Progestins and place preference conditioning after paced mating

When female rats pace their coital interaction, a reward state evaluated by conditioned place preference is induced. Progesterone (P) is essential for the expression of proceptive behavior and for the induction of CPP. However, the functional significance of ring A reduction of P for the induction of this state during estrous is unsettled. In the present study, we evaluated whether ring A-reduced metabolites of P are involved in the reward state induced when the females are allowed to pace their sexual contacts. Ovariectomized (ovx) female rats treated with estradiol benzoate (EB, 5 microg) and P (13 microg), Megestrol acetate (MA; 13 microg ), 5 alpha-pregnan-20 dione (5 alphaDHP; 3 microg), or 5 beta-pregnan-3 alpha-ol-20-one (5 beta,3 alpha-Pgl; 3 microg) were used. Progestins were dissolved in propylene glycol and intravenously (iv) injected through an indwelling jugular catheter before females were tested for pacing behavior. After 15 intromissions or one ejaculation, females were gently placed in the nonpreferred compartment of a CPP box. Paced mating in all groups treated with progestins induced a clear change of preference. The administration of progestins alone did not induce CPP. These results suggest that P and ring A-reduced metabolites facilitate the reward state following pacing.     

Artificial vaginocervical stimulation induces a conditioned place preference in female rats

Female rats express a conditioned place preference (CPP) for a context paired with mating. During a mating encounter, the female rat is exposed to several different types of stimuli, including, but not limited to, vaginocervical stimulation and social contact. The present experiment tested the hypothesis that two components of the mating interaction, vaginocervical stimulation or social contact, each induce a CPP in female rats. During conditioning rats received nonpaced mating, artificial vaginocervical stimulation, social interaction or a control treatment. Rats expressed a CPP for the context paired with nonpaced mating or artificial vaginocervical stimulation whereas social interaction and the control treatment did not induce a CPP. The present findings highlight the important role that vaginocervical stimulation plays in the reinforcing effects of mating in female rats.     

Hormonal and testing conditions for the induction of conditioned place preference by paced mating

The ability to control or pace the sexual interaction has important physiological and behavioral consequences for the female rat. Paced mating favors reproduction and induces a positive affective state as revealed by conditioned place preference (CPP). In the present experiment we evaluated: 1) If paced mating induces CPP in naturally cycling females; 2) If females developed a positive affective state if they paced the sexual interaction through a 1- or a 3-hole pacing chamber; 3) If females that mate with the same male without pacing the sexual interaction develop CPP. In the first experiment intact females were divided in 4 different groups; 2 paced the sexual interaction until receiving 1 or 3 ejaculations; the other 2 groups mated, without pacing the sexual interaction, until receiving 1 or 3 ejaculations. Only the group that paced the sexual interaction until receiving 3 ejaculations developed a positive affective state. In experiments 2 and 3 hormonally treated ovariectomized females were used. In experiment 2 females were allowed to pace the sexual interaction through a 1- or a 3-hole pacing chamber: A clear positive affective state was induced in both testing conditions. Finally, in experiment 3 females did not develop CPP for non-paced sex despite the fact that they mated with the same male in the conditioning sessions. These results demonstrate that the pattern of vaginocervical stimulation that the females received by engaging in approach and avoidance behaviors to pace the sexual interaction can induce a positive affective state in naturally cycling females. They also confirm the existence of a threshold of vaginocervical stimulation for paced mating to induce CPP in female rats.     

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.     

Infusions of naloxone into the medial preoptic area, ventromedial nucleus of the hypothalamus, and amygdala block conditioned place preference induced by paced mating behavior

Paced mating induces positive affect as revealed by conditioned place preference (CPP) in female rats. It has been suggested that endogenous opioids are involved in the generation of this positive affect since systemic administration of the opioid antagonist naloxone blocks mating-induced CPP. Several brain structures, including the medial preoptic area (mPOA), the ventromedial nucleus of the hypothalamus (VMH), the amygdala (Me), and the nucleus accumbens (Acb) have been implicated in the control of female sexual behavior. However, it is not known if these structures also participate in the positive affect produced by paced mating. To this end we determined the effects of intracranial administration of naloxone methiodide into the mPOA, VMH, Me and Acb on conditioned place preference induced by paced mating in female rats. Regardless of the site of infusion 5 μg of naloxone did not affect any of the sexual behavior parameters measured during copulation. When CPP was evaluated, the groups infused with naloxone into the mPOA, the VMH, and the Me before each conditioning session did not develop place preference. Only the group infused with naloxone in the Acb and the control groups did so. These results demonstrate that opioid receptors within the mPOA, VMH and Me are necessary for the rewarding aspects of paced mating. We suggest that the Me and VMH are important for the transmission of sensory information produced by copulation while the mPOA is the site where the positive affect is originated.     

Male Syrian hamsters demonstrate a conditioned place preference for sexual behavior and female chemosensory stimuli

Sexual behavior is a natural reward for many rodent species, and it often includes chemosensory-directed components. Chemosensory stimuli themselves may also be rewarding. Conditioned place preference (CPP) is one paradigm frequently used to test the rewarding properties of a range of stimuli. Males and females of several rodent species show a CPP for sexual behavior; however, it is currently unknown whether sexual behavior can induce a CPP in male Syrian hamsters. As male Syrian hamsters are an animal model commonly used for investigation of the neurobiology of sexual behavior, understanding the rewarding components of sexual stimuli will better direct future research on brain regions and neurotransmitters involved in these behaviors. Experiment 1 tested the prediction that male hamsters show a CPP for sexual behavior. Female chemosensory stimuli are essential for the display of sexual behavior in male hamsters; however, the rewarding properties of female chemosensory stimuli contained in vaginal secretions (VS) are uncertain. Therefore, experiment 2 tested the prediction that male hamsters show a CPP for VS. This study is the first demonstration that both sexual behavior and VS induce a CPP in male hamsters. Thus, female chemosensory stimuli are a natural reward in a species that is dependent on these stimuli for reproductive fitness.     

Lesions of orexin neurons block conditioned place preference for sexual behavior in male rats

The hypothalamic neuropeptide orexin (hypocretin) mediates reward related to drugs of abuse and food intake. However, a role for orexin in sexual reward has yet to be investigated. Orexin neurons are activated by sexual behavior, but endogenous orexin does not appear to be essential for sexual performance and motivation in male rats. Therefore, the goal of the current study was to test the hypothesis that orexin is critically involved in processing of sexual reward in male rats. First, it was demonstrated following exposure to conditioned contextual cues associated with sexual behavior in a conditioned place preference paradigm that cFos expression is induced in orexin neurons, indicating activation of orexin neurons by cues predicting sexual reward. Next, orexin-cell specific lesions were utilized to determine the functional role of orexin in sexual reward processing. Hypothalami of adult male rats were infused with orexin-B-conjugated saporin, resulting in greater than 80% loss of orexin neurons in the perifornical-dorsomedial and lateral hypothalamus. Orexin lesions did not affect expression of sexual behavior, but prevented formation of conditioned place preference for a sexual behavior paired chamber. In contrast, intact sham-treated males or males with partial lesions developed a conditioned place preference for mating. Orexin lesioned males maintained the ability to form a conditioned place aversion to lithium chloride-induced visceral illness, indicating that orexin lesions did not disrupt associative contextual memory. Overall, these findings suggest that orexin is not essential for sexual performance or motivation, but is critical for reward processing and conditioned cue-induced seeking of sexual behavior.     

Sexual reward in male rats: effects of sexual experience on conditioned place preferences associated with ejaculation and intromissions

Various behavioral models and studies have provided evidence suggesting that male rat sexual behavior has rewarding and reinforcing properties. However, there is little information regarding the rewarding values of the different components of sexual behavior. Therefore, this study used a conditioned place preference (CPP) paradigm to address whether ejaculation and intromissions differ in their rewarding incentive values. We also addressed whether the differential rewarding values were dependent on prior sexual experience. Sexually naïve and experienced males received one pairing of either intromissions or ejaculation with one of the chambers in the CPP box. The amount of time spent in each chamber of the CPP apparatus after conditioning was then measured. Both sexually naïve and sexually experienced males formed a CPP for ejaculation, while only sexually naïve, and not sexually experienced, males formed a CPP for intromissions. Moreover, in sexually naïve males, multiple pairings of ejaculation with the designated chamber resulted in a CPP relative to the control chamber paired with display of intromissions. These data support the hypothesis that there is a hierarchy of rewarding sexual behavior, with ejaculation being the most rewarding component, and that the rewarding incentive value of other components of sexual behavior is dependent upon prior sexual experience.     

断乳前棕色田鼠幼仔对双亲和可卡因的条件位置偏爱（英文）

个体间的社会互作是一种天然奖赏,这种社会性奖赏诱导的条件位置偏爱(Conditioned place preference,CPP)是通过环境信息和社会互作奖赏效应间建立条件反射形成的,与药物奖赏诱导的CPP相似。棕色田鼠(Microtus mandarinus)是一种社会性单配制田鼠,具有紧密的亲-子联系和社会互作;雄鼠对断乳前幼仔也提供较高水平的亲本抚育。幼仔强化能够诱导母鼠及父鼠形成CPP,但双亲对幼仔是否也具有强化效应还不清楚。为探讨断乳前幼仔与双亲形成的奖赏联系,本实验检测了出生后13-17 d和19-23 d两个发育龄段的棕色田鼠幼仔对母鼠、父鼠以及可卡因(20 mg/kg)的CPP反应。数据显示在分别用母鼠、父鼠或可卡因强化后,两个年龄段的幼仔在CPP箱的强化室与非强化室所处时间没有显著性差异。这些结果表明断乳前棕色田鼠幼仔不能形成对母鼠、父鼠及可卡因的位置偏爱。     

Effect of rhynchophylline on conditioned place preference on expression of NR2B in methamphetamine-dependent mice

Objective

To study the effect of rhynchophylline on N-methyl d-aspartate receptor subtype 2B subunit in hippocampus of Methamphetamine-induced conditioned place preference (CPP) mice.

Methods

Place preference mice models were established by methamphetamine; the expression of NR2B was observed by immunohistochemistry technique and Western blot.

Results

Methamphetamine (4 mg/kg)-induced place preference mice model was successfully established; ketamine (15 mg/kg), rhynchophylline (40 mg/kg) and rhynchophylline (80 mg/kg) can eliminate place preference; Immunohistochemistry showed that the number of NR2B-positive neurons in hippocampus was increased in the methamphetamine model group, whereas less NR2B-positive neurons were found in the ketamine group, low and high dosage rhynchophylline group. Western blot showed that the expression of NR2B protein was significantly increased in the model group, whereas less expression was found in the ketamine group, low and high dosage rhynchophylline group.

Conclusions

NR2B plays an important role in the formation of methamphetamine-induced place preference in mice. Rhynchophylline reversed the expression of NR2B in the hippocampus demonstrates the potential effect of mediates methamphetamine induced rewarding effect.     

The effects of prenatal PCBs on adult female paced mating reproductive behaviors in rats

Polychlorinated biphenyls (PCBs) are a family of toxicants that persist in measurable quantities in human and wildlife tissues, despite their ban in production in 1977. Some PCB mixtures can act as endocrine disrupting chemicals (EDCs) by mimicking or antagonizing the actions of hormones in the brain and periphery. When exposure to hormonally active substances such as PCBs occurs during vulnerable developmental periods, particularly prenatally or in early postnatal life, they can disrupt sex-specific patterning of the brain, inducing permanent changes that can later be manifested as improper sexual behaviors. Here, we investigated the effects of prenatal exposure to the PCB mixture Aroclor (A) 1221 on adult female reproductive behaviors in a dose-response model in the Sprague-Dawley rat. Using a paced mating paradigm that permits the female to set the timing of mating and control contact with the male during copulation, we were able to uncover significant differences in female-typical sexual activities in A1221-exposed females. Specifically, A1221 causes significant effects on mating trial pacing, vocalizations, ambulation and the female's likelihood to mate. The results further demonstrate that the intermediate treatment group has the greatest number of disrupted endpoints, suggestive of non-linear dose responses to A1221. These data demonstrate that the behavioral phenotype in adulthood is disrupted by low, ecologically relevant exposures to PCBs, and the results have implications for reproductive success and health in wildlife and women.     

Changes in microRNA expression profile in hippocampus during the acquisition and extinction of cocaine-induced conditioned place preference in rats

Background

MicroRNA (miRNA) emerges as important player in drug abuse. Yet, their expression profile in neurological disorder of cocaine abuse has not been well characterized. Here, we explored the changes of miRNA expression in rat hippocampus following repeated cocaine exposure and subsequent abstinence from cocaine treatment.

Results

Conditioned place preference (CPP) procedure was used to assess the acquisition and extinction of cocaine-seeking behavior in rats. MiRNA microarray was performed to examine miRNAs levels in rat hippocampus. Quantitative RT-PCR was conducted to further confirm results in microarray study. Finally, bioinformatic predictions were made to suggest potential target genes of cocaine-responsive miRNA in this study. MiRNA array found that 34 miRNA levels were changed in rat hippocampus while acquiring cocaine CPP and 42 miRNAs levels were altered after the cocaine-induced CPP were extinguished, as compared to normal controls. The findings from qRT-PCR study support results from microarray analysis.

Conclusions

The current study demonstrated dynamic changes in miRNA expression in rat hippocampus during the acquisition and extinction of cocaine-induced CPP. Some miRNAs which have been previously reported to be involved in brain disorders and drug abuse, including miR-133b, miR-134, miR-181c, miR-191, miR-22, miR-26b, miR-382, miR-409-3p and miR-504, were found to be changed in their expression following repeated cocaine exposure and subsequent abstinence from cocaine treatment. These findings may extend our understanding of the regulatory network underlying cocaine abuse and may provide new targets for the future treatment of drug abuse.     

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.     

Maternal influences on the sexual behavior and reproductive success of the female rat

In many species, including humans, there is evidence for parental effects on within-sex variations in reproductive behavior. In the present studies we found that variations in postnatal maternal care were associated with individual differences in female sexual behavior in the rat. Females born to and reared by dams that showed enhanced pup licking/grooming (i.e., High LG mothers) over the first week postpartum showed significantly reduced sexual receptivity and alterations in the pacing of male mounting (i.e., longer inter-intromission intervals) observed in a paced mating test. There were minimal effects on the sexual behavior of the male offspring. The female offspring of High LG mothers showed a reduced lordosis rating, a decreased mount:intromission ratio, received fewer ejaculations and were less likely to achieve pregnancy following mating in the paced mating context. The data suggest maternal influences on the sexual development of the female rat that are functionally relevant for reproductive success. Together with previous studies these findings imply that maternal care can ‘program’ reproductive strategies in the female rat.     

Hormonal status and test condition, but not sexual experience, modulate partner preference in female rats

A series of experiments was conducted to determine the contributions of hormonal status, test condition, and sexual experience to the display of partner preference by female rats. Preference for a sexually active male rat over a sexually receptive female rat was assessed in independent groups of female rats tested in a condition limiting physical contact (No Contact) and a condition allowing for sexual interaction (Contact). Although hormonal status and test condition influenced the preference for a sexually active male, repeated testing and sexual experience had no effect. Experiment 1 demonstrated that independent of test condition, preference for the male is stronger in estrogen- and progesterone-primed rats than in rats receiving the vehicle. Moreover, independent of hormone condition, rats tested in the No Contact condition exhibit a stronger preference for the male than rats tested in the Contact condition, reflecting in part the active pacing of mating stimulation by sexually receptive rats tested in the Contact condition. Experiment 2 showed that the overall pattern of partner preference in proestrous and diestrous rats was similar to that observed in ovariectomized, estrogen- and progesterone-primed, and oil-treated rats, respectively. In Experiment 3, rats primed with estrogen alone did not exhibit a preference for the male even though fully receptive. Experiments 4 and 5 demonstrated that sexual experience does not affect the expression of preference for the male in estrogen- and progesterone-primed rats. The present findings demonstrate that the female rat's preference for the male is stable across repeated tests and is not affected by sexual experience. Our results also confirm that gonadal hormones influence the expression of a preference for a sexually active male versus a sexually receptive female and demonstrate that the magnitude of preference is modulated by test conditions.     

Attenuation of cocaine-induced conditioned place preference by Polygala tenuifolia root extract

A recent investigation indicated that Polygala tenuifolia Willdenow extract (PTE) possesses a potential antipsychotic effect. In this study, we examined the effects of PTE on the cocaine-induced changes in locomotor activity, conditioned place preference (CPP), fos-related antigen-immunoreactivity (FRA-IR), and activator protein (AP)-1 DNA binding activity. Cocaine-induced behavioral effects (hyperlocomotion and CPP) occurred in parallel with increases in FRA-IR and AP-1 DNA binding activity in the nucleus accumbens. These responses induced by cocaine were consistently attenuated by concurrent treatment with PTE (25 mg or 50 mg/kg/day, i.p. x 7). The adenosine A2A receptor antagonist, 1,3,7-trimethyl-8-(3-chlorostyrl)xanthine (0.5 or 1.0 mg/kg, i.p.), reversed the PTE-mediated pharmacological action in a dose related manner; neither the adenosine A(1) receptor antagonist, 8-cyclopentyl-1,3-dimethylxanthine (0.5 or 1.0 mg/kg, i.p.) nor the A2B receptor antagonist, alloxazine (1.5 or 3.0 mg/kg, i.p.) significantly affected this pharmacological action. Our results suggest that PTE prevents cocaine-induced behavioral effects, at least in part, via the activation of the adenosine A2A receptor.     

Modulation of neuropeptide FF (NPFF) receptors influences the expression of amphetamine-induced conditioned place preference and amphetamine withdrawal anxiety-like behavior in rats

Many data indicate that endogenous opioid system is involved in amphetamine-induced behavior. Neuropeptide FF (NPFF) possesses opioid-modulating properties. The aim of the present study was to determine whether pharmacological modulation of NPFF receptors modify the expression of amphetamine-induced conditioned place preference (CPP) and amphetamine withdrawal anxiety-like behavior, both processes relevant to drug addiction/abuse. Intracerebroventricular (i.c.v.) injection of NPFF (5, 10, and 20 nmol) inhibited the expression of amphetamine CPP at the doses of 10 and 20 nmol. RF9, the NPFF receptors antagonist, reversed inhibitory effect of NPFF (20 nmol, i.c.v.) at the doses of 10 and 20 nmol and did not show any effect in amphetamine- and saline conditioned rats. Anxiety-like effect of amphetamine withdrawal was measured 24h after the last (14 days) amphetamine (2.5mg/kg, i.p.) treatment in the elevated plus-maze test. Amphetamine withdrawal decreased the percent of time spent by rats in the open arms and the percent of open arms entries. RF9 (5, 10, and 20 nmol, i.c.v.) significantly reversed these anxiety-like effects of amphetamine withdrawal and elevated the percent of time spent by rats in open arms at doses of 5 and 10 nmol, and the percent of open arms entries in all doses used. NPFF (20 nmol) pretreatment inhibited the effect of RF9 (10 nmol). Our results indicated that stimulation or inhibition of NPFF receptors decrease the expression of amphetamine CPP and amphetamine withdrawal anxiety, respectively. These findings may have implications for a better understanding of the processes involved in amphetamine dependence.     

Variability in nicotine conditioned place preference and stress‐induced reinstatement in mice: Effects of sex,initial chamber preference,and guanfacine

Relapse to smoking occurs at higher rates in women compared with men, especially when triggered by stress. Studies suggest that sex‐specific interactions between nicotine reward and stress contribute to these sex differences. Accordingly, novel treatment options targeting stress pathways, such as guanfacine, an α2‐adrenergic receptor agonist, may provide sex‐sensitive therapeutic effects. Preclinical studies are critical for elucidating neurobiological mechanisms of stress‐induced relapse and potential therapies, but rodent models of nicotine addiction are often hindered by large behavioral variability. In this study, we used nicotine conditioned place preference to investigate stress‐induced reinstatement of nicotine preference in male and female mice, and the effects of guanfacine on this behavior. Our results showed that overall, nicotine induced significant place preference acquisition and swim stress‐induced reinstatement in both male and female mice, but with different nicotine dose‐response patterns. In addition, we explored the variability in nicotine‐dependent behaviors with median split analyses and found that initial chamber preference in each sex differentially accounted for variability in stress‐induced reinstatement. In groups that showed significant stress‐induced reinstatement, pretreatment with guanfacine attenuated this behavior. Finally, we evaluated neuronal activation by Arc immunoreactivity in the infralimbic cortex, prelimbic cortex, anterior insula, basolateral amygdala, lateral central amygdala and nucleus accumbens core and shell. Guanfacine induced sex‐dependent changes in Arc immunoreactivity in the infralimbic cortex and anterior insula. This study demonstrates sex‐dependent relationships between initial chamber preference and stress‐induced reinstatement of nicotine conditioned place preference, and the effects of guanfacine on both behavior and neurobiological mechanisms.     

Estrogen treatment during development alters adult partner preference and reproductive behavior in female laboratory rats

There is broad acceptance for the idea that during development estradiol ‘organizes’ many aspects of reproductive behavior including partner preferences in the laboratory rat. With respect to partner preference, this idea is drawn from studies where estrogen action was in someway blocked, either through aromatase or estrogen receptor inhibition, during development in male rats. The lack of estrogens neonatally results in a decrease in the male rat's preference for females. In this study, the effect of early postnatal estradiol treatment on the partner preferences of female rats was examined as a further test of the hypothesis that male-typical partner preference is dependent upon early exposure to estrogens. Our principal finding was that increased postnatal estradiol exposure during development affected partner preference in the expected direction, and this effect was seen under several adult hormonal and behavioral testing conditions. Female rats that received exogenous estradiol during development spent more time with an estrous female and less time with a sexually active male than did cholesterol treated females. The estradiol treatment also disrupted normal female sexual behavior, receptivity, and proceptivity.