Neurobiology of Mice Selected for High Voluntary Wheel-running Activity

Selective breeding of house mice has been used to study theevolution of locomotor behavior. Our model consists of 4 replicatelines selectively bred for high voluntary wheel running (High-Runner)and 4 bred randomly (Control). The major changes in High-Runnerlines appear to have taken place in the brain rather than incapacities for exercise. Their neurobiological profile resemblesfeatures of human Attention Deficit Hyperactivity Disorder (ADHD)and is also consistent with high motivation for exercise asa natural reward. Both ADHD and motivation for natural rewards(such as food and sex), as well as drugs of abuse, have beenassociated with alterations in function of the neuromodulatordopamine, and High-Runner mice respond differently to dopaminedrugs. In particular, drugs that block the dopamine transporterprotein (such as Ritalin and cocaine) reduce the high-intensityrunning of High-Runner mice but have little effect on Controlmice. In preliminary studies of mice exercised on a treadmill,brain dopamine concentrations did not differ, suggesting thatchanges in the dopamine system may have occurred downstreamof dopamine production (e.g., receptor expression or transduction).Brain imaging by immunohistochemical detection of c-Fos identifiedseveral key regions (prefrontal cortex, nucleus accumbens, caudate-putamen,lateral hypothalamus) that appear to play a role in the differentialresponse to Ritalin and in the increased motivation for runningin High-Runner mice. The activation of other brain regions,such as the hippocampus, was closely associated with wheel runningitself. Chronic wheel running (several weeks) also increasedthe production of new neurons to apparently maximal levels inthe hippocampus, but impaired learning in High-Runner mice.We discuss the biomedical implications of these findings.     

Evolution of hindlimb bone dimensions and muscle masses in house mice selectively bred for high voluntary wheel‐running behavior

We have used selective breeding with house mice to study coadaptation of morphology and physiology with the evolution of high daily levels of voluntary exercise. Here, we compared hindlimb bones and muscle masses from the 11th generation of four replicate High Runner (HR) lines of house mice bred for high levels of voluntary wheel running with four non‐selected control (C) lines. Mass, length, diameter, and depth of the femur, tibia‐fibula, and metatarsal bones, as well as masses of gastrocnemius and quadriceps muscles, were compared by analysis of covariance with body mass or body length as the covariate. Mice from HR lines had relatively wider distal femora and deeper proximal tibiae, suggesting larger knee surface areas, and larger femoral heads. Sex differences in bone dimensions were also evident, with males having thicker and shorter hindlimb bones when compared with females. Several interactions between sex, linetype, and/or body mass were observed, and analyses split by sex revealed several cases of sex‐specific responses to selection. A subset of the HR mice in two of the four HR lines expressed the mini‐muscle phenotype, characterized mainly by an ～50% reduction in hindlimb muscle mass, caused by a Mendelian recessive mutation, and known to have been under positive selection in the HR lines. Mini‐muscle individuals had elongated distal elements, lighter and thinner hindlimb bones, altered 3rd trochanter muscle insertion positions, and thicker tibia‐fibula distal widths. Finally, several differences in levels of directional or fluctuating asymmetry in bone dimensions were observed between HR and C, mini‐ and normal‐muscled mice, and the sexes. This study demonstrates that skeletal dimensions and muscle masses can evolve rapidly in response to directional selection on locomotor behavior.     

Shape‐shift: Semicircular canal morphology responds to selective breeding for increased locomotor activity

Variation in semicircular canal morphology correlates with locomotor agility among species of mammals. An experimental evolutionary mouse model was used to test the hypotheses that semicircular canal morphology (1) evolves in response to selective breeding for increased locomotor activity, (2) exhibits phenotypic plasticity in response to early‐onset chronic exercise, and (3) is unique in individuals possessing the minimuscle phenotype. We examined responses in canal morphology to prolonged wheel access and selection in laboratory mice from four replicate lines bred for high voluntary wheel‐running (HR) and four nonselected control (C) lines. Linear measurements and a suite of 3D landmarks were obtained from 3D reconstructions of μCT‐scanned mouse crania (μCT is microcomputed tomography). Body mass was smaller in HR than C mice and was a significant predictor of both radius of curvature and 3D canal shape. Controlling for body mass, radius of curvature did not differ statistically between HR and C mice, but semicircular canal shape did. Neither chronic wheel access nor minimuscle affected radius of curvature or canal shape These findings suggest that semicircular canal morphology is responsive to evolutionary changes in locomotor behavior, but the pattern of response is potentially different in small‐ versus large‐bodied species.     

Baseline and stress-induced plasma corticosterone concentrations of mice selectively bred for high voluntary wheel running

The hypothalamic-pituitary-adrenal (HPA) axis is important in regulating energy metabolism and in mediating responses to stressors, including increasing energy availability during physical exercise. In addition, glucocorticoids act directly on the central nervous system and influence behavior, including locomotor activity. To explore potential changes in the HPA axis as animals evolve higher voluntary activity levels, we characterized plasma corticosterone (CORT) concentrations and adrenal mass in four replicate lines of house mice that had been selectively bred for high voluntary wheel running (HR lines) for 34 generations and in four nonselected control (C) lines. We determined CORT concentrations under baseline conditions and immediately after exposure to a novel stressor (40 min of physical restraint) in mice that were housed without access to wheels. Resting daytime CORT concentrations were approximately twice as high in HR as in C mice for both sexes. Physical restraint increased CORT to similar concentrations in HR and C mice; consequently, the proportional response to restraint was smaller in HR than in C animals. Adrenal mass did not significantly differ between HR and C mice. Females had significantly higher baseline and postrestraint CORT concentrations and significantly larger adrenal glands than males in both HR and C lines. Replicate lines showed significant variation in body mass, length, baseline CORT concentrations, and postrestraint CORT concentrations in one or both sexes. Among lines, both body mass and length were significantly negatively correlated with baseline CORT concentrations, suggesting that CORT suppresses growth. Our results suggest that selection for increased locomotor activity has caused correlated changes in the HPA axis, resulting in higher baseline CORT concentrations and, possibly, reduced stress responsiveness and a lower growth rate.     

Voluntary Exercise and Its Effects on Body Composition Depend on Genetic Selection History

Little is known about how genetic variation affects the capacity for exercise to change body composition. We examined the extent to which voluntary exercise alters body composition in several lines of selectively bred mice compared to controls. Lines studied included high runner (HR) (selected for high wheel running), M16 (selected for rapid weight gain), Institute of Cancer Research (ICR) (randomly bred as control for M16), M16i (an inbred line derived from M16), HE (selected for high percentage of body fat while holding body weight constant), LF (selected for low percentage of body fat), C57BL/6J (common inbred line), and the F1 between HR and C57BL/6J. Body weight and body fat were recorded before and after 6 days of free access to running wheels in males and females that were individually caged. Total food intake was measured during this 6‐day period. All pre‐ and postexercise measures showed significant strain effects. While HR mice predictably exercised at higher levels, all other selection lines had decreased levels of wheel running relative to ICR. The HR × B6 F1 ran at similar levels to HR demonstrating complete dominance for voluntary exercise. Also, all strains lost body fat after exercise, but the relationships between exercise and changes in percent body were not uniform across genotypes. These results indicate that there is significant genetic variation for voluntary exercise and its effects on body composition. It is important to carefully consider genetic background and/or selection history when using mice to model effects of exercise on body composition, and perhaps, other complex traits as well.     

Effects of early‐life exposure to Western diet and wheel access on metabolic syndrome profiles in mice bred for high voluntary exercise

Experimental studies manipulating diet and exercise have shown varying effects on metabolic syndrome components in both humans and rodents. To examine the potential interactive effects of diet, exercise and genetic background, we studied mice from four replicate lines bred (52 generations) for high voluntary wheel running (HR lines) and four unselected control lines (C). At weaning, animals were housed for 60 days with or without wheels and fed either a standard chow or Western diet (WD, 42% kcal from fat). Four serial (three juvenile and one adult) blood samples were taken to measure fasting total cholesterol (TC), high‐density lipoprotein cholesterol (HDL‐C), triglycerides and glucose. Western diet was obesogenic for all mice, even after accounting for the amount of wheel running and kilojoules consumed. Western diet significantly raised glucose as well as TC and HDL‐C concentrations. At the level of individual variation (repeatability), there was a modest correlation (r = 0.3–0.5) of blood lipids over time, which was reduced with wheel access and/or WD. Neither genetic selection history nor wheel access had a statistically significant effect on blood lipids. However, HR and C mice had divergent ontogenetic trajectories for body mass and caloric intake. HR mice also had lower adiposity, an effect that was dependent on wheel access. The environmental factors of diet and wheel access had pronounced effects on body mass, food consumption and fasting glucose concentrations, interacting with each other and/or with genetic strain. These data underscore the importance (and often unpredictable nature) of genotype‐by‐environment and environment‐by‐environment interactions when studying body weight regulation.     

How to run far: multiple solutions and sex-specific responses to selective breeding for high voluntary activity levels

The response to uniform selection may occur in alternate ways that result in similar performance. We tested for multiple adaptive solutions during artificial selection for high voluntary wheel running in laboratory mice. At generation 43, the four replicate high runner (HR) lines averaged 2.85-fold more revolutions per day as compared with four non-selected control (C) lines, and females ran 1.11-fold more than males, with no sex-by-linetype interaction. Analysis of variance indicated significant differences among C lines but not among HR for revolutions per day. By contrast, average speed varied significantly among HR lines, but not among C, and showed a sex-by-linetype interaction, with the HR/C ratio being 2.02 for males and 2.45 for females. Time spent running varied among both HR and C lines, and showed a sex-by-linetype interaction, with the HR/C ratio being 1.52 for males but only 1.17 for females. Thus, females (speed) and males (speed, but also time) evolved differently, as did the replicate selected lines. Speed and time showed a trade-off among HR but not among C lines. These results demonstrate that uniform selection on a complex trait can cause consistent responses in the trait under direct selection while promoting divergence in the lower-level components of that trait.     

不同背景的同伴强化及催产素处理对雌性棕色田鼠可卡因条件位置偏爱的影响

同伴间的社会互作是一种天然奖赏,能够影响成瘾药物使用的敏感性。催产素（Oxytocin,OT)能够调节社会行为,并提高社会互作的奖赏价值。然而不同背景的同伴互作以及与OT合并使用是否对可卡因的奖赏效应有不同的影响尚不清楚。棕色田鼠(Microtus mandarinus)是一种单配制田鼠,个体间具有较复杂的社会行为。利用雌性棕色田鼠,我们首先检测了可卡因(20 mg/kg)单独强化以及与不同背景关系的同伴（熟性雌性、陌生雌性和陌生雄性）同时强化诱导的条件位置偏爱（conditioned place preference, CPP）及持续时间;其次检测了实验鼠外周注射OT (1 mg /kg)并给予不同背景同伴强化对可卡因CPP的影响。结果表明,可卡因单独强化时,实验鼠能够形成可卡因CPP并能持续至3周;用熟悉的雌性同伴强化时,实验鼠对可卡因CPP的维持时间缩短;用陌生的雌性或雄性同伴强化时可抑制可卡因CPP的形成。实验鼠注射OT后,用熟悉雌性或陌生雄性同伴分别强化时会抑制或反转可卡因CPP。这些结果表明不同背景关系的同伴强化对可卡因奖赏效应的影响不同。OT可促进同伴强化的奖赏价值,降低动物对可卡因的偏爱,且该效应因强化同伴的背景而不同。     

Mechanisms of Metabonomic for a Gateway Drug: Nicotine Priming Enhances Behavioral Response to Cocaine with Modification in Energy Metabolism and Neurotransmitter Level

Nicotine, one of the most commonly used drugs, has become a major concern because tobacco serves as a gateway drug and is linked to illicit drug abuse, such as cocaine and marijuana. However, previous studies mainly focused on certain genes or neurotransmitters which have already been known to participate in drug addiction, lacking endogenous metabolic profiling in a global view. To further explore the mechanism by which nicotine modifies the response to cocaine, we developed two conditioned place preference (CPP) models in mice. In threshold dose model, mice were pretreated with nicotine, followed by cocaine treatment at the dose of 2 mg/kg, a threshold dose of cocaine to induce CPP in mice. In high-dose model, mice were only treated with 20 mg/kg cocaine, which induced a significant CPP. ¹H nuclear magnetic resonance based on metabonomics was used to investigate metabolic profiles of the nucleus accumbens (NAc) and striatum. We found that nicotine pretreatment dramatically increased CPP induced by 2 mg/kg cocaine, which was similar to 20 mg/kg cocaine-induced CPP. Interestingly, metabolic profiles showed considerable overlap between these two models. These overlapped metabolites mainly included neurotransmitters as well as the molecules participating in energy homeostasis and cellular metabolism. Our results show that the reinforcing effect of nicotine on behavioral response to cocaine may attribute to the modification of some specific metabolites in NAc and striatum, thus creating a favorable metabolic environment for enhancing conditioned rewarding effect of cocaine. Our findings provide an insight into the effect of cigarette smoking on cocaine dependence and the underlying mechanism.     

Cdh13 and AdipoQ gene knockout alter instrumental and Pavlovian drug conditioning

Genome‐wide association studies in humans have suggested that variants of the cadherin‐13 (CDH13) gene are associated with substance use disorder, subjective response to amphetamine, and attention deficit hyperactivity disorder. To examine the role of the Cdh13 and its peptide ligand adiponectin (AdipoQ) in addiction‐related behaviors, we assessed Cdh13 knockout (KO) rats and AdipoQ KO mice using intravenous cocaine self‐administration and conditioned place preference (CPP) paradigms. During intravenous cocaine self‐administration, male Cdh13 heterozygous (+/?) and KO (?/?) rats showed increased cue‐induced reinstatement compared with wild‐type (WT) rats when presented with a cocaine‐paired stimulus, whereas female Cdh13 rats showed no differences across genotype. Cdh13 ?/? rats showed higher responding for a saccharin reinforcer and learned the choice reaction time (RT) task more slowly than WTs. However, we found no differences between Cdh13 ?/? and +/+ rats in responding for sensory reinforcement, number of premature responses in the RT task, tendency to approach a Pavlovian food cue, CPP and locomotor activation to cocaine (10 or 20 mg/kg). In AdipoQ ?/? mice, there was a significant increase in CPP to methamphetamine (1 mg/kg) but not to a range of d‐amphetamine doses (0.5, 1, 2 and 4 mg/kg). Taken together, these data suggest that Cdh13 and AdipoQ regulate sensitivity to psychomotor stimulants and palatable rewards without producing major changes in other behaviors. In humans, these two genes may regulate sensitivity to natural and drug rewards, thus influencing susceptibility to the conditioned drug effects and relapse.     

Repeated Cocaine Exposure Facilitates the Expression of Incentive Motivation and Induces Habitual Control in Rats

There is growing evidence that mere exposure to drugs can induce long-term alterations in the neural systems that mediate reward processing, motivation, and behavioral control, potentially causing the pathological pursuit of drugs that characterizes the addicted state. The incentive sensitization theory proposes that drug exposure potentiates the influence of reward-paired cues on behavior. It has also been suggested that drug exposure biases action selection towards the automatic execution of habits and away from more deliberate goal-directed control. The current study investigated whether rats given repeated exposure to peripherally administered cocaine would show alterations in incentive motivation (assayed using the Pavlovian-to-instrumental transfer (PIT) paradigm) or habit formation (assayed using sensitivity to reward devaluation). After instrumental and Pavlovian training for food pellet rewards, rats were given 6 daily injections of cocaine (15 mg/kg, IP) or saline, followed by a 10-d period of rest. Consistent with the incentive sensitization theory, cocaine-treated rats showed stronger cue-evoked lever pressing than saline-treated rats during the PIT test. The same rats were then trained on a new instrumental action with a new food pellet reward before undergoing a reward devaluation testing. Although saline-treated rats exhibited sensitivity to reward devaluation, indicative of goal-directed performance, cocaine-treated rats were insensitive to this treatment, suggesting a reliance on habitual processes. These findings, when taken together, indicate that repeated exposure to cocaine can cause broad alterations in behavioral control, spanning both motivational and action selection processes, and could therefore help explain aberrations of decision-making that underlie drug addiction.     

Little and often? Maintaining continued performance in an automated T-maze for mice

Operant and maze tasks in mice are limited by the small number of trials possible in a session before mice lose motivation. We hypothesized that by manipulating reward size and session length, motivation, and hence performance, would be maintained in an automated T-maze. We predicted that larger rewards and shorter sessions would improve acquisition; and smaller rewards and shorter sessions would maintain higher and less variable performance. Eighteen C57BL/6J mice (9 per sex) acquired (criterion 8/10 correct) and performed a spatial discrimination, with one of 3 reward sizes (.02, .04, or .08 g) and one of 3 session schedules (15, 30, or 45 min sessions). Each mouse had a total of 360 min of access to the maze per night, for two nights, and averaged 190 trials. Analysis used split-plot GLM with contrasts testing for linear effects. Acquisition of the discrimination was unaffected by reward size or session length/interval. After-criterion average performance improved as reward size decreased. After-criterion variability in performance was also affected. Variability increased as reward size increased. Session length/interval did not affect any outcome. We conclude that an automated maze, with suitable reward sizes, can sustain performance with low variability, at 5-10 times faster than traditional methods.     

Genetic variations and physical activity as determinants of limb bone morphology: an experimental approach using a mouse model

To gain insight into past human physical activity, anthropologists often infer functional loading history from the morphology of limb bone remains. It is assumed that, during life, loading had a positive, dose-dependent effect on bone structure that can be identified despite other effects. Here, we investigate the effects of genetic background and functional loading on limb bones using mice from an artificial selection experiment for high levels of voluntary wheel running. Growing males from four replicate high runner (HR) lines and four replicate nonselected control (C) lines were either allowed or denied wheel access for 2 months. Using μCT, femoral morphology was assessed at two cortical sites (mid-diaphysis, distal metaphysis) and one trabecular site (distal metaphysis). We found that genetic differences between the linetypes (HR vs. C), between the replicate lines within linetype, and between individuals with and without the so-called "mini-muscle" phenotype (caused by a Mendelian recessive gene that halves limb muscle mass) gave rise to significant variation in nearly all morphological indices examined. Wheel access also influenced femoral morphology, although the functional response did not generally result in enhanced structure. Exercise caused moderate periosteal enlargement, but relatively greater endocortical expansion, resulting in significantly thinner cortices and reduced bone area in the metaphysis. The magnitude of the response was independent of distance run. Mid-diaphyseal bone area and area moments, and trabecular morphology, were unaffected by exercise. These results underscore the strong influence of genetics on bone structure and the complexity by which mechanical stimuli may cause alterations in it.     

伏隔核壳部巴氯芬灌注阻断吗啡成瘾小鼠条件位置性偏爱记忆再巩固

氨基丁酸B型受体(GABAB受体)是治疗药物成瘾的潜在靶点,伏隔核壳部(nucleus accumbens shell, AcbSh)是成瘾环路的关键节点,但AcbSh GABA_B受体与记忆再巩固的关系尚不清楚。本文旨在探讨AcbSh微量灌注GABA_B受体激动剂巴氯芬(baclofen, BLF)对吗啡奖赏记忆再巩固及复吸行为的影响。建立吗啡条件位置性偏爱(conditioned place preference, CPP)小鼠模型,采用吗啡奖赏记忆提取激活实验,对比观察环境线索激活吗啡奖赏记忆后,双侧AcbSh灌注BLF对吗啡CPP、吗啡激发CPP重建以及自主活动量的影响。结果表明,吗啡奖赏记忆激活后,Acb Sh单次注入0.06nmol/0.2μL/侧或0.12nmol/0.2μL/侧BLF显著抑制吗啡CPP,且吗啡激发不能重建CPP,而0.01nmol/0.2μL/侧BLF灌注不能抑制吗啡CPP。激活后注入生理盐水及未激活组BLF灌注均未抑制CPP。无论是否激活吗啡奖赏记忆,BLF注入AcbSh都不影响小鼠自主活动。以上结果提示,AcbSh GABA_B受体参与了吗啡CPP的记忆再巩固。记忆激活后激动AcbSh GABA_B受体可通过阻断吗啡CPP的记忆再巩固,消除奖赏记忆,抑制复吸行为。     

Methylphenidate and cocaine have a similar in vivo potency to block dopamine transporters in the human brain.

The reinforcing effects of cocaine and methylphenidate have been linked to their ability to block dopamine transporters (DAT). Though cocaine and methylphenidate have similar in vitro affinities for DAT the abuse of methylphenidate in humans is substantially lower than of cocaine. To test if differences in in vivo potency at the DAT between these two drugs could account for the differences in their abuse liability we compared the levels of DAT occupancies that we had previously reported separately for intravenous methylphenidate in controls and for intravenous cocaine in cocaine abusers. DAT occupancies were measured with Positron Emission Tomography using [11C]cocaine, as a DAT ligand, in 8 normal controls for the methylphenidate study and in 17 active cocaine abusers for the cocaine study. The ratio of the distribution volume of [11C]cocaine in striatum to that in cerebellum, which corresponds to Bmax/Kd +1, was used as measure of DAT availability. Parallel measures were obtained to assess the cardiovascular effects of these two drugs. Methylphenidate and cocaine produced comparable dose-dependent blockade of DAT with an estimated ED50 (dose required to block 50% of the DAT) for methylphenidate of 0.07 mg/kg and for cocaine of 0.13 mg/kg. Both drugs induced similar increases in heart rate and blood pressure but the duration of the effects were significantly longer for methylphenidate than for cocaine. The similar in vivo potencies at the DAT for methylphenidate than for cocaine are in agreement with their reported relative in vitro affinities (Ki 390 nM and 640 nM respectively), which is likely to reflect the similar degree of uptake (8-10% of the injected dose) and regional distribution of these two drugs in the human brain. Thus, differences in the in vivo potency of these two drugs at the DAT cannot be responsible for the differences in their rate of abuse in humans. Other variables i.e. longer duration of methylphenidate's side effects may counterbalance its reinforcing effects.     

Ghrelin knockout mice show decreased voluntary alcohol consumption and reduced ethanol-induced conditioned place preference

Recent work suggests that stomach-derived hormone ghrelin receptor (GHS-R1A) antagonism may reduce motivational aspects of ethanol intake. In the current study we hypothesized that the endogenous GHS-R1A agonist ghrelin modulates alcohol reward mechanisms. For this purpose ethanol-induced conditioned place preference (CPP), ethanol-induced locomotor stimulation and voluntary ethanol consumption in a two-bottle choice drinking paradigm were examined under conditions where ghrelin and its receptor were blocked, either using ghrelin knockout (KO) mice or the specific ghrelin receptor (GHS-R1A) antagonist “JMV2959”. We showed that ghrelin KO mice displayed lower ethanol-induced CPP than their wild-type (WT) littermates. Consistently, when injected during CPP-acquisition, JMV2959 reduced CPP-expression in C57BL/6 mice. In addition, ethanol-induced locomotor stimulation was lower in ghrelin KO mice. Moreover, GHS-R1A blockade, using JMV2959, reduced alcohol-stimulated locomotion only in WT but not in ghrelin KO mice. When alcohol consumption and preference were assessed using the two-bottle choice test, both genetic deletion of ghrelin and pharmacological antagonism of the GHS-R1A (JMV2959) reduced voluntary alcohol consumption and preference. Finally, JMV2959-induced reduction of alcohol intake was only observed in WT but not in ghrelin KO mice. Taken together, these results suggest that ghrelin neurotransmission is necessary for the stimulatory effect of ethanol to occur, whereas lack of ghrelin leads to changes that reduce the voluntary intake as well as conditioned reward by ethanol. Our findings reveal a major, novel role for ghrelin in mediating ethanol behavior, and add to growing evidence that ghrelin is a key mediator of the effects of multiple abused drugs.     

Shift of circadian feeding pattern by high-fat diets is coincident with reward deficits in obese mice

Recent studies provide evidence that high-fat diets (HF) trigger both i) a deficit of reward responses linked to a decrease of mesolimbic dopaminergic activity, and ii) a disorganization of circadian feeding behavior that switch from a structured meal-based schedule to a continuous snacking, even during periods normally devoted to rest. This feeding pattern has been shown to be a cause of HF-induced overweight and obesity. Our hypothesis deals with the eventual link between the rewarding properties of food and the circadian distribution of meals. We have investigated the effect of circadian feeding pattern on reward circuits by means of the conditioned-place preference (CPP) paradigm and we have characterized the rewarding properties of natural (food) and artificial (cocaine) reinforcers both in free-feeding ad libitum HF mice and in HF animals submitted to a re-organized feeding schedule based on the standard feeding behavior displayed by mice feeding normal chow ("forced synchronization"). We demonstrate that i) ad libitum HF diet attenuates cocaine and food reward in the CPP protocol, and ii) forced synchronization of feeding prevents this reward deficit. Our study provides further evidence that the rewarding impact of food with low palatability is diminished in mice exposed to a high-fat diet and strongly suggest that the decreased sensitivity to chow as a positive reinforcer triggers a disorganized feeding pattern which might account for metabolic disorders leading to obesity.     

Attribution and Expression of Incentive Salience Are Differentially Signaled by Ultrasonic Vocalizations in Rats

During Pavlovian incentive learning, the affective properties of rewards are thought to be transferred to their predicting cues. However, how rewards are represented emotionally in animals is widely unknown. This study sought to determine whether 50-kHz ultrasonic vocalizations (USVs) in rats may signal such a state of incentive motivation to natural, nutritional rewards. To this end, rats learned to anticipate food rewards and, across experiments, the current physiological state (deprived vs. sated), the type of learning mechanism recruited (Pavlovian vs. instrumental), the hedonic properties of UCS (low vs. high palatable food), and the availability of food reward (continued vs. discontinued) were manipulated. Overall, we found that reward-cues elicited 50-kHz calls as they were signaling a putative affective state indicative of incentive motivation in the rat. Attribution and expression of incentive salience, however, seemed not to be an unified process, and could be teased apart in two different ways: 1) under high motivational state (i.e., hunger), the attribution of incentive salience to cues occurred without being expressed at the USVs level, if reward expectations were higher than the outcome; 2) in all experiments when food rewards were devalued by satiation, reward cues were still able to elicit USVs and conditioned anticipatory activity although reward seeking and consumption were drastically weakened. Our results suggest that rats are capable of representing rewards emotionally beyond apparent, immediate physiological demands. These findings may have translational potential in uncovering mechanisms underlying aberrant and persistent motivation as observed in drug addiction, gambling, and eating disorders.     

Neuropeptide FF (NPFF) reduces the expression of cocaine-induced conditioned place preference and cocaine-induced sensitization in animals

The endogenous brain opioid system is believed to play an important role in mediating reward mechanisms. Opioid innervation is high in many limbic regions and reinforcing actions of many drugs of abuse, including cocaine, are thought to be mediated via endogenous opioid system. The aim of the present study was to indicate whether the anti-opioid peptide, neuropeptide FF (NPFF; FLFQPQRF-NH₂) was able to modify the rewarding effect of cocaine (5 mg/kg) measured in the expression of conditioned place preference (CPP) test in rats and the expression of sensitization to hyperlocomotor effect of cocaine (10 mg/kg) in mice. Our results indicate that NPFF (5, 10, and 20 nmol) given intracerebroventricularly (i.c.v.) inhibited the expression of cocaine-induced CPP at the dose of 10 nmol (P < 0.01) and 20 nmol (P < 0.001). Moreover, NPFF inhibited the expression of cocaine-induced sensitization to its hyperlocomotor effect at the dose of 20 nmol (P < 0.05) and acute hyperlocomotor effect of cocaine at doses of 5 nmol (P < 0.01), 10 nmol (P < 0.01), and 20 nmol (P < 0.05). Our study suggests that NPFF may participate in a rewarding effect of cocaine measured in the CPP paradigm. On the other hand, our experiments indicate that NPFF is involved in the mechanism of expression of sensitization to cocaine hyperlocomotion but this effect seems to be non-specific because NPFF also inhibited the acute hyperlocomotor effect of cocaine.