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Opiate addiction is now a major public health problem. Perinatal insults and exposure to opiates such as morphine in utero are well known to affect development of the hypothalamic-pituitary-adrenal (HPA)-axis of the offspring adversely and are associated with a higher risk of developing neurobehavioral problems. Oxycodone is now one of the most frequently abused pain killers during pregnancy, however limited data are available regarding whether and how perinatal oxycodone exposure (POE) alters neurobehavioral outcomes of the offspring. We demonstrated that exposure to 0.5 mg/kg/day oxycodone in utero was associated with hyperactivity in adult rats in an open field. No significant effects of POE were detected on isolation induced ultrasonic vocalizations in the early postnatal period or on learning and memory in the water maze in adult offspring. Our findings are consistent with hyperactivity problems identified in children exposed to opiates in utero.

NMDAR-mediated excitotoxicity has been implicated in some of the impairments following fetal ethanol exposure. Previous studies suggest that both neuronal cell death and some of the behavioral deficits can be reduced by NMDAR antagonism during withdrawal, including antagonism of a subpopulation of receptors containing NR2B subunits. To further investigate NR2B involvement, we selected a compound, CP-101,606 (CP) which binds selectively to NR2B/2B stoichiometries, for both in vitro and in vivo analyses. For the in vitro study, hippocampal explants were exposed to ethanol for 10 days and then 24 h following removal of ethanol, cellular damage was quantified via propidium iodide fluorescence. In vitro ethanol withdrawal-associated neurotoxicity was prevented by CP (10 and 25 nM). In vivo ethanol exposure was administered on PNDs 1-7 with CP administered 21 h following cessation. Activity (PNDs 20-21), motor skills (PNDs 31-33), and maze navigation (PNDs 43-44) were all susceptible to ethanol insult; treatment with CP (15 mg/kg) rescued these deficits. Our findings show that CP-101,606, a drug that blocks the NR2B/2B receptor, can reduce some of the damaging effects of "3rd trimester" alcohol exposure in our rodent model. Further work is clearly warranted on the neuroprotective potential of this drug in the developing brain.

Neonatal ethanol (EtOH) exposure is associated with central nervous system dysfunction and neurotoxicity in rats. Increases in polyamine levels have been implicated as one underlying mechanism for some of EtOH’s effects on the developing brain. In this study we addressed whether the inhibition of polyamine biosynthesis by α-difluoromethylornithine (DFMO) could reduce behavioral deficits induced by early EtOH exposure. Male and female rat pups received ethanol (6 g/kg/day EtOH i.g.), or isocaloric maltose (control) from postnatal days (PND) 1–8. On PND 8, animals were injected with either saline or DFMO (500 mg/kg, s.c.) immediately following the final neonatal treatment. Subjects were tested for isolation-induced ultrasonic vocalizations (USV) on PND 16; spontaneous activity in an open field apparatus on PND 20 and 21; and balance on PND 31. Animals exposed to EtOH neonatally displayed an increased latency to the first USV and reduced frequencies of USV, hyperactivity and preference for the center of the open field and poorer balance relative to controls. DFMO minimized these deficits in latency to the first USV and balance. These data provide further support that polyamines play a role in some of the functional deficits associated with EtOH exposure during early development and that reducing polyamine activity can improve outcome.

In the present study, we examined the effects of acamprosate for its ability to reduce handling induced convulsions (HICs) during alcohol withdrawal. Diazepam was used as a positive control. Swiss Webster male mice received three daily IP injections of alcohol (2.5 g/kg) or alcohol (2.5 g/kg) + methylpyrazole (4-MP) (9 mg/kg). (4-MP, being an alcohol dehydrogenase inhibitor slows down the breakdown of alcohol. 4-MP in combination with alcohol exhibits a dramatic increase in blood alcohol level compared to alcohol alone). Ten hours following the last alcohol injection, the mice were picked up by the tail and examined for their seizure susceptibility (HICs). Diazepam, a benzodiazepine known to reduce seizures during alcohol withdrawal, significantly reduced these HICs at doses of 0.25, 0.5 and 1mg/kg (p’s < 0.001). Acamprosate, an anti-relapse compound used clinically in newly abstinent alcoholics, also reduced these HICs at doses of 100, 200 and 300mg/kg (p’s < 0.05). This study supports the use of acamprosate during periods of alcohol withdrawal as well as during abstinence.