N-acetylcysteine blocks serotonin 1B agonist-induced OCD-related behavior in mice.

Glutamate-modulating agents are of increasing interest in obsessive-compulsive disorder (OCD). Current pharmacotherapies for OCD target the serotonin and dopamine systems, and are limited in efficacy. N-acetylcysteine (NAC) is an over-the-counter amino acid supplement that inhibits glutamate neurotransmission and has been shown in preliminary studies to reduce symptoms in OCD and related compulsive disorders. Despite growing interest in NAC as a novel psychiatric medication, no studies currently exist examining the effects of NAC in animal models of compulsive disorders. Here, we investigate NAC in a well-validated mouse model of OCD that is predictive of treatment efficacy as well as the time course for therapeutic onset of OCD medications. NAC (60 mg/kg/day or 120 mg/kg/day) was administered via the drinking water of mice for 3 weeks prior to behavioral testing. Mice were tested in the delayed alternation task (DAT) and open field test following acute serotonin 1B receptor (5-HT1B) agonist challenge to induce OCD-related behavior. We found that both doses of NAC blocked 5-HT1B agonist-induced deficits on the DAT. In a separate study, we administered NAC (60 mg/kg/day) for 1 week or 3 weeks in the drinking water of mice prior to examining OCD-related behavior. We found that blockade of 5-HT1B agonist-induced OCD-like behavior is present at 3 weeks, but not 1 week, of NAC treatment. Together, our findings suggest that NAC is a novel OCD treatment with potential utility as monotherapy and therapeutic effects that emerge on a time-course similar to established medications. (PsycINFO Database Record

Effects of oxytocin on serotonin 1B agonist-induced autism-like behavior in mice.

Social impairments in autism remain poorly understood and without approved pharmacotherapies. Novel animals models are needed to elucidate mechanisms and evaluate novel treatments for the social deficits in autism. Recently, serotonin 1B receptor (5-HT1B) agonist challenge in mice was shown to induce autism-like behaviors including perseveration, reduced prepulse inhibition, and delayed alternation deficits. However, the effects of 5-HT1B agonists on autism-related social behaviors in mice remain unknown. Here, we examine the effects of 5-HT1B agonist challenge on sociability and preference for social novelty in mice. We also examine the effects of 5-HT1B agonist treatment on average rearing duration, a putative rodent measure of non-selective attention. Non-selective attention is an associated feature of autism that is also not well understood. We show that 5-HT1B receptor activation reduces sociability, preference for social novelty, and rearing in mice. In addition, we examine the ability of oxytocin, an off-label treatment for the social impairments in autism, to reverse 5-HT1B agonist-induced social and attention deficits in mice. We show that oxytocin restores social novelty preference in mice treated with a 5-HT1B agonist. We also show that oxytocin attenuates 5-HT1B agonist-induced sociability and rearing deficits in mice. Our results suggest that 5-HT1B agonist challenge provides a useful pharmacological mouse model for aspects of autism, and implicate 5-HT1B in autism social and attention deficits. Moreover, our findings suggest that oxytocin may treat the social deficits in autism through a mechanism involving 5-HT1B.

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

RATIONALE: 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. OBJECTIVES: 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. METHODS: Mice were tested on the DAT after acute treatment with saline, 3 or 6 mg/kg RU24969 (5-HT1B/1A agonist), 0.3 or 3 mg/kg 8-OH-DPAT (5-HT1A agonist), or co-injection with 3 mg/kg RU24969 and 5 mg/kg GR127935 (5-HT1B/1D antagonist). Separate mice were pretreated chronically (28 days) with 10 mg/kg fluoxetine and then tested on the DAT after acute treatment with 3 mg/kg RU24969, 0.3 mg/kg 8-OH-DPAT, or saline. RESULTS: Both doses of RU24969 decreased accuracy and increased latency on the DAT, and GR127935 blocked RU24969-induced effects on accuracy. The 0.3 mg/kg 8-OH-DPAT did not affect the DAT performance, whereas 3 mg/kg increased omissions on the DAT. Finally, RU24969-induced DAT deficits were absent in fluoxetine-pretreated mice. CONCLUSIONS: 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.