Acute serotonin 1B/1A receptor activation impairs behavioral flexibility in C57BL/6J mice.

Pharmacological activation of the serotonin (5-HT) 1B and 5-HT1A receptors has been shown to induce OCD-like perseverative circling and locomotor stereotypy in rodents. Although, several studies have examined how activation of these receptors facilitates these motor-associated OCD-like behaviors, it is not known how acute 5-HT1B and 5-HT1A activation impacts behavioral inflexibility, a common trait related to OCD. The current study examined how acute 5-HT1B/1A receptor agonist RU24969 treatment at 0.01, 0.1, and 1.0 mg/kg impacted behavioral flexibility in both female and male C57BL/6J mice. Behavioral flexibility was tested using a spatial reversal learning task, with probabilistic reward contingencies. In addition, locomotor activity and anxiety-like behaviors were also measured. RU24969 at 0.1 and 1.0 mg/kg impaired behavioral flexibility in both female and male C57BL/6J mice. RU24969 treatment at 1.0 mg/kg reduced locomotor activity in male mice, although RU24969 treatment did not significantly reduce locomotor activity in female mice. In the open field, 1.0 mg/kg elevated anxiety-like behavior in male mice only. Overall, these results demonstrate that acute 5-HT1B and 5-HT1A receptor activation leads to impairments in behavioral flexibility, a common trait associated with OCD.

Serotonin 6 receptor modulation reduces locomotor activity in C57BL/6J mice.

The serotonin 6 receptor (5-HT6) is a more recently identified therapeutic target for several neuropsychiatric disorders. While the 5-HT6 receptor has gained interest as a target for novel therapeutics, determining the basic sex differences is lacking in the literature. To address this, the present study examined the effects of 5-HT6 receptor modulation on locomotor activity and open field measures of anxiety in C57BL/6J mice. Female and male mice were tested after acute treatment with either 5-HT6 receptor antagonist SB 271046 or 5-HT6 receptor agonist EMD 386088. Acute 5-HT6 receptor blockade with SB 271046 attenuated locomotor activity in C57BL6/J mice, irrespective of sex. When locomotor activity was analyzed for six 10 min time blocks, 0.1, 5, or 15 mg/kg of SB 271046 reduced locomotor activity for the initial 40 min of testing, but only 5 and 15 mg/kg SB 271046 exhibited a reduction in locomotor activity for at least 60 min. EMD 386088 only attenuated locomotor activity when mice were treated with the high dose of 15 mg/kg EMD 386088. This was true for all time blocks except for the 40-50 min time block. In addition, EMD 386088 at the 15 mg/kg dose reduced locomotor activity in female mice more than males during the 20-30 and 30-40 minute time blocks. Analysis of the anxiolytic properties of 5-HT6 receptor modulation via the open field, showed that SB 271046 did not demonstrate anxiogenic properties in either sex at the doses tested. Instead, 15 mg/kg EMD 386088 produced an anxiogenic effect in both female and male mice. Together these findings highlight the differing impact of specific 5-HT6 receptor modulation on locomotor activity in C57BL/6J mice.

Serotonin 6 receptor blockade reduces repetitive behavior in the BTBR mouse model of autism spectrum disorder.

Autism spectrum disorder (ASD) is characterized by the expression of restricted repetitive behaviors (RRBs) and impairments in social recognition and communication. Previous studies have found that specific serotonin (5-HT) receptor modulation can attenuate repetitive behaviors expressed in specific mouse strains. The present study examined how 5-HT6 receptor blockade impacts the expression of repetitive behaviors in two different mouse strains that demonstrate elevated restricted, repetitive behavior and impairments in social behavior. BTBR T+ Itpr3tf /J (BTBR), C58/J (C58) and control C57BL/6J strains were behaviorally tested after acute treatment with the 5-HT6 receptor antagonist BGC 20-761 (BGC) or vehicle. BTBR mice express high levels of self-grooming behavior while C58 mice display high rates of repetitive jumping behavior. Similarly, the effect of 5-HT6 receptor blockade was also tested on social approach behaviors in both strains. BGC significantly reduced repetitive grooming in both female and male BTBR mice compared to vehicle-treated BTBR mice. BGC treatment did not attenuate social approach impairments in either female or male BTBR mice compared to vehicle-treated BTBR mice. Follow-up dose response studies were conducted on repetitive grooming and locomotor activity in BTBR mice. All doses reduced repetitive grooming in female and male BTBR mice. Acute treatment with BGC only reduced locomotor activity with the lower doses. In C58 mice, BGC treatment did not significantly attenuate flipping or general social approach behaviors. Instead, BGC significantly increased social sniff time in female C58 mice. While 5-HT6 receptor blockade did not attenuate the social impairments found in BTBR mice, this treatment did increase sniff time in female C58 mice. Although the lower doses of BGC deduced locomotion, the higher dose attenuated repetitive grooming in BTBR mice while sparing locomotor activity. Together these findings suggest the therapeutic effects of 5-HT6 receptor blockade are complex and may be specific to the types of repetitive behaviors expressed.

Differences in the expression of restricted repetitive behaviors in female and male BTBR T + tf/J mice.

Autism spectrum disorder (ASD) is characterized by the expression of restricted repetitive behaviors (RRBs) and impairments in social recognition and communication. Epidemiological studies demonstrate males are three times more likely than females to be affected. Although this is the case, more recent studies suggest females may be underrepresented in these numbers due to standard clinical measures of RRBs and social behaviors. In addition, many studies examining mouse models of ASD exclude females due to the sex disparity in diagnoses. The present study examined how female and male BTBR T + Itpr3tf /J (BTBR) compare to control C57BL/6J mice on tests of RRBs (probabilistic reversal learning, repetitive grooming, spontaneous alternation, and marble burying) and social behaviors (three chambered social approach task). Utilizing a spatial reversal learning test with 80/20 probabilistic feedback, in which ASD individuals have exhibited deficits, we find that female BTBR mice do not show the same impairment found in male BTBR mice. Interestingly, control female C57BL/6J mice required more trials to reach criterion. Female BTBR mice expressed comparable rates of repetitive grooming, marble burying and spontaneous alternation compared to female C57BL/6J mice. Male BTBR mice expressed higher rates of grooming behavior and locomotor activity compared to male C57BL/6J mice, as found in previous studies. Similarly, male BTBR mice showed a reduction in both measures of social approach compared to controls. Both male and female BTBR mice showed a reduction in sniff time for the stranger mouse compared to controls. Together these findings demonstrate how female BTBR mice do not display the RRB profile expressed by male BTBR mice. Testing of repetitive behaviors in ASD needs to better reflect the sex differences in how RRBs manifest in females compared to their extensively researched male counterparts.

5-HT6 receptor agonist EMD386088 impairs behavioral flexibility and working memory.

Serotonin 6 (5-HT6) receptors are primarily expressed in the central nervous system and to an even further extent brain regions responsible for learning and memory. Recent studies have demonstrated 5-HT6 receptor involvement in pathophysiological processes highlighting their therapeutic possibilities. Most research concerning the effects of 5-HT6 receptor modulation has focused on blockade despite paradoxical findings that 5-HT6 agonists and antagonists can both have pro-cognitive effects. The current experiments examine the effects of the 5-HT6 receptor agonist EMD386088 on behavioral flexibility and working memory. C57BL/6J mice received systemic injections of either 0, 2, or 4 mg/kg EMD386088 before being tested on probabilistic reversal learning, spontaneous alternation, and locomotor activity. In the probabilistic reversal learning task, the high dose of 4 mg/kg significantly impaired performance requiring more trials to reach criterion. The same dose significantly increased perseverative type errors, suggesting that the probabilistic reversal learning impairment was due to an inability to inhibit the previously learned choice pattern, rather than maintaining the new optimal choice pattern. Acute EMD386088 administration at 2 mg/kg significantly impaired spontaneous alternation performance, while the high dose of 4 mg/kg did not reach significance. These learning impairments were not due to an overall locomotor impairment as evidenced by comparable locomotor activity scores. Acute systemic 5-HT6 receptor activation with EMD386088 led to impaired behavior flexibility and working memory performance. Current findings support previous research suggesting that novel therapeutics directed at down regulation of 5-HT6 receptors may be effective in attenuating working memory and behavioral flexibility impairments commonly found in neuropsychiatric disorders such as Alzheimer's and schizophrenia.