Effect of neonatal nomifensine exposure on adult behavior and brain monoamines in rats

Abstract

The aim of the study was to examine the effects of early postnatal exposure to nomifensine, an inhibitor of catecholamine uptake, on concurrent active (REM) sleep, on later alcohol related behavior and on monoamine concentrations in various brain regions of rats. For these purposes rats were given daily injections of 10 mg/kg nomifensine s.c. between the 7th and the 18th postnatal days. During the nomifensine exposure active sleep, expressed as a percentage of total sleeping time, was reduced. At one month of age, the nomifensine rats showed increased ambulation and had lower defecation scores in the open-field than the controls. Neonatal exposure to nomifensine increased voluntary intake of 10% (v/v) alcohol when the rats were 2-3 months of age. The rats, however, did not exhibit preservation in the T-maze, and similarly to control rats suppressed drinking 0.1 M lithium chloride even when thirsty. Measurement of cerebral monoamine concentrations at the age of 3 months suggested that neonatal nomifensine treatment interferes with the noradrenergic and serotonergic systems in several regions of the brain. Concentrations of noradrenaline and 5-hydroxyindoleacetic acid (5-HIAA) were decreased in the cerebral cortex and frontal cortex, concentration of 5-HIAA was decreased in the neostriatum, and concentrations of noradrenaline, 5-hydroxytryptamine (5-HT) and 5-HIAA were elevated in the lower brain stem. Taken together, these findings show that exposure to nomifensine during the 2nd and 3rd postnatal weeks suppresses neonatal active sleep, causes changes in the adult open-field behavior, and increases voluntary alcohol intake, perhaps due to a long-lasting alteration in brain monoamines.

Early-life exposure to the SSRI paroxetine exacerbates depression-like behavior in anxiety/depression-prone rats

“…While many findings are consistent across studies, there are discrepancies that likely stem from technical variations, including using different (a) antidepressant drugs [chlorimpramine, fluoxetine, citalopram, paroxetine, desipramine, zimeldine, LU-10-134C, nomifensine]; (b) route of drug administration [oral, intraperitoneal injection, osmotic minipump]; (c) species (mouse/rat) or strain used; and (d) timing of drug administration – during pregnancy (Vorhees et al, 1994, Bairy et al, 2007, Forcelli and Heinrichs, 2008, Van den Hove et al, 2008); portions of the first three postnatal weeks (Mirmiran et al, 1981, Hilakivi and Hilakivi, 1987, Hilakivi et al, 1987a, Hilakivi et al, 1987b, Hilakivi et al, 1988, Feenstra et al, 1996, Hansen et al, 1997, Kinney et al, 1997, Vijayakumar and Meti, 1999, Yannielli et al, 1999, Ansorge et al, 2004, Maciag et al, 2006a, Maciag et al, 2006b, Popa et al, 2008, Lee, 2009, Weaver et al, 2010, Simpson et al, 2011); or throughout gestation and the first three postnatal weeks (Lisboa et al, 2007, Bourke et al, 2013b). The vast majority of these studies focus on the effects of neonatal antidepressant exposure on male offspring with the exception of perhaps only one or two studies that also examine effects in females (Lisboa et al, 2007, McAllister et al, 2012).…”

“…Importantly, these behavioral effects are reasonably consistent across several studies, regardless of the specific SSRI or tricyclic antidepressant used. Neonatal antidepressant exposure-induced behavioral abnormalities are accompanied by myriad 5-HT system changes, including reduced neuronal firing in 5-HT neurons of the dorsal raphe (Kinney et al, 1997), diminished expression of tryptophan hydroxylase (TPH2) and SERT in the raphe (Maciag et al, 2006a), reduced 5-HT fiber density in the hippocampus (Weaver et al, 2010), and altered monoamine levels in multiple brain regions (Hilakivi et al, 1987a, Feenstra et al, 1996, Vijayakumar and Meti, 1999, Yannielli et al, 1999). …”

Structural Effects and Neurofunctional Sequelae of Developmental Exposure to Psychotherapeutic Drugs: Experimental and Clinical Aspects

“…Decreased hypothalamic 5-HT levels following neonatal clomipramine treatment provided further evidence for a down-regulation of 5-HT systems (Feenstra et al, 1996). Moreover, nomifensine administration to rodents in the early postnatal period induced changes in open field behavior and increased voluntary alcohol intake in adults because of long-lasting alterations in brain monoamines (Hilakivi et al, 1987).…”

The ontogeny of mammalian sleep: a reappraisal of alternative hypotheses

“…On the other hand, numerous studies have shown that monoamine uptake inhibitors or monoamine‐directed psychotropics/stimulants reduce bAS and adult REM sleep in similar ways (Shimizu and Himwich 1968a, b, 1969; Mirmiran et al . 1981; Hilakivi et al . 1987b).…”