Sweetened ethanol drinking during social isolation: enhanced intake, resistance to genetic heterogeneity and the emergence of a distinctive drinking pattern in adolescent mice.

With its ease of availability during adolescence, sweetened ethanol ('alcopops') is consumed within many contexts. We asked here whether genetically based differences in social motivation are associated with how the adolescent social environment impacts voluntary ethanol intake. Mice with previously described differences in sociability (BALB/cJ, C57BL/6J, FVB/NJ and MSM/MsJ strains) were weaned into isolation or same-sex pairs (postnatal day, PD, 21), and then given continuous access to two fluids on PDs 34-45: one containing water and the other containing an ascending series of saccharin-sweetened ethanol (3-6-10%). Prior to the introduction of ethanol (PDs 30-33), increased water and food intake was detected in some of the isolation-reared groups, and controls indicated that isolated mice also consumed more 'saccharin-only' solution. Voluntary drinking of 'ethanol-only' was also higher in a subset of the isolated groups on PDs 46-49. However, sweetened ethanol intake was increased in all isolated strain × sex combinations irrespective of genotype. Surprisingly, blood ethanol concentration (BEC) was not different between these isolate and socially housed groups 4 h into the dark phase. Using lickometer-based measures of intake in FVB mice, we identified that a predominance of increased drinking during isolation transpired outside of the typical circadian consumption peak, occurring ≈8.5 h into the dark phase, with an associated difference in BEC. These findings collectively indicate that isolate housing leads to increased consumption of rewarding substances in adolescent mice independent of their genotype, and that for ethanol this may be because of when individuals drink during the circadian cycle.

The roots of empathy: Through the lens of rodent models.

Empathy is a phenomenon often considered dependent on higher-order emotional control and an ability to relate to the emotional state of others. It is, by many, attributed only to species having well-developed cortical circuits capable of performing such complex tasks. However, over the years, a wealth of data has been accumulated showing that rodents are capable not only of sharing emotional states of their conspecifics, but also of prosocial behavior driven by such shared experiences. The study of rodent empathic behaviors is only now becoming an independent research field. Relevant animal models allow precise manipulation of neural networks, thereby offering insight into the foundations of empathy in the mammalian brains. Here we review the data on empathic behaviors in rat and mouse models, their neurobiological and neurophysiological correlates, and the factors influencing these behaviors. We discuss how simple rodent models of empathy enhance our understanding of how brain controls empathic behaviors.

Hypervigilance for fear after basolateral amygdala damage in humans.

Recent rodent research has shown that the basolateral amygdala (BLA) inhibits unconditioned, or innate, fear. It is, however, unknown whether the BLA acts in similar ways in humans. In a group of five subjects with a rare genetic syndrome, that is, Urbach-Wiethe disease (UWD), we used a combination of structural and functional neuroimaging, and established focal, bilateral BLA damage, while other amygdala sub-regions are functionally intact. We tested the translational hypothesis that these BLA-damaged UWD-subjects are hypervigilant to facial expressions of fear, which are prototypical innate threat cues in humans. Our data indeed repeatedly confirm fear hypervigilance in these UWD subjects. They show hypervigilant responses to unconsciously presented fearful faces in a modified Stroop task. They attend longer to the eyes of dynamically displayed fearful faces in an eye-tracked emotion recognition task, and in that task recognize facial fear significantly better than control subjects. These findings provide the first direct evidence in humans in support of an inhibitory function of the BLA on the brain's threat vigilance system, which has important implications for the understanding of the amygdala's role in the disorders of fear and anxiety.

The social defeat animal model of depression shows diminished levels of orexin in mesocortical regions of the dopamine system, and of dynorphin and orexin in the hypothalamus.

Anhedonia is a core symptom of clinical depression. Two brain neuropeptides that have been implicated in anhedonia symptomology in preclinical depression models are dynorphin and orexin; which are concentrated along lateral hypothalamic dopamine reward pathways. These affect regulating neuropeptides modulate each other's function, implicating an interactive dysfunction between them in anhedonia symptomology. But whether their influences are modified or imbalanced within the hypothalamus or dopamine system in anhedonic preclinical depression models is not yet clear. We used radioimmunoassay to determine this in the rat social defeat model of depression; at a time that anhedonic sexual disinterest was expressed. In tissue samples of the medial prefrontal cortex (mPFC), ventral tegmental area (VTA) and nucleus accumbens, basal dynorphin levels were similar to normal animals. But orexin was reduced in the VTA and mPFC. Also, dynorphin and orexin were both diminished in the hypothalamus which is noteworthy since nearly all hypothalamic orexin cells co-express dynorphin. These findings suggest that orexin and dynorphin function may be imbalanced between the hypothalamus and mesocortical dopaminergic brain regions in depression.

Selective breeding for 50 kHz ultrasonic vocalization emission produces alterations in the ontogeny and regulation of rough-and-tumble play.

Ultrasonic vocalizations (USVs) are emitted by rodents and can signal either negative or positive affective states in social and nonsocial contexts. Our recent work has utilized selective breeding based upon the emission of 50 kHz USVs in response to standard cross species hand play-namely experimenters 'tickling' rats. Previous work has shown that high-tickle responsive animals (i.e., rats emitting abundant 50 kHz USVs) are gregarious and express enhanced positive emotional behaviors relative to animals exhibiting low 50 kHz USVs. The present study extends this work by examining the developmental profile of play behavior and the suppression of play behavior by predator (cat) odor in juvenile high-line and low-line animals. Results support dissociations in key play measures between these groups, with high-line animals emitting more dorsal contacts during play and low-line animals emitting more pinning behavior. For cat-odor induced play suppression, we found that high-line animals exhibit elevated suppression of play for a prolonged period compared to low-line rats. In contrast, low-line animals returned to normal levels of play just 1 day post-predator odor experience. These findings support the idea that emotional arousal may differ between these selectively bred groups, and extends previous work by demonstrating a possible influence of altered emotional learning and conditioning in these phenotypically different animals. One possibility is that high-line animals exhibit enhanced associative learning abilities leading to stronger negative contextual conditioning. These findings suggest that selection for positive or negative social-emotional phenotypes may also segregate genes that control emotional learning abilities in unanticipated ways.

Positive emotional learning is regulated in the medial prefrontal cortex by GluN2B-containing NMDA receptors.

In rats, hedonic ultrasonic vocalizations (USVs) is a validated model of positive affect and is best elicited by rough-and-tumble play. Here we report that modulation of GluN2B-containing NMDA receptors (NMDAR) in the medial prefrontal cortex (MPFC) is involved in positive emotional learning. Rough and tumble play increased both GluN1 and GluN2B NMDAR subunit mRNA and protein levels in the frontal cortex. GLYX-13, a GluN2B-preferring, NMDAR glycine-site partial agonist (1 mg/kg, i.v.) significantly increased positive emotional learning whereas the GluN2B receptor-specific antagonist, ifenprodil (10 mg/kg, i.p.), inhibited positive emotional learning. Animals selectively bred for low rates of hedonic USVs were returned to wild-type levels of positive emotional learning following GLYX-13 treatment. MPFC microinjections of GLYX-13 (0.1-10 µg/side) significantly increased rates of positive emotional learning. Thus GluN2B-containing NMDARs may be involved in positive emotional learning in the MPFC by similar mechanisms as spatial/temporal learning in the hippocampus.

Uncovering the molecular basis of positive affect using rough-and-tumble play in rats: a role for insulin-like growth factor I.

Positive emotional states have been shown to confer resilience to depression and anxiety in humans, but the molecular mechanisms underlying these effects have not yet been elucidated. In laboratory rats, positive emotional states can be measured by 50-kHz ultrasonic vocalizations (hedonic USVs), which are maximally elicited by juvenile rough-and-tumble play behavior. Using a focused microarray platform, insulin-like growth factor I (IGFI) extracellular signaling genes were found to be upregulated by hedonic rough-and-tumble play but not depressogenic social defeat. Administration of IGFI into the lateral ventricle increased rates of hedonic USVs in an IGFI receptor (IGFIR)-dependent manner. Lateral ventricle infusions of an siRNA specific to the IGFIR decreased rates of hedonic 50-kHz USVs. These results show that IGFI plays a functional role in the generation of positive affective states and that IGFI-dependent signaling is a potential therapeutic target for the treatment of depression and anxiety.

Rats selectively bred for low levels of 50 kHz ultrasonic vocalizations exhibit alterations in early social motivation.

In rats, the rates of 50 kHz ultrasonic vocalizations (USVs) can be used as a selective breeding phenotype and variations in this phenotype can be an indicator of affective states. The 50 kHz USV is elicited by rewarding stimuli (e.g., food, sexual behavior) and therefore can express a positive affective state. Conversely, the 22 kHz USV is elicited by aversive stimuli (e.g., presence of a predator, social defeat) indicating a negative affective state. In the present study, we tested the effect of selectively breeding for 50 kHz USVs on a variety of maternal social/emotional behaviors in young rat pups (PND 10-12). These measures consisted of an assessment of isolation calls and conditioned odor preference paradigm. Results indicate that animals selected for low levels of 50 kHz USVs show the greatest alterations in social behaviors compared to the control animals. The low line animals had an increase in isolation calls tested during place preference conditioning and a decrease in 50 kHz ultrasonic calls in all conditions. These same low line animals failed to show a typical preference for a maternally-associated odor during the place preference test. The different social behaviors of the high line animals did not consistently vary from those of the control group. These results have important implications for the study of genetic and epigenetic mechanisms underlying emotional states, and possibly contribute to the research underlying the emotional changes in developmental disorders such as autistic spectrum disorder by providing a novel animal model that displays communication deficits that are interdependent with significant social behavioral impairments.

Social reward among juvenile mice.

Mammalian social relationships, such as mother-offspring attachments and pair bonds, can directly affect reproductive output. However, conspecifics approach one another in a comparatively broad range of contexts, so conceivably there are motivations for social congregation other than those underlying reproduction, parental care or territoriality. Here, we show that reward mediated by social contact is a fundamental aspect of juvenile mouse sociality. Employing a novel social conditioned place preference (SCPP) procedure, we demonstrate that social proximity is rewarding for juvenile mice from three inbred strains (A/J, C57BL/6J and DBA/2J), while mice from a fourth strain (BALB/cJ) are much less responsive to social contact. Importantly, this strain-dependent difference was not related to phenotypic variability in exploratory behavior or contextual learning nor influenced by the genetic background associated with maternal care or social conditioning. Furthermore, the SCPP phenotype was expressed early in development (postnatal day 25) and did not require a specific sex composition within the conditioning group. Finally, SCPP responses resulted from an interaction between two specifiable processes: one component of the interaction facilitated approach toward environments that were associated with social salience, whereas a second component mediated avoidance of environmental cues that predicted social isolation. We have thus identified a genetically prescribed process that can attribute value onto conditions predicting a general form of social contact. To our knowledge, this is the first definitive evidence to show that genetic variation can influence a form of social valuation not directly related to a reproductive behavior.

Modeling depression: social dominance-submission gene expression patterns in rat neocortex.

Gene expression profiles in the cortex of adult Long-Evans rats as a function of a stressful social loss and victory in inter-male fighting encounters were examined. This social dominance and subordination model has been postulated to simulate early changes in the onset of depression in the losers. Microarrays were fabricated containing 45mer oligonucleotides spotted in quadruplicate and representing 1178 brain-associated genes. Dynamic range, discrimination power, accuracy and reproducibility were determined with standard mRNA "spiking" studies. Gene expression profiles in dominant and subordinate animals were compared using a "universal" reference design [Churchill GA (2002) Fundamentals of experimental design for cDNA microarrays. Nat Genet 32 (Suppl):490-495]. Data were analyzed by significance analysis of microarrays using rank scores [Tusher VG, Tibshirani R, Chu G (2001) Significance analysis of microarrays applied to the ionizing radiation response. Proc Natl Acad Sci USA 98:5116-5121; van de Wiel MA (2004) Significance analysis of microarrays using rank scores. Kwantitatieve Methoden 71:25-37]. Ontological analyses were then performed using the GOMiner algorithm [Zeeberg BR, Feng W, Wang G, Wang MD, Fojo AT, Sunshine M, Narasimhan S, Kane DW, Reinhold WC, Lababidi S, Bussey KJ, Riss J, Barrett JC, Weinstein JN (2003) GoMiner: a resource for biological interpretation of genomic and proteomic data. Genome Biol 4(4):R28]. And finally, genes of special interest were further studied using quantitative reverse transcriptase polymerase chain reaction. Twenty-two transcripts were statistically significantly differentially expressed in the neocortex between dominant and subordinate animals. Ontological analyses revealed that significant gene changes were clustered primarily into functional neurochemical pathways associated with protein biosynthesis and cytoskeletal dynamics. The most robust of these were the increased expression of interleukin-18, heat shock protein 27, beta3-tubulin, ribosome-associated membrane protein 4 in subordinate animals. Interleukin-18 has been found to be over-expressed in human depression and panic disorder as well as other physiological stress paradigms [Takeuchi M, Okura T, Mori T, Akita K, Ohta T, Ikeda M, Ikegami H, Kurimoto M (1999) Intracellular production of interleukin-18 in human epithelial-like cell lines is enhanced by hyperosmotic stress in vitro. Cell Tissue Res 297(3):467-473] and heat shock proteins have been shown to be involved in the pathogenesis of many neurodegenerative and psychiatric disorders [Iwamoto K, Kakiuchi C, Bundo M, Ikeda K, Kato T (2004) Molecular characterization of bipolar disorder by comparing gene expression profiles of postmortem brains of major mental disorders. Mol Psychiatry 9(4):406-416; Pongrac JL, Middleton FA, Peng L, Lewis DA, Levitt P, Mirnics K (2004) Heat shock protein 12A shows reduced expression in the prefrontal cortex of subjects with schizophrenia. Biol Psychiatry 56(12):943-950]. Thus, the gene expression changes that we have observed here are consistent with and extend the observations found in the clinical literature and link them to the animal model used here thereby reinforcing its use to better understand the genesis of depression and identify novel therapeutic targets for its treatment.

Chronomics of autism and suicide.

We examine whether autism may be influenced by non-photic environmental factors, among others, in a California database consisting of the number of cases added quarterly to the system between 1993 and 2004. Instead of a precise calendar (1.0)-year-long spectral component, we detect unseen primarily helio- and geomagnetic signatures, including a newly discovered near-transyear of 1.09-year length. In this case, it overrides any undetected seasonal effects, the topic of much previous unrewarding research, also analyzed herein without overcoming the limitation by stacking. Since we could not get additional data on autism, data on suicides, the final "detachment" and failure to bond, were also analyzed, again revealing a spectrum of non-photic signatures. What we do not see and do not anticipate can exist and can override the seasons, as resolved time-microscopically by chronomics, the study of chronomes (time structures). Just as spatial microscopy and electron microscopy resolved infectious agents, so does microscopy in time resolve the signature of environmental agents in human behavior in health and disease.

Dynamic interactions of behavior and amine neurochemistry in acquisition and maintenance of social rank in crayfish.

This review summarizes a set of experimental approaches with which we explore fighting behavior in crayfish and the importance of aminergic systems in its control. Our results illustrate that agonistic behavior in crustaceans can be characterized within a quantitative framework, that different types of behavioral plasticity in aggressive behavior are in need of physiological explanation, and that pharmacological intervention involving serotonergic systems produces characteristic changes in fighting. Moreover, we attempt to identify changes in neurochemistry during the acquisition of social status. Many of the studies presented here summarize ongoing work. Nonetheless, results to date complement and extend previous detailed physiological, morphological and biochemical studies exploring the roles of amines in aggression.

Nucleus accumbens amphetamine microinjections unconditionally elicit 50-kHz ultrasonic vocalizations in rats.

The authors have hypothesized that, in adult rats, 50-kHz ultrasonic vocalizations (USVs) index a state characterized by high arousal and expectations of reward. This study was conducted to investigate whether dopamine agonism of the nucleus accumbens (NAcc) could evoke such an appetitive state, by examining the effects of NAcc amphetamine (AMPH) microinjections on USVs. Intra-NAcc AMPH injections (0.3, 1.0, 3.0, 10.0 microg unilaterally) produced robust, dose-dependent increases in 50-kHz USVs, which could not be accounted for by concomitant increases in locomotor activity (LA). However, AMPH injections into dorsal control caudate putamen sites produced a modest, dose-dependent increase in LA without significant increases in 50-kHz USVs. These findings indicate that NAcc AMPH microinjections selectively evoke 50-kHz USVs in rats, supporting the notion that dopamine elevations in the NAcc may unconditionally elicit a state of reward anticipation.

Evaluation of rat ultrasonic vocalizations as predictors of the conditioned aversive effects of drugs.

RATIONALE: Since cues that predict aversive outcomes can elicit both avoidance and 20 kHz ultrasonic vocalizations (USVs) in adult rats, 20 kHz USVs may also index the conditioned aversive effects of drugs. OBJECTIVE: We evaluated whether exposure to compartments associated with drugs with aversive effects would selectively increase 20 but not 50 kHz USVs in rats. METHOD: Rats were injected with naloxone (NAL) or lithium chloride (LiCl) and placed in one compartment or with saline (VEH) and placed in another compartment for three 50-min conditioning sessions. 20 kHz USVs, 50 kHz USVs, and time spent in each chamber were recorded during subsequent 15-min testing sessions during which rats had access to both compartments (expt 1) or were confined to the drug- or VEH-paired compartment (expt 2). RESULTS: In expt 1, animals conditioned either with NAL (0.3 and 3.0 mg/kg) or LiCl (10 and 30 mg/kg) emitted increased 20 kHz USVs in the drug-paired compartment, relative to VEH-conditioned controls. Conditioning with high doses of both drugs also increased conditioned place aversion and decreased emission of 50 kHz USVs. In expt 2, restriction of animals to the compartment paired with high doses of NAL and LiCl also increased emission of 20 kHz USVs and decreased 50 kHz USVs, relative to VEH-conditioned controls. CONCLUSIONS: In rats, cues associated with drugs with aversive effects increase 20 kHz USVs and decrease 50 kHz USVs, suggesting that USVs may provide a useful model for predicting the conditioned aversive effects of drugs.

Tickling induces reward in adolescent rats.

In adolescent rats, 50-kHz vocalizations are most evident during tickling and rough-and-tumble play. The following experiments evaluated whether 50-kHz vocalizations reflect positive social affect by determining (1) if tickling is a rewarding event, (2) if social or isolate housing conditions differentially influence the response (since housing condition has been found to effect the reward magnitude of social encounters), and (3) if drugs that work on mu-opiate receptors, which has been hypothesized to control positive social affect, modulate tickling. Tickling was positively reinforcing as demonstrated by elevated operant behavior, conditioned place preference, and approach measures. A significant negative correlation between vocalization rate and approach latency measures was found. Social housing reduced tickle-induced vocalizations and approach speeds compared to isolate housing. Naloxone (1 mg/kg) increased vocalization in the socially housed rats and decreased it in isolated Subjects (Ss). These findings suggest that tickling can be used to induce positive social affect in rodents, and that it is modulated by endogenous opioids.

50-kHz chirping (laughter?) in response to conditioned and unconditioned tickle-induced reward in rats: effects of social housing and genetic variables.

In these studies the incidence of conditioned and unconditioned 50-kHz ultrasonic vocalizations (USVs) in young rats was measured in response to rewarding manual tickling by an experimenter. We found that isolate-housed animals vocalize much more then socially housed ones, and when their housing conditions are reversed, they gradually shift their vocalization tendencies. Isolate-housed animals also show quicker acquisition of instrumental tasks for tickling, and exhibit less avoidance of tickling as compared to socially housed Ss. Isolate-housed animals also show rapid acquisition of 50-kHz USVs to a conditioned stimulus that predicts tickle reward, while socially housed animals do not. We successfully bred for high and low vocalization rates in response to tickling within four generations. The high tickle line showed quicker acquisition of an instrumental task for, as well as less avoidance of, tickling as compared to the random and low tickle lines. They also played more. Lastly, we found that the glutamate antagonist MK-801 can reduce tickle-induced 50-kHz USVs, but is resistant to opioid, dopamine and cholinergic stimulant and blocking agents. Overall, these results suggest that tickle evoked 50-kHz USVs may be a useful behavioral marker of positive social affect in rats. Difficulties with such concepts are also discussed.

Anticipation of rewarding electrical brain stimulation evokes ultrasonic vocalization in rats.

Adult rats emit increased rates of 50-kHz ultrasonic vocalizations (USVs) before receiving social and pharmacological rewards. This study sought to determine whether anticipation of rewarding electrical stimulation of the brain (ESB) would also elicit these vocalizations. In Experiments 1 and 2, rats showed increased 50-kHz USVs before receiving experimenter-delivered ventral tegmental area (VTA) and lateral hypothalamic (LH) ESB on a fixed time 20-s schedule. In Experiments 3 and 4, rats increased their rate of 50-kHz USVs in response to cues that predicted the opportunity to self-stimulate the VTA or LH. Interestingly, unexpected termination of either type of ESB evoked 20-kHz, rather than 50-kHz, USVs. In Experiment 5, a cue that predicted daily 1-hr feeding sessions increased 50-kHz USVs, whereas a cue that predicted footshock decreased 50-kHz USVs. These effects could not be explained simply by changes in locomotor activity or general arousal. Together, these findings support the hypothesis that short 50-kHz USVs may selectively index a state of reward anticipation in rats.

The role of nucleus accumbens dopamine in motivated behavior: a unifying interpretation with special reference to reward-seeking.

Studies addressing behavioral functions of dopamine (DA) in the nucleus accumbens septi (NAS) are reviewed. A role of NAS DA in reward has long been suggested. However, some investigators have questioned the role of NAS DA in rewarding effects because of its role in aversive contexts. As findings supporting the role of NAS DA in mediating aversively motivated behaviors accumulate, it is necessary to accommodate such data for understanding the role of NAS DA in behavior. The aim of the present paper is to provide a unifying interpretation that can account for the functions of NAS DA in a variety of behavioral contexts: (1) its role in appetitive behavioral arousal, (2) its role as a facilitator as well as an inducer of reward processes, and (3) its presently undefined role in aversive contexts. The present analysis suggests that NAS DA plays an important role in sensorimotor integrations that facilitate flexible approach responses. Flexible approach responses are contrasted with fixed instrumental approach responses (habits), which may involve the nigro-striatal DA system more than the meso-accumbens DA system. Functional properties of NAS DA transmission are considered in two stages: unconditioned behavioral invigoration effects and incentive learning effects. (1) When organisms are presented with salient stimuli (e.g., novel stimuli and incentive stimuli), NAS DA is released and invigorates flexible approach responses (invigoration effects). (2) When proximal exteroceptive receptors are stimulated by unconditioned stimuli, NAS DA is released and enables stimulus representations to acquire incentive properties within specific environmental context. It is important to make a distinction that NAS DA is a critical component for the conditional formation of incentive representations but not the retrieval of incentive stimuli or behavioral expressions based on over-learned incentive responses (i.e., habits). Nor is NAS DA essential for the cognitive perception of environmental stimuli. Therefore, even without normal NAS DA transmission, the habit response system still allows animals to perform instrumental responses given that the tasks take place in fixed environment. Such a role of NAS DA as an incentive-property constructor is not limited to appetitive contexts but also aversive contexts. This dual action of NAS DA in invigoration and incentive learning may explain the rewarding effects of NAS DA as well as other effects of NAS DA in a variety of contexts including avoidance and unconditioned/conditioned increases in open-field locomotor activity. Particularly, the present hypothesis offers the following interpretation for the finding that both conditioned and unconditioned aversive stimuli stimulate DA release in the NAS: NAS DA invigorates approach responses toward 'safety'. Moreover, NAS DA modulates incentive properties of the environment so that organisms emit approach responses toward 'safety' (i.e., avoidance responses) when animals later encounter similar environmental contexts. There may be no obligatory relationship between NAS DA release and positive subjective effects, even though these systems probably interact with other brain systems which can mediate such effects. The present conceptual framework may be valuable in understanding the dynamic interplay of NAS DA neurochemistry and behavior, both normal and pathophysiological.

Fetal and neonatal exposure to trimethylolpropane phosphate alters rat social behavior and emotional responsivity.

The proconvulsant compound trimethylolpropane phosphate (TMPP) was evaluated for its effects on motor, social, and emotional behaviors. Long Evans rats were treated prenatally for 13 days and/or neonatally for 10 days. Behavioral tests were performed during treatment and several days after treatment. Beginning on gestation day 9, and continuing for 13 days, 20 dams received once daily i.p. injections. Half were treated with distilled water, the other 10 received 0.2 mg TMPP/kg body weight. No external malformations were observed in the live-born offspring of TMPP- or vehicle-exposed dams. On postnatal day 3 one-half the pups were cross-fostered to dams that had the opposite treatment as their biological mothers. Also on postnatal day 3, pups were divided into two groups, one receiving injections of distilled water, the other receiving injections of 0.2 mg TMPP/kg body weight. Ten daily injections were administered i.p., beginning postnatal day 3. Motor behaviors were evaluated in step-down and paw lift tasks and no group differences were found. At 18 days of age, one half the pups were separated from the dam and their littermates. The other half of the pups continued to be housed with the dam and remaining littermates until postnatal day 50. Social interaction was measured in juvenile play and adult social investigation. Emotional responsivity was assessed in open field activity, elevated plus-maze exploration, and ultrasonic distress vocalizations. Complex interactions were found for measures of social interaction and emotional responsivity related to drug treatment, housing condition, and sex. Due to the observed sex differences. it is hypothesized that the action of TMPP may involve a change in the hormonal systems that control the differentiation of related sex-typical behaviors.

Paradoxical effects of serotonin and opioids in pemoline-induced self-injurious behavior.

Self-injurious behavior (SIB) is a symptom of various psychiatric disorders with differing etiologies. Although no generally effective pharmacological treatment of SIB is available, subsets of individuals exhibiting SIB have been found to respond to opioid antagonists and selective serotonin reuptake inhibitors (SSRIs). The present study evaluated the efficacy of these two treatments in the pemoline-induced model of self-biting behavior (SBB) in rats. Using a factorial design, adult rats receiving daily pemoline at 100 mg/kg or the peanut oil vehicle were pretreated with either distilled water vehicle (1 cc/kg), naltrexone (1 mg/kg), or paroxetine (1 mg/kg). Each day, animals were rated on the severity of SBB and also periodically behavioral changes were evaluated using various other outcome measures. Paroxetine significantly increased the severity of SBB induced by pemoline, while naltrexone only marginally increased the SBB. These results were not expected and suggest that further studies into the role of serotonin agonists and antagonists are needed in evaluating this model.