Lasting neurobehavioral abnormalities in rats after neonatal activation of serotonin 1A and 1B receptors: possible mechanisms for serotonin dysfunction in autistic spectrum disorders

Abstract

Rationale: Perinatal exposure of rats to selective serotonin reuptake inhibitors (SSRIs) produces sensory and social abnormalities paralleling those seen in autistic spectrum disorders (ASDs). However, the possible mechanism(s) by which this exposure produces behavioral abnormalities is unclear.

Objective: We hypothesized that the lasting effects of neonatal SSRI exposure are a consequence of abnormal stimulation of 5-HT1A and/or 5-HT1B receptors during brain development. We examined whether such stimulation would result in lasting sensory and social deficits in rats in a manner similar to SSRIs using both direct agonist stimulation of receptors as well as selective antagonism of these receptors during SSRI exposure.

Methods: Male and female rat pups were treated from postnatal days 8 to 21. In Experiment 1, pups received citalopram (20 mg/kg/day), saline, (±)-8-hydroxy-dipropylaminotetralin hydrobromide (8-OH-DPAT; 0.5 mg/kg/day) or 7-trifluoromethyl-4(4-methyl-1-piperazinyl)-pyrrolo[1,2-a]-quinoxaline dimaleate (CGS-12066B; 10 mg/kg/day). In Experiment 2, a separate cohort of pups received citalopram (20 mg/kg/day), or saline which was combined with either N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-2-pyridinylcyclo-hexanecarboxamide maleate (WAY-100635; 0.6 mg/kg/day) or N-[4-methoxy-3-(4-methyl-1-piperazinyl)phenyl]-2'-methyl-4'-(5-methyl-1,2,4-oxadiazol-3-yl)-1-1'-biphenyl-4-carboxamide (GR-127935; 6 mg/kg/day) or vehicle. Rats were then tested in paradigms designed to assess sensory and social response behaviors at different time points during development.

Results: Direct and indirect neonatal stimulation of 5-HT1A or 5-HT1B receptors disrupts sensory processing, produces neophobia, increases stereotypic activity, and impairs social interactions in manner analogous to that observed in ASD.

Conclusion: Increased stimulation of 5-HT1A and 5-HT1B receptors plays a significant role in the production of lasting social and sensory deficits in adult animals exposed as neonates to SSRIs.

Fig. 1

Effect on neonatal drug exposure on locomotor activity in response to a novel tone. Data represent the mean ± SEM of SAL (saline; n = 80), CTM (citalopram, SSRI; n = 73), 8-OH-DPAT (5-HT_1A receptor agonist; n = 46), and CGS 12066B (5-HT_1B receptor agonist; n= 31) male and female rats. *p < 0.05 vs. SAL, +p < 0.05 vs. pretone baseline, Fisher’s least significant difference test.

Fig. 2

Effect on neonatal drug exposure on boxing, following/chasing, stereotypic behavior and rearing during juvenile play. Data represent the mean ±SEM of SAL (saline; n = 74), CTM (citalopram, SSRI; n = 66), 8-OH-DPAT (5-HT_1A receptor agonist; n= 32), and CGS 12066B (5-HT_1B receptor agonist; n= 29) male and female rats. *p < 0.05 vs. saline, Fisher’s least significant difference test.

Fig. 3

Effect of neonatal drug exposure on the number of interactions with conspecific in relation with interaction with object. Data represents the mean ± SEM of the ratio of contacts with the conspecifics enclosure to that of the novel object for SAL (saline; n = 68), CTM (citalopram, SSRI; n = 56), 8-OH-DPAT (5-HT_1A receptor agonist; n= 37), and CGS 12066B (5-HT_1B receptor agonist; n = 29) male and female rats. *p < 0.05 compared to saline, Fisher’s least significant difference test.

Fig. 4

Effect on neonatal drug exposure on locomotor activity in response to a novel tone. Data represent the mean ± SEM of saline (SAL; n = 21), citalopram (CTM, SSRI; n = 24), CTM + GR 127935 (SSRI + 5-HT_1B receptor antagonist; n = 23), and CTM + WAY 100635 (SSRI + 5-HT_1A receptor antagonist; n = 23) male and female rats. *p < 0.05 vs. SAL, +p < 0.05 vs. pretone baseline, Fisher’s least significant difference test.

Fig. 5

Effect on neonatal drug exposure on boxing, following/chasing, stereotypic behavior and rearing during juvenile play. Data represent the mean ±SEM of saline (SAL; n = 24), citalopram (CTM, SSRI; n = 26), CTM + GR 127935 (SSRI + 5-HT_1B receptor antagonist; n = 18), and CTM + WAY 100635 (SSRI + 5-HT_1A receptor antagonist; n = 24) male and female rats. *p < 0.05 vs. saline, Fisher’s least significant difference test.

Fig. 6

Effect of neonatal drug exposure on the number of interactions with conspecific in relation with interaction with object. Data represents the mean ± SEM of the ratio of contacts with the conspecifics enclosure to that of the novel object for saline (SAL; n = 28), citalopram (CTM, SSRI; n= 23), CTM + GR 127935 (SSRI + 5-HT_1B receptor antagonist; n = 15), and CTM + WAY 100635 (SSRI + 5-HT_1A receptor antagonist; n = 12) male and female rats. *p < 0.05 compared to saline, Fisher’s least significant difference test.