Prenatal immune challenge in rats: effects of polyinosinic-polycytidylic acid on spatial learning, prepulse inhibition, conditioned fear, and responses to MK-801 and amphetamine.

Prenatal maternal immune activation increases risk for schizophrenia and/or autism. Previous data suggest that maternal weight change in response to the immune activator polyinosinic-polycytidylic (Poly IC) in rats influences the severity of effect in the offspring as does the exposure period. We treated gravid Sprague-Dawley rats from E14 to 18 with 8mg/kg/day Poly IC or saline. The Poly IC group was divided into those that gained the least weight or lost (Poly IC (L)) and those that gained the most (Poly IC (H)) weight. There were no effects of Poly IC on anxiety (elevated zero-maze, open-field, object burying), or Morris water maze cued learning or working memory or Cincinnati water maze egocentric learning. The Poly IC (H) group males had decreased acoustic startle whereas Poly IC (L) females had reduced startle and increased PPI. Poly IC offspring showed exaggerated hyperactivity in response to amphetamine (primarily in the Poly IC (H) group) and attenuated hyperactivity in response to MK-801 challenge (primarily in the Poly IC (L) group). Poly IC (L) males showed reduced cued conditioned freezing; both sexes showed less time in the dark in a light-dark test, and the Poly IC groups showed impaired Morris water maze hidden platform acquisition and probe performance. The data demonstrate that offspring from the most affected dams were more affected than those from less reactive dams indicating that degree of maternal immune activation predicts severity of effects on offspring behavior.

Neonatal +-methamphetamine exposure in rats alters adult locomotor responses to dopamine D1 and D2 agonists and to a glutamate NMDA receptor antagonist, but not to serotonin agonists.

Neonatal exposure to (+)-methamphetamine (Meth) results in long-term behavioural abnormalities but its developmental mechanisms are unknown. In a series of experiments, rats were treated from post-natal days (PD) 11-20 (stage that approximates human development from the second to third trimester) with Meth or saline and assessed using locomotor activity as the readout following pharmacological challenge doses with dopamine, serotonin and glutamate agonists or antagonists during adulthood. Exposure to Meth early in life resulted in an exaggerated adult locomotor hyperactivity response to the dopamine D1 agonist SKF-82958 at multiple doses, a high dose only under-response activating effect of the D2 agonist quinpirole, and an exaggerated under-response to the activating effect of the N-methyl-d-aspartic acid (NMDA) receptor antagonist, MK-801. No change in locomotor response was seen following challenge with the 5-HT releaser p-chloroamphetamine or the 5-HT2/3 receptor agonist, quipazine. These are the first data to show that PD 11-20 Meth exposure induces long-lasting alterations to dopamine D1, D2 and glutamate NMDA receptor function and may suggest how developmental Meth exposure leads to many of its long-term adverse effects.

Distinct periods of developmental sensitivity to the effects of 3,4-(±)-methylenedioxymethamphetamine (MDMA) on behaviour and monoamines in rats.

Previous findings showed allocentric and egocentric learning deficits in rats after MDMA treatment from postnatal days (PD) 11-20 but not after treatment from PD 1-10. Shorter treatment periods (PD 1-5, 6-10, 11-15, or 16-20) resulted in allocentric learning deficits averaged across intervals but not for any interval individually and no egocentric learning deficits individually or collectively. Whether this difference was attributable to treatment length or age at the start of treatment was unclear. In the present experiment rat litters were treated on PD 1-10, 6-15, or 11-20 with 0, 10, or 15 mg/kg MDMA q.i.d. at 2-h intervals. Two male/female pairs/litter received each treatment. One pair/litter received acoustic startle with prepulse inhibition, straight channel swimming, Cincinnati water maze (CWM), and conditioned fear in a latent inhibition paradigm. The other pair/litter received locomotor activity, straight channel swimming, Morris water maze (MWM), and locomotor activity retest with MK-801 challenge. MDMA impaired CWM learning following PD 6-15 or 11-20 exposure. In MWM acquisition, all MDMA-treated groups showed impairment. During reversal and shift, the PD 6-15 and PD 11-20 MDMA-treated groups were significantly impaired. Reductions in locomotor activity were most evident after PD 6-15 treatment while increases in acoustic startle were most evident after PD 1-10 treatment. After MK-801 challenge, MDMA-treated offspring showed less locomotion compared to controls. Region-specific changes in brain monoamines were also observed but were not significantly correlated with behavioural changes. The results show that PD 11-20 exposure to MDMA caused the largest long-term cognitive deficits followed by PD 6-15 exposure with PD 1-10 exposure least affected. Other effects, such as those upon MK-801-stimulated locomotion showed greatest effects after PD 1-10 MDMA exposure. Hence, each effect has a different window of developmental susceptibility.

Neonatal (+)-methamphetamine increases brain derived neurotrophic factor, but not nerve growth factor, during treatment and results in long-term spatial learning deficits.

In this study, brain derived neurotrophic factor (BDNF) and nerve growth factor (NGF) were examined at five time points [postnatal day (P)11, 15, 20, 21, and 68 (the latter with or without behavioral testing)] during and after P11-20 (+)-methamphetamine (MA) (10 mg/kg 4 x day) treatment. BDNF in MA-treated animals was elevated on P15 and P20 in the hippocampus but not in the hypothalamus and was unchanged on P11 and P21. On P68 (1 h after Morris water maze testing) MA-treated offspring showed a trend toward higher levels of BDNF in the hippocampus than saline-treated animals. MA treatment increased NGF levels in the hippocampus but only on P20. No effect of MA treatment was observed in the elevated zero maze. MA-treated offspring had increased latencies, cumulative distances, path lengths, and first bearings in the Morris water maze. The findings indicate that early MA exposure induces hippocampal BDNF increases that precede the later emergence of spatial learning deficits.