Neuropeptide FF (NPFF) reduces the expression of morphine- but not of ethanol-induced conditioned place preference in rats

Neuropeptide FF (NPFF) has been described as an anti-opioid peptide. It plays a role in opioid antinociception, dependence and tolerance. Previous study has indicated that 1DMe ([D-Tyr(1), (NMe)Phe(3)]NPFF), a stable analog of NPFF, inhibits acquisition of the rewarding effect of morphine but not of ethanol in mice. The rewarding effects of these drugs were measured in the unbiased paradigm of conditioned place preference (CPP). The present study examines the influence of NPFF on the expression of morphine- and ethanol-induced CPP in the biased procedure in rats. Our experiments showed that NPFF, given intracerebroventricularly (i.c.v.) at the doses of 5, 10 and 20 nmol, inhibited the expression of morphine-induced CPP. NPFF gave itself, neither induced place preference nor aversion, although a tendency to aversive effect was seen at the highest dose of 20 nmol. NPFF did not indicate fear behavior in the elevated plus maze test, and did not disturb locomotor activity of rats. However, NPFF was unable to inhibit the expression of ethanol-induced CPP. Probably this effect is due to the fact that ethanol reward is a more complex process and apart from the role of opioids, there are other neurotransmitters also involved in this mechanism. These results suggest that NPFF is involved in the expression of morphine reward. Moreover, our study supports an anti-opioid character of this peptide.     

The conditioned place preference paradigm in rats: effect of bupropion

The effect of bupropion in the conditioned place preference paradigm in rats is described. In doses between 10 and 50 mg/kg i.p. bupropion increased the time rats spent in a shuttle box compartment conditioned to this compound. This effect of bupropion was not blocked by pretreatment of the animals with 0.1 mg/kg i.p. haloperidol or 50 mg/kg i.p. sulpiride. The same doses of the neuroleptics did, however, attenuate locomotor hyperactivity induced by bupropion. Bupropion thus seems to belong to the group of CNS stimulants whose effect in the conditioned place preference paradigm is not blocked by neuroleptics.     

大鼠杏仁核5—HT3受体参与免疫调制

实验通过大鼠侧脑室和杏仁核给予5－HT3受体激动剂1－phenylbiguanide(PBG),用3H－TdR掺入法测定脾细胞丝裂原（concanavalin A,Con A和lipopolysaccharide,LPS)刺激增殖效应,用活化脾细胞增殖法测定IL－2生成,MTT法测定自然杀伤（natural killer,NK)细胞活性和用放射免疫测定血浆皮质酮水平,以探讨大鼠杏仁核5－HT3受体在免疫调控中的作用。结果表明：5－HT3受体拮抗剂granisetron(GNT,0.1-0.4mg/kg ip)剂量依赖地增强Con A和LPS刺激的脾细胞增殖,作用在连续给药5d最明显,双侧脑室给予PBG（5ug/side)可增强ConA和LPS刺激的脾细胞增殖效应,作用在连续给药3d最明显,双侧和单侧中共杏仁核给予PBG0．5ug均增强ConA刺激的脾细胞增殖和IL－2生成,底内侧杏仁核给予同剂量PBG仅增强LPS刺激的脾细胞增殖效应,不影响ConA刺激的脾细胞增殖和IL－2生成,中央杏仁核给予PBG升高血浆皮质酮的作用较底侧杏仁核给予等量PBG引起的升高血浆皮质酮作用明显（P＜0．01）,侧脑室,中央杏仁核和底内杏仁核给予PBG对丝裂原刺激的脾细胞增殖效应影响不同,但均被同时同部位给予GNT所拮抗,提示杏仁核中央核和底内侧核的5－HT3受体可能以不同方式参与ConA或LPS刺激的脾细胞增殖效应的调制。     

Roles of 5-HT receptors in the release and action of secretin on pancreatic secretion in rats

5-Hydroxytryptamine (serotonin, 5-HT) is a hormone and neurotransmitter regulating gastrointestinal functions. 5-HT receptors are widely distributed in gastrointestinal mucosa and the enteric nervous system. Duodenal acidification stimulates not only the release of both 5-HT and secretin but also pancreatic exocrine secretion. We investigated the effect of 5-HT receptor antagonists on the release of secretin and pancreatic secretion of water and bicarbonate induced by duodenal acidification in anesthetized rats. Both the 5-HT(2) receptor antagonist ketanserin and the 5-HT(3) receptor antagonist ondansetron at 1-100 microg/kg dose-dependently inhibited acid-induced increases in plasma secretin concentration and pancreatic exocrine secretion. Neither the 5-HT(1) receptor antagonists pindolol and 5-HTP-DP nor the 5-HT(4) receptor antagonist SDZ-205,557 affected acid-evoked release of secretin or pancreatic secretion. None of the 5-HT receptor antagonists affected basal pancreatic secretion or plasma secretin concentration. Ketanserin or ondansetron at 10 microg/kg or a combination of both suppressed the pancreatic secretion in response to intravenous secretin at 2.5 and 5 pmol x kg(-1) x h(-1) by 55-75%, but not at 10 pmol x kg(-1) x h(-1). Atropine (50 microg/kg) significantly attenuated the inhibitory effect of ketanserin on pancreatic secretion but not on the release of secretin. These observations suggest that 5-HT(2) and 5-HT(3) receptors mediate duodenal acidification-induced release of secretin and pancreatic secretion of fluid and bicarbonate. Also, regulation of pancreatic exocrine secretion through 5-HT(2) receptors may involve a cholinergic pathway in the rat.     

Adult rats exposed to early-life social isolation exhibit increased anxiety and conditioned fear behavior, and altered hormonal stress responses

Social isolation of rodents during development is thought to be a relevant model of early-life chronic stress. We investigated the effects of early-life social isolation on later adult fear and anxiety behavior, and on corticosterone stress responses, in male rats. On postnatal day 21, male rats were either housed in isolation or in groups of 3 for a 3 week period, after which, all rats were group-reared for an additional 2 weeks. After the 5-week treatment, adult rats were examined for conditioned fear, open field anxiety-like behavior, social interaction behavior and corticosterone responses to restraint stress. Isolates exhibited increased anxiety-like behaviors in a brightly-lit open field during the first 10 min of the test period compared to group-reared rats. Isolation-reared rats also showed increased fear behavior and reduced social contact in a social interaction test, and a transient increase in fear behavior to a conditioned stimulus that predicted foot-shock. Isolation-reared rats showed similar restraint-induced increases in plasma corticosterone as group-reared controls, but plasma corticosterone levels 2 h after restraint were significantly lower than pre-stress levels in isolates. Overall, this study shows that isolation restricted to an early part of development increases anxiety-like and fear behaviors in adulthood, and also results in depressed levels of plasma corticosterone following restraint stress.     

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.     

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.     

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.     

Clitoral stimulation induces conditioned place preference and Fos activation in the rat

The present study examined the ability of clitoral stimulation (CLS) to induce conditioned place preference (CPP) and Fos protein in the brain. Ovariectomized, hormone-primed Long-Evans rats were randomly assigned to receive either distributed CLS (1 stimulation every 5 s for 1 min prior to being placed in one distinctive side of a nonbiased CPP box for 2 min, after which the cycle of stimulation and CPP exposure were repeated for 4 more cycles, totaling 60 stimulations) or continuous CLS (1 stimulation per second for 1 min with 2 min in one side of the CPP box, repeated for 4 more cycles, totaling 300 stimulations). Two days later, females were placed into the other side of the CPP box without prior stimulation. CPP was tested after 5 sequential exposures each of CLS and no stimulation. Females given distributed stimulation developed a significant CPP whereas females given continuous stimulation did not. CLS induced Fos in hypothalamic and limbic structures, including the nucleus accumbens, piriform cortex, arcuate nucleus, and dorsomedial portion of the ventromedial hypothalamus, compared to no stimulation. However, distributed CLS induced more Fos in the medial preoptic area than continuous CLS or no stimulation. In contrast, continuous CLS induced more Fos in the posteroventral medial amygdala compared to no stimulation. These data indicate that CLS induces a reward state in the rat and a pattern of Fos activation in regions of the brain that process genitosensory input, incentive salience, and reward.     

Serotonin 5-HT3 receptors in the central nervous system

The 5-HT₃ receptor is a ligand-gated ion channel activated by serotonin (5-HT). Although originally identified in the peripheral nervous system, the 5-HT₃ receptor is also ubiquitously expressed in the central nervous system. Sites of expression include several brain stem nuclei and higher cortical areas such as the amygdala, hippocampus, and cortex. On the subcellular level, both presynaptic and postsynaptic 5-HT₃ receptors can be found. Presynaptic 5-HT₃ receptors are involved in mediating or modulating neurotransmitter release. Postsynaptic 5-HT₃ receptors are preferentially expressed on interneurons. In view of this specific expression pattern and of the well-established role of 5-HT as a neurotransmitter shaping development, we speculate that 5-HT₃ receptors play a role in the formation and function of cortical circuits.     

The role of putative 5-HT1A and 5-HT1B receptors in the control of feeding in rats

8-hydroxy-2(di-n-propylamino)tetraline (8-OH-DPAT) and 5-methoxy-3(1,2,3,6-tetrahydro-4-pyridinyl)1H indole succinate (RU 24969), two agonists on the putative serotonin 1A and serotonin 1B receptors, were used for exploring the role of these sites in the inhibitory effect of serotonin (5-HT) on feeding. In free-feeding rats, 2.5-5 mg/kg RU 24969 significantly reduced food intake while doses of 8-OH-DPAT ranging from 0.125 to 0.5 mg/kg increased eating. The effects of the highest doses were associated with hyperlocomotion and hyperreactivity for RU 24969 and a typical motor syndrome (flat body posture and forepaw treading) for 8-OH-DPAT. The motor syndrome caused by 0.5 mg/kg 8-OH-DPAT was much more obvious in food-deprived rats in which food intake was also markedly reduced. RU 24969 1.25 and 5 mg/kg reduced food intake by food-deprived rats and caused hyperlocomotion not different from that in free-feeding animals. Pretreatment with metergoline (2 mg/kg i.p.) prevented the effect of 5 mg/kg RU 24969 on food intake by food-deprived rats but had no effect on the reduction of eating caused by 0.5 mg/kg 8-OH-DPAT. The motor syndrome caused by 8-OH-DPAT was not changed by metergoline but the hyperlocomotion caused by RU 24969 was potentiated. Haloperidol (0.1 mg/kg i.p.) completely blocked the hyperlocomotion but did not change the reduction of food intake caused by RU 24969 in food-deprived rats. It is suggested that the putative serotonin 1B receptors specifically mediate the inhibitory effect of 5-HT on feeding whereas serotonin 1A sites act by enhancing eating only in free-feeding animals.     

Activation of 5-HT(1A) receptors attenuates tachycardia induced by restraint stress in rats

To better understand the central mechanisms that mediate increases in heart rate (HR) during psychological stress, we examined the effects of systemic and intramedullary (raphe region) administration of the serotonin-1A (5-HT(1A)) receptor agonist 8-hydroxy-2-(di-n-propylamino)tetraline (8-OH-DPAT) on cardiac changes elicited by restraint in hooded Wistar rats with preimplanted ECG telemetric transmitters. 8-OH-DPAT reduced basal HR from 356 +/- 12 to 284 +/- 12 beats/min, predominantly via a nonadrenergic, noncholinergic mechanism. Restraint stress caused tachycardia (an initial transient increase from 318 +/- 3 to 492 +/- 21 beats/min with a sustained component of 379 +/- 12 beats/min). beta-Adrenoreceptor blockade with atenolol suppressed the sustained component, whereas muscarinic blockade with methylscopolamine (50 microg/kg) abolished the initial transient increase, indicating that sympathetic activation and vagal withdrawal were responsible for the tachycardia. Systemic administration of 8-OH-DPAT (10, 30, and 100 microg/kg) attenuated stress-induced tachycardia in a dose-dependent manner, and this effect was suppressed by the 5-HT(1A) antagonist WAY-100635 (100 microg/kg). Given alone, the antagonist had no effect. Systemically injected 8-OH-DPAT (100 microg/kg) attenuated the sympathetically mediated sustained component (from +85 +/- 19 to +32 +/- 9 beats/min) and the vagally mediated transient (from +62 +/- 5 to +25 +/- 3 beats/min). Activation of 5-HT(1A) receptors in the medullary raphe by microinjection of 8-OH-DPAT mimicked the antitachycardic effect of the systemically administered drug but did not affect basal HR. We conclude that tachycardia induced by restraint stress is due to a sustained increase in cardiac sympathetic activity associated with a transient vagal withdrawal. Activation of central 5-HT(1A) receptors attenuates this tachycardia by suppressing autonomic effects. At least some of the relevant receptors are located in the medullary raphe-parapyramidal area.     

Exogenous melatonin delays gastric emptying rate in rats: role of CCK2 and 5-HT3 receptors.

Pineal hormone melatonin is proposed as a potential treatment for severe sleep disturbances, and various gastrointestinal disorders. It was shown that melatonin increases intestinal motility and influences the activity of myoelectric complexes of the gut. The aim of the study was to evaluate the mechanisms of the effect of exogenous melatonin on gastric emptying rate. Male Sprague-Dawley rats were fitted with gastric cannulas under anesthesia. The rate of gastric emptying of saline was determined after instillation into the gastric fistula, from the volume and phenol red concentrations recovered after 5 min. Melatonin injected intraperitoneally (ip; 0.001-100 mg/kg) delayed gastric emptying rate of saline at 3 and 10 mg/kg doses. When administered ip 15 min before melatonin (10 mg/kg) injections, CCK2 (L-365,260, 1 mg/kg) or 5-HT3 receptor (ramosetrone, 50 microg/kg) blockers abolished melatonin-induced delay in gastric emptying rate, while the blockade of sympathetic ganglia (bretylium tosylate, 15 mg/kg) significantly reduced the delay in gastric emptying rate. CCK1 receptor blocker (L-364,718, 1 mg/kg) had no significant effect on the delaying action of melatonin. Our results indicate that pharmacological doses of melatonin delay gastric emptying via mechanisms that involve CCK2 and 5-HT3 receptors. Moreover, it appears that exogenous melatonin inhibits gastric motility in part by activating sympathetic neurons.     

Individual and combined effects of methamphetamine and ketamine on conditioned place preference and NR1 receptor phosphorylation in rats

Methamphetamine (MA), a commonly abused psychostimulant, induces the drug dependence by enhancing the dopamine-mediated neurotransmission. Ketamine (KET) is a non-competitive N-methyl-D-aspartate receptor antagonist, which can be actually mixed with MA for polydrug abuse. In the present study, the individual and combined effects of KET (10 mg/kg, i.p.) and MA (1 mg/kg, i.p.) on conditioned place preference in rats were investigated. The alterations of serine 897 phosphorylations of NR1 receptors in the striatum and ventral tegmental area of after-conditioning rats were measured immunochemically. The results showed repeated administrations of MA, KET and their combination, at the doses studied, all could induce psychological dependences evaluated by conditioned place preference. KET was not able to suppress the MA-induced place preference. The modulations of NR1 phosphorylations in basal ganglia were partly responsible to place preference. Although the alterations induced by KET were not significant in most areas we studied, MA showed a significant increase in the ventral tegmental area but a marked decrease in caudate putamen and nucleus accumbens. Such alterations were much more significant when KET and MA were combined. These results have important implications for public awareness of harm with combined drug abuse. Further investigations toward the specific interaction of the two drugs are necessary.     

Structural basis of ligand recognition in 5-HT3 receptors

The 5‐HT₃ receptor is a pentameric serotonin‐gated ion channel, which mediates rapid excitatory neurotransmission and is the target of a therapeutically important class of anti‐emetic drugs, such as granisetron. We report crystal structures of a binding protein engineered to recognize the agonist serotonin and the antagonist granisetron with affinities comparable to the 5‐HT₃ receptor. In the serotonin‐bound structure, we observe hydrophilic interactions with loop E‐binding site residues, which might enable transitions to channel opening. In the granisetron‐bound structure, we observe a critical cation–π interaction between the indazole moiety of the ligand and a cationic centre in loop D, which is uniquely present in the 5‐HT₃ receptor. We use a series of chemically tuned granisetron analogues to demonstrate the energetic contribution of this electrostatic interaction to high‐affinity ligand binding in the human 5‐HT₃ receptor. Our study offers the first structural perspective on recognition of serotonin and antagonism by anti‐emetics in the 5‐HT₃ receptor.     

5-HT3 receptors in selective animal models of cognition

Role of 5-HT3 receptors in cholinergic hypofunctional models of cognitive impairment in the elevated plus maze model and a passive avoidance model is studied. Cognitive impairment was caused by scopolamine (1 mg/kg, ip) in mice and 5-HT3 ligands mCPBG (1 and 5 mg/kg, ip) and ondansetron (0.5 and 5 mg/kg, ip) were administered before the pre-learning phase to study the effects on acquisition, while post-learning administration was used to determine the effects on consolidation. Ondansetron improved acquisition and retention in cholinergic hypofunctional models while mCPBG potentiated selected impaired cognitive indices. The results indicate the role of 5-HT3 receptors in cognition and that an ideal evaluation of 5-HT3 ligands in cognition should distinguish true cognitive effects from locomotor, motivational and emotional effects.     

Peripheral 5-carboxamidotryptamine induces hindlimb scratching by stimulating 5-HT1A receptors in rats.

Treatment of rats with 5-carboxamidotryptamine (5-CT) or 5-methoxy-tryptamine (5-MeOT) induces a hindlimb scratch response. These compounds have high affinity for 5-HT1A and 5-HT1D receptors. The selective 5-HT1A receptor agonist N,N-dipropyl-5-CT (DP-5-CT) also induced hindlimb scratching while the selective 5-HT1D receptor agonist, sumatriptan, did not. 5-CT-induced hindlimb scratching was inhibited dose-dependently by several 5-HT1A antagonists (BMY 7378, NAN-190, MDL 73005EF and pindobind-5-HT1A) as well as the non-selective 5-HT antagonist, methiothepin. Pretreatment of rats with the serotonin (5-HT) synthesis inhibitor, p-chlorophenylalanine (PCPA) or the 5-HT depleting agent, reserpine, markedly attenuated 5-CT-induced hindlimb scratching. These data suggest that hindlimb scratching induced by 5-HT agonists may not be centrally mediated but rather may be mediated by a neuronal 5-HT1A receptor localized outside the blood-brain barrier.     

CCK and 5-HT act synergistically to suppress food intake through simultaneous activation of CCK-1 and 5-HT3 receptors

Cholecystokinin (CCK) and serotonin (5-HT) systems have been shown to cooperate interdependently in control of food intake. To assess mechanisms by which CCK and 5-HT systems interact in control of food intake we examined: (1) participation of CCK-1 and 5-HT3 receptors in 5-HT-induced suppression of sucrose intake; (2) the interaction between CCK and 5-HT in suppression of food intake; (3) the role of CCK-1 and 5-HT3 receptors in mediating this interaction. Intraperitoneal administration of 5-HT (0.25, 0.5 and 1.0 mg/kg) significantly reduced intake compared to control in a dose responsive fashion (r2=0.989). Suppression of food intake by 5-HT was significantly attenuated by prior treatment with the 5-HT3 receptor antagonist ondansetron at each 5-HT dose tested (P<0.05), while blockade of CCK-1 receptors by lorglumide had no effect on 5-HT-induced suppression of intake. Administration of CCK-8 (0.5 microg/kg) or 5-HT (0.5 mg/kg) alone significantly reduced sucrose intake by 22.9 and 22.2% respectively, compared to control (P<0.0001). Co-administration of CCK and 5-HT resulted in a synergistic suppression of intake leading to an overall 48.4% reduction in sucrose intake compared to saline (P<0.0001). Concomitant CCK-1 and 5-HT3 receptor blockade by lorglumide and ondansetron respectively, resulted in a complete reversal of the combined CCK and 5-HT-induced suppression of intake. Independent administration of lorglumide or ondansetron did not alter intake compared to control. These studies provide evidence that 5-HT causes suppression in food intake by acting at 5-HT3, not CCK-1 receptors. Furthermore, CCK and 5-HT interact to produce an enhanced suppression of food intake, an effect mediated through concomitant activation of CCK-1 and 5-HT3 receptors.     

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.     

Various resistance of motor preference in rats exposed to forced retraining

Adult Wistar rats were trained to get food from a narrow tube under conditions of free choice of a limb. After reaching a stable level of using the preferred limb, rats (n = 35) were forced to relearn the acquired skill for reaching food with a unpreferred paw. When afterwards the rats returned to the initial conditions of free choice of a limb, 12 animals (34%) did not recover their initial preference, 8 rats (23%) were ambidextrous, and 15 animals (43%) returned to the originally preferred paw. The results demonstrated different resistance of the initial limb preference to forced retraining in different animals. It is suggested that the process of retraining per se is not the only and sufficient condition of the change in "handedness". It also suggested that the different resistance of initial preference to forced retraining reflects individual differences in a degree (intensity) of this preference, which are predetermined by internal, probably by genetic factors.