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1.  Age-dependent effects of repeated amphetamine exposure on working memory in rats 
Behavioural brain research  2013;242:84-94.
Cognitive dysfunction is a hallmark of chronic psychostimulant misuse. Adolescents may have heightened risk of developing drug-induced deficits because their brains are already undergoing widespread changes in anatomy and function as a normal part of development. To address this hypothesis, we performed two sets of experiments where adolescent and young adult rats were pre-exposed to saline or amphetamine (1 or 3 mg/kg) and subsequently tested in a prefrontal cortex (PFC)-sensitive working memory task. A total of ten injections of AMPH or saline (in control rats) were given every other day over the course of 19 days. After rats reached adulthood (> 90 days old), cognitive performance was assessed using operant-based delayed matching-to-position (DMTP) and delayed nonmatching-to-position (DNMTP) tasks. DNMTP was also assessed following challenges with amphetamine (0.1–1.25 mg/kg), and ketamine (5.0–10 mg/kg). In experiment one, we also measured the locomotor response following the first and tenth pre-exposure to amphetamine and after an amphetamine challenge given at the conclusion of operant testing. Compared to adult-exposed groups, adolescents were less sensitive to the psychomotor effects of amphetamine. However, they were more vulnerable to exposure-induced cognitive impairments. For example, adolescent-exposed rats displayed delay-dependent deficits in accuracy, increased sensitivity to proactive interference, and required more training to reach criterion. Drug challenges produced deficits in DNMTP performance, but these were not dependent on pre-exposure group. These studies demonstrate age of exposure-dependent effects of amphetamine on cognition in a PFC-sensitive task, suggesting a heightened sensitivity of adolescents to amphetamine-induced neuroplasticity.
doi:10.1016/j.bbr.2012.12.044
PMCID: PMC3566264  PMID: 23291159
adolescence; amphetamine; sensitization; working memory; matching-to-position
2.  Deletion of striatal adenosine A2A receptor spares latent inhibition and prepulse inhibition but impairs active avoidance learning 
Behavioural brain research  2012;242:54-61.
Following early clinical leads, the adenosine A2AR receptor (A2AR) has continued to attract attention as a potential novel target for treating schizophrenia; especially against the negative and cognitive symptoms of the disease because of A2AR’s unique modulatory action over glutamatergic in addition to dopaminergic signaling. Through the antagonistic interaction with the dopamine D2 receptor, and by regulating glutamate release and N-methyl-d-aspartate receptor function, striatal A2AR is ideally positioned to fine-tune the dopamine-glutamate balance whose disturbance is implicated in the pathophysiology of schizophrenia. However, the precise function of striatal A2ARsin the regulation of schizophrenia-relevant behavior is poorly understood. Here, we tested the impact of conditional striatum-specific A2AR knockout (st-A2AR-KO) on latent inhibition (LI) and prepulse inhibition (PPI) – behavior that is tightly regulated by striatal dopamine and glutamate. These are two common cross-species translational tests for the assessment of selective attention and sensorimotor gating deficits reported in schizophrenia patients; and enhanced performance in these tests is associated with antipsychotic drug action. We found that neither LI nor PPI was significantly affected in st-A2AR-KO mice; although a deficit in active avoidance learning was identified in these animals. The latter phenotype, however, was not replicated in another form of aversive conditioning – conditioned taste aversion. Hence, the present study shows that neither learned inattention (as measured by LI) nor sensory gating (as indexed by PPI) requires the integrity of striatal A2ARs– a finding that may undermine the hypothesized importance of A2AR in the genesis and/or treatment of schizophrenia.
doi:10.1016/j.bbr.2012.12.024
PMCID: PMC3566338  PMID: 23276608
Adenosine; A2A receptor; latent inhibition; Prepulse inhibition; schizophrenia
3.  Post-weaning Social Isolation Impairs Observational Fear Conditioning 
Behavioural brain research  2013;242:142-149.
Many mammals can utilize social information to learn by observation of conspecifics (social learning). Social learning of fear is expected to be especially advantageous for survival. However, disruption of social development in early life can impair social cognition and might also be expected to disrupt social learning. Social isolation during a critical period of adolescence disrupts social development. The purpose of this study was to determine whether disruption of social development through post-weaning social isolation leads to impairments of social fear learning. Rats were reared in isolation or pair-housed from immediately post-weaning, for 3 weeks. Social fear learning in rats was acquired by observation of tone-footshock pairings administered to a conspecific. Isolation-reared rats displayed less conditioned freezing than pair-housed rats when tested the next day. This reduction of conditioned freezing was correlated with conspecific-oriented behaviors during conditioning, was measured despite similarities in demonstrator behaviors, and occurred despite a manipulation that equalized freezing during conditioning between the pair-housed and isolation-reared rats. The results could not be explained by abnormal sensitization to a repeated tone or deficits in freezing or direct fear conditioning. These results demonstrate that observational fear conditioning is impaired by social isolation, and provide a model to study impaired social affective learning. Impaired social cognition, manifested as inability to recognize or appropriately interpret social cues, is a symptom of several psychiatric disorders. Better understanding of the mechanisms of impaired social fear learning can lead to novel treatments for social cognition symptoms of psychiatric disorders.
doi:10.1016/j.bbr.2012.12.050
PMCID: PMC3566364  PMID: 23295398
social; learning; observational; fear; conditioning; isolation-rearing
4.  EFFECTS OF MINOCYCLINE ON SPATIAL LEARNING, HIPPOCAMPAL NEUROGENESIS AND MICROGLIA IN AGED AND ADULT MICE 
Behavioural brain research  2012;242:17-24.
Age-related priming of microglia and release of inflammatory cytokines, such as interleukin-1β (IL-1β) and interleuekin-6 (IL-6) have been associated with deficits in cognitive function. The present study assessed whether treatment with minocycline could improve spatial cognition in aged mice, and whether these improvements in behavior were associated with reduced microglia activation and an enhancement in hippocampal neurogenesis. Adult (3 months) and aged (22 months) male BALB/c mice received minocycline in their drinking water or control mice received distilled water for 20 days. Mice received BrdU to label dividing cells on days 8–17. Spatial learning was measured using the water maze. Immunohistochemistry was conducted to measure number of BrdU positive neurons and number and size of microglia by detection of Iba-1 in the dentate gyrus molecular layer. Further, hippocampal samples were collected to measure changes in IL-1β, IL-6, and CD74 expression. The data show that aged mice have increased hippocampal expression of IL-1β, IL-6, and CD74 relative to adults. Minocycline treatment significantly improved acquisition of the water maze in aged mice but not adults. Minocycline reduced the average size of Iba-1 positive cells and total Iba-1 counts, but did not affect hippocampal cytokine gene expression. Minocycline increased neurogenesis in adults but not aged mice. Collectively, the data indicate that treatment with minocycline may recover some aspects of cognitive decline associated with aging, but the effect appears to be unrelated to adult hippocampal neurogenesis.
doi:10.1016/j.bbr.2012.12.032
PMCID: PMC3725815  PMID: 23274840
Microglia; water maze; hippocampus; aging; IL-1β; IL-6; CD74; Iba-1 cytokines
5.  Cocaine deprivation effect: Cue abstinence over weekends boosts anticipatory 50-kHz ultrasonic vocalizations in rats 
Behavioural brain research  2010;214(1):75-79.
In drug dependence studies, rats are often tested daily with short breaks (such as weekends) spent untested in their home cages. Research on alcohol models has suggested that breaks from continuous testing can transiently enhance self-administration (termed the “alcohol deprivation effect”). The present study explored whether the salience of cocaine-access cues is increased after skipping weekend cocaine and cue exposures. Ultrasonic vocalizations (USVs) of the 50-kHz class are emitted by rats exposed to intravenous cocaine and have been shown to increase with repeated drug exposure at the same dose level (sensitization). The present study found that over the course of several weeks of cocaine self- or yoked-administration pre-drug cues signaling forthcoming access or delivery of cocaine elicited marked amounts of anticipatory 50-kHz USVs, and that weekend deprivation from cues and cocaine exaggerated further the level of calling (more calls on Mondays compared to Fridays). Anticipatory USVs extinguished less rapidly when weekend access to unreinforced cues was denied. The results may have clinical implications, in that intermittently avoiding cues or context may enhance drug cue salience and resistance to extinction.
doi:10.1016/j.bbr.2010.04.057
PMCID: PMC3969444  PMID: 20470830
addiction; craving; cocaine; ultrasonic vocalization; deprivation effect; expectancy
6.  Repeated Intravenous Amphetamine Exposure: Rapid and Persistent Sensitization of 50-kHz Ultrasonic Trill Calls in Rats 
Behavioural brain research  2008;197(1):205-209.
Short 50-kilohertz (kHz) range frequency-modulated ultrasonic vocalizations (USVs) produced by rats and mice are unconditionally elicited by drugs of abuse or electrical stimulation that increase dopamine activity in the nucleus accumbens, and it has been suggested that they reflect “positive affect” or incentive motivational states associated with appetitive behavior. The repeated administration of amphetamine is known to not only produce “psychomotor” sensitization, but also to facilitate a number of appetitive behaviors, including conditioned drug pursuit behavior. We were interested, therefore, in whether amphetamine-induced 50-kHz USVs would also increase with repeated drug exposure. USV recordings were made during 5-min sessions immediately after a saline infusion, and again 4-5 hours later, after 1.0 mg/kg intravenous amphetamine exposure. These sessions took place every other day over a 5-day period. A challenge dose of 1.0 mg/kg amphetamine was administered 2 weeks later to determine whether sensitization would persist. The initial amphetamine infusion increased 50-kHz USVs relative to the saline infusion. This effect was enhanced over trials and during the amphetamine challenge two weeks later. Classification of 50-kHz range call types revealed that complex frequency-modulated trill calls were sensitized by amphetamine, but not flat 50-kHz calls. It is possible that 50-kHz USV recordings could provide a potentially valuable behavioral measure of sensitization linked to enhanced incentive salience and increased tendency to self-administer drugs of abuse.
doi:10.1016/j.bbr.2008.08.037
PMCID: PMC3969445  PMID: 18809437
7.  Role of oxidative stress in methamphetamine-induced dopaminergic toxicity mediated by protein kinase Cδ 
Behavioural brain research  2012;232(1):98-113.
This study examined the role of protein kinase C (PKC) isozymes in methamphetamine (MA)-induced dopaminergic toxicity. Multiple-dose administration of MA did not significantly alter PKCα, PKCβI, PKCβII, or PKCζ expression in the striatum, but did significantly increase PKCδ expression. Gö6976 (a co-inhibitor of PKCα and -β), hispidin (PKCβ inhibitor), and PKCζ pseudosubstrate inhibitor (PKCζ inhibitor) did not significantly alter MA-induced behavioral impairments. However, rottlerin (PKCδ inhibitor) significantly attenuated behavioral impairments in a dose-dependent manner. In addition, MA-induced behavioral impairments were not apparent in PKCδ knockout (–/–) mice. MA-induced oxidative stress (i.e., lipid peroxidation and protein oxidation) was significantly attenuated in rottlerin-treated mice and was not apparent in PKCδ (–/–) mice. Consistent with this, MA-induced apoptosis (i.e., terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling-positive apoptotic cells) was significantly attenuated in rottlerin-treated mice. Furthermore, MA-induced increases in the dopamine (DA) turnover rate and decreases in tyrosine hydroxylase (TH) activity and the expression of TH, dopamine transporter (DAT), and vesicular monoamine transporter 2 (VMAT2) were not significantly observed in rottlerin-treated or PKCδ (–/–) mice. Our results suggest that PKCδ gene expression is a key mediator of oxidative stress and dopaminergic damage induced by MA. Thus, inhibition of PKCδ may be a useful target for protection against MA-induced neurotoxicity.
doi:10.1016/j.bbr.2012.04.001
PMCID: PMC3964682  PMID: 22512859
Methamphetamine; PKC isozymes; PKCδ gene deletion; Rottlerin; dopamine; oxidative stress
8.  Rapid Auditory Processing and Learning Deficits in Rats With P1 versus P7 Neonatal Hypoxic-Ischemic Injury 
Behavioural brain research  2006;172(1):114-121.
Hypoxia-ischemia (HI) is associated with premature birth, and injury during term birth. Many infants experiencing HI later show disruptions of language, with research suggesting that rapid auditory processing (RAP) deficits, or impairments in the ability to discriminate rapidly changing acoustic signals, play a causal role in emergent language problems. We recently bridged these lines of research by showing RAP deficits in rats with unilateral-HI injury induced on postnatal day 1, 7, or 10 (P1, P7, or P10; 23). While robust RAP deficits were found in HI animals, it was suggested that our within-age sample size did not provide us with sufficient power to detect Age-at-injury differences within HI groups.
The current study sought to examine differences in neuropathology and behavior following unilateral-HI injury in P1 vs. P7 pups. Ages chosen for HI induction reflect differential stages of neurodevelopmental maturity, and subsequent regional differences in vulnerability to reduced blood flow/oxygen (modeling premature/term HI injury). Results showed that during the juvenile period, both P1 and P7 HI groups exhibited significant RAP deficits, but the deficit in the P1 HI group resolved with repeated testing (compared to shams). However, P7 HI animals showed lasting deficits in RAP and spatial learning/memory through adulthood. The current findings are in accord with evidence that HI injury during different stages of developmental maturity (Age-at-injury) leads to differential neuropathologies, and provide the novel observation that in rats, P1 vs. P7 induced pathologies are associated with different patterns of auditory processing and learning/memory deficits across the lifespan.
doi:10.1016/j.bbr.2006.05.003
PMCID: PMC3960850  PMID: 16765458
language impairment; prematurity; low birth weight
9.  Larval Ethanol Exposure Alters Free-running Circadian Rhythm and per Locus Transcription in Adult D. melanogaster period Mutants 
Behavioural brain research  2012;241:50-55.
Alcohol consumption causes disruptions in a variety of daily rhythms, including the circadian free-running rhythm. A previous study conducted in our laboratories has shown that larval ethanol exposure alters the free-running period in adult Canton-S Drosophila melanogaster. Few studies, however, have explored the effect of alcohol exposure on organisms exhibiting circadian periods radically different than (normal) 24-hours. We reared Canton-S, period long, and period short Drosophilamelanogaster larvae on 10%-ethanol supplemented food, and assessed their adult free-running locomotor activity and period transcript at ZT 12. We demonstrate that in Canton-S larval ethanol exposure shortens the adult free-running locomotor activity but does not significantly alter period mRNA levels at ZT 12. Period long mutants exposed to larval ethanol had significantly shortened adult free-running locomotor activity rhythms and decreased period mRNA levels, while period short mutants lengthened their free-running rhythm and showed increased period mRNA levels at ZT 12 after being exposed to larval ethanol. These results indicate that the effects of ethanol on the circadian clock might depend upon the baseline circadian period of the organism or that period mutant gene expression is sensitive to developmental ethanol treatment.
doi:10.1016/j.bbr.2012.11.035
PMCID: PMC3552313  PMID: 23219838
ethanol; circadian; period; Drosophila; mutant; rhythm
10.  Neural changes after training to perform cognitive tasks 
Behavioural brain research  2012;241:235-243.
Cognitive operations requiring working memory rely on the activity of neurons in areas of the association cortex, most prominently the lateral prefrontal cortex. Human imaging and animal neurophysiological studies indicate that this activity is shaped by learning, though much is unknown about how much training alters neural activity and cortical organization. Results from non-human primates demonstrate that prior to any training in cognitive tasks, prefrontal neurons respond to stimuli, exhibit persistent activity after their offset, and differentiate between matching and non-matching stimuli presented in sequence. A number of important changes also occur after training in a working memory task. More neurons are recruited by the stimuli and exhibit higher firing rates, particularly during the delay period. Operant stimuli that need to be recognized in order to perform the task elicit higher overall rates of responses, while the variability of individual discharges and correlation of discharges between neurons decrease after training. New information is incorporated in the activity of a small population of neurons highly specialized for the task and in a larger population of neurons that exhibit modest task related information, while information about other aspects of stimuli remains present in neuronal activity. Despite such changes, the relative selectivity of the dorsal and ventral aspect of the lateral prefrontal cortex is not radically altered with regard to spatial and non-spatial stimuli after training. Collectively, these results provide insights on the nature and limits of cortical plasticity mediating cognitive tasks.
doi:10.1016/j.bbr.2012.12.017
PMCID: PMC3552071  PMID: 23261872
prefrontal cortex; cognitive training; monkey; neurophysiology; neuron
11.  PWZ-029, AN INVERSE AGONIST SELECTIVE FOR α5 GABAA RECEPTORS, IMPROVES OBJECT RECOGNITION, BUT NOT WATER-MAZE MEMORY IN NORMAL AND SCOPOLAMINE-TREATED RATS 
Behavioural brain research  2012;241:206-213.
Inverse agonism at the benzodiazepine site of α5 subunit-containing GABAA receptors is an attractive approach for the development of putative cognition-enhancing compounds, which are still far from clinical application. Several ligands with binding and/or functional selectivity for α5 GABAA receptors have been synthesized and tested in a few animal models. PWZ-029 is an α5 GABAA selective inverse agonist whose memory enhancing effects were demonstrated in the passive avoidance task in rats and in Pavlovian fear conditioning in mice. In the present study we investigated the effects of PWZ-029 administration in novel object recognition test and Morris water maze, in normal and scopolamine-treated rats. All the three doses of PWZ-029 (2, 5 and 10 mg/kg) improved object recognition after the 24-h delay period, as shown by significant differences between the exploration times of the novel and old object, and the respective discrimination indices. PWZ-029 (2 mg/kg) also successfully reversed the 0.3 mg/kg scopolamine-induced deficit in recognition memory after the 1-h delay. In the Morris water maze test, PWZ-029 (5, 10 and 15 mg/kg) did not significantly influence swim patterns, either during five acquisition days or during the treatment-free probe trial. PWZ-029 (2, 5 and 10 mg/kg) also proved to be ineffective in the reversal of the 1 mg/kg scopolamine-induced memory impairment in the water maze. The present mixed results encourage use of a variety of tests and experimental conditions in order to increase the predictability of preclinical testing of selective α5 GABAA inverse agonists.
doi:10.1016/j.bbr.2012.12.016
PMCID: PMC3556169  PMID: 23261875
GABA; inverse agonist; memory; object recognition; water maze
12.  Loss of dysbindin-1 in mice impairs reward-based operant learning by increasing impulsive and compulsive behavior 
Behavioural brain research  2012;241:173-184.
The dystrobrevin-binding protein 1 (DTNBP1) gene, which encodes the dysbindin-1 protein, is a potential schizophrenia susceptibility gene. Polymorphisms in the DTNBP1 gene have been associated with altered cognitive abilities. In the present study, dysbindin-1 null mutant (dys−/−), heterozygous (dys+/−), and wild-type (dys+/+) mice, on a C57BL/6J genetic background, were tested in either a match to sample or nonmatch to sample visual discrimination task. This visual discrimination task was designed to measure rule learning and detect any changes in response timing over the course of testing. Dys−/− mice displayed significant learning deficits and required more trials to acquire this task. However, once criterion was reached, there were no differences between the genotypes on any behavioral measures. Dys−/− mice exhibited increased compulsive and impulsive behaviors compared to control littermates suggesting the inability to suppress incorrectly-timed responses underlies their increased time to acquisition. Indeed, group comparisons of behavior differences between the first and last day of testing showed that only dys−/− mice consistently decreased measures of perseverative, premature, timeout, and total responses. These findings illustrate how some aspects of altered cognitive performance in dys−/− mice might be related to increased impulsive and compulsive behaviors, analogous to cognitive deficits in some individuals with psychiatric disorders.
doi:10.1016/j.bbr.2012.12.021
PMCID: PMC3556458  PMID: 23261874
dysbindin; impulsivity; compulsivity; timing; schizophrenia; operant learning
13.  Impulsive-choice patterns for food in genetically lean and obese Zucker rats 
Behavioural brain research  2012;241:214-221.
Behavioral-economic studies have shown that differences between lean and obese Zuckers in food consumption depend on the response requirement for food. Since a response requirement inherently increases the delay to reinforcement, differences in sensitivity to delay may also be a relevant mechanism of food consumption in the obese Zucker rat. Furthermore, the endocannabinoid neurotransmitter system has been implicated in impulsivity, but studies that attempt to characterize the effects of cannabinoid drugs (e.g., rimonabant) on impulsive choice may be limited by floor effects. The present study aimed to characterize impulsive-choice patterns for sucrose using an adjusting-delay procedure in genetically lean and obese Zuckers. Ten lean and ten obese Zucker rats chose between one lever that resulted in one pellet after a standard delay (either 1 s or 5 s) and a second lever that resulted in two or three pellets after an adjusting delay. After behavior stabilized under baseline, rimonabant (0–10 mg/kg) was administered prior to some choice sessions in the two-pellet condition. Under baseline, obese Zuckers made more impulsive choices than leans in three of the four standard-delay/pellet conditions. Additionally, in the 2-pellet condition, rimonabant increased impulsive choice in lean rats in the 1-s standard-delay condition; however, rimonabant decreased impulsive choice in obese rats in the 1-s and 5-s standard-delay conditions. These data suggest that genetic factors that influence impulsive choice are stronger in some choice conditions than others, and that the endocannabinoid system may be a relevant neuromechanism.
doi:10.1016/j.bbr.2012.12.013
PMCID: PMC3629838  PMID: 23261877
adjusting-delay procedure; cannabinoids; delay discounting; impulsive choice; obese Zucker rat; rimonabant
14.  An automated maze task for assessing hippocampus-sensitive memory in mice☆ 
Behavioural Brain Research  2014;261(100):249-257.
Highlights
•Alternation procedures in rodents are highly sensitive to manipulations of the hippocampus.•However as they require hand testing, they are low throughput and stressful for the animal.•An automated maze was developed for assessing alternation performance in mice.•Alternation performance was shown to be impaired in mice with lesions to the hippocampus.
Memory deficits associated with hippocampal dysfunction are a key feature of a number of neurodegenerative and psychiatric disorders. The discrete-trial rewarded alternation T-maze task is highly sensitive to hippocampal dysfunction. Normal mice have spontaneously high levels of alternation, whereas hippocampal-lesioned mice are dramatically impaired. However, this is a hand-run task and handling has been shown to impact crucially on behavioural responses, as well as being labour-intensive and therefore unsuitable for high-throughput studies. To overcome this, a fully automated maze was designed. The maze was attached to the mouse's home cage and the subject earned all of its food by running through the maze. In this study the hippocampal dependence of rewarded alternation in the automated maze was assessed. Bilateral hippocampal-lesioned mice were assessed in the standard, hand-run, discrete-trial rewarded alternation paradigm and in the automated paradigm, according to a cross-over design. A similarly robust lesion effect on alternation performance was found in both mazes, confirming the sensitivity of the automated maze to hippocampal lesions. Moreover, the performance of the animals in the automated maze was not affected by their handling history whereas performance in the hand-run maze was affected by prior testing history. By having more stable performance and by decreasing human contact the automated maze may offer opportunities to reduce extraneous experimental variation and therefore increase the reproducibility within and/or between laboratories. Furthermore, automation potentially allows for greater experimental throughput and hence suitability for use in assessment of cognitive function in drug discovery.
doi:10.1016/j.bbr.2013.12.009
PMCID: PMC3923974  PMID: 24333574
Automated; Hippocampus; Maze; Mouse
15.  A Drug-Paired Taste Cue Elicits Withdrawal and Predicts Cocaine Self-Administration 
Behavioural brain research  2012;240:87-90.
Addiction is a chronic disease where periods of abstinence are riddled with instances of craving, withdrawal, and eventual relapse to escalated drug use. Cues previously associated with drug use can have a deleterious effect on this cycle by precipitating withdrawal symptoms. Here we focus specifically on the relationship between avoidance of a drug-paired taste cue and the ability of the drug-paired cue to elicit withdrawal and, ultimately, drug seeking and taking. We used a rat model of drug addiction and naloxone-induced loss of body weight to test whether a taste cue elicits withdrawal in anticipation of drug availability. Experiment 1 investigated the ability of a taste cue to elicit signs of withdrawal when it predicted experimenter-administered morphine (15 mg/kg, i.p.). In Experiment 2, a saccharin taste cue was paired with the opportunity to actively self-administer cocaine (0.167 mg/infusion, i.v.). The results show that presentation of a morphine- or cocaine-paired taste cue is sufficient to elicit naloxone-induced withdrawal symptoms, and greater withdrawal predicts greater cocaine self-administration in rats.
doi:10.1016/j.bbr.2012.10.057
PMCID: PMC3538898  PMID: 23174208
Cocaine; Morphine; Withdrawal; Naloxone; Taste Cue; Reward Comparison
16.  An Antiprogestin, CDB4124, Blocks Progesterone’s Attenuation of the Negative Effects of a Mild Stress on Sexual Behavior 
Behavioural brain research  2012;240:21-25.
These experiments were designed to test the hypothesis that a progesterone receptor antagonist would block progesterone’s ability to reduce the negative effects of a 5 min restraint on female rat sexual behavior. Ovariectomized Fisher rats were injected with 10 μg estradiol benzoate. Two days later, rats were injected subcutaneously (sc) with the progesterone receptor antagonist, CDB4124 (17 α-acetoxy-21-methoxy-11β-[4-N,N-dimethyaminopheny]-19-norpregna-4,9-dione-3,20-dione) (60 mg/kg), or vehicle (20% DMSO + propylene glycol). One hr later, rats were injected sc with 500 μg progesterone or vehicle (sesame seed oil). Rats were assigned to one of three different treatment conditions: (1) (ECV) estradiol benzoate, CDB4124, sesame seed oil vehicle, (2) (ECP) estradiol benzoate, CDB4124, progesterone, and (3) (EVP) estradiol benzoate, DMSO/propylene glycol vehicle, progesterone. That afternoon sexual behavior was examined before and after a 5 min restraint experience. Before restraint, lordosis behavior was comparable across treatment conditions but only progesterone-treated rats exhibited proceptive behavior. CDB4124 did not block progesterone’s induction of proceptivity. However, after restraint, CDB4124 attenuated the positive effects of progesterone on all sexual behaviors examined. The restraint experience inhibited sexual behavior in rats treated with estradiol benzoate and CDB4124 and in rats treated with estradiol benzoate, CDB4124, and progesterone but not in rats given estradiol benzoate and progesterone without CDB4124. These findings are consistent with the hypothesis that progesterone receptors mediate progesterone’s ability to reduce the negative sexual behavioral effects of a mild stressor.
doi:10.1016/j.bbr.2012.11.002
PMCID: PMC3538906  PMID: 23153933
sexual receptivity; lordosis; ovariectomized rats; proceptivity; stress; progesterone receptors
17.  Differences in sensitivity to ethanol-induced conditioned taste aversions emerge after pre- or post-pubertal gonadectomy in male and female rats 
Behavioural brain research  2012;240:69-75.
We have previously demonstrated that gonadectomy either prior to (early) or after (late) puberty elevated ethanol consumption in males to levels similar to intact adult females—effects that were attenuated by testosterone replacement. To assess whether alterations in the aversive effects of ethanol might contribute to gonadectomy-associated increases in ethanol intake in males, the present study examined the impact of gonadectomy on conditioned taste aversions (CTA) to ethanol in male and female Sprague-Dawley rats. Animals were gonadectomized, received sham surgery (SH) or non-manipulated (NM) on postnatal (P) day 23 (early) or 67 (late) and tested for CTA to ethanol in adulthood. Water-deprived rats were given 1 hr access every-other-day to 10% sucrose followed by an injection of ethanol (0, 1 g/kg) for 5 test sessions. Test data were analyzed to determine the first day significant aversions emerged in each ethanol group (i.e., sucrose intakes significantly less than their saline-injected counterparts). Early gonadectomized males acquired the CTA more rapidly than did early SH and NM males (day 1 vs 3 and 4 respectively), whereas a gonadectomy-associated enhancement in ethanol CTA was not evident in late males. Among females, gonadectomy had little impact on ethanol-induced CTA, with females in all groups showing an aversion by the first or second day, regardless of surgery age. These data suggest that previously observed elevations in ethanol intake induced by either pre- or post-pubertal gonadectomy in males are not related simply to gonadectomy-induced alterations in the aversive effects of ethanol indexed via CTA.
doi:10.1016/j.bbr.2012.11.020
PMCID: PMC3538918  PMID: 23195111
Conditioned taste aversion; ethanol sensitivity; gonadal hormones; sex differences; puberty; rat
18.  Nicotinic agonist-induced improvement of vigilance in mice in the 5-choice continuous performance test 
Behavioural brain research  2012;240:119-133.
Impaired attentional processing is prevalent in numerous neuropsychiatric disorders and may negatively impact other cognitive and functional domains. Nicotine – a nonspecific nicotinic acetylcholine receptor (nAChR) agonist – improves vigilance in healthy subjects and schizophrenia patients as measured by continuous performance tests (CPTs), but the nAChR mediating this effect remains unclear. Here we examine the effects of: a) nicotine; b) the selective α7 nAChR agonist PNU 282987; and c) the selective α4β2 nAChR agonist ABT-418 alone and in combination with scopolamine-induced disruption of mouse 5-choice (5C-)CPT performance. This task requires the inhibition of responses to non-target stimuli as well as active responses to target stimuli, consistent with human CPTs.
C57BL/6N mice were trained to perform the 5C-CPT. Drug effects were examined in extended session and variable stimulus-duration challenges of performance. Acute drug effects on scopolamine-induced disruption in performance were also investigated.
Nicotine and ABT-418 subtly but significantly improved performance of normal mice and attenuated scopolamine-induced disruptions in the 5C-CPT. PNU 282–987 had no effects on performance.
The similarity of nicotine and ABT-418 effects provides support for an α4β2 nAChR mechanism of action for nicotine-induced improvement in attention/vigilance. Moreover, the data provide pharmacological predictive validation for the 5C-CPT because nicotine improved and scopolamine disrupted normal performance of the task, consistent with healthy humans in the CPT. Future studies using more selective agonists may result in more robust improvements in performance.
doi:10.1016/j.bbr.2012.11.028
PMCID: PMC3538919  PMID: 23201359
nicotine; continuous performance test; attention; impulsivity; nicotinic acetylcholine receptors; scopolamine
19.  Nogo-A Inhibition Induces Recovery from Neglect in Rats 
Behavioural brain research  2007;187(2):262-272.
Neglect is a complex human cognitive spatial disorder typically induced by damage to prefrontal or posterior parietal association cortices. Behavioral treatments for neglect rarely generalize outside of the therapeutic context or across tasks within the same therapeutic context. Recovery, when it occurs, is spontaneous over the course of weeks to months, but often it is incomplete. A number of studies have indicated that anti-Nogo-A antibodies can be used to enhance plasticity and behavioral recovery following damage to motor cortex, and spinal cord. In the present studies the anti-Nogo-A antibodies IN-1, 7B12, or 11C7 were applied intraventricularly to adult rats demonstrating severe neglect produced by unilateral medial agranular cortex lesions in rats. The three separate anti-Nogo-A antibody groups were treated immediately following the medial agranular cortex lesions. Each of the three antibodies induced dramatic significant behavioral recovery from neglect relative to controls. Severing the corpus callosum to destroy inputs from the contralesional hemisphere resulted in reinstatement of severe neglect, pointing to a possible role of interhemispheric mechanisms in behavioral recovery from neglect.
doi:10.1016/j.bbr.2007.09.018
PMCID: PMC3932712  PMID: 17963852
Neglect; Hemineglect; Nogo; IN-1; 7B12; 11C7; Recovery
20.  Antidepressant-like effects of curcumin in WKY rat model of depression is associated with an increase in hippocampal BDNF 
Behavioural brain research  2012;239:27-30.
Curcumin is the principal active ingredient found in turmeric (Curcuma longa), a plant used in traditional Asian diets and herbal medicines. It is known to have a wide range of biological actions including antidepressant-like effects which have been observed in stress-induced depression models. This study was designed to investigate the antidepressant potential of curcumin in a non-induced model of depression. Moreover, since brain derived neurotrophic factor (BDNF) has been implicated in antidepressant effects of many drugs, we also evaluated the effects of curcumin on BDNF in the hippocampus. Adult male Wistar Kyoto (WKY) rats, a putative model of depression, were injected acutely or chronically (10 d) with 50, 100, and 200mg/kg curcumin. Open field locomotor activity (OFLA) and forced swim test (FST), a measure of helplessness, were measured 1 hour after acute and 18–20 hours after last chronic injection. Results showed a dose-dependent reduction of immobility in the FST by curcumin in both acute and chronic studies, without any significant effect on OFLA. The effect of higher chronic curcumin dose in FST was still evident a week later. Chronic curcumin also resulted in a dose-dependent increase in hippocampal BDNF. This data provides evidence for an antidepressant-like effect of curcumin, possibly through increased neurotrophic activity, in the WKY model of depression, and support the notion that curcumin may prove an effective and lasting natural antidepressant.
doi:10.1016/j.bbr.2012.10.049
PMCID: PMC3525727  PMID: 23142609
21.  MC4-R signaling within the nucleus accumbens shell, but not the lateral hypothalamus, modulates ethanol palatability in rats 
Behavioural brain research  2012;239:51-54.
The Melanocortin (MC) system is one of the crucial neuropeptidergic systems that modulate energy balance. The roles of endogenous MC and MC-4 receptor (MC4-R) signaling within the hypothalamus in the control of homeostatic aspects of feeding are well established. Additional evidence points to a key role for the central MC system in ethanol consumption. Recently, we have shown that nucleus accumbens (NAc), but not lateral hypothalamic (LH), infusion of a selective MC4-R agonist decreases ethanol consumption. Given that MC signaling might contribute to non-homeostatic aspects of feeding within limbic circuits, we assessed here whether MC4-R signaling within the NAc and the lateral hypothalamus (LH) alters normal ingestive hedonic and/or aversive responses to ethanol in rats as measured by a taste reactivity test. Adult male Sprague-Dawley rats were given NAc- or LH- bilateral infusion of the selective MC4-R agonist cyclo (NH-CH2-CH2-CO-His-D-Phe-Arg-Trp-Glu)-NH2 (0, 0.75 or 1.5 µg/0.5µl/site) and following 30 min, the animals received 1 ml of ethanol solution (6% w/v) intraoral for 1 minute and aversive and hedonic behaviors were recorded. We found that NAc-, but not LH-administration, of a selective MC4-R agonist decreased total duration of hedonic reactions and significantly increased aversive reactions relative to saline-infused animals which support the hypothesis that MC signaling within the NAc may contribute to ethanol consumption by modulating non-homeostatic aspects (palatability) of intake.
doi:10.1016/j.bbr.2012.10.055
PMCID: PMC3525742  PMID: 23146409
ethanol; palatability; MC4 receptors; lateral hypothalamus; nucleus accumbens; taste reactivity
22.  Effects of Sodium Butyrate on Methamphetamine-Sensitized Locomotor Activity 
Behavioural brain research  2012;239:139-147.
Neuroadaptations associated with behavioral sensitization induced by repeated exposure to methamphetamine (MA) appear to be involved in compulsive drug pursuit and use. Increased histone acetylation, an epigenetic effect resulting in altered gene expression, may promote sensitized responses to psychostimulants. The role of histone acetylation in the expression and acquisition of MA-induced locomotor sensitization was examined by measuring the effect of histone deacetylase inhibition by sodium butyrate (NaB). For the effect on expression, vehicle or NaB (630 mg/kg, intraperitoneally) was administered 30 min prior to MA challenge in mice treated repeatedly with MA (10 days of 2 mg/kg MA) or saline (10 days), and then locomotor response to MA challenge was measured. NaB treatment increased the locomotor response to MA in both acutely MA treated and sensitized animals. For acquisition, NaB was administered 30 min prior to each MA exposure (10 days of 1 or 2 mg/kg), but not prior to the MA challenge test. Treatment with NaB during the sensitization acquisition period significantly increased locomotor activation by MA in sensitized mice only. NaB alone did not significantly alter locomotor activity. Acute NaB or MA, but not the combination, appeared to increase striatal acetylation at histone H4. Repeated treatment with MA, but not NaB or MA plus NaB, increased striatal acetylation at histone H3. Although increased histone acetylation may alter the expression of genes involved in acute locomotor response to MA and in the acquisition of MA-induced sensitization, results for acetylation at H3 and H4 showed little correspondence with behavior.
doi:10.1016/j.bbr.2012.10.046
PMCID: PMC3546510  PMID: 23137698
sensitization; psychostimulant; histone acetylation; epigenetics; addiction
23.  Daily treadmill exercise attenuates cocaine cue-induced reinstatement and cocaine induced locomotor response but increases cocaine-primed reinstatement 
Behavioural brain research  2012;239:8-14.
Exercise affects neuroplasticity and neurotransmission including dopamine (DA), which modulates drug-taking behavior. Previous research in rodents has shown that exercise may attenuate the rewarding effects of drugs of abuse. The present study examined the effects of high and low exercise on cocaine responses in male Wistar rats that had been trained to self-administer and were compared to a group of sedentary rats. High exercise rats (HE) ran daily on a treadmill for 2 h and low exercise (LE) ran daily for 1 h. After 6 weeks of this exercise regimen, rats were tested over 2 days for reinstatement (day 1: cue-induced reinstatement; day 2: cocaine-primed reinstatement). During cue-induced reinstatement, the sedentary rats showed the expected increase in active lever responses when compared to maintenance, whereas these increased responses were inhibited in the exercised rats (HE and LE). During cocaine-primed reinstatement, however, there was a significant increase in active lever presses when compared to maintenance only in the HE group. This data suggests that chronic exercise during abstinence attenuates the cue-induced reinstatement seen in the sedentary rats by 26% (LE) and 21% (HE). In contrast, only the high exercise rats exhibited sensitized cocaine-seeking behavior (active lever presses) following cocaine-primed reinstatement. Finally, while sedentary rats increased locomotor activity during cocaine-primed reinstatement over that seen with cocaine during maintenance, this was not observed in the exercised rats, suggesting that exercise may interfere with the sensitized locomotor response during cocaine reinstatement.
doi:10.1016/j.bbr.2012.10.035
PMCID: PMC3596018  PMID: 23103403
Dopamine; Exercise; Cocaine; Self-administration; Relapse; Abstinence
24.  Working memory for temporal order is impaired after selective neonatal hippocampal lesions in adult rhesus macaques 
Behavioural brain research  2012;239:55-62.
A previous study in this laboratory demonstrated, for the first time, that neonatal lesions of the hippocampus impair monitoring working memory, as measured by a self-order task, but spare recency memory, as measured by the session-unique delayed nonmatching task. To substantiate and extend this novel finding, we assessed working memory in these same animals using a serial order memory task. In humans and non-human primates the serial order memory task has been shown to be dependent upon the integrity of the dorsolateral prefrontal cortex. Additionally, the serial order task has the ability to examine the integrity of non-dorsolateral dependent working memory functions, providing specificity to conclusions drawn from this task. Thus, monkeys with neonatal lesions of the hippocampus and sham-operated control subjects were tested on two versions of the serial order memory task (3 and 4 object). The results of this study demonstrated that neonatal hippocampal lesions did not impair performance on the 3-object version of the task, confirming our previous finding of intact non-dlPFC dependent working memory. In contrast, these same animals showed a significant impairment on the dlPFC dependent phase of the 4-object serial order task. This finding was further confirmed through a series of probe trials. These results, in combination with our earlier finding, suggest that early lesions of the hippocampus may have impacted the function of the dlPFC or its interactions with the hippocampus.
doi:10.1016/j.bbr.2012.10.043
PMCID: PMC3804023  PMID: 23137699
dlPFC; schizophrenia; hippocampus; monkey
25.  Levo-Tetrahydropalmatine Decreases Ethanol Drinking and Antagonizes Dopamine D2 Receptor-Mediated Signaling in the Mouse Dorsal Striatum 
Behavioural brain research  2013;244:58-65.
An herb derived compound, levo-tetrahydropalmatine (L-THP), attenuates self-administration of cocaine and opiates in rodents. Since L-THP mainly antagonizes dopamine D2 receptors (D2R) in the brain, it is likely to regulate other addictive behaviors as well. Here, we examined whether L-THP regulates ethanol drinking in C57BL/6J mice using a two-bottle choice drinking experiment. L-THP treated mice consumed less ethanol compared to vehicle-treated mice during the 15% ethanol drinking session while water consumption remained similar between each group. We then examined the molecular basis underlying the pharmacological effect of L-THP in mice. Our results indicated that a single injection L-THP increased active phosphorylated forms of PKA, AKT and ERK in the caudate-putamen (CPu), but not in the nucleus accumbens (NAc), of alcohol naïve mice. Interestingly, we found that systematic treatment with L-THP for 4 consecutive days while mice were drinking 15% ethanol increased pPKA levels in the CPu, but not in the NAc. In contrast to the effect of acute L-THP treatment, no differences were detected for pAKT or pERK in either striatal regions. Together, our findings suggest that reduction of ethanol drinking by L-THP treatment is possibly correlated with D2R-mediated PKA signaling in the CPu.
doi:10.1016/j.bbr.2013.01.028
PMCID: PMC3922614  PMID: 23376703
L-THP; ethanol drinking; dopamine D2 receptor; striatum

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