Changes in maternal and fetal nicotine distribution after maternal administration of monoclonal nicotine-specific antibody to rats

Abstract

Vaccination against nicotine to elicit the production of nicotine-specific antibodies is a potential treatment for tobacco addiction which reduces nicotine distribution from serum to brain. Vaccination of pregnant rats also reduces the distribution of maternally-administered nicotine to fetal brain. Whether this is due to maternal antibody reducing the transfer of nicotine from mother to fetus, or to fetal antibody altering the distribution of nicotine within the fetus, is not clear. In the current study, passive immunization of rats with the murine monoclonal nicotine-specific antibody Nic311 was used as a surrogate for vaccination because antibody transfer to the fetus was anticipated to be lower than with vaccination. Pregnant rats received nicotine from gestational day (GD) 18-20 as frequent i.v. boluses to simulate nicotine exposure from smoking. Nic 311 was administered at doses of 30, 80 or 240 mg/kg on GD19. Fetal serum Nic311 levels on GD20 were <3% of concurrent maternal levels, but concentrations of up to 20 ug/ml in fetal serum were obtained owing to the very high levels in maternal serum. Accumulation of the chronically administered nicotine, measured on GD20, was not changed by Nic311 treatment in either maternal or fetal brain. The early distribution of nicotine to maternal brain, measured 5 min after a dose, was markedly reduced by Nic311, while the early distribution of nicotine to whole fetus and fetal brain was not substantially altered.. These data suggest that the limited transfer of Nic311 to the fetus in turn limits the ability of Nic311 to reduce nicotine distribution to fetal brain.

Vaccination against nicotine alters the distribution of nicotine delivered via cigarette smoke inhalation to rats

“…Groups of 12 rats were anesthetized and received 36 mg/kg of Nic311 or nonspecific IgG control. This Nic311 dose has been shown to alter nicotine distribution to approximately the same extent as active immunization with 3′-AmNic-rEPA [34]. Rats were studied one day later, to allow sufficient time for distribution of Nic311 [25], by placing the unanesthetized animals in the WBE unit for 2 hr with smoke parameters as noted above.…”

Nicotine on the developing brain

“…Although non-nicotine tobacco smoke constituents have been reported to impact fetal brain development [ 11 ], nicotine alone is likely the major contributor to the harmful effects of maternal tobacco use on their offspring. Animal studies have shown that nicotine readily crosses the placental barrier to interact with receptors widely distributed throughout the fetus and richly expressed in the fetal brain [ 12 , 13 ]. These nAChRs are functional [ 14 ] and are upregulated by maternal nicotine intake [ 15 ].…”

The Fate and Function of Therapeutic Antiaddiction Monoclonal Antibodies across the Reproductive Cycle of Rats

“…Another advantage is that anti-PCP and anti-METH mAbs do not seem to cross blood-organ barriers such as the brain and testis to any great extent, but they do effectively remove PCP and METH from these organs (Proksch et al, 2000;Laurenzana et al, 2003a). This redistribution of target drug out of brain tissue is the mechanism of action for the neuroprotection mediated by these antiaddiction mAb medications (Laurenzana et al, 2003b;Keyler et al, 2006;Pentel et al, 2006). These findings suggest the potential for similar effects at the maternal blood-brain barrier, fetal blood-brain barrier, and blood-placental barrier, as suggested by studies in nearterm, nicotine-treated pregnant rats (Keyler et al, 2005a,b).…”