Article

Essential role for orbitofrontal serotonin 1B receptors in obsessive-compulsive disorder-like behavior and serotonin reuptake inhibitor response in mice.

Committee on Neurobiology, University of Chicago, IL 60637, USA.
Biological psychiatry (Impact Factor: 9.47). 09/2011; 70(11):1039-48. DOI: 10.1016/j.biopsych.2011.07.032
Source: PubMed

ABSTRACT 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.

0 Followers
 · 
146 Views
  • [Show abstract] [Hide abstract]
    ABSTRACT: Acute administration of serotonergic agonist, meta-chlorophenylpiperazine (mCPP), attenuates performance of compulsive checking in an animal model of obsessive-compulsive disorder (OCD). It is not known whether mCPP has a similar effect on development of compulsive checking. The objective of the study was to examine whether similar mechanisms mediate the development versus the performance of compulsive checking in the rat model. Four groups of male rats (N = 14/group) were tested: two experimental groups co-injected with D2/D3 dopamine agonist quinpirole (0.25 mg/kg) and mCPP (0.625 mg/kg or 1.25 mg/kg), and two control groups, one co-injected with quinpirole and saline, the other receiving injections of saline. The time course of development of compulsive checking across injections 1 to 10 in quinpirole-treated rats was compared to rats co-injected with quinpirole and mCPP. Results showed that during the course of chronic treatment, mCPP (1.25 mg/kg) significantly attenuated performance of checking behavior. However, when these rats were retested for expression of compulsive checking (that is, with an injection of quinpirole only), their profile of compulsive checking was no different from the control rats treated throughout with quinpirole only. Findings show that mCPP inhibits performance of compulsive checking but does not block quinpirole from inducing the neural substrate underlying this compulsive behavior. Hence, a separate mechanism underlies the induction of compulsive checking and the performance of it. It is suggested that development of the OCD endophenotype reflects neuroplastic changes produced by repeated dopamine D2/D3 receptor stimulation, while stimulation of serotonergic receptors mediates a negative feedback signal that shuts down the motor performance of checking.
    Psychopharmacology 02/2014; DOI:10.1007/s00213-014-3505-6 · 3.99 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Interest in the therapeutic potential of psychedelic substances has recently resumed. During an early phase of human psychedelic research, their therapeutic application in different pathologies had been suggested, and the first evidence for efficacy was provided. The range of recent clinical applications of psychedelics spans from cluster headaches and obsessive-compulsive disorder to addiction and the treatment of fear and anxiety in patients suffering from terminal illness, indicating potentially different therapeutic mechanisms. A variety of approaches in psychotherapy emphasize subjective experiences, such as so-called peak experiences or afterglow phenomena, as differentially mediating therapeutic action. This review aims to re-evaluate earlier and recent concepts of how psychedelic substances may exert beneficial effects. After a short outline of neurophenomenological aspects, we discuss different approaches to how psychedelics are used in psychotherapy. Finally, we summarize evidence for the relationship between subjective experiences and therapeutic success. While the distinction between pharmacological and psychological action obviously cannot be clear-cut, they do appear to contribute differently from each other when their effects are compared with regard to pathologies.
    Journal of Psychopharmacology 02/2015; DOI:10.1177/0269881114568040 · 2.81 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: One of the leading biological models of Obsessive-compulsive disorder (OCD) is the frontal-striatal-thalamic model. The present study undertakes an extensive exploration of the variability in genes related to the regulation of the frontal-striatal-thalamic system in a sample of early-onset OCD trios. To this end, we genotyped 266 single nucleotide polymorphisms (SNPs) in 35 genes in 84 OCD probands and their parents. Finally 75 complete trios were included in the analysis. 20 SNPs were overtransmitted from parents to early-onset OCD probands and presented nominal pointwise p < 0.05 values. Three of these polymorphisms achieved p < 2x10(-4) , the significant p-value after Bonferroni corrections: rs8190748 and rs992990 localized in GAD2 and rs2000292 in HTR1B. When we stratified our sample according to gender, different trends were observed between males and females. In males, SNP rs2000292 (HTR1B) showed the lowest p-value (p = 0.0006), whereas the SNPs in GAD2 were only marginally significant (p = 0.01). In contrast, in females HTR1B polymorphisms were not significant, whereas rs8190748 (GAD2) showed the lowest p-value (p = 0.0006). The results we report here are in agreement with several lines of evidence that indicate a role for the serotonin and GABA pathways in the risk of early-onset OCD and with the gender differences in OCD pathophysiology reported elsewhere. However, our results need to be replicated in studies with larger cohorts in order to confirm these associations.
    Genes Brain and Behavior 02/2014; DOI:10.1111/gbb.12128 · 3.51 Impact Factor

Full-text (2 Sources)

Download
42 Downloads
Available from
May 16, 2014