Novelty preference predicts place preference conditioning to morphine and its oral consumption in rats

Sensation seeking is frequently observed among drug addicts. This behaviour has been modelled in non-primate animals as novelty seeking. We previously determined that novelty preference did not predict amphetamine-induced place conditioning but was positively correlated with the consumption of a low concentrated amphetamine solution. Here, we studied the relationship between novelty seeking and the vulnerability to rewarding and reinforcing effects of morphine. Wistar rats were selected according to their novelty preference. In this model, animals have free choice between a new compartment and a "familiar" compartment to which they were previously exposed during two 30-min sessions, 24 h apart. We measured oral morphine consumption when this drug was presented in tap water (25 or 50 mg/l) in free choice with water or when it was presented (50 mg/l) in a 5% (w/v) sucrose solution in free choice with a sucrose solution. The oral consumption of quinine was also measured. The rewarding effect of morphine (1.25 and 5 mg/kg; i.p.) was determined in a conditioned place preference paradigm. Whereas high and low novelty seekers did not differ in reactivity to the aversive taste of quinine, preference for novelty was associated with a greater oral morphine consumption as well as an increased conditioned place preference induced by the 5 mg/kg dose of morphine. The present results support the hypothesis that novelty preference predisposes to drug abuse.     

Strain differences in the rewarding and dopamine-releasing effects of morphine in rats

Studies examining differential sensitivity to psychoactive drugs in mice suggest that genotype may play a critical role. Furthermore, an involvement of genotype in mediating individual differences in sensitivity to the rewarding effects of several drugs of abuse has also been postulated. The aim of this study was to examine the conditioned rewarding and dopamine-releasing effects of morphine in two outbred rat strains commonly used in addiction research. Additionally, the behavioural and neuroendocrine responses of these strains to the stress of novelty were also examined. Basal locomotor activity was higher in Wistar rats than Sprague-Dawley following exposure to a novel environment. In contrast, elevations in plasma corticosteroid levels following novelty exposure did not differ between the two strains. In a counterbalanced place preference conditioning procedure, increasing doses of morphine (1.0–10.0 mg/kg SC) produced significant conditioned place preferences (CPP) in both Wistar and Sprague-Dawley strains. However, Wistar rats required a significantly larger dose of morphine (5.0 mg/kg) to produce a significant CPP than the Sprague-Dawley rats. In the latter strain, CPP occurred with doses of 3.0 mg/kg and greater. In parallel microdialysis experiments, both strains showed significant dose-related increases in dopamine release in the nucleus accumbens following acute morphine challenge (1.0–10.0 mg/kg SC). Again in Wistar rats, a larger dose of morphine was necessary to produce a significant increase in comparison to Sprague-Dawley rats. These results show that genetically distinct rat strains can show differential sensitivity to opioids, more specifically to drug-seeking responses.     

Morphine conditioned place preference and locomotion: the effect of confinement during training

The effect of confinement during conditioning on subsequent test levels of locomotor activity and conditioned place preference (CPP) was investigated by giving rats discrimination training with morphine and saline in the presence of different tactile floor cues in an open field. Groups of rats were trained under one of three levels of confinement (not confined, confined to 1/4, or confined to 1/16 of the open field) and tested for locomotor activity and CPP in the entire open field after receiving a saline injection. Confined rats subsequently spent less time on the morphinepaired floor cues (CS+) and were more active throughout the open field during the test than rats not confined during conditioning. Rats confined to the smallest area spent the least time on the CS+ and were the most active. It is suggested that confinement may preserve the novelty of the testing environment, which in turn may interfere with rats' usual responses to incentive drug-paired stimuli. These findings may have important implications for versions of the CPP technique in which training and testing environments differ considerably.     

An assessment of novelty-seeking behavior in alcohol-preferring and nonpreferring rats

This study examined novelty-seeking behavior in rat populations selectively bred for high and low alcohol-drinking behavior. In Experiment 1, and "odor-enhanced" novel environment produced greater behavioral activation in P compared to NP rats. In Experiment 2, the activity of high alcohol-drinking P and HAD rats was enhanced to a greater extent following the presentation of novel odors in a familiar arena, compared to the NP and LAD rats. The results suggest that, when measuring locomotor activity, alcohol-preferring rats are more reactive to novelty than their nonpreferring counterparts. Experiments 3 and 4, however, did not support the hypothesis that novelty seeking is associated with genetic vulnerability to high alcohol-drinking behavior. When measuring nose-poking behavior in response to novel odors and preference for a novel vs. a familiar chamber, behavior of the preferring lines did not differ from that of the nonpreferring lines, although P rats were more active in the place-preference paradigm. The overall results indicate that the relationship between novelty and alcohol drinking is only modestly associated, and is observed under specific conditions. Moreover, this study underscores the importance of using multiple measures when assessing complex behaviors such as novelty seeking.     

Differences in drug-induced place conditioning between BALB/c and C57Bl/6 mice

The influence of genotype on the rewarding effects of morphine (0, 1, 3, and 9 mg/kg), amphetamine (0, 0.5, 1, and 2 mg/kg), and cocaine (0, 2.5, 5, and 10 mg/kg) was examined in a place-conditioning paradigm. Two strains of mice, the BALB/cByJIco and the C57BL/6JIco, were used, notably because of their high difference in novelty-seeking behavior. Indeed, high novelty seeking has been associated with an increased risk for using drugs of abuse. Results clearly show that C57BL/6 mice display a conditioned place preference for stimuli paired with morphine, amphetamine, or cocaine. In contrast, BALB/c mice demonstrated place preference to morphine and place aversion to amphetamine, while cocaine was ineffective at the doses tested. No treatment induced differences in the locomotion measured in a drug-free condition. Results may be related to differences at the behavioral (difference in novelty seeking) or neurochemical level (differences in catecholaminergic or opioidergic neurotransmission).     

Conditioned place preference: no tolerance to the rewarding properties of morphine

The effect of repeated morphine administration on conditioned place preference (CPP) using a novel treatment schedule, i.e., drug treatment was always contingent with the conditioned environmental stimuli, was investigated. We also examined whether changes in the μ- and κ-opioid receptor binding occurred in the brain of morphine-treated animals. Intraperitoneal (i.p.) administration of morphine (2 and 10 mg/kg) induced a place preference after 8 daily conditioning trials (4 morphine injections on alternate trials), the level of preference being the same with the two doses of the opiate. No change in place preference was observed in the morphine-treated rats at 2 mg/kg, when animals were further trained up to a total of 32 conditioning trials (16 morphine injections). Conversely, after 20 conditioning trials (10 morphine injections), a stronger CPP response developed in the morphine-treated rats at 10 mg/kg. Signs of morphine withdrawal were never detected in morphine-treated rats during the experiment. Loss of body weight (index of opiate dependence) was not observed either 24 h or 48 h after the last morphine administration. μ- and κ-opioid receptor density and affinity were not affected by repeated morphine administrations at either dose. The results demonstrate that no tolerance develops to the rewarding properties of morphine. Indeed, a sensitisation effect may occur at increasing doses of the opiate. Furthermore, changes in the rewarding effect of morphine are not dependent upon alterations in opioid receptors involved in the reinforcing mechanisms. Received: 31 October 1996 / Accepted: 7 February 1997     

Strain differences in response to escapable and inescapable novel environments and their ability to predict amphetamine-induced locomotor activity

Rationale. Locomotor response to novelty predicts locomotor and reinforcing effects of psychostimulant drugs in outbred rats. Among Lewis and Fischer 344 (F344) inbred rats this association is less clear, perhaps due to strain-selective differences in responses to novelty. Objective. We examined responses to novel inescapable and escapable environments and to novel objects in these strains. Methods. Experiment 1 utilized a place conditioning procedure. Rats were confined to one side for 8 days and then allowed access to both this (familiar) and the novel sides. Experiment 2 assessed locomotor response within an inescapable environment. On another occasion, contacts with novel objects within a novel environment were tabulated. Corticosterone levels and fecal boli were measured. Whether these responses predicted amphetamine-induced locomotor activity was determined. To further assess genetic contributions to this association, experiment 3 assessed novelty responses in F1 hybrid Lewis-F344 rats. Results. Lewis rats showed greater novelty-seeking behavior in the escapable environment but lower locomotor activity in the inescapable environment compared to F344 rats. There were no strain differences in novel object contacts, corticosterone, or fecal boli responses. Baseline corticosterone levels and activity levels in the novel environment were positively correlated with amphetamine activity based on data from all rats. However, novelty and amphetamine-induced activity showed non-significant negative correlations in F344 and Lewis rats. Yet, F1 rats showed a significant positive correlation between these variables, even though some of their other responses were Lewis-like or F344-like. Conclusions. These data suggest that responses to different novelty situations are strain-dependent. Electronic Publication     

Low and high locomotor responsiveness to cocaine predicts intravenous cocaine conditioned place preference in male Sprague-Dawley rats

Outbred, male Sprague-Dawley rats can be classified as either low or high cocaine responders (LCRs or HCRs, respectively) based on cocaine-induced locomotor activity in an open-field arena. This difference reflects cocaine's ability to inhibit the striatal dopamine transporter and predicts development of sensitization. To investigate the relationship between initial cocaine locomotor responsiveness and cocaine reward, here we first classified rats as either LCRs or HCRs in a conditioned place preference (CPP) apparatus. Subsequently, we conducted cocaine conditioning trials, twice-daily over 4 days with vehicle and cocaine (10 mg/kg, i.p. or 1 mg/kg, i.v.). When cocaine was administered by the i.p. route, similar to previous findings in the open-field, LCRs and HCRs were readily classified and locomotor sensitization developed in LCRs, but not HCRs. However, cocaine CPP was not observed. In contrast, when cocaine was administered by the i.v. route, the LCR/HCR classification not only predicted sensitization, but also CPP, with only LCR rats exhibiting sensitization and cocaine conditioning. Our findings show that the initial locomotor response to cocaine can predict CPP in male Sprague-Dawley rats under conditions when place conditioning develops, and that LCRs may be more prone to develop conditioning in the context of cocaine reward.     

Immediate and long-term behavioral effects of a single nicotine injection in adolescent and adult rats

We examined the acute rewarding as well as the long-term psychomotor altering effects of nicotine in early adolescent and adult male Sprague-Dawley rats. Place conditioning was used to examine nicotine-induced reward after a single drug pairing. A single pairing of nicotine with the initially non-preferred side of the place conditioning apparatus produced a conditioned place preference (CPP) in early adolescent but not adult animals. One month later, animals were given a nicotine challenge and locomotor activity observed in the open field to characterize age differences in the lasting alterations resulting from this single injection. Adult rats showed tolerance to the locomotor depressant effects of a low dose of nicotine whereas adolescent rats showed tolerance to a higher dose. Regardless of treatment group, animals tested during adolescence responded to the nicotine challenge with less hypoactivity when compared with animals tested as adults. The present results are in agreement with previous studies showing that early adolescent rats are more sensitive to nicotine's rewarding effects and are in accord with studies showing a unique profile of neurobehavioral alterations following nicotine exposure when compared with adults. Such findings are extended here by showing that these differences are seen following only a single pretreatment dose and persist for at least one month after pretreatment.     

Morphine-induced place conditioning in Fischer and Lewis rats: acquisition and dose-response in a fully biased procedure

The Fischer (F344) and Lewis (LEW) rat strains differ on a variety of behavioral assays examining the effects of morphine, with many of the differences observed during acquisition of behavioral responses. The results of these studies and others examining endogenous physiology and the biochemical effects of morphine suggest that F344 rats are more sensitive to morphine than LEW rats. However, LEW animals have shown greater conditioned place preferences (CPP) to 4 mg/kg than F344 rats. CPP is a popular assay of drug reward in which acquisition of the preference can be measured across multiple conditioning cycles, yet this aspect of CPP has not been assessed in F344 and LEW rats. As part of an ongoing effort to fully characterize the conditioned rewarding effects of abused drugs in these strains, the present study assessed the effects of 0, 1, 4 and 10 mg/kg subcutaneous (SC) morphine in adult male F344 and LEW rats (n=12/strain/dose). A fully biased place conditioning procedure was employed where morphine's effects were paired with the initially non-preferred chamber on Day 1, saline was paired with the preferred chamber on Day 2 and drug-free access to the entire apparatus was allowed on Day 3. This conditioning and testing regimen was repeated for four consecutive cycles. The F344 animals acquired CPP at 1 mg/kg only; this effect emerged after only two conditioning cycles. LEW rats never acquired a CPP at any dose tested. Peak blood morphine levels following SC injections of 1, 4 or 10 mg/kg revealed no significant strain or dose effects. These behavioral data are consistent with the hypothesis that F344 rats are more sensitive to the rewarding effects of morphine than LEW rats. Additional implications for the Fischer-Lewis model of drug abuse and the utility of CPP acquisition procedures are discussed.     

Morphine sex-dependently induced place conditioning in adult Wistar rats

The present study was conducted to investigate the potential sex-differences in morphine-induced conditioned place preference. A 3-day unbiased conditioning procedure was used to establish conditioned place preference in adult male and female Wistar rats (weighing 200-250 g). The effect of morphine on locomotor activity of subjects was also studied. Naloxone (0.5-2 mg/kg, i.p.), a selective antagonist of mu-opioid receptor or sulpiride (0.5-2 mg/kg, s.c.), a selective antagonist of dopamine D(2) receptor was administered, during conditioning, to indicate the receptor-mediated mechanisms governing upon possible sex-differences to the opioid response. Results show that morphine (0.5-10 mg/kg, s.c.) differently produced a significant place preference in female and male Wistar rats. Although, the opioid maximum response in both sexes was observed at 7.5 mg/kg, but, it was found that female rats acquired conditioned place preference at a lower dose (0.5 mg/kg, s.c.) of morphine compared to male rats. Moreover, the increase in morphine-induced response at higher doses (5-10 mg/kg, s.c.) was more pronounced in females than the males, indicating that female Wistar rats are more sensitive to the place conditioning induced by morphine. Also, the females were more sensitive to locomotor activation induced by morphine at least at one dose (7.5 mg/kg). Animals' body-weight at 10 mg/kg of opioid was increased, the effect that was not dependent to sex. The results also demonstrate that naloxone (1 and 2 mg/kg, i.p.) induced a significant place preference in two sexes with no significant effect on animals' locomotor activity. The antagonist in males but not in females showed a significant effect on animals' body-weight. Naloxone (0.5-2 mg/kg, i.p.) prior-administration to morphine, during conditioning, attenuated the opioid response in two sexes. The attenuation of the morphine response was more pronounced in males than the other sex at the higher dose (2 mg/kg) of the antagonist. In addition, the preadministration of naloxone, during morphine conditioning, both attenuated the drug-induced hyperactivity in females and decreased the animals' body-weight, albeit more effectively in females than the males. Sulpiride injections (1 and 2 mg/kg s.c.), during the conditioning period, induced a significant aversion in males but not in females with no significant effect either on locomotor activity or body-weight in both sexes. When sulpiride (0.5-2 mg/kg, s.c.), during conditioning, was morphine pre-injected, the antagonist at higher doses significantly attenuated the opioid response in males, reflecting the involvement of dopamine D(2) receptor in sex-dependent morphine-conditioned place preference. Prior-injections of sulpiride to morphine produced a significant effect on locomotor activity of females. The effect of the antagonist preinjections on body-weight was also observed in males. Present results indicate sex-differences both in reinforcing and locomotor activity effects of morphine in Wistar rats.     

Mid- to late gestational morphine exposure does not alter the rewarding properties of morphine in adult male rats

Prenatal exposure to drugs of abuse often leads to physiological and neurobiological abnormalities including decreased brain and body weight, cognitive deficits and behavioral alterations. A handful of studies showed increased vulnerability to drug abuse in prenatally drug-exposed offspring. Our work also demonstrated that prenatal exposure to analgesic doses of morphine during gestation days 11-18 increases mu-opioid receptor density in the nucleus accumbens and central amygdala of adult male rats. Both the nucleus accumbens and central amygdala play important roles in modulating drug-induced reward via the mesolimbic dopaminergic system. Therefore, two types of behavioral paradigms were used to test the hypothesis that the same prenatal morphine exposure would enhance the rewarding effects of morphine, making drug-exposed offspring more vulnerable to abuse this drug in adulthood. All experiments were performed with adult male offspring of saline-injected, morphine-injected or non-injected (control) dams. (1) The unbiased conditioned place preference (CPP) paradigm was used to investigate whether prenatal morphine exposure sensitizes adult male rats to non-contingent morphine reward. These adult animals were conditioned with 0.1, 0.3, 1, 3 or 5 mg/kg morphine. All control, prenatally saline- and morphine-exposed male rats preferred the morphine-paired compartment relative to the saline-paired compartment. However, the magnitude of morphine CPP in adult male rats was not dependent on the conditioning dose of morphine or prenatal morphine exposure. (2) Intravenous morphine self-administration was used to assess the behavioral response to contingent morphine reward. Each rat self-administered one of four doses of morphine (0.3, 1, 2 or 3 mg/kg/infusion). Morphine self-administration was not altered in prenatally morphine-exposed adult male offspring. Control males self-administered significantly less morphine at the lowest dose of morphine than both prenatally saline- and morphine-exposed males. Although our data show that prenatal exposure to an analgesic dose of morphine during the time of opioid receptor appearance does not enhance morphine CPP or self-administration, they do not exclude the possibility that this prenatal morphine exposure enhances the rewarding properties of other drugs of abuse.     

丰富环境对高、低反应性大鼠吗啡条件性位置偏爱的影响

目的:比较不同环境(丰富环境、孤立环境)对不同反应性大鼠(高反应性、低反应性)吗啡条件性位置偏爱(conditioned place preference,CPP)的影响。方法:出生后40d♂SD大鼠120只,以旷场测验区分出高、低反应性大鼠各40只,然后在高、低反应性大鼠中各随机取20只进行丰富环境干预,另外20只进行孤立环境干预,干预时间42d。从干预d30后,再对各组大鼠(丰富环境高反应鼠、孤立环境高反应鼠、丰富环境低反应鼠、孤立环境低反应鼠随机取半)进行吗啡CPP训练及测试。结果:总体上讲,接受丰富环境干预的大鼠其吗啡CPP程度不如孤立环境干预大鼠显著(P<0.05)。接受丰富环境和孤立环境干预的大鼠均表现为高反应鼠CPP比低反应鼠显著(P<0.05)。高反应大鼠经孤立环境干预后,其CPP程度最高。结论:环境干预和个体的易感性存在交互作用,丰富环境可降低吗啡的犒赏效应,弱化大鼠的成瘾行为,可能是预防成瘾行为发生的保护因素。     

Failure of rewarding and locomotor stimulant doses of morphine to promote adult rat 50-kHz ultrasonic vocalizations

Rationale

Frequency-modulated 50-kHz ultrasonic vocalizations (USVs) are emitted by adult rats in response to psychostimulants and non-pharmacological appetitive stimuli and thus have been proposed to model positive affect.

Objective

The main aim was to determine whether rewarding doses of morphine increase 50-kHz call rate or alter the relative prevalence of the trill call subtype.

Methods

In experiment 1, USVs were recorded from adult male Long?CEvans rats after subchronic morphine (1?mg/kg subcutaneous (SC)) administration, acute challenge with morphine (1 and 3?mg/kg SC) or amphetamine (1?mg/kg IP, positive control), and in conjunction with locomotor activity tests with morphine (1 and 3?mg/kg SC). In experiments 2 and 3, the USV altering, rewarding, and locomotor effects of morphine were examined using a conditioned place preference (CPP) procedure.

Results

In experiment 1, morphine (1?mg/kg) initially suppressed calling; rats became tolerant to this effect with repeated exposure. Tested subsequently in singly- and pair-tested rats, morphine markedly decreased USVs but significantly increased locomotor activity. In experiments 2 and 3, morphine produced a significant CPP without increasing either unconditioned or conditioned USV emission. Morphine did not detectably alter the relative prevalence of 50-kHz call subtypes.

Conclusions

Although 50-kHz calls, and the trill call subtype in particular, have been proposed as an animal model of positive mood, not all euphoriant drugs acutely increase the rate of 50-kHz calling or consistently promote trill calls.     

Pharmacological blockade or genetic knockout of the NOP receptor potentiates the rewarding effect of morphine in rats

The Nociceptin/OrphaninFQ (NOP) system is believed to be involved in drug abuse and addiction. We have recently demonstrated that activation of the NOP receptor, by systemic administration of the NOP receptor agonist Ro65-6570, attenuated the rewarding effect of various opioids in conditioned place preference (CPP) in rats and this attenuating effect was reversed by the NOP receptor antagonist J-113397. The present study demonstrates that co-administration of J-113397 (4.64 mg/kg, i.p.) during conditioning, facilitates morphine-induced CPP. Moreover, we found that NOP receptor knockout rats (oprl1(-/-)) are more sensitive to the rewarding effect of morphine than wildtype control rats. Thus, pharmacological or genetic inactivation of the NOP system rendered rats more susceptible to the rewarding effect of morphine. These findings support the suggestion that the endogenous NOP system attenuates the rewarding effect of opioids and therefore offers a therapeutic target for the treatment of drug abuse and addiction.     

Neurosteroids and reward: allopregnanolone produces a conditioned place aversion in rats

The neurosteroid 3alpha-hydroxy-5alpha-pregnan-20-one (allopregnanolone) has been reported to have rewarding properties in mice tested for place conditioning. Another study found that allopregnanolone reduced dopamine (DA) output in the nucleus accumbens (NAc) of rats. As many rewarding stimuli increase accumbens DA, these results may appear contradictory. Thus, the present study examined the rewarding properties of allopregnanolone in rats tested for place conditioning using an unbiased conditioning procedure. In control studies, a place preference was observed following conditioning with intraperitoneal (2.0 mg/kg) or intracerebroventricular (i.c.v.) (100 microg/0.5 microl) amphetamine. Conditioning with i.c.v. allopregnanolone produced a significant aversion at a dose of 5.0 microg (in 5.0 microl) and a near aversion at 25.0 microg (in 8.3 microl); doses of 0 microg (i.e., vehicle alone, in 10 microl) or 30.0 microg (in 10 microl) produced little effect on place preference. During conditioning, locomotor activity was stimulated by amphetamine using either route of administration, but allopregnanolone had no significant main effect on locomotor activity. Thus, there was a dissociation between the effects of drugs on locomotor activity vs. place conditioning. Results show that i.c.v. amphetamine produces a place preference, whereas allopregnanolone produces either no effect or an aversion, depending on the dose.     

High impulsivity predicting vulnerability to cocaine addiction in rats: some relationship with novelty preference but not novelty reactivity, anxiety or stress

Rationale

Impulsivity is a vulnerability marker for drug addiction in which other behavioural traits such as anxiety and novelty seeking (??sensation seeking??) are also widely present. However, inter-relationships between impulsivity, novelty seeking and anxiety traits are poorly understood.

Objective

The objective of this paper was to investigate the contribution of novelty seeking and anxiety traits to the expression of behavioural impulsivity in rats.

Methods

Rats were screened on the five-choice serial reaction time task (5-CSRTT) for spontaneously high impulsivity (SHI) and low impulsivity (SLI) and subsequently tested for novelty reactivity and preference, assessed by open-field locomotor activity (OF), novelty place preference (NPP), and novel object recognition (OR). Anxiety was assessed on the elevated plus maze (EPM) both prior to and following the administration of the anxiolytic drug diazepam, and by blood corticosterone levels following forced novelty exposure. Finally, the effects of diazepam on impulsivity and visual attention were assessed in SHI and SLI rats.

Results

SHI rats were significantly faster to enter an open arm on the EPM and exhibited preference for novelty in the OR and NPP tests, unlike SLI rats. However, there was no dimensional relationship between impulsivity and either novelty-seeking behaviour, anxiety levels, OF activity or novelty-induced changes in blood corticosterone levels. By contrast, diazepam (0.3?C3?mg/kg), whilst not significantly increasing or decreasing impulsivity in SHI and SLI rats, did reduce the contrast in impulsivity between these two groups of animals.

Conclusions

This investigation indicates that behavioural impulsivity in rats on the 5-CSRTT, which predicts vulnerability for cocaine addiction, is distinct from anxiety, novelty reactivity and novelty-induced stress responses, and thus has relevance for the aetiology of drug addiction.     

The effect of previous exposure to nicotine on nicotine place preference

Rationale

Prior exposure to drugs of abuse may increase or decrease the reinforcing effects of the drug in later consumptions. Based on the initial locomotor activity (LA) response to an acute drug administration or to novelty in an open-field arena, animals can be classified as low or high LA responders (LR or HR). Few studies have used this classification with nicotine, and the results are controversial. Some authors suggested that nicotine can induce conditioned-place preference (CPP) following prior nicotine exposure, whereas others suggested that previous nicotine exposure extinguishes nicotine-CPP.

Objective

To explore if the administration of nicotine in a novel environment without explicit behavioral consequences to classify animals in low and high nicotine responders (LNR and HNR) could affect the establishment of nicotine CPP in male Sprague–Dawley rats.

Results

Prior exposure to a single dose of nicotine (0.4 mg/kg, subcutaneously) induced CPP in LNR rats after 14 days of conditioning (seven-trial) but not after two or eight conditioning days. In contrast, HNR rats did not show CPP under any condition. In addition, our results indicated that previous exposure to nicotine decreased its rewarding effects in eight conditioning days CPP (four-trial), which can be regularly established without prior exposure to nicotine.

Conclusion

The results suggested that response to a single exposure to nicotine predicts the acquisition of nicotine preference in a 14-day conditioning protocol only for LNR rats. Thus, our findings demonstrated the relevance of using LNR and HNR classification when the individual susceptibility to nicotine preference is studied.     

Morphine-induced place preference: involvement of cholinergic receptors of the ventral tegmental area

In the present study, the effects of intra-ventral tegmental area injections of cholinergic agents on morphine-induced conditioned place preference were investigated by using an unbiased 3-day schedule of place conditioning design in rats. The conditioning treatments with subcutaneous injections of morphine (0.5-7.5 mg/kg) induced a significant dose-dependent conditioned place preference for the drug-associated place. Intra-ventral tegmental area injection of an anticholinesterase, physostigmine (2.5 and 5 microg/rat) or nicotinic acetylcholine receptor agonist, nicotine (0.5 and 1 microg/rat) with an ineffective dose of morphine (0.5 mg/kg) elicited a significant conditioned place preference. Furthermore, intra-ventral tegmental area administration of muscarinic acetylcholine receptor antagonist, atropine (1-4 microg/rat) or nicotinic acetylcholine receptor antagonist, mecamylamine (5 and 7.5 microg/rat) dose-dependently inhibited the morphine (5 mg/kg)-induced place preference. Atropine or mecamylamine reversed the effect of physostigmine or nicotine on morphine response respectively. The injection of physostigmine, but not atropine, nicotine or mecamylamine, into the ventral tegmental area alone produced a significant place aversion. Moreover, intra-ventral tegmental area administration of the higher doses of physostigmine or atropine, but not nicotine or mecamylamine decreased the locomotor activity. We conclude that muscarinic and nicotinic acetylcholine receptors in the ventral tegmental area may critically mediate the rewarding effects of morphine.     

Effects of beta-funaltrexamine and naloxonazine on single-trial morphine-conditioned place preference and locomotor activity

The current study assessed the ability of the selective irreversible mu-opioid receptor antagonists beta-funaltrexamine (betaFNA) and naloxonazine (NALZ) to alter the locomotor and rewarding effects of a single intravenous injection of morphine using the conditioned place preference (CPP) model. In the first experiment, rats were conditioned with a single injection of morphine (10 mg/kg iv) paired with one compartment of a CPP apparatus and then were tested for CPP at either 1 or 7 days after conditioning. Rats showed hypoactivity following acute morphine on the conditioning trial and showed CPP when tested either 1 or 7 days later. In the next experiments, rats were pretreated with betaFNA (20 mg/kg sc, 20 h before conditioning), NALZ (15 or 30 mg/kg sc, 24 h before conditioning) or saline and then were conditioned with a single injection of morphine (10 mg/kg iv) or saline. Pretreatment with NALZ alone, but not betaFNA, significantly decreased locomotor activity; neither antagonist alone produced a significant shift in preference for either compartment of the CPP apparatus. Pretreatment with either betaFNA or NALZ blocked completely morphine-induced hypoactivity, but neither antagonist had a significant effect on morphine CPP. These results indicate that mu-opioid receptors are more critically involved in acute morphine-induced hypoactivity than in acute morphine reward.