Behavioral consequences of the downstream products of ethanol metabolism involved in alcohol use disorder.

Research concerning Alcohol Use Disorder (AUD) has previously focused primarily on either the behavioral or chemical consequences experienced following ethanol intake, but these areas of research have rarely been considered in tandem. Compared with other drugs of abuse, ethanol has been shown to have a unique metabolic pathway once it enters the body, which leads to the formation of downstream metabolites which can go on to form biologically active products. These metabolites can mediate a variety of behavioral responses that are commonly observed with AUD, such as ethanol intake, reinforcement, and vulnerability to relapse. The following review considers the preclinical and chemical research implicating these downstream products in AUD and proposes a chemobehavioral model of AUD.

Neurochemical Mediation of Affiliation and Aggression Associated With Pair-Bonding.

BACKGROUND: The neuropeptides vasopressin and corticotropin-releasing factor facilitate, while serotonin inhibits, aggression. How the brain is wired to coordinate interactions between these functionally opposed neurotransmitters to control behavioral states is poorly understood. METHODS: Pair-bonded male prairie voles (Microtus ochrogaster) were infused with a retrograde tracer, Fluoro-Gold, and tested for affiliation and aggression toward a female partner or novel female subject. Subsequent immunocytochemical experiments examined neuronal activation using Fos and neurochemical/neuroreceptor profiles on brain areas involved in these social behaviors. Finally, a series of behavioral pharmacologic and real-time in vivo brain microdialysis experiments were performed on male prairie voles displaying affiliation or aggression. RESULTS: We localized a subpopulation of excitatory vasopressin neurons in the anterior hypothalamus that may gate corticotropin-releasing factor output from the amygdala to the anterior hypothalamus and then the lateral septum to modulate aggression associated with mate guarding. Conversely, we identified a subset of inhibitory serotonergic projection neurons in the dorsal raphe that project to the anterior hypothalamus and may mediate the spatiotemporal release of neuropeptides and their interactions in modulating aggression and affiliation. CONCLUSIONS: Together, this study establishes the medial extended amygdala as a major neural substrate regulating the switch between positive and negative affective states, wherein several neurochemicals converge and interact to coordinate divergent social behaviors.

Episodic Social Stress-Escalated Cocaine Self-Administration: Role of Phasic and Tonic Corticotropin Releasing Factor in the Anterior and Posterior Ventral Tegmental Area.

Intermittent social defeat stress escalates later cocaine self-administration. Reward and stress both activate ventral tegmental area (VTA) dopamine neurons, increasing downstream extracellular dopamine concentration in the medial prefrontal cortex and nucleus accumbens. The stress neuropeptide corticotropin releasing factor (CRF) and its receptors (CRF-R1, CRF-R2) are located in the VTA and influence dopaminergic activity. These experiments explore how CRF release and the activation of its receptors within the VTA both during and after stress influence later cocaine self-administration in rats.In vivo microdialysis of CRF in the VTA demonstrated that CRF is phasically released in the posterior VTA (pVTA) during acute defeat, but, with repeated defeat, CRF is recruited into the anterior VTA (aVTA) and CRF tone is increased in both subregions. Intra-VTA antagonism of CRF-R1 in the pVTA and CRF-R2 in the aVTA during each social defeat prevented escalated cocaine self-administration in a 24 h "binge." VTA CRF continues to influence cocaine seeking in stressed animals long after social defeat exposure. Unlike nonstressed controls, previously stressed rats show significant cocaine seeking after 15 d of forced abstinence. Previously stressed rats continue to express elevated CRF tone within the VTA and antagonism of pVTA CRF-R1 or aVTA CRF-R2 reverses cocaine seeking. In conclusion, these experiments demonstrate neuroadaptive changes in tonic and phasic CRF with repeated stress, that CRF release during stress may contribute to later escalated cocaine taking, and that persistently elevated CRF tone in the VTA may drive later cocaine seeking through increased activation of pVTA CRF-R1 and aVTA CRF-R2. SIGNIFICANCE STATEMENT: Corticotropin releasing factor (CRF) within the ventral tegmental area (VTA) has emerged as a likely candidate molecule underlying the fundamental link between stress history and escalated drug self-administration. However, the nature of CRF release in the VTA during acute and repeated stress, as well as its role in enduring neuroadaptations driving later drug taking and seeking, are poorly understood. These experiments explore how CRF is released and interacts with its receptors in specific regions of the VTA both during and after stress to fuel later escalated cocaine taking and seeking behavior. Understanding these acute and persistent changes to the VTA CRF system may lead to better therapeutic interventions for addiction.

Escalated Aggression in Animal Models: Shedding New Light on Mesocorticolimbic Circuits.

Recent developments promise to significantly advance the understudied behavioral and neurobiology of aggression: (1) Animal models that capture essential features of human violence and callousness have been developed. These models range from mice that have been selectively bred for short attack latencies, monogamous prairie voles, and glucocorticoid-compromised rats to rodents and non-human primates that escalate their aggression after consuming or when withdrawing from alcohol. (2) Optogenetic stimulation and viral vector-based approaches have begun to identify overlapping and distinctive neural microcircuits and intracellular molecules for adaptive vs. excessive, maladaptive aggressive behavior in several rodent models. Projections from hypothalamic and mesencephalic neurons to the medial prefrontal cortex contain microcircuits that appear pivotal for the escalation of aggression.

Oxytocin reverses amphetamine-induced deficits in social bonding: evidence for an interaction with nucleus accumbens dopamine.

Drug addiction has devastating consequences on social behaviors and can lead to the impairment of social bonding. Accumulating evidence indicates that alterations in oxytocin (OT) and dopamine (DA) neurotransmission within brain reward circuitry may be involved. We investigated this possibility, as well as the therapeutic potential of OT for drug-induced social deficits, using the prairie vole (Microtus ochrogaster)-a socially monogamous rodent that forms enduring pair bonds between adult mates. We demonstrate that repeated exposure to the commonly abused psychostimulant amphetamine (AMPH) inhibits the formation of partner preferences (an index of pair bonding) in female prairie voles. AMPH exposure also altered OT and DA neurotransmission in regions that mediate partner preference formation: it decreased OT and DA D2 receptor immunoreactivity in the medial prefrontal cortex (mPFC) and nucleus accumbens (NAcc), respectively, and increased NAcc DA levels. Administration of OT directly into the mPFC of AMPH-exposed voles restored partner preferences, and altered NAcc DA levels, and this effect was dependent on OT receptor activation. Together, these data suggest that repeated AMPH exposure impairs pair bonding through an OT-mediated mechanism, and that OT and DA systems within brain reward circuitry may interact to mediate the complex relationship between drug abuse and social bonding. Further, these results provide empirical support for the idea that the central OT system may represent an important target for the treatment of social deficits in addiction.

Sex, drugs, and violence: neuromodulation of attachment and conflict in voles.

Prairie voles (Microtus ochrogaster) are a rodent species that display socially monogamous pair-bonds, a behavior illustrated by several types of social interactions such as mating-induced partner preference, selective aggression toward conspecific strangers, and bi-parental care. Therefore, this species has provided an excellent opportunity for the study of pair-bonding and its underlying neurochemical mechanisms. This chapter discusses the utility of this unique rodent in the study of attachment and conflict, and reviews recent findings illustrating the neuromodulatory mechanisms underlying mating-induced partner preference and aggression. Finally, implications of research using this animal model in human mental health are also discussed.

Genetics of aggression in voles.

Prairie voles (Microtus ochrogaster) are socially monogamous rodents that form pair bonds-a behavior composed of several social interactions including attachment with a familiar mate and aggression toward conspecific strangers. Therefore, this species has provided an excellent opportunity for the study of pair bonding behavior and its underlying neural mechanisms. In this chapter, we discuss the utility of this unique animal model in the study of aggression and review recent findings illustrating the neurochemical mechanisms underlying pair bonding-induced aggression. Implications of this research for our understanding of the neurobiology of human violence are also discussed.

Amphetamine alters behavior and mesocorticolimbic dopamine receptor expression in the monogamous female prairie vole.

We have recently established the socially monogamous prairie vole (Microtus ochrogaster) as an animal model with which to investigate the involvement of mesocorticolimbic dopamine (DA) in the amphetamine (AMPH)-induced impairment of social behavior. As the majority of our work, to date, has focused on males, and sex differences are commonly reported in the behavioral and neurobiological responses to AMPH, the current study was designed to examine the behavioral and neurobiological effects of AMPH treatment in female prairie voles. We used a conditioned place preference (CPP) paradigm to determine a dose-response curve for the behavioral effects of AMPH in female prairie voles, and found that conditioning with low to intermediate (0.2 and 1.0 mg/kg), but not very low (0.1 mg/kg), doses of AMPH induced a CPP. We also found that exposure to a behaviorally relevant dose of AMPH (1.0 mg/kg) induced an increase in DA concentration in the nucleus accumbens (NAcc) and caudate putamen but not the medial prefrontal cortex or ventral tegmental area (VTA). Finally, repeated AMPH exposure (1.0 mg/kg once per day for 3 consecutive days; an injection paradigm that has been recently shown to alter DA receptor expression and impair social bonding in male prairie voles) increased D1, but not D2, receptor mRNA in the NAcc, and decreased D2 receptor mRNA and D2-like receptor binding in the VTA. Together, these data indicate that AMPH alters mesocorticolimbic DA neurotransmission in a region- and receptor-specific manner, which, in turn, could have profound consequences on social behavior in female prairie voles.

The neurobiology of pair bonding: insights from a socially monogamous rodent.

The formation of enduring relationships between adult mates (i.e., pair bonds) is an integral aspect of human social behavior and has been implicated in both physical and psychological health. However, due to the inherent complexity of these bonds and the relative rarity with which they are formed in other mammalian species, we know surprisingly little about their underlying neurobiology. Over the past few decades, the prairie vole (Microtus ochrogaster) has emerged as an animal model of pair bonding. Research in this socially monogamous rodent has provided valuable insight into the neurobiological mechanisms that regulate pair bonding behaviors. Here, we review these studies and discuss the neural regulation of three behaviors inherent to pair bonding: the formation of partner preferences, the subsequent development of selective aggression toward unfamiliar conspecifics, and the bi-parental care of young. We focus on the role of vasopressin, oxytocin, and dopamine in the regulation of these behaviors, but also discuss the involvement of other neuropeptides, neurotransmitters, and hormones. These studies may not only contribute to the understanding of pair bonding in our own species, but may also offer insight into the underlying causes of social deficits noted in several mental health disorders.

The role of mesocorticolimbic dopamine in regulating interactions between drugs of abuse and social behavior.

The use of addictive drugs can have profound short- and long-term consequences on social behaviors. Similarly, social experiences and the presence or absence of social attachments during early development and throughout life can greatly influence drug intake and the susceptibility to drug abuse. The following review details this reciprocal interaction, focusing on common drugs of abuse (e.g., psychostimulants, opiates, alcohol and nicotine) and social behaviors (e.g., maternal, sexual, play, aggressive and bonding behaviors). The neural mechanisms underlying this interaction are discussed, with a particular emphasis on the involvement of the mesocorticolimbic dopamine system.

Anterior hypothalamic vasopressin regulates pair-bonding and drug-induced aggression in a monogamous rodent.

After pair-bonding, male prairie voles (Microtus ochrogaster) display aggression toward novel females but not toward their female partner. Here we show that this selective aggression in pair-bonded male prairie voles is associated with increased release of vasopressin (AVP) in the anterior hypothalamus (AH). Pharmacological activation of AVP-V1a receptors (V1aR) in the AH induced selective aggression in sexually naive males, whereas V1aR blockade diminished selective aggression in pair-bonded males. Pair-bonded males also showed an increased density in V1aR binding in the AH compared to their sexually naive counterparts and overexpression of V1aR in the AH, by viral vector-mediated gene transfer, facilitated aggression toward novel females. These data demonstrate that AH-AVP is both necessary and sufficient in the regulation of selective aggression associated with pair-bonding. In the second part of this study, we examined the effects of amphetamine (AMPH) exposure on female-directed aggression and revealed the potential role of AH-AVP underlying this behavior. Repeated AMPH administration in sexually naive male prairie voles enhanced V1aR expression in the AH and induced aggression toward a familiar or unfamiliar female. In addition, this AMPH-induced aggression was blocked by intra-AH administration of a V1aR antagonist. Together, our data reveal a socioneurobiological mechanism, highlighting a critical role of AH-AVP in the regulation of aggression induced by pair-bonding or drug experience in socially monogamous male prairie voles.

Masculinized finger-length ratios of boys, but not girls, are associated with attention-deficit/hyperactivity disorder.

Gonadal hormones may exert permanent organizational effects on sexually dimorphic finger-length ratios and sexually dimorphic behavior expressed in childhood attention deficit-hyperactivity disorder (ADHD). This study extended recent work examining associations between finger-length ratios (specifically, 2D:4D) and ADHD in a well-characterized, clinically diagnosed, community-recruited sample of boys and girls. A multistage, diagnostic procedure was utilized to identify 113 children with ADHD and 137 non-ADHD comparison children. Right-hand digit ratios showed significant mean differences by gender, as well as associations with ADHD diagnosis. Boys with ADHD had more masculinized digit ratios than control-group boys. More masculine right 2D:4D and 3D:4D ratios were correlated with parent- and teacher-rated inattentive and hyperactive-impulsive symptoms in boys but not in girls. Masculinized finger-length ratios were associated with hyperactive-impulsive and oppositional- defiant symptoms, but associations were largest with symptoms of inattention. It is concluded that prenatal, organizational effects of gonadal hormones may play a role in the development of ADHD and contribute to explaining sex differences in the prevalence rates of this childhood disorder.

Genetic and environmental influences on 2D:4D finger length ratios: a study of monozygotic and dizygotic male and female twins.

Recent studies have shown significant sex differences in the pattern of 2D:4D finger length ratios in humans and several other mammalian species. In humans, these ratios are suggested to be negatively correlated with prenatal exposure to testosterone, positively correlated with prenatal estrogen, and exhibit sex specific patterns of association with sexually dimorphic clinical phenotypes. However, the relative contributions of genetic and environmental influences on digit ratios in men and women are currently unknown. Therefore, the purpose of the current study was to examine genetic and environmental influences on 2D:4D ratios in twins. Participants included 146 monozygotic (MZ) and 154 dizygotic (DZ) adult male and female twins participating in the Michigan State University Twin Study of Behavioral Adjustment and Development. Overall, biometric model-fitting analyses indicated significant additive genetic and nonshared environmental influences on digit ratios. Findings suggest greater similarity between 2D:4D ratios in MZ relative to DZ twins that can be accounted for by genetic and nonshared environmental factors.

Homosexual mating preferences from an evolutionary perspective: sexual selection theory revisited.

Studies in evolutionary psychology and sexual selection theory show that heterosexual men prefer younger mating partners than heterosexual women in order to ensure reproductive success. However, previous research has generally not examined differences in mating preferences as a function of sexual orientation or the type of relationship sought in naturalistic settings. Given that homosexual men seek partners for reasons other than procreation, they may exhibit different mating preferences than their heterosexual counterparts. Moreover, mating preferences may show important differences depending on whether an individual is seeking a long-term versus a short-term relationship. The purpose of the present study was to examine these issues by comparing partner preferences in terms of age and relationship type between homosexual and heterosexual men placing internet personal advertisements. Participants included 439 homosexual and 365 heterosexual men who placed internet ads in the U.S. or Canada. Ads were coded for the participant's age, relationship type (longer-term or short-term sexual encounter) sought, and partner age preferences. Significantly more homosexual than heterosexual men sought sexual encounters, although men (regardless of sexual orientation) seeking sexual encounters preferred a significantly wider age range of partners than men seeking longer-term relationships. These findings suggest that partner preferences are independent of evolutionary drives to procreate, since both types of men preferred similar ages in their partners. In addition, they highlight the importance of examining relationship type in evolutionary studies of mating preferences, as men's partner preferences show important differences depending upon the type of relationship sought.

Anterior hypothalamic neural activation and neurochemical associations with aggression in pair-bonded male prairie voles.

Male prairie voles (Microtus ochrogaster) display mating-induced pair bonding indicated by social affiliation with their female partners and aggression toward unfamiliar conspecifics. In the present study, we characterized their aggression associated with pair bonding and examined the related neuronal activation and neurochemical architecture. Males that were pair-bonded for 2 weeks displayed intense levels of aggression toward a female or male conspecific stranger but maintained a high level of social affiliation with their familiar female partners. These social interactions induced increases in neural activation, indicated by increased density of Fos-immunoreactive staining (Fos-ir) in several brain regions including the bed nucleus of the stria terminalis (BNST), medial preoptic area (MPOA), paraventricular nucleus (PVN), anterior cortical (AcA), and medial nuclei (MeA) of the amygdala. In the anterior hypothalamus (AH), increased density of Fos-ir staining was found specifically to be associated with aggression toward unfamiliar female or male strangers. In addition, higher densities of AH cells that were stained for tyrosine hydroxylase (TH) or vasopressin (AVP) were also labeled with Fos-ir in these males displaying aggression toward a conspecific stranger compared with males displaying social affiliation toward their female partner. Together, our results indicate that dopamine and vasopressin in the AH may be involved in the regulation of enduring aggression associated with pair bonding in male prairie voles.

Preliminary evidence that gonadal hormones organize and activate disordered eating.

OBJECTIVE: Eating disorders are more common in females than in males. Gender differences may be due to organizational (i.e. prenatal) and activational (i.e. post-natal) gonadal hormone effects that influence sex differences in behavior. This preliminary set of studies examined these effects by investigating relationships between eating disorder symptoms, prenatal testosterone exposure, and adult levels of estrogen in women. METHOD: We examined organizational associations by investigating relationships between disordered eating and finger-length ratios, which are known to be somatic markers of prenatal testosterone exposure. Participants included 113 adult female twins drawn from the community. Disordered eating was assessed with the total score from the Minnesota Eating Behavior Survey (MEBS). Finger lengths were hand scored using a ruler and photocopies of both hands. We also investigated activational influences by examining associations between circulating levels of estradiol and disordered eating symptoms. Two independent samples of adult females (n's = 24 and 25) drawn from the community were used for this study. Disordered eating was again assessed with the MEBS total score, while saliva samples were used for assessing estradiol. RESULTS: Positive associations were found between disordered eating and both finger-length ratios and circulating estradiol levels. CONCLUSIONS: Findings suggest that lower levels of prenatal testosterone exposure and higher adult levels of estradiol are associated with increased eating disorder symptoms. We hypothesize that the relatively low level of testosterone before birth in females permits their brains to respond to estrogens at puberty, when the hormones activate the genes contributing to disordered eating in vulnerable girls.

A review and primer of molecular genetic studies of anorexia nervosa.

Recent research on anorexia nervosa (AN) has focused on examining the genetic underpinnings of its etiology. The current article reviews molecular genetic studies that have focused on this aspect of AN development. Medline and PsychInfo literature searches, in addition to close inspection of study reference sections, were used to identify studies that examined the genetic diathesis for AN. Findings from association studies indicate some role for the serotonin system in the development of AN. Genomic regions on chromosomes 1 and 10 are also likely to harbor susceptibility genes for AN as well as a range of eating pathologies. Findings corroborate those of neurobiologic studies suggesting that alterations in serotonergic functioning may contribute to the pathogenesis of AN. Nonetheless, future molecular genetic research would benefit from larger and more sustained investigations of candidate genes in homogeneous phenotypes.