Longitudinal stability of reward and relief drinking phenotypes in community and treatment-seeking individuals who engage in heavy drinking.

BACKGROUND: Precision medicine approaches aim to improve treatment outcomes by identifying which treatments work best for specific individual phenotypes. In the treatment of alcohol use disorder (AUD), precision medicine approaches have been proposed based on phenotypes characterized by individuals who drink primarily to enhance rewarding experiences (i.e., reward drinking) or those who drink primarily to relieve negative states (i.e., relief drinking). This study examined these phenotypes across treatment- and nontreatment-seeking individuals and the stability of the phenotypes over time. METHODS: We used latent profile and latent transition analyses to identify and assess longitudinal stability (over 3 or 4 months) of reward and relief drinking subgroups within a nontreatment-seeking community sample that engaged in hazardous drinking (n = 189) and two treatment-seeking samples of individuals with AUD enrolled in two large clinical trials (n = 1726, n = 1383). We examined prospective associations with alcohol consumption and consequences at long-term follow-up (15 or 18 months). RESULTS: Results supported four subgroups: low reward/low relief, low reward/high relief, high reward/low relief, and high reward/high relief. The community sample contained more individuals classified within the high reward/low relief subgroup than treatment-seeking samples. Subgroups were generally more stable over time in the community sample than in the treatment-seeking samples. Alcohol consumption and consequences decreased over time for the treatment-seeking samples, with consequences and drinking frequency decreasing for the community sample. Participants classified within the high reward/high relief and low reward/high relief groups reported the most consequences and consumption at long-term follow-up. CONCLUSION: Reward and relief drinking phenotypes can be identified within community and treatment-seeking samples of individuals who drink heavily. The phenotypic subgroups appear to be stable over time in the absence of treatment, change somewhat during treatment, and provide utility in predicting alcohol consumption and consequences.

Anxiety and Alzheimer's disease pathogenesis: focus on 5-HT and CRF systems in 3xTg-AD and TgF344-AD animal models.

Dementia remains one of the leading causes of morbidity and mortality in older adults. Alzheimer's disease (AD) is the most common type of dementia, affecting over 55 million people worldwide. AD is characterized by distinct neurobiological changes, including amyloid-beta protein deposits and tau neurofibrillary tangles, which cause cognitive decline and subsequent behavioral changes, such as distress, insomnia, depression, and anxiety. Recent literature suggests a strong connection between stress systems and AD progression. This presents a promising direction for future AD research. In this review, two systems involved in regulating stress and AD pathogenesis will be highlighted: serotonin (5-HT) and corticotropin releasing factor (CRF). Throughout the review, we summarize critical findings in the field while discussing common limitations with two animal models (3xTg-AD and TgF344-AD), novel pharmacotherapies, and potential early-intervention treatment options. We conclude by highlighting promising future pharmacotherapies and translational animal models of AD and anxiety.

Characterizing the effects of 2-phenylethylamine and coyote urine on unconditioned and conditioned defensive behaviors in adolescent male and female Long-Evans hooded rats.

Predator odors provide critical information to prey species allowing them to gage potential threat via the detection of semiochemicals called kairomones. Recent reports indicate that the commercially available predator odor coyote urine (CU), and to a lesser extent 2-phenylethylamine (PEA), induce innate defensive behaviors in adult rats and mice. The aim of the present study was to see if the defense-inducing effects of CU and PEA would extend to adolescents. Specifically, we evaluated the ability of CU and PEA to induce unconditioned and conditioned defensive behavior in predator-odor naïve adolescent male and female Long-Evans hooded rats. An additional group of males were exposed to the non-predatory aversive odor formalin to control for potential general aversive properties of the odorants. The data revealed that in males, both CU and PEA, but not formalin induced measures of risk assessment, whereas CU and formalin produced avoidance of the odor source. In partial contrast, both CU and PEA produced avoidance of the odor source and increased measures of risk assessment in females. Surprisingly males failed to show any measures of defense during the cue+context conditioning test trial. In contrast, in females both odorants produced marginal effects during re-exposure to the conditioning context, with CU inducing conditioned avoidance and PEA inducing conditioned risk assessment. We conclude that commercially available CU and PEA elicit a moderate defensive profile compared to previous reports examining cat fur/skin odor in male and female adolescent rats. Future research needs to examine additional concentrations of the odorants to determine if a more robust unconditioned defensive profile (e.g., freezing) can be induced by these predator odors, and whether the defensive profile responds to standard anxiolytic drugs.

Differential effects of chronic stress on anxiety-like behavior and contextual fear conditioning in the TgF344-AD rat model of Alzheimer's disease.

Alzheimer's disease (AD) is a progressive neurodegenerative brain disorder that leads to severe cognitive and functional impairments. Many AD patients also exhibit neuropsychiatric symptoms, such as anxiety and depression, prior to the clinical diagnosis of dementia. Chronic stress is associated with numerous adverse health consequences and disease states, and AD patients exhibit altered stress systems. Thus, stress may represent a causal link between neuropsychiatric symptoms and AD. To address this possibility, we examined the effects of chronic stress in the TgF344-AD rat model that co-expresses the mutant human amyloid precursor protein (APPsw) and presenilin 1 (PS1ΔE9) genes. Adult male transgenic (Tg+) and wild-type (WT) rats (6-7.5 months of age), with and without a history of chronic restraint stress, were tested for footshock-induced conditioned fear and for anxiety-like behavior in the elevated plus-maze. We found that non-stressed Tg+ rats showed increased anxiety-like behavior compared to non-stressed WT rats. In contrast, Tg+ and WT rats did not differ in levels of freezing immediately following footshock or during contextual re-exposure. Additionally, stressed Tg+ rats were not significantly different from stressed WT rats on any measures of anxiety or fear. Thus, while stress has been linked as a risk factor for AD-related pathology, it appears from the present findings that two weeks of daily restraint stress did not further enhance anxiety- or fear-like behaviors in TgF344-AD rats.

Blocking serotonin 2A (5-HT2A) receptors attenuates the acquisition of methamphetamine-induced conditioned place preference in adult female rats.

Methamphetamine withdrawal can induce intense cravings leading to relapse. Contexts/cues paired with chronic methamphetamine use develop incentive motivational properties, promoting future drug-seeking and taking behavior. Research has shown that, in adult male rats, the selective 5-HT2A receptor antagonist M100907 attenuates the acquisition of methamphetamine-induced conditioned place preference (CPP), a measure that examines conditioned associations between the rewarding properties of drugs and contexts. However, these findings have not been extended to adult female rats. The present study investigated the effects of M100907 on the acquisition of methamphetamine-CPP in adult female rats. During conditioning, rats were administered M100907 (0, 0.025, 0.25 mg/kg, i.p.) 15 min before methamphetamine (1 mg/kg, i.p.) and then placed into their initially non-preferred chamber for 30 min, or administered saline and placed into their initially preferred chamber for 30 min. Conditioning sessions were separated by four hours. Following four days of conditioning, the effects of M100907 on the acquisition of methamphetamine-CPP were assessed during a 15 min drug-free test trial. Pretreatment with M100907 dose-dependently attenuated the acquisition of methamphetamine-induced CPP. Blocking 5-HT2A receptors with a low dose of the selective antagonist M100907 attenuated the rewarding effects of methamphetamine in adult female rats. These data provide further evidence that the 5-HT2A receptor subtype is involved in the behavioral effects of methamphetamine.

Anxiety and Alzheimer's disease: Behavioral analysis and neural basis in rodent models of Alzheimer's-related neuropathology.

Alzheimer's disease (AD) pathology is commonly associated with cognitive decline but is also composed of neuropsychiatric symptoms including psychological distress and alterations in mood, including anxiety and depression. Emotional dysfunction in AD is frequently modeled using tests of anxiety-like behavior in transgenic rodents. These tests often include the elevated plus-maze, light/dark test and open field test. In this review, we describe prototypical behavioral paradigms used to examine emotional dysfunction in transgenic models of AD, specifically anxiety-like behavior. Next, we summarize the results of studies examining anxiety-like behavior in transgenic rodents, noting that the behavioral outcomes using these paradigms have produced inconsistent results. We suggest that future research will benefit from using a battery of tests to examine emotional behavior in transgenic AD models. We conclude by discussing putative, overlapping neurobiological mechanisms underlying AD-related neuropathology, stress and anxiety-like behavior reported in AD models.

Chemogenetic inhibition of ventral hippocampal CaMKIIα-expressing neurons attenuates anxiety- but not fear-like defensive behaviors in male Long-Evans hooded rats.

Previous research has implicated the ventral pole of the hippocampus in regulating anxiety. However, most rat studies examining the specific contribution of the ventral hippocampus have utilized techniques that have nonspecific effects and/or create nonreversible damage to the region. The present study sought to characterize the role of ventral hippocampal CaMKIIα-expressing neurons in modulating anxiety- and fear-like behavior during exposure to a variety of threatening stimuli. Five weeks prior to testing, adult male Long-Evans hooded rats received ventral hippocampal viral-vector infusions expressing either AAV8-CaMKIIα-hM4D-mCherry (DREADD) or AAV8-CaMKIIα-EGFP (GFP). DREADD transfection allowed for the specific, noninvasive and temporary inhibition of the ventral hippocampus (vHC) immediately before threat presentation. Rats were evaluated for behaviors congruent with anxiety- or fear-like defensive states during testing in the elevated plus-maze (EPM) and light-dark test (LDT), or post footshock freezing and footshock-induced contextual freezing, respectively. Analyses revealed a significant effect of vHC inhibition that was dependent on the type of threat exposure. Specifically, DREADD-induced silencing of vHC neurons reduced anxiety-like behavior in the EPM and LDT, without reliably affecting footshock-induced fear. These data add to a growing literature implicating the vHC as a key region involved in controlling the expression of anxiety in rodents, primates and humans.

Methamphetamine and social rewards interact to produce enhanced conditioned place preference in male adolescent rats.

Elucidating the influence of social context on drug reward is critical for understanding substance use disorders. Adolescents demonstrate enhanced sensitivity to drug and social rewards. However, the extent to which methamphetamine interacts with social reward in adolescents has not been thoroughly examined. Therefore, the present study used the conditioned place preference (CPP) model to examine the relationship between methamphetamine and social rewards in adolescent male rats. Sprague-Dawley rats (PND 30) were randomly assigned to one of the following four conditioning groups: saline alone (SA), methamphetamine alone (MA), saline with a social partner (SS) or methamphetamine with a social partner (MS). Testing occurred in a two-chamber biased apparatus across seven consecutive days using parameters presumed to be sub-threshold for establishing social- and methamphetamine-induced CPP. Similar to previous reports for nicotine and cocaine, the present results indicate that rats receiving methamphetamine with a social partner (i.e., MS) during conditioning demonstrated a significantly greater preference shift compared to all other groups. These findings further highlight the importance of social context in influencing the magnitude of drug reward during adolescence.

Coyote urine, but not 2-phenylethylamine, induces a complete profile of unconditioned anti-predator defensive behaviors.

Predator odors from various sources (e.g. fur/skin, urine, feces) provide prey animals valuable information that allows them to gage potential environmental threat via the detection of semiochemicals called kairomones. However, studies in rodents have revealed inconsistent and often conflicting results, which may occur from any combination of factors, including source and freshness of the odorant, sex, and genetic strain of the prey animal and/or predator. Regardless of cause, few odorants tested, if any, have lived up to the potent unconditioned predator odor stimuli - cat fur/skin odor - that induces a complete profile of innate unconditioned defensive behaviors (e.g., avoidance, risk assessment and freezing) and produces rapid aversive conditioned responses, both of which are sensitive to standard anxiolytic/anxiogenic drugs. Therefore, the present study investigated the effectiveness of coyote urine and 2-phenylethylamine (PEA), two commercially available predator odor cues, in satisfying the first of these criteria in predator odor naïve, adult male Long-Evans hooded rats. The data revealed that coyote urine, but not PEA, was effective in inducing a complete profile of anti-predator defensive behaviors characterized by avoidance, risk assessment, freezing and a reduction in exploratory behavior. We conclude that commercially available coyote urine satisfies the first criterion of a defense inducing unconditioned predator odor stimulus. In order to fully validate the use of coyote urine as an anxiety- and/or fear-like threat stimulus, future research needs to examine whether it produces aversive conditioning and whether the defensive profile induced by the odorant responds to standard anxiolytic drugs.

Preclinical support for the therapeutic potential of zolmitriptan as a treatment for cocaine use disorders.

Serotonin 1B receptor (5-HT1BR) agonists enhance cocaine intake in rats during daily self-administration but attenuate cocaine intake after prolonged abstinence. Here we investigated whether the less selective but clinically available 5-HT1D/1BR agonist, zolmitriptan, produces similar effects. Male and free-cycling female Sprague-Dawley rats were trained to lever press for cocaine (0.75 mg/kg, i.v.) or sucrose (45 mg pellet) reinforcement until performance rates stabilized. Rats then received zolmitriptan (3.0, 5.6, and 10 mg/kg, s.c.) prior to testing for its effects on response and reinforcement rates. Under cocaine testing conditions, rats had access to the training dose for the first hour followed by a lower cocaine dose (0.075 mg/kg, i.v.) for the second hour. Zolmitriptan decreased cocaine intake at both cocaine doses and in both sexes even without a period of abstinence and without altering sucrose intake. A separate group of rats underwent identical training procedures and were tested for effects of the selective 5-HT1B and 5-HT1D receptor antagonists, SB224289 (3.2, 5.6, and 10 mg/kg, s.c.) and BRL15572 (0.3, 1.0, and 3.0 mg/kg, i.p.), respectively, alone or in combination with zolmitriptan (5.6 mg/kg, s.c.) under identical cocaine testing procedures as above. The zolmitriptan-induced decrease in cocaine intake was reversed by SB224289 and to a lesser extent by BRL15572, suggesting that the effects of zolmitriptan involve both 5-HT1B and 5-HT1D receptors. Neither zolmitriptan, SB224289, or BRL15572 altered locomotor activity at the doses effective for modulating cocaine intake. These findings suggest that zolmitriptan has potential for repurposing as a treatment for cocaine use disorders.

Antagonizing serotonin 2A (5-HT2A) receptors attenuates methamphetamine-induced reward and blocks methamphetamine-induced anxiety-like behaviors in adult male rats.

BACKGROUND: Methamphetamine is a highly addictive and abused psychostimulant. Symptoms of methamphetamine withdrawal including drug craving and anxiety that can drive relapse. Currently, there is no FDA approved treatment for methamphetamine use disorder, highlighting the need for research examining the neural mechanisms underlying psychostimulant-induced behaviors. Research indicates that the 5-HT2A receptor antagonist M100907 attenuates several psychostimulant-induced behaviors, including conditioned place preference (CPP). However, these findings have not been extended to methamphetamine. The present study investigated the effects of M100907 on acquisition of methamphetamine-CPP and methamphetamine-induced anxiety-like behavior. METHODS: Adult male rats were tested across eight consecutive days. Prior to methamphetamine administration (0 or 1 mg/kg, i.p.), rats were pretreated with their assigned dose of M100907 (0, 0.0025 .025 or 0.25 mg/kg, i.p.) and were placed into their initially non-preferred chamber. After four methamphetamine conditioning sessions, the effects of M100907 on methamphetamine-induced CPP were assessed. Following CPP testing, rats were screened for anxiety-like behaviors in the elevated plus-maze. RESULTS: Pretreatment with M100907 attenuated methamphetamine-induced CPP without producing any observable rewarding or aversive effects in methamphetamine naïve rats. Additionally, M100907 blocked methamphetamine-induced increases in anxiety-like behavior and attenuated some indices of anxiety in methamphetamine naïve rats. CONCLUSIONS: Results suggest that blocking 5-HT2A receptors with the selective antagonist M100907 attenuates the rewarding effects of methamphetamine and does not produce any rewarding or aversive effects alone. Further, M100907 pretreatment blocked the anxiety-inducing effects of methamphetamine. Collectively, these data suggest that the 5-HT2A receptor subtype represents a novel target for treating methamphetamine use disorder.

The Therapeutic Effectiveness of Full Spectrum Hemp Oil Using a Chronic Neuropathic Pain Model.

BACKGROUND: Few models exist that can control for placebo and expectancy effects commonly observed in clinical trials measuring 'Cannabis' pharmacodynamics. We used the Foramen Rotundum Inflammatory Constriction Trigeminal Infraorbital Nerve injury (FRICT-ION) model to measure the effect of "full-spectrum" whole plant extracted hemp oil on chronic neuropathic pain sensitivity in mice. METHODS: Male BALBc mice were submitted to the FRICT-ION chronic neuropathic pain model with oral insertion through an incision in the buccal/cheek crease of 3 mm of chromic gut suture (4-0). The suture, wedged along the V2 trigeminal nerve branch, creates a continuous irritation that develops into secondary mechanical hypersensitivity on the snout. Von Frey filament stimuli on the mouse whisker pad was used to assess the mechanical pain threshold from 0-6 h following dosing among animals (n = 6) exposed to 5 µL of whole plant extracted hemp oil combined with a peanut butter vehicle (0.138 mg/kg), the vehicle alone (n = 3) 7 weeks post-surgery, or a naïve control condition (n = 3). RESULTS: Mechanical allodynia was alleviated within 1 h (d = 2.50, p < 0.001) with a peak reversal effect at 4 h (d = 7.21, p < 0.001) and remained significant throughout the 6 h observation window. There was no threshold change on contralateral whisker pad after hemp oil administration, demonstrating the localization of anesthetic response to affected areas. CONCLUSION: Future research should focus on how whole plant extracted hemp oil affects multi-sensory and cognitive-attentional systems that process pain.

Moderate prenatal alcohol exposure reduces parvalbumin expressing GABAergic interneurons in the dorsal hippocampus of adult male and female rat offspring.

Prenatal alcohol exposure (PAE) negatively impacts hippocampal development and impairs hippocampal-sensitive learning and memory. However, hippocampal neural adaptations in response to moderate PAE are not completely understood. To explore the effects of moderate PAE on GABAergic interneuron expression, this study used a rat model of moderate PAE to examine the effects of PAE on parvalbumin (PARV)-positive cells in fields CA1, CA3 and the dentate gyrus (DG) of the dorsal hippocampus (dHC). Long-Evans dams were given daily access to 5 % (vol/vol) ethanol or saccharine (SAC) control solutions throughout the course of gestation. Offspring were divided into four separate groups: PAE (n = 7) or SAC (n = 7) males, or PAE (n = 8) or SAC (n = 8) females. All rats were aged to adulthood and, following testing in the Morris water task, their brains were analyzed for the expression of the GABAergic neuronal marker PARV. We report a main effect of PAE on GABAergic expression, with significant reductions in PARV-positive cells in area CA3 for males and the DG for females. There was also a trend for a reduction in PARV expressing neurons in fields CA1 and CA3 in females. The results are discussed in relation to hippocampal GABAergic interneuron function, PAE and behavior.

Effects of estrus cycle stage on defensive behavior in female Long-Evans hooded rats.

This study investigated the influence of the estrus cycle in mediating cat odor-induced unconditioned and conditioned defensive behaviors in female Long-Evans hooded rats. Unconditioned defensive behaviors were assessed during predatory cue exposure; conditioned defensive behaviors were examined 24 h after threat exposure. Estrus phases were determined by microscopic examination of vaginal smears within 10 min of completing the behavioral tests. Compared to no-odor controls, female rats exposed to cat odor exhibited both unconditioned and conditioned defensive behaviors, including elevated levels of freezing, risk assessment and avoidance. Rats in proestrus and estrus exhibited reduced levels of defensive behavior during the unconditioned test trial compared to subjects in diestrus and metestrus. Specifically, estrus stages characterized by high levels of circulating estrogens and progesterone were associated with reduced immobility (i.e. freezing) and enhanced active defense (i.e. risk assessment), profiles that may enable mate seeking and subsequent reproduction in potentially dangerous or novel environments. These results suggest a specific role for ovarian hormone fluctuations in mediating unconditioned fear- and anxiety-like defensive behaviors during exposure to predatory odors.

Anxiety-like behavior as an early endophenotype in the TgF344-AD rat model of Alzheimer's disease.

Alzheimer's disease (AD) is characterized by progressive cognitive decline and the presence of aggregates of amyloid beta (plaques) and hyperphosphorylated tau (tangles). Early diagnosis through neuropsychological testing is difficult due to comorbidity of symptoms between AD and other types of dementia. As a result, there is a need to identify the range of behavioral phenotypes expressed in AD. In the present study, we utilized a transgenic rat (TgF344-AD) model that bears the mutated amyloid precursor protein as well as presenilin-1 genes, resulting in progressive plaque and tangle pathogenesis throughout the cortex. We tested young adult male and female TgF344-AD rats in a spatial memory task in the Morris water maze and for anxiety-like behavior in the elevated plus-maze. Results indicated that regardless of sex, TgF344-AD rats exhibited increased anxiety-like behavior in the elevated plus-maze, which occurred without significant deficits in the spatial memory. Together, these results indicate that enhanced anxiety-like behavior represents an early-stage behavioral marker in the TgF344-AD rat model.

Effects of a 5-HT1B Receptor Agonist on Locomotion and Reinstatement of Cocaine-Conditioned Place Preference after Abstinence from Repeated Injections in Mice.

5-HT1B receptors (5-HT1BRs) modulate behavioral effects of cocaine. Here we examined the effects of the 5-HT1BR agonist 5-propoxy-3-(1,2,3,6-tetrahydro-4-pyridinyl)-1H-pyrrolo[3,2-b]pyridine (CP94253) on spontaneous and cocaine-induced locomotion and on cocaine-primed reinstatement of conditioned place preference (CPP) in male mice given daily repeated injections of either saline or cocaine (15 mg/kg, IP) for 20 days. In the locomotor activity experiment, testing occurred both 1 and 20 days after the final injection. In the CPP experiment, mice underwent conditioning procedures while receiving the last of their daily injections, which were given either during or ≥2 h after CPP procedures. The CPP procedural timeline consisted of baseline preference testing (days 12-13 of the chronic regimen), conditioning (days 14-19, 2 daily 30-min sessions separated by 5 h), CPP test (day 21), extinction (days 22-34; no injections), CPP extinction test (day 35), and reinstatement test (day 36). Mice that had not extinguished received additional extinction sessions prior to reinstatement testing on day 42. On test days, mice were pretreated with either saline or CP94253 (10 mg/kg, IP). Testing began 30 min later, immediately after mice were primed with either saline or cocaine (5 mg/kg for locomotion; 15 mg/kg for reinstatement). We found that CP94253 increased spontaneous locomotion in mice receiving repeated injections of either saline or cocaine when tested 1 day after the last injection, but had no effect on spontaneous locomotion after 20 days abstinence from repeated injections. Surprisingly, cocaine-induced locomotion was sensitized regardless of whether the mice had received repeated saline or cocaine. CP94253 attenuated expression of the sensitized locomotion after 20 days abstinence. A control experiment in noninjected, drug-naïve mice showed that CP94253 had no effect on spontaneous or cocaine-induced locomotion. Mice reinstated cocaine-CPP when given a cocaine prime, and CP94253 pretreatment attenuated cocaine reinstatement.The findings suggest that stress from repeated saline injections and/or co-housing with cocaine-injected mice may cross-sensitize with cocaine effects on locomotion and that CP94253 attenuates these effects, as well as reinstatement of cocaine-CPP. This study supports the idea that 5-HT1BR agonists may be useful anti-cocaine medications.

Curiosity as an approach to ethoexperimental analysis: Behavioral neuroscience as seen by students and colleagues of Bob Blanchard.

This review is a synopsis of an International Behavioral Neuroscience Society (IBNS) symposium which focused on the elements of Behavioral Neuroscience for which Robert J. Blanchard was a Pioneer, Leading Expert, Advocate, Mentor, and Sage. Bob Blanchard's work demonstrably changed our broad understanding of animal behavior, and led the way to experimental design and analysis for studies of animal behavior that helped to clarify the deep complexity and subtleties of behavior. Bob's impact on the field of Behavioral Neuroscience includes the behavior, neurocircuitry, neurochemistry, and pharmacology related to social interactions, aggressive behavior, defensive behaviors, flight, freezing, threat, attack, risk assessment, anxiety disorders, animal models, models of social behavior, and autism. The methods and designs developed by Bob Blanchard over a lifetime have been adopted by scientists around the world, and form a standard of excellence in the field. The article addresses these topics in a way that presents developments in the field, describes the newest research data, and pays tribute to a great scientist and founder of this field of work, Bob Blanchard.

Effects of sex and housing on social, spatial, and motor behavior in adult rats exposed to moderate levels of alcohol during prenatal development.

Persistent deficits in social behavior, motor behavior, and behavioral flexibility are among the major negative consequences associated with exposure to ethanol during prenatal development. Prior work from our laboratory has linked moderate prenatal alcohol exposure (PAE) in the rat to deficits in these behavioral domains, which depend upon the ventrolateral frontal cortex (Hamilton et al., 2014) [20]. Manipulations of the social environment cause modifications of dendritic morphology and experience-dependent immediate early gene expression in ventrolateral frontal cortex (Hamilton et al., 2010) [19], and may yield positive behavioral outcomes following PAE. In the present study we evaluated the effects of housing PAE rats with non-exposed control rats on adult behavior. Rats of both sexes were either paired with a partner from the same prenatal treatment condition (ethanol or saccharin) or from the opposite condition (mixed housing condition). At four months of age (∼3 months after the housing manipulation commenced), social behavior, tongue protrusion, and behavioral flexibility in the Morris water task were measured as in (Hamilton et al., 2014) [20]. The behavioral effects of moderate PAE were primarily limited to males and were not ameliorated by housing with a non-ethanol exposed partner. Unexpectedly, social behavior, motor behavior, and spatial flexibility were adversely affected in control rats housed with a PAE rat (i.e., in mixed housing), indicating that housing with a PAE rat has broad behavioral consequences beyond the social domain. These observations provide further evidence that moderate PAE negatively affects social behavior, and underscore the importance of considering potential negative effects of housing with PAE animals on the behavior of critical comparison groups.

Effects of the 5-HT2C receptor agonist CP809101 in the amygdala on reinstatement of cocaine-seeking behavior and anxiety-like behavior.

Serotonin 2C receptor (5-HT2CR) agonists attenuate reinstatement of cocaine-seeking behavior. These receptors are found throughout the limbic system, including the basolateral amygdala (BlA), which is involved in forming associations between emotional stimuli and environmental cues, and the central amygdala (CeA), which is implicated in the expression of conditioned responding to emotional stimuli. This study investigated whether 5-HT2CRs in the amygdala are involved in cue and cocaine-primed reinstatement of cocaine-seeking behavior. Rats were trained to self-administer cocaine (0.75 mg/kg, i.v.) which that was paired with light and tone cues, and then subsequently they underwent daily extinction training. Rats then received bilateral microinfusions of the 5-HT2CR agonist CP809101 (0.01-1.0 µg/0.2 µl/side) into either the BlA or CeA prior to tests for cue or cocaine-primed (10 mg/kg, i.p.) reinstatement. Rats were also tested for CP809101 effects on anxiety-like behavior on the elevated plus-maze (EPM). Surprisingly, intra-BlA CP809101 had no effect on cue reinstatement, though it did increase anxiety-like behavior on the EPM. Intra-CeA infusions of CP809101 attenuated cocaine-primed reinstatement, an effect that was prevented with concurrent administration of the 5-HT2CR antagonist SB242084 (0.1 µg/0.2 µl/side). CP809101 had no effect on cue reinstatement or anxiety-like behavior on the EPM. These findings suggest that 5-HT2CRs in the BlA modulate anxiety, whereas those in the CeA modulate incentive motivational effects induced by cocaine priming injections.