Table IV.
Sex-specific effects of perinatal exposure to GABAergic drugs on brain development and behavior.
| Treatment | Endpoint | Male vs female | Reference |
|---|---|---|---|
| Diazepam (DZ), 1.5mg/kg/day SC, E14–20, Wistar rats | Open field activity (OFA) and acoustic startle reflex in adulthood. | M-DZ: reduced total distance traveled, higher rearing frequency. | (Cannizzaro et al. 2001) |
| F-DZ: less time spent in central squares. | |||
| M-DZ and F-DZ: higher acoustic startle amplitude | |||
| DZ 2.5 – 10 mg/kg/day, E14–20, rats. | Dopamine-β-hydroxylase (DBH)-ir and corticotropin releasing factor (CRF) neurons in adult males. | M-DZ: Decreased DBH-ir and CRF neurons in paraventricular nucleus of the hypothalamus. | (Inglefield et al. 1993) |
| 1–2.5 mg/kg/day, E14–20, rats | Elevated plus maze DZ | M-DZ: more time spent in open arms; | (Kellogg et al. 1991) |
| F-DZ: no difference. | |||
| Social interaction in adult rats. | M-DZ: increased in unfamiliar but decreased in familiar environment. | ||
| F-DZ: decreased in unfamiliar environment. | |||
| DZ 10 mg/kg/day prenatally, rats | Acquisition or retention of a simultaneous choice discrimination task in adults. | DZ in 2nd gestational week: No effect. | (Frieder et al. 1984) |
| DZ in 3rd gestational week: impaired in males. | |||
| DZ given E3–18: impaired in both sexes, worse in F. | |||
| DZ 2.5 mg/kg/day prenatally or postnatally. | OFA, continuously reinforced lever-pressing responses in adults. | DZ in 3rd gestational week: no sex differences in adulthood. | (Guillamon et al. 1990) |
| DZ at PN0–16: no sex differences in OFA; impaired level-pressing behavior in M only. | |||
| DZ 1–2.5 mg/kg/day, postnatally, Wistar rats | Maternal behavior. | DZ at PN0–16: Positive effects in both F and M. | (Del Cerro et al. 1995; Segovia et al. 1996) |
| DZ 2.5 mg/kg/day E14–21, Wistar rats | Neonatal reflexes (cliff aversion, forelimb pacing and grasping, bar holding). | Offspring-DZ: delayed appearance of neonatal reflexes. | (Nicosia et al. 2003) |
| DZ prenatal (E14–21) or postnatal (PN0–21) Wistar rats | PTZ seizures (PN50). | Offspring-DZ: M>F | (Nicosia et al. 2003) |
| Prenatal DZ. | Sensitivity of GABAA receptors to Cl-, sensitivity to bicuculline. | Offspring-DZ: Altered sensitivity in adults; in M environmental stressors further alter these effects. | Reviewed in (Kellogg 1999) |
| Prenatal (E15–20) exposure to antiepileptics (AEDs: Phenobarbital 2mg/kg/day, clonazepam 0.15mg/kg/day, valproic acid 20 mg/kg/day), Sprague-Dawley rats. | Spontaneous alternation (PN43–45). | Controls:M: persevered, F: random alternations. | (Sobrian and Nandedkar 1986) |
| AED in utero: M: random alternations, F: persevered. | |||
| Spontaneous activity (PN43–45) | M-clonazepam: hypoactive. | (Sobrian and Nandedkar 1986) | |
| F-phenobarbital/valproic acid: hyperactive. | |||
| Prenatal benzodiazepine(BZ) antagonists: Ro15-1788 (10–20 mg/kg/day) or CGS8216, 2nd half of pregnancy (Swiss Webster albino mice). | Righting reflex (PN1–14); | Righting reflex: prenatal treatments resulted in sporadic days with significant changes. | (Pankaj and Brain 1991) |
| Resident-intruder test | M-Ro: immobility, more attacks. | ||
| (PN21). | F-Ro: more digging, immobility. | ||
| M-CGSP: less grooming. | |||
| F-CGS: less defensive. | |||
| Alprazolam (AL) 0.32 mg/kg/day E18, C57BL/6 mice. | Social play, sleep/wake patterns, aggression at prejuvenile (PN17), juvenile (PN25), adults. | Offspring-AL (PN17): Less desire to escape, isolated behavior, shorter awake periods. | (Christensen et al. 2003) |
| M-AL (juvenile, adult): more aggression on food restriction and cage changing. | |||
M: male; F: female; AED: antiepileptic; AL: alprazolam; BZ: benzodiazepine; CRF: corticotropin releasing factor; DBH: dopamine-β-hydroxylase; DZ: diazepam; E: embryonic day; OFA: open field activity; PN: postnatal day; PTZ: pentyleneterazole; M-DZ or F-DZ: male or female offspring exposed to DZ; M-AL or F-AL: male or female offspring exposed to AL; M-Ro or F-Ro: male or female offspring exposed to Ro15-1788; M-CGS or F-CGS: male or female offspring exposed to CGS8216.