The reinforcing property and the rewarding aftereffect of wheel running in rats: a combination of two paradigms

Wheel running reinforces the behavior that generates it and produces a preference for the context that follows it. The goal of the present study was to demonstrate both of these effects in the same animals. Twelve male Wistar rats were first exposed to a fixed-interval 30 s schedule of wheel-running reinforcement. The operant was lever-pressing and the reinforcer was the opportunity to run for 45 s. Following this phase, the method of place conditioning was used to test for a rewarding aftereffect following operant sessions. On alternating days, half the rats responded for wheel-running reinforcement while the other half remained in their home cage. Upon completion of the wheel-running reinforcement sessions, rats that ran and rats that remained in their home cages were placed into a chamber of a conditioned place preference (CPP) apparatus for 30 min. Each animal received six pairings of a distinctive context with wheel running and six pairings of a different context with their home cage. On the test day, animals were free to move between the chambers for 10 min. Results showed a conditioned place preference for the context associated with wheel running; however, time spent in the context associated with running was not related to wheel-running rate, lever-pressing rate, or post-reinforcement pause duration.     

Augmented cocaine conditioned place preference in rats pretreated with systemic ghrelin

The physiological mechanism through which food restriction (FR) enhances the biobehavioral actions of psychostimulants is unknown but may involve the gut peptide ghrelin. Plasma levels of ghrelin are increased by FR and reduced by eating. Moreover, systemically administered ghrelin crosses into the brain and is known to augment the locomotor-stimulating effects of cocaine [COC: Wellman et al., 2005]. This study sought to determine whether pretreatment with ghrelin (5 nmol) would enhance the rewarding properties of COC (0.0, 0.312, 0.625, or 1.25 mg/kg i.p.) as measured by conditioned place preference (CPP). Adult male Sprague–Dawley rats were given free access to both sides of a CPP chamber to determine initial side preference. The rats were then confined for 30 min to either their preferred side or non-preferred side on 8 consecutive days. When rats were confined to the least preferred side, each was injected with 0.5 ml (i.p.) of either ghrelin (5 nmol) or saline 1 h before the conditioning trial and then injected (i.p.) with one of the COC doses immediately prior to the conditioning trial. On alternate days, rats were injected with vehicle one hour before and again immediately before the conditioning trial. Place preference scores were computed as the differences in time (min) spent on the least preferred side of the chamber for the pre-test and the postconditioning test, covaried by the initial degree of preference (% time spent on the black side during the pre-test). These analyses indicated a significant interaction between ghrelin pretreatment and COC dose on changes in preference scores. Significantly higher place preference scores were noted for rats treated with either 0.312 or 0.625 mg/kg COC doses, but only when these COC doses were preceded by administration of 5 nmol ghrelin. In contrast, saline pretreated rats exhibited significant CPP at the 1.25 mg/kg COC dose, but the ghrelin pretreated group did not. These results provide partial support for the contention that ghrelin pretreatment can augment the rewarding effects of sub-threshold doses of COC in a CPP procedure. Moreover, these findings are consistent with the view that ghrelin may play a role in the capacity of FR to augment psychostimulant action.     

Vasopressin deficiency and circadian rhythms during food-restriction stress

Vasopressin-containing, Long-Evans (LE) rats and vasopressin-deficient, Brattleboro (DI) rats were monitored for activity and core body temperature via telemetry. Rats were exposed to a 12-12 light-dark cycle and allowed to habituate with ad lib access to food and water. The habituation period was followed by an experimental period of 23 h of food-restriction stress in which a 1-h feeding period was provided during the light cycle. Although both strains of animals showed nocturnal activity and temperature rhythms during the habituation period, DI rats were more active than LE rats. The DI rats also had a lower body temperature in the dark. During the experimental period, both strains exhibited a phase shift of activity and body temperature correlating with the presentation of food. The DI rats developed a diurnal shift more rapidly than LE rats. The DI animals showed a dramatic increase in activity during the light phase and a marked decrease in body temperature during the dark phase. The LE animals showed a significant attenuation of activity, but maintained both nocturnal and diurnal temperature peaks throughout the food-restricted condition.     

A Procedure to Study the Effect of Prolonged Food Restriction on Heroin Seeking in Abstinent Rats

In human drug addicts, exposure to drug-associated cues or environments that were previously associated with drug taking can trigger relapse during abstinence. Moreover, various environmental challenges can exacerbate this effect, as well as increase ongoing drug intake.The procedure we describe here highlights the impact of a common environmental challenge, food restriction, on drug craving that is expressed as an augmentation of drug seeking in abstinent rats.Rats are implanted with chronic intravenous i.v. catheters, and then trained to press a lever fori.v. heroin over a period of 10-12 days. Following the heroin self-administration phase the rats are removed from the operant conditioning chambers and housed in the animal care facility for a period of at least 14 days. While one group is maintained under unrestricted access to food (sated group), a second group (FDR group) is exposed to a mild food restriction regimen that results in their body weights maintained at 90% of their nonrestricted body weight. On day 14 of food restriction the rats are transferred back to the drug-training environment, and a drug-seeking test is run under extinction conditions (i.e. lever presses do not result in heroin delivery).The procedure presented here results in a highly robust augmentation of heroin seeking on test day in the food restricted rats. In addition, compared to the acute food deprivation manipulations we have used before, the current procedure is a more clinically relevant model for the impact of caloric restriction on drug seeking. Moreover, it might be closer to the human condition as the rats are not required to go through an extinction-training phase before the drug-seeking test, which is an integral component of the popular reinstatement procedure.     

Neuropeptide S inhibits the acquisition and the expression of conditioned place preference to morphine in mice

Neuropeptide S (NPS), a recently identified bioactive peptide, was reported to regulate arousal, anxiety, motoring and feeding behaviors. NPS precursor and NPS receptor mRNA were found in the amygdala, the ventral tegmental area (VTA) and the substantia nigra, the area thought to modulate rewarding properties of drugs. In the present study, we examined the influence of NPS on the rewarding action of morphine, using the unbiased conditioned place preference (CPP) paradigm. Morphine (1, 3 and 6 nmol, i.c.v.) induced a significant place preference. For testing the effect of NPS on the acquisition of morphine CPP, mice were given the combination of NPS and morphine on the conditioning days, and without drug treatment on the followed test day. To study the effect of NPS on the expression of morphine CPP, mice received the treatment of saline/morphine on the conditioning days, and NPS on the test day, 15 min before the placement in the CPP apparatus. Our results showed that NPS (0.3-10 nmol) alone neither induced place preference nor aversion, however, NPS (1 and 3 nmol) blocked the acquisition of CPP induced by 3 nmol morphine, and acquisition of 6 nmol morphine-induced CPP was also reduced by NPS (6 and 10 nmol). Moreover, the expression of CPP induced by 6 nmol morphine was also inhibited by NPS (0.1, 1 and 10 nmol). These results revealed the involvement of NPS in rewarding activities of morphine, and demonstrated the interaction between NPS system and opioid system for the first time.     

Importance of GluA1 subunit-containing AMPA glutamate receptors for morphine state-dependency

In state-dependency, information retrieval is most efficient when the animal is in the same state as it was during the information acquisition. State-dependency has been implicated in a variety of learning and memory processes, but its mechanisms remain to be resolved. Here, mice deficient in AMPA-type glutamate receptor GluA1 subunits were first conditioned to morphine (10 or 20 mg/kg s.c. during eight sessions over four days) using an unbiased procedure, followed by testing for conditioned place preference at morphine states that were the same as or different from the one the mice were conditioned to. In GluA1 wildtype littermate mice the same-state morphine dose produced the greatest expression of place preference, while in the knockout mice no place preference was then detected. Both wildtype and knockout mice expressed moderate morphine-induced place preference when not at the morphine state (saline treatment at the test); in this case, place preference was weaker than that in the same-state test in wildtype mice. No correlation between place preference scores and locomotor activity during testing was found. Additionally, as compared to the controls, the knockout mice showed unchanged sensitization to morphine, morphine drug discrimination and brain regional μ-opioid receptor signal transduction at the G-protein level. However, the knockout mice failed to show increased AMPA/NMDA receptor current ratios in the ventral tegmental area dopamine neurons of midbrain slices after a single injection of morphine (10 mg/kg, s.c., sliced prepared 24 h afterwards), in contrast to the wildtype mice. The results indicate impaired drug-induced state-dependency in GluA1 knockout mice, correlating with impaired opioid-induced glutamate receptor neuroplasticity.     

Wheel-running and rest activity pattern interaction in two octodontids (Octodon degus, Octodon bridgesi)

Wheel-running and other non-photic stimuli influence the rest-activity pattern of diurnal and nocturnal mammals. A day to night inversion of phase preference of activity was described among Octodon degus, when exposed to ad-libitum wheel running. We have studied the rest-activity pattern response in presence of ad libitum wheel-running in wild-captured male individuals from two species of genus Octodon: O. degus (n = 9, crepuscular-diurnal) and O. bridgesi (n = 3, nocturnal). After two months of habituation to laboratory conditions, recordings were performed in isolation chambers under a 12:12 light-dark schedule with or without access to a running wheel. Actograms were constructed from data obtained by an automated acquisition system. O. bridgesi were also recorded under constant darkness, with or without access to wheel-running. Entrained to the light-dark schedule, a crepuscular pattern of activity was evident for O. degus, whereas O. bridgesi displayed a robust nocturnal chronotype. The activity of O. degus observed during the dark phase was enhanced when wheel-running was allowed. No significant change in phase preference was observed for O. bridgesi when wheel-running was allowed. A lengthening of endogenous period was observed in O. bridgesi after wheel-running exposure under constant darkness. Nocturnal and diurnal octodontids exhibit different masking responses to wheel-running.     

Behavioral consequences of exposure to a high fat diet during the post-weaning period in rats

We explored the impact of exposure to an obesogenic diet (High Fat–High Sucrose; HFS) during the post-weaning period on sweet preference and behaviors linked to reward and anxiety. All rats were fed chow. In addition a HFS-transient group had access to this diet for 10 days from post-natal (PN) day 22 and a HFS-continuous group continued access until adult. Behavioral tests were conducted immediately after PN 32 (adolescence) or after PN 60 (adult) and included: the condition place preference (CPP) test for chocolate, sugar and saccharin preference (anhedonia), the elevated plus maze (anxiety-like behavior) and the locomotor response to quinpirole in the open field. Behavior was unaltered in adult rats in the HFS-transient group, suggesting that a short exposure to this obesogenic food does not induce long-term effects in food preferences, reward perception and value of palatable food, anxiety or locomotor activity. Nevertheless, rats that continued to have access to HFS ate less chocolate during CPP training and consumed less saccharin and sucrose when tested in adolescence, effects that were attenuated when these rats became adult. Moreover, behavioral effects linked to transient HFS exposure in adolescence were not sustained if the rats did not remain on that diet until adult. Collectively our data demonstrate that exposure to fat and sucrose in adolescence can induce immediate reward hypofunction after only 10 days on the diet. Moreover, this effect is attenuated when the diet is extended until the adult period, and completely reversed when the HFS diet is removed.     

第四脑室注射Orexin-A对大鼠饮食摄取条件性位置偏爱的影响

目的:探讨第四脑室注射orexin-A(OXA)对大鼠饮食摄取条件性位置偏爱的影响。方法:将30只大鼠随机分成3组,即对照组,低剂量组和高剂量组,第四脑室分别注射生理盐水(NS)、orexin-A或orexin-A受体拮抗剂SB334867,观察大鼠按压杠杆获取蔗糖的次数和最高频率的变化。再选择30只大鼠,第四脑室注射orexin-A和SB334867,观察大鼠对高脂饮食(HF)食物的摄入量。另选取30只大鼠第四脑室注射orexin-A或SB334867,将大鼠置于条件位置偏爱箱来检测大鼠对HF条件性位置偏爱的变化。结果:与对照组相比,24小时禁食大鼠,第四脑室注射orexin-A,可显著增加大鼠按压杠杆获取蔗糖的次数和最高频率(P0.05)。而SB334867可显著降低大鼠按压杠杆获取蔗糖次数以及最大频率(P0.05)。第四脑室注射orexin-A,可使大鼠HF摄入量显著增加(P0.05),第四脑室注射SB334867,不影响大鼠HF摄入量,但会抑制普通饮食的摄入(P0.05)。第四脑室注射orexin-A能增强对HF饮食位置偏爱性的表达,注射SB334867后会显著抑制大鼠对HF饮食位置偏爱性的表达(P0.05)。结论:第四脑室注射Orexin-A可影响大鼠摄食行为,增加高脂饮食的摄入量,增强对HF饮食位置偏爱性的表达。     

Conditioned place preference induced by sexual interaction in female rats.

The present study was undertaken to establish whether the conditioned place preference paradigm can be utilized to investigate and elucidate the neuroendocrine basis of the appetitive elements of female sexual behavior. Females were exposed to a male with which copulation occurred in a distinctive compartment of the place preference apparatus and did not receive an incentive in the alternative compartment. After six pairings to each compartment a place preference test was conducted. Both estradiol benzoate and estradiol benzoate plus progesterone treated, ovariectomized females showed a preference for the compartment associated with sexual interaction. A second group of estradiol plus progesterone treated females was exposed to a male with which copulation occurred in one compartment of the place preference apparatus and to a sexually active, but caged, male in the other. The females tended to prefer the compartment paired with the caged male. After noncontingent intromissions, immediately preceding an additional test, the females showed a place preference for the compartment paired with sexual interaction. The presented observations indicate the potential use of the place preference procedure in studying opposing motivational processes associated with the unconditioned sequence of responses that characterize the species-specific pattern of sexual behavior.     

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。     

Vasopressin neuropeptides and acquisition of heroin and cocaine self-administration in rats

The effect of the vasopressin neuropeptide des-glycinamide (Arg8)-vasopressin (DGAVP) on reducing the acquisition of intravenous heroin self-administration in rats was analyzed. When rats reduced in body weight were allowed to self-administer heroin for 1 h per day in the presence of a fixed time, non contingent food delivery schedule, it appeared that heroin intake was related in an orderly way to the unit dose of heroin delivered. DGAVP decreased heroin intake during days 4 and 5 of acquisition, especially when a high dose of heroin was delivered. DGAVP decreased heroin intake more effectively when rats were tested without the food delivery schedule and for 6 h instead of 1 h sessions per day. Structure activity relationship studies revealed that the peptide (pGlu4, Cyt6)AVP-(4-8) was the shortest active sequence mimicking the effect of DGAVP and that this peptide was somewhat more potent than DGAVP in this respect. The peptide (pGlu4,Cyt6)AVP-(4-9) increased the heroin intake of the rats. DGAVP and (pGlu4,Cyt6)-AVP-(4-8) also decreased cocaine intake of body weight reduced rats given the opportunity to self-administer cocaine intravenously in daily 6 h sessions. It is concluded that vasopressin neuropeptides may decrease the reinforcing efficacy of heroin and cocaine during acquisition of drug self-administration rather than interact with nutritional and environmental factors influencing drug taking behavior.     

Female rats exhibit a conditioned place preference for nonpaced mating

Paced, but not nonpaced, mating behavior is reported to induce a conditioned place preference (CPP) in female rats. Contrary to these previous findings, Experiment 1 showed that female rats that received 15 intromissions from a single male rat during each of five conditioning sessions exhibited a CPP for the compartment associated with mating when the intromissions were delivered via a paced or nonpaced paradigm. Experiment 2 demonstrated that nonpaced mating induced a CPP when a single male delivered the 15 intromissions but not when the male was replaced following ejaculation and a new male allowed to complete the requisite number of intromissions. These findings invite reevaluation of the reinforcing aspects of mating behavior in female rats.     

A neuropeptide FF agonist blocks the acquisition of conditioned place preference to morphine in C57Bl/6J mice

Neuropeptide FF behaves as an opioid-modulating peptide that seems to be involved in morphine tolerance and physical dependence. Nevertheless, the effects of neuropeptide FF agonists on the rewarding properties of morphine remain unknown. C57BL6 mice were conditioned in an unbiased balanced paradigm of conditioned place preference to study the effect of i.c.v. injections of 1DMe (D-Tyr1(NMe)Phe3]NPFF), a stable agonist of the neuropeptide FF system, on the acquisition of place conditioning by morphine or alcohol (ethanol). Morphine (10 mg/kg, i.p.) or ethanol (2 g/kg, i.p.) induced a significant place preference. Injection of 1DMe (1-20 nmol), given 10 min before the i.p. injection of the reinforcing drug during conditioning, inhibited the rewarding effect of morphine but had no effect on the rewarding effect of ethanol. However, a single injection of 1DMe given just before place preference testing was unable to inhibit the rewarding effects of morphine. By itself, 1DMe was inactive but an aversive effect of this agonist could be evidenced if the experimental procedure was biased. These results suggest that neuropeptide FF, injected during conditioning, should influence the development of rewarding effects of morphine and reinforce the hypothesis of strong inhibitory interactions between neuropeptide FF and opioids.     

Scheduled daily mating induces circadian anticipatory activity rhythms in the male rat

Daily schedules of limited access to food, palatable high calorie snacks, water and salt can induce circadian rhythms of anticipatory locomotor activity in rats and mice. All of these stimuli are rewarding, but whether anticipation can be induced by neural correlates of reward independent of metabolic perturbations associated with manipulations of food and hydration is unclear. Three experiments were conducted to determine whether mating, a non-ingestive behavior that is potently rewarding, can induce circadian anticipatory activity rhythms in male rats provided scheduled daily access to steroid-primed estrous female rats. In Experiment 1, rats anticipated access to estrous females in the mid-light period, but also exhibited post-coital eating and running. In Experiment 2, post-coital eating and running were prevented and only a minority of rats exhibited anticipation. Rats allowed to see and smell estrous females showed no anticipation. In both experiments, all rats exhibited sustained behavioral arousal and multiple mounts and intromissions during every session, but ejaculated only every 2-3 days. In Experiment 3, the rats were given more time with individual females, late at night for 28 days, and then in the midday for 28 days. Ejaculation rates increased and anticipation was robust to night sessions and significant although weaker to day sessions. The anticipation rhythm persisted during 3 days of constant dark without mating. During anticipation of nocturnal mating, the rats exhibited a significant preference for a tube to the mating cage over a tube to a locked cage with mating cage litter. This apparent place preference was absent during anticipation of midday mating, which may reflect a daily rhythm of sexual reward. The results establish mating as a reward stimulus capable of inducing circadian rhythms of anticipatory behavior in the male rat, and reveal a critical role for ejaculation, a modulatory role for time of day, and a potential confound role for uncontrolled food intake.     

Participation of the dopaminergic brain system in effects of glucocorticoid hormones

Following the conditioning with dexamethasone, a dose-dependent place preference in non-preferred compartment was observed on the second test day in male Wistar rats. Amphetamine in subthreshold dose exerted no effect if administered alone and induced a place preference in an unbiased paradigm after pre-treatment with dexamethasone. Administration of D2-dopamine receptors' antagonist sulpiride 30 min prior to dexamethasone conditioning completely blocked the acquisition of the place preference. The D1-dopamine receptors' antagonist SCH23390 exerted no effect on the place conditioning. The findings suggest that the D2-dopamine receptors take part in conditioned place preference with dexamethasone.     

Involvement of kappa type opioids on ethanol drinking

The effects of the administration of the kappa agonist dynorphin1-17 and/or the kappa antagonist MR-2266-BS on ethanol preference was investigated using a paradigm by which rats develop alcohol preference. Administration of dynorphin shortly before or after the conditioning session (forced ethanol exposure) failed to affect later ethanol preference. However, dynorphin treatment prior to the first choice session reduced ethanol preference during the three consecutive testing days. This effect was reversed by the simultaneous administration of the kappa antagonist MR-2266-BS. The results of the present study provide further support for evidence of the involvement of dynorphinergic systems on drinking behavior and suggest that kappa-type opioid mechanisms may be involved in the consumption and development of preference to ethanol in rats.     

Chronic deep brain stimulation in the rat nucleus accumbens and its effect on morphine reinforcement.

In order to explore a novel method for the treatment of drug abuse, we evaluated the effect of chronic deep brain stimulation (DBS) of the rat nucleus accumbens (NAc) on morphine reinforcement, using a DBS apparatus and an implant method we developed. Thirty-two adult rats weighing 240-260 g were divided into three groups, which included a DBS group (n = 10, administration of surgery, morphine and DBS), a sham DBS group (n = 12, administration of surgery and morphine) and a control group (n = 10, administration of physiological saline). The DBS electrode was stereotaxically implanted into the core of unilateral NAc and connected to an implantable pulse generator. Then, they were fixed to the rat skull. One week later, the rats in each group were intraperitoneally injected with morphine at an increasing dose (10-60 mg/kg) once daily. The rats in the DBS group were administered a 130-Hz high-frequency stimulation (HFS) once daily. A 900-second conditioned place preference (CPP) paradigm was used for determining the effect of electrical stimulation on morphine reinforcement in rats. The data showed that 7-10 days later, the preference score of the DBS group was significantly lower than that of the sham DBS group. The results suggest that chronic HFS of the rat NAc can block CPP induced by morphine and attenuate morphine reinforcement.     

Effects of fear on the behaviour of rats in an enclosed maze

Female rats chosen on the basis of their open-field defecation scores to comprise high and low defecating groups were tested for 5 min on each of 5 consecutive days in an enclosed Y-maze. High defecators entered fewer maze arms and showed more rapid habituation of arm entries but overall alternation percentages did not differentiate the groups. High defecators also showed a preference for the novel arm on their very first choice between this and the previously visited (familiar) arm, and possible reasons for this are indicated. The results are discussed in terms of differences in fearfulness between the groups and extend the generality of statements about fear and exploration while avoiding problems inherent when fear is manipulated by varying apparatus factors.     

Observer choices during experimental foraging tasks in brown capuchin monkeys (Cebus apella)

We investigated whether capuchin monkeys (Cebus apella) would choose to observe a high- or low-status adult female from their group during experimental foraging tests. The subject was located in the center of a test chamber, with a low- and high-ranking demonstrator on either side of two partitions. A peephole allowed the subject to observe the models by looking through either respective partition. Each model was trained on one of the two different methods, lift or pull, for retrieving food from a foraging apparatus. There were 22 subjects and four models. During the 40-trial test sessions, subjects could choose which model they would watch in each trial. It was predicted that subjects would prefer observing the model with whom it was closer in rank, and therefore share greater affiliation with. Results showed that only half the subjects showed a preference and that preference was not linked to status. Relatedness played a larger role in determining if a subject showed a preference for a model, and a correlation was found for relatedness and observer preference. After the observer preference tests, subjects were presented with the foraging apparatus to determine if they displayed a preference for one of the two tasks. The majority of subjects (17/22) showed a preference for the pull method, suggesting that this method may have been more salient to the monkeys in this study.