsRB were present in 64.4% of patients with GTS (107/166) and categorised into 3 major groups: a ‘tic-like’ group (24.3%–40/166) characterised by RB such as touching, counting, ‘just right’ and symmetry searching; an ‘OCD-like’ group (20.5%–34/166) with washing and checking rituals; and a ‘mixed’ group (13.2%–22/166) with both ‘tics-like’ and ‘OCD-like’ types of RB present in the same patient. In 6.3% of patients, RB could not be classified into any of these groups and were thus considered ‘undetermined’.ConclusionsThe results confirm the phenomenological heterogeneity of RB in GTS patients and allows to distinguish two types: tic-like behaviours which are very likely an integral part of GTS; and OCD-like behaviours, which can be considered as a comorbid condition of GTS and were correlated with higher score of complex tics, neuroleptic and SSRIs treatment frequency and less successful socio-professional adaptation. We suggest that a meticulous semiological analysis of RB in GTS patients will help to tailor treatment and allow to better classify patients for future pathophysiologic studies.Trial RegistrationClinicalTrials.gov NCT00169351

SLITRK5, a protein that links striatal deficits to OCD-like behaviours in mice

Slitrk5 deficiency impairs corticostriatal circuitry and leads to obsessive-compulsive-like behaviors in mice Shmelkov et al. (2010) Nature Medicine 16(5): 598–602

A Novel, Multiple Symptom Model of Obsessive-Compulsive-Like Behaviors in Animals

Current animal models of obsessive-compulsive disorder (OCD) typically involve acute, drug-induced symptom provocation or a genetic association with stereotypies or anxiety. None of these current models demonstrate multiple OCD-like behaviors. Neonatal rats were treated with the tricyclic antidepressant clomipramine or vehicle between days 9 and 16 twice daily and behaviorally tested in adulthood. Clomipramine exposure in immature rats produced significant behavioral and biochemical changes that include enhanced anxiety (elevated plus maze and marble burying), behavioral inflexibility (perseveration in the spontaneous alternation task and impaired reversal learning), working memory impairment (e.g., win-shift paradigm), hoarding, and corticostriatal dysfunction. Dopamine D2 receptors were elevated in the striatum, whereas serotonin 2C, but not serotonin 1A, receptors were elevated in the orbital frontal cortex. This is the first demonstration of multiple symptoms consistent with an OCD-like profile in animals. Moreover, these behaviors are accompanied by biochemical changes in brain regions previously identified as relevant to OCD. This novel model of OCD demonstrates that drug exposure during a sensitive period can program disease-like systems permanently, which could have implications for current and future therapeutic strategies for this and other psychiatric disorders.