Sex differences in the reward value of familiar mates in prairie voles.

The rewarding properties of social interactions facilitate relationship formation and maintenance. Prairie voles are one of the few laboratory species that form selective relationships, manifested as "partner preferences" for familiar partners versus strangers. While both sexes exhibit strong partner preferences, this similarity in outward behavior likely results from sex-specific neurobiological mechanisms. We recently demonstrated that in operant trials, females worked hardest for access to familiar conspecifics of either sex, while males worked equally hard for access to any female, indicating a sex difference in social motivation. As tests were performed with one social target at a time, males might have experienced a ceiling effect, and familiar females might be more relatively rewarding in a choice scenario. Here we performed an operant social choice task in which voles lever-pressed to gain temporary access to either the chamber containing their mate or one containing a novel opposite-sex vole. Females worked hardest to access their mate, while males pressed at similar rates for either female. Individual male behavior was heterogeneous, congruent with multiple mating strategies in the wild. Voles exhibited preferences for favorable over unfavorable environments in a non-social operant task, indicating that lack of social preference does not reflect lack of discrimination. Natural variation in oxytocin receptor genotype at the intronic single nucleotide polymorphism NT213739 was associated with oxytocin receptor density, and predicted individual variation in stranger-directed aggressive behavior. These findings suggest that convergent preference behavior in male and female voles results from sex-divergent pathways, particularly in the realm of social motivation.

Natural variation in the oxytocin receptor gene and rearing interact to influence reproductive and nonreproductive social behavior and receptor binding.

Individual variation in social behavior offers an opportunity to explore gene-by-environment interactions that could contribute to adaptative or atypical behavioral profiles (e.g., autism spectrum disorders). Outbred, socially monogamous prairie voles provide an excellent model to experimentally explore how natural variations in rearing and genetic diversity interact to shape reproductive and nonreproductive social behavior. In this study, we manipulated rearing (biparental versus dam-only), genotyped the intronic NT213739 single nucleotide polymorphism (SNP) of the oxytocin receptor gene (Oxtr), and then assessed how each factor and their interaction related to reciprocal interactions and partner preference in male and female adult prairie voles. We found that C/T subjects reared biparentally formed more robust partner preferences than T/T subjects. In general, dam-only reared animals huddled less with a conspecific in reproductive and nonreproductive contexts, but the effect of rearing was more pronounced in T/T animals. In line with previous literature, C/T animals exhibited higher densities of oxytocin receptor (OXTR) in the striatum (caudoputamen, nucleus accumbens) compared to T/T subjects. There was also a gene-by-rearing interaction in the striatum and insula of females: In the insula, T/T females expressed varying OXTR densities depending on rearing. Overall, this study demonstrates that significant differences in adult reproductive and nonreproductive social behavior and OXTR density can arise due to natural differences in Oxtr, experimental manipulations of rearing, and their interaction.

Evaluating the stability of individual variation in social and nonsocial behavioural types using prairie voles (Microtus ochrogaster).

Prairie voles (Microtus ochrogaster) exhibit remarkable individual variation in social behaviour, suggesting differences in behavioural types. To date, however, there has been little assessment of whether these behavioural types are stable across test sessions, nor to what extent internal states and external contexts (domains) drive individual differences. Here we examined the individual consistency of social (huddling) and non-social (distance moved) behaviour across repeated, long-duration tests, in same-sex cagemate (SS-CM), same-sex stranger (SS-S), opposite-sex stranger (OS-S), and standard partner preference test (PPT) contexts. The SS-CM and SS-S tests were repeated multiple times (SS-CM 1-2; SS-S 1-5) to assess state-dependent variation. A second cohort was used to determine the replicability of findings. Overall, there was a general lack of stability in huddling behavior. It was inconsistent across repeated sessions of the same test type and between types of tests, suggesting a strong contribution of state-dependent variation. Non-social behaviour was more consistent and appeared more domain-dependent and less state-dependent than huddling. Translational and comparative studies of individual variation would likely benefit from testing across multiple contexts and employing repetitive testing paradigms to account for state-dependent variation.

Patterns of cell death in the perinatal mouse forebrain.

The importance of cell death in brain development has long been appreciated, but many basic questions remain, such as what initiates or terminates the cell death period. One obstacle has been the lack of quantitative data defining exactly when cell death occurs. We recently created a "cell death atlas," using the detection of activated caspase-3 (AC3) to quantify apoptosis in the postnatal mouse ventral forebrain and hypothalamus, and found that the highest rates of cell death were seen at the earliest postnatal ages in most regions. Here we have extended these analyses to prenatal ages and additional brain regions. We quantified cell death in 16 forebrain regions across nine perinatal ages from embryonic day (E) 17 to postnatal day (P) 11 and found that cell death peaks just after birth in most regions. We found greater cell death in several regions in offspring delivered vaginally on the day of parturition compared with those of the same postconception age but still in utero at the time of collection. We also found massive cell death in the oriens layer of the hippocampus on P1 and in regions surrounding the anterior crossing of the corpus callosum on E18 as well as the persistence of large numbers of cells in those regions in adult mice lacking the pro-death Bax gene. Together these findings suggest that birth may be an important trigger of neuronal cell death and identify transient cell groups that may undergo wholesale elimination perinatally. J. Comp. Neurol. 525:47-64, 2017. © 2016 Wiley Periodicals, Inc.

Oxytocin in the nucleus accumbens shell reverses CRFR2-evoked passive stress-coping after partner loss in monogamous male prairie voles.

Loss of a partner can have severe effects on mental health. Here we explore the neural mechanisms underlying increased passive stress-coping, indicative of depressive-like behavior, following the loss of the female partner in the monogamous male prairie vole. We demonstrate that corticotropin-releasing factor receptor 2 (CRFR2) in the nucleus accumbens shell mediates social loss-induced passive coping. Further, we show that partner loss compromises the oxytocin system through multiple mechanisms. Finally, we provide evidence for an interaction of the CRFR2 and oxytocin systems in mediating the emotional consequences of partner loss. Our results suggest that chronic activation of CRFR2 and suppression of striatal oxytocin signaling following partner loss result in an aversive emotional state that may share underlying mechanisms with bereavement. We propose that the suppression of oxytocin signaling is likely adaptive during short separations to encourage reunion with the partner and may have evolved to maintain long-term partnerships. Additionally, therapeutic strategies targeting these systems should be considered for treatment of social loss-mediated depression.

Epigenetics and sex differences in the brain: A genome-wide comparison of histone-3 lysine-4 trimethylation (H3K4me3) in male and female mice.

Many neurological and psychiatric disorders exhibit gender disparities, and sex differences in the brain likely explain some of these effects. Recent work in rodents points to a role for epigenetics in the development or maintenance of neural sex differences, although genome-wide studies have so far been lacking. Here we review the existing literature on epigenetics and brain sexual differentiation and present preliminary analyses on the genome-wide distribution of histone-3 lysine-4 trimethylation in a sexually dimorphic brain region in male and female mice. H3K4me3 is a histone mark primarily organized as 'peaks' surrounding the transcription start site of active genes. We microdissected the bed nucleus of the stria terminalis and preoptic area (BNST/POA) in adult male and female mice and used ChIP-Seq to compare the distribution of H3K4me3 throughout the genome. We found 248 genes and loci with a significant sex difference in H3K4me3. Of these, the majority (71%) had larger H3K4me3 peaks in females. Comparisons with existing databases indicate that genes and loci with increased H3K4me3 in females are associated with synaptic function and with expression atlases from related brain areas. Based on RT-PCR, only a minority of genes with a sex difference in H3K4me3 has detectable sex differences in expression at baseline conditions. Together with previous findings, our data suggest that there may be sex biases in the use of epigenetic marks. Such biases could underlie sex differences in vulnerabilities to drugs or diseases that disrupt specific epigenetic processes.

Drinking alcohol has sex-dependent effects on pair bond formation in prairie voles.

Alcohol use and abuse profoundly influences a variety of behaviors, including social interactions. In some cases, it erodes social relationships; in others, it facilitates sociality. Here, we show that voluntary alcohol consumption can inhibit male partner preference (PP) formation (a laboratory proxy for pair bonding) in socially monogamous prairie voles (Microtus ochrogaster). Conversely, female PP is not inhibited, and may be facilitated by alcohol. Behavior and neurochemical analysis suggests that the effects of alcohol on social bonding are mediated by neural mechanisms regulating pair bond formation and not alcohol's effects on mating, locomotor, or aggressive behaviors. Several neuropeptide systems involved in the regulation of social behavior (especially neuropeptide Y and corticotropin-releasing factor) are modulated by alcohol drinking during cohabitation. These findings provide the first evidence to our knowledge that alcohol has a direct impact on the neural systems involved in social bonding in a sex-specific manner, providing an opportunity to explore the mechanisms by which alcohol affects social relationships.

Variation in vasopressin receptor (Avpr1a) expression creates diversity in behaviors related to monogamy in prairie voles.

Polymorphisms in noncoding regions of the vasopressin 1a receptor gene (Avpr1a) are associated with a variety of socioemotional characteristics in humans, chimpanzees, and voles, and may impact behavior through a site-specific variation in gene expression. The socially monogamous prairie vole offers a unique opportunity to study such neurobiological control of individual differences in complex behavior. Vasopressin 1a receptor (V1aR) signaling is necessary for the formation of the pair bond in males, and prairie voles exhibit greater V1aR binding in the reward-processing ventral pallidum than do asocial voles of the same genus. Diversity in social behavior within prairie voles has been correlated to natural variation in neuropeptide receptor expression in specific brain regions. Here we use RNA interference to examine the causal relationship between intraspecific variation in V1aR and behavioral outcomes, by approximating the degree of naturalistic variation in V1aR expression. Juvenile male prairie voles were injected with viral vectors expressing shRNA sequences targeting Avpr1a mRNA into the ventral pallidum. Down-regulation of pallidal V1aR density resulted in a significant impairment in the preference for a mated female partner and a reduction in anxiety-like behavior in adulthood. No effect on alloparenting was detected. These data demonstrate that within-species naturalistic-like variation in V1aR expression has a profound effect on individual differences in social attachment and emotionality. RNA interference may prove to be a useful technique to unite the fields of behavioral ecology and neurogenetics to perform ethologically relevant studies of the control of individual variation and offer insight into the evolutionary mechanisms leading to behavioral diversity.

Cell death atlas of the postnatal mouse ventral forebrain and hypothalamus: effects of age and sex.

Naturally occurring cell death is essential to the development of the mammalian nervous system. Although the importance of developmental cell death has been appreciated for decades, there is no comprehensive account of cell death across brain areas in the mouse. Moreover, several regional sex differences in cell death have been described for the ventral forebrain and hypothalamus, but it is not known how widespread the phenomenon is. We used immunohistochemical detection of activated caspase-3 to identify dying cells in the brains of male and female mice from postnatal day (P) 1 to P11. Cell death density, total number of dying cells, and regional volume were determined in 16 regions of the hypothalamus and ventral forebrain (the anterior hypothalamus, arcuate nucleus, anteroventral periventricular nucleus, medial preoptic nucleus, paraventricular nucleus, suprachiasmatic nucleus, and ventromedial nucleus of the hypothalamus; the basolateral, central, and medial amygdala; the lateral and principal nuclei of the bed nuclei of the stria terminalis; the caudate-putamen; the globus pallidus; the lateral septum; and the islands of Calleja). All regions showed a significant effect of age on cell death. The timing of peak cell death varied between P1 to P7, and the average rate of cell death varied tenfold among regions. Several significant sex differences in cell death and/or regional volume were detected. These data address large gaps in the developmental literature and suggest interesting region-specific differences in the prevalence and timing of cell death in the hypothalamus and ventral forebrain.

The role of early life experience and species differences in alcohol intake in microtine rodents.

Social relationships have important effects on alcohol drinking. There are conflicting reports, however, about whether early-life family structure plays an important role in moderating alcohol use in humans. We have previously modeled social facilitation of alcohol drinking in peers in socially monogamous prairie voles. We have also modeled the effects of family structure on the development of adult social and emotional behaviors. Here we assessed whether alcohol intake would differ in prairie voles reared by both parents compared to those reared by a single mother. We also assessed whether meadow voles, a closely related species that do not form lasting reproductive partnerships, would differ in alcohol drinking or in the effect of social influence on drinking. Prairie voles were reared either bi-parentally (BP) or by a single mother (SM). BP- and SM-reared adult prairie voles and BP-reared adult meadow voles were given limited access to a choice between alcohol (10%) and water over four days and assessed for drinking behavior in social and non-social drinking environments. While alcohol preference was not different between species, meadow voles drank significantly lower doses than prairie voles. Meadow voles also had significantly higher blood ethanol concentrations than prairie voles after receiving the same dose, suggesting differences in ethanol metabolism. Both species, regardless of rearing condition, consumed more alcohol in the social drinking condition than the non-social condition. Early life family structure did not significantly affect any measure. Greater drinking in the social condition indicates that alcohol intake is influenced similarly in both species by the presence of a peer. While the ability of prairie voles to model humans may be limited, the lack of differences in alcohol drinking in BP- and SM-reared prairie voles lends biological support to human studies demonstrating no effect of single-parenting on alcohol abuse.

Neuroanatomical evidence for reciprocal regulation of the corticotrophin-releasing factor and oxytocin systems in the hypothalamus and the bed nucleus of the stria terminalis of the rat: Implications for balancing stress and affect.

Activation of corticotrophin releasing factor (CRF) neurons in the paraventricular nucleus of the hypothalamus (PVN) is necessary for establishing the classic endocrine response to stress, while activation of forebrain CRF neurons mediates affective components of the stress response. Previous studies have reported that mRNA for CRF2 receptor (CRFR2) is expressed in the bed nucleus of the stria terminalis (BNST) as well as hypothalamic nuclei, but little is known about the localization and cellular distribution of CRFR2 in these regions. Using immunofluorescence with confocal microscopy, as well as electron microscopy, we demonstrate that in the BNST CRFR2-immunoreactive fibers represent moderate to strong labeling on axons terminals. Dual-immunofluorescence demonstrated that CRFR2-fibers co-localize oxytocin (OT), but not arginine-vasopressin (AVP), and make perisomatic contacts with CRF neurons. Dual-immunofluorescence and single cell RT-PCR demonstrate that in the hypothalamus, CRFR2 immunoreactivity and mRNA are found in OT, but not in CRF or AVP-neurons. Furthermore, CRF neurons of the PVN and BNST express mRNA for the oxytocin receptor, while the majority of OT/CRFR2 neurons in the hypothalamus do not. Finally, using adenoviral-based anterograde tracing of PVN neurons, we show that OT/CRFR2-immunoreactive fibers observed in the BNST originate in the PVN. Our results strongly suggest that CRFR2 located on oxytocinergic neurons and axon terminals might regulate the release of this neuropeptide and hence might be a crucial part of potential feedback loop between the hypothalamic oxytocin system and the forebrain CRF system that could significantly impact affective and social behaviors, in particular during times of stress.

Parental division of labor, coordination, and the effects of family structure on parenting in monogamous prairie voles (Microtus ochrogaster).

Family relationships help shape species-typical social and emotional development, but our understanding of how this shaping occurs is still relatively limited. Prairie voles are a socially monogamous and biparental species that is well situated to complement traditional animal models, such as rats and mice, in investigating the effects of family experience. In this series of studies, we aimed to test hypotheses relating to how prairie vole families function under undisturbed, standard laboratory conditions. In the first study, we compared the parental behavior of primiparous biparental (BP) and single-mother (SM) prairie vole family units for 12 postnatal days and then tested for sex differences, behavioral coordination, and family structure effects. Under BP conditions, nest attendance was coordinated and shared equally by both sexes, while pup-directed and partner-directed licking and grooming (LG) were coordinated in a sex and social-context-dependent manner. Contrary to our expectations, SMs showed no evidence of strong parental compensation in response to the lack of the father, indicating a minimal effect of family structure on maternal behavior but a large effect on pup care. In the second study, we examined the effects of these BP and SM rearing conditions on family dynamics in the next generation and found that SM-reared adult parents exhibited lower rates of pup-directed LG in comparison to BP-reared counterparts. Situated in the context of human family dynamics and psychology, these results suggest that the study in prairie voles may help improve our understanding of family systems and how perturbations to these systems can affect adults and offspring.

Toward an integrative understanding of social behavior: new models and new opportunities.

Social interactions among conspecifics are a fundamental and adaptively significant component of the biology of numerous species. Such interactions give rise to group living as well as many of the complex forms of cooperation and conflict that occur within animal groups. Although previous conceptual models have focused on the ecological causes and fitness consequences of variation in social interactions, recent developments in endocrinology, neuroscience, and molecular genetics offer exciting opportunities to develop more integrated research programs that will facilitate new insights into the physiological causes and consequences of social variation. Here, we propose an integrative framework of social behavior that emphasizes relationships between ultimate-level function and proximate-level mechanism, thereby providing a foundation for exploring the full diversity of factors that underlie variation in social interactions, and ultimately sociality. In addition to identifying new model systems for the study of human psychopathologies, this framework provides a mechanistic basis for predicting how social behavior will change in response to environmental variation. We argue that the study of non-model organisms is essential for implementing this integrative model of social behavior because such species can be studied simultaneously in the lab and field, thereby allowing integration of rigorously controlled experimental manipulations with detailed observations of the ecological contexts in which interactions among conspecifics occur.

The impact of early life family structure on adult social attachment, alloparental behavior, and the neuropeptide systems regulating affiliative behaviors in the monogamous prairie vole (microtus ochrogaster).

Early social attachments lie at the heart of emotional and social development in many mammals, including humans. In nature, monogamous prairie voles (Microtus ochrogaster) experience considerable natural variation in early social attachment opportunities due to differences in family structure [e.g., single-mothers (SM), solitary breeding pairs, and communal groups]. We exploited some of this natural variation in family structure to examine the influence of early social environment on the development of adult social behavior. First, we characterized the parental care received by pups reared biparentally (BP) or by SM in the laboratory. Second, we examined whether BP- and SM-reared offspring differed in adult nurturing, bonding, and emotional behaviors. Finally, we investigated the effects of rearing condition on neuropeptide systems that regulate adult social behavior [oxytocin (OT), vasopressin, and corticotropin-releasing factor, (CRF)]. Observations revealed that SM-reared pups were exposed more frequently (P < 0.01), licked and groomed less (P < 0.01), and matured more slowly (P < 0.01) than BP-reared pups. In adulthood, there were striking socio-behavioral differences: SM-reared females showed low spontaneous, pup-directed alloparental behavior (P < 0.01) and both males and females from the SM-reared condition showed delayed partner preference formation. While rearing did not impact neuropeptide receptor densities in the ventral forebrain as we predicted, SM-reared animals, particularly females, had increased OT content (P < 0.01) and greater dorsal raphe CRF2 densities (P < 0.05) and both measures correlated with licking and grooming experienced during the first 10 days of life. These results suggest that naturalistic variation in social rearing conditions can introduce diversity into adult nurturing and attachment behaviors.

Evaluation of two automated metrics for analyzing partner preference tests.

The partner preference test (PPT) is commonly used to examine sexual and social preferences in rodents. The test offers experimental subjects a choice between two stimulus animals, and time spent with each is used to calculate a preference score. In monogamous prairie voles (Microtus ochrogaster), the PPT has been paramount to the study of pair bonding. Although powerful, use of the PPT in voles has depended primarily on human manual scoring. Manual scoring is time-consuming and is susceptible to bias and fatigue, limiting the use of the PPT in high-throughput studies. Here we compared manual scoring (real-time and 16x) and two automated scoring metrics: "social proximity" and "immobile social contact". We hypothesized that "immobile social contact" would provide data most comparable to manually scored "huddling", and thus be the most sensitive measure of partner preference in prairie voles. Each automated metric produced data that highly correlated with manual scoring (R>0.90); however, "immobile social contact" more closely reflected manually scored huddling (R=0.99; P<0.001). "Social proximity" and "immobile social contact" were then used to detect group partner preferences in four data sets that varied by cohabitation length and sex. "Immobile social contact" revealed a significant partner preference in each data set; "social proximity" detected partner preferences in only three of the four. Our results demonstrate the utility of automated systems in high-throughput PPTs, and further confirm that automated systems capable of scoring "immobile social contact" yield results indistinguishable from manual scoring.

WITHDRAWN: Evaluation of two automated systems for analyzing partner preference tests.

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The CRF system mediates increased passive stress-coping behavior following the loss of a bonded partner in a monogamous rodent.

Social relationships significantly influence physiology and behavior, including the hypothalamo-pituitary-adrenal axis, anxiety, and mental health. Disruption of social bonds through separation or death often results in profound grieving, depression, and physical illness. As the monogamous prairie vole forms enduring, selective pair bonds with the mating partner, they provide an animal model to study the physiological consequences of pair bonding and, thus, the loss of the bonded partner. Male prairie voles were paired with a novel female or male sibling. After 5 days, half of the males of each group were separated from the partner. Elevated plus-maze, forced swim, and tail suspension tests were used to assess anxiety-like and passive stress-coping behaviors indicative of depressive-like behavior. Following 4 days of separation from the female but not the male partner, experimental males displayed increased passive stress-coping. This effect was abolished by long-term intracerebroventricular infusion of a nonselective corticotropin-releasing factor (CRF) receptor antagonist without disrupting the bond itself. Both CRF type 1 and 2 receptors were involved in the emergence of passive stress-coping behavior. Furthermore, pairing with a female was associated with elevated CRF mRNA in the bed nucleus of the stria terminalis, and partner loss elicited a pronounced increase in circulating corticosteroid and adrenal weight. We speculate that the CRF system may mediate an aversive affect following separation from the female partner, which may facilitate proximity seeking between the pair-bonded individuals. Hence, the prairie vole model may provide insights into brain mechanisms involved in the psychopathological consequences of partner loss.

Differential synaptic plasticity of the corticostriatal and thalamostriatal systems in an MPTP-treated monkey model of parkinsonism.

Two cardinal features of Parkinson's disease (PD) pathophysiology are a loss of glutamatergic synapses paradoxically accompanied by an increased glutamatergic transmission to the striatum. The exact substrate of this increased glutamatergic drive remains unclear. The striatum receives glutamatergic inputs from the thalamus and the cerebral cortex. Using vesicular glutamate transporters (vGluTs) 1 and 2 as markers of the corticostriatal and thalamostriatal afferents, respectively, we examined changes in the synaptology and relative prevalence of striatal glutamatergic inputs in methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated monkeys using electron microscopic immunoperoxidase and confocal immunofluorescence methods. Our findings demonstrate that the prevalence of vGluT1-containing terminals is significantly increased in the striatum of MPTP-treated monkeys (51.9 +/- 3.5% to 66.5 +/- 3.4% total glutamatergic boutons), without any significant change in the pattern of synaptic connectivity; more than 95% of vGluT1-immunolabeled terminals formed axo-spinous synapses in both conditions. In contrast, the prevalence of vGluT2-immunoreactive terminals did not change after MPTP treatment (21.7 +/- 1.3% vs. 21.6 +/- 1.2% total glutamatergic boutons). However, a substantial increase in the ratio of axo-spinous to axo-dendritic synapses formed by vGluT2-immunoreactive terminals was found in the pre-caudate and post-putamen striatal regions of MPTP-treated monkeys, suggesting a certain degree of synaptic reorganization of the thalamostriatal system in parkinsonism. About 20% of putative glutamatergic terminals did not show immunoreactivity in striatal tissue immunostained for both vGluT1 and vGluT2, suggesting the expression of another vGluT in these boutons. These findings provide striking evidence that suggests a differential degree of plasticity of the corticostriatal and thalamostriatal system in PD.

The effects of norepinephrine transporter inactivation on locomotor activity in mice.

BACKGROUND: Acute administration of different classes of antidepressants can enhance or reduce spontaneous locomotor activity in a novel environment, but the effects of chronic antidepressant treatment on spontaneous locomotor activity in novel and familiar environments are less well characterized. Because norepinephrine is an important regulator of spontaneous locomotor activity, we speculated that norepinephrine transporter blockade contributes to the effects of some antidepressants on spontaneous locomotor activity. METHODS: Antidepressant drugs (reboxetine, desipramine, imipramine, venlafaxine, bupropion) were administered acutely (intraperitoneal) or chronically (via osmotic minipump) to control and norepinephrine transporter knockout mice, and spontaneous locomotor activity in novel or familiar environments was recorded. RESULTS: Acute treatment with most norepinephrine transporter-blocking antidepressants decreased spontaneous locomotor activity in a novel environment, whereas chronic treatment decreased spontaneous locomotor activity in both novel and familiar environments. The exception was bupropion, a dual norepinephrine transporter/dopamine transporter blocker, which tended to increase spontaneous locomotor activity. Coadministration of reboxetine and the dopamine transporter blocker GBR 12909 also increased spontaneous locomotor activity. Norepinephrine transporter knockout mice had low basal spontaneous locomotor activity, which was increased by bupropion, whereas reboxetine had no effect in norepinephrine transporter knockout mice. CONCLUSIONS: Acute or chronic inactivation of the norepinephrine transporter decreases spontaneous locomotor activity in novel and familiar environments unless coupled with dopamine transporter blockade.

The effects of chronic norepinephrine transporter inactivation on seizure susceptibility in mice.

Epilepsy and depression are comorbid disorders, but the mechanisms underlying their relationship have not been identified. Traditionally, many antidepressants have been thought to increase seizure incidence, although this remains controversial, and it is unclear which medications should be used to treat individuals suffering from both epilepsy and depression. Since the neurotransmitter norepinephrine (NE) has both antidepressant and anticonvulsant properties, we speculated that NE transporter (NET) inhibitor antidepressants might be therapeutic candidates for comorbid individuals. To test this idea, we assessed the effects of chronic administration (via osmotic minipump) of the selective NET inhibitor reboxetine on flurothyl-induced seizures in mice. We found that reboxetine had both proconvulsant and anticonvulsant properties; it lowered both seizure threshold and maximal seizure severity. NET knockout (NET KO) mice essentially phenocopied the effects of reboxetine on flurothyl-induced seizures, and the trends were extended to pentylenetetrazole and maximal electroshock seizures (MES). Furthermore, reboxetine had no further effect in NET KO mice, demonstrating the specificity of reboxetine for the NET. We next tested the chronic and acute effects of other classes of antidepressants (desipramine, imipramine, sertraline, bupropion, and venlafaxine) on seizure susceptibility. Only venlafaxine was devoid of proconvulsant activity, and retained some anticonvulsant activity. These results suggest that chronic antidepressant drug treatment has both proconvulsant and anticonvulsant effects, and that venlafaxine is a good candidate for the treatment of epilepsy and depression comorbidity.