Nicotine Therapy in Adulthood Reverses the Synaptic and Behavioral Deficits Elicited by Prenatal Exposure to Phenobarbital

Abstract

A major objective in identifying the mechanisms underlying neurobehavioral teratogenicity is the possibility of designing therapies that reverse or offset drug-or toxicant-induced neural damage. In our previous studies, we identified deficits in hippocampal muscarinic cholinergic receptor-induced membrane translocation of protein kinase C (PKC)g as the likely mechanism responsible for adverse behavioral effects of prenatal phenobarbital exposure. We therefore explored whether behavioral and synaptic defects could be reversed in adulthood by nicotine administration. Pregnant mice were given milled food containing phenobarbital to achieve a daily dose of 0.5-0.6 g/kg from gestational days 9-18. In adulthood, offspring showed deficits in the Morris maze, a behavior dependent on the integrity of septohippocampal cholinergic synaptic function, along with the loss of the PKCg response. Phenobarbital-exposed and control mice then received nicotine (10 mg/kg/day) for 14 days via osmotic minipumps. Nicotine reversed the behavioral deficits and restored the normal response of hippocampal PKCg to cholinergic receptor stimulation. The effects were regionally specific, as PKCg in the cerebellum was unaffected by either phenobarbital or nicotine; furthermore, in the hippocampus, PKC isoforms unrelated to the behavioral deficits showed no changes. Nicotine administration thus offers a potential therapy for reversing neurobehavioral deficits originating in septohippocampal cholinergic defects elicited by prenatal drug or toxicant exposures.

Transplantation of neural progenitors enhances production of endogenous cells in the impaired brain

“…Muscarinic manipulation implicated the muscarinic signaling cascade, involving G proteins, Ca 2 þ elevation and PKC, in the proliferation of neural precursors. 64 In our model, prenatal heroin exposure induced defects of the cholinergic innervation, 16,17,23,45 terminating in PKC inactivation, 16,21,41,46 thus serving as a possible explanation for prenatal heroin inhibition of endogenous neural precursors proliferation. It is possible that the muscarinic signaling cascade may be part of, and/ or play a synergistic role to, the cytokine system, whose role in neurogenesis has been suggested by other investigators.…”

“…[42][43][44] On the biochemical/molecular level, prenatal heroin induced both pre-and postsynaptic hyperactivity in the hippocampal cholinergic innervation, 16,17,23,45 converging on a total abolishment of the specific cholinergic-induced activation of PKCg. 16,21,41,46 This appears to be a major mechanism of these behavioral defects.…”

A chick model for the mechanisms of mustard gas neurobehavioral teratogenicity

“…We were able to reverse neurobehavioral teratogenicity in the mouse model by manipulating the regulating pathways [41], neural grafting [31] and nicotine therapy [4]. Similar models for the reversal of neuroteratogenicity in rodents were demonstrated, for example, fetal alcohol syndrome [32].…”

“…It is not surprising that SM alters PKC, since in addition to its known role as a blistering agent, SM targets both, the cholinergic system [11] and the signaling protein, PKC [27]. The regulation of PKC activation by acetylcholine was demonstrated in our previous studies [4,16].…”

Development of Male Sexual Function After Prenatal Modulation of Cholinergic System

“…The mechanisms of action of many chemical factors on the developing fetal brain during early ontogenesis are in most cases mediated by alterations in the formation and functioning of brain neurotransmitter systems, including the cholinergic system, whose CNS function is associated with memory, learning, and behavioral processes (Yamada et al, 1986;Buzsaki, 1989;Everitt & Robbins, 1998;Levin & Slotkin, 1988;Zoli et al, 1999). During the period of neuron development, actions on cholinergic mechanisms lead to delays in cell differentiation which correlate with cognitive and behavioral deficits in fertile offspring (Yamada et al, 1986;Levin & Simon, 1998;Beer et al, 2005). Prenatal exposure to neurotoxins (nicotine, organochlorine compounds, barbiturates), which have cholinotropic properties, produces long-lasting changes in neurotransmitter functions in early ontogenesis with the subsequent development of neurobehavioral anomalies and affective disorders in pubescent individuals (Seidler et al, 1992;Barinaga, 1996;Slotkin, 2004).…”