Differential effects of novelty exposure on place preference conditioning to amphetamine and its oral consumption

Rationale Sensation/novelty seeking is frequently observed in drug abusers. Rats with high locomotor activity in response to inescapable novelty may be more prone to drug addiction. However, it is not clear whether this response to novelty represents reactivity to the novelty-induced stress or seeking for novelty.Objectives We have compared the influence of the response to novelty—presented in a forced stressful or in a free choice non-stressful manner—on vulnerability to addictive properties of amphetamine.Methods Wistar rats were selected according to their (i) reactivity to inescapable novelty and (ii) novelty preference. For this purpose, animals were exposed during two 30-min sessions, 24 h apart, to the same compartment; their motor activity during the first session was used as an index of reactivity. On the third day, they were allowed to choose between this "familiar" environment and a novel one. Rewarding properties of amphetamine (0.2–3.2 mg/kg, s.c.) were determined by place conditioning. Amphetamine oral consumption (10–50 mg/l) in a free-choice paradigm was measured over a period of 32 days.Results Reactivity to novelty and novelty preference were not correlated. Reactivity to inescapable novelty predicted place conditioning induced by the lowest dose of amphetamine, whereas preference for novelty did not. High responders to inescapable novelty consumed less amphetamine than low responders. Novelty preference was positively correlated to amphetamine oral consumption only at the lowest concentration.Conclusions Reactivity to inescapable novelty and novelty preference represent different behavioural components, which are related differentially with amphetamine place conditioning and its oral consumption.     

Individual differences in activity predict locomotor activity and conditioned place preference to amphetamine in both adolescent and adult rats

Individual and developmental differences in novelty seeking have been implicated in differential sensitivity to psychostimulants in rodents, but findings are mixed. The extent to which age differences in activity in a novel arena depended on test duration was examined by comparing adolescent and adult rats after 5 and after 60 min of testing (session 1). Rats were tested again after amphetamine or saline administration 24 h later (session 2) to examine whether activity in a novel arena predicts sensitivity to locomotor-activating effects of amphetamine. Data from two experiments were used to examine consistency of the findings. Only activity in 60 min sessions produced a consistent age difference (adolescent < adult) and predicted activity after amphetamine in session 2. Session 1 activity also predicted saline activity in session 2, indicating that individual differences in activity is a stable trait. A third data set was used to determine whether general (saline) and amphetamine-induced activity predicted magnitude of conditioned place preference (CPP) in late-adolescent and adult rats. Age was not a significant predictor, but CPP was positively associated with amphetamine activity and negatively associated with saline activity. Thus, in contrast to enhanced psychostimulant sensitivity in high novelty-seekers, rats higher in general activity are less sensitive to amphetamine conditioned place preference.     

Naloxone enhances the expression of morphine-induced conditioned place preference

The present study examined the effects of naloxone on acquisition and expression of morphine-induced conditioned place preference (CPP). Three groups of rats were given morphine (5 mg/kg, SC), both morphine and naloxone (1 mg/kg, SC), or saline paired with a distinctive environment. On alternating days they were given saline paired with another distinctive environment. After four exposures to each environment, the animals were given a preference test in which they had access to both environments simultaneously while under the influence of either naloxone (1 mg/kg, SC) or saline. Morphine-conditioned animals showed CPP evident as an increased amount of time spent in the drug-associated environment relative to saline controls. Rats given both naloxone and morphine during conditioning, and saline on the test day, did not show CPP. In contrast, morphine-conditioned animals given naloxone on the test day showed stronger CPP than morphine-conditioned animals given saline. These findings indicate that naloxone blocks the acquisition, but enhances the expression of morphine-induced CPP. In a separate experiment, the effects of naloxone on locomotor activity were determined during the CPP test. The results indicated that naloxone decreased locomotor activity. In morphine-conditioned animals only, naloxone also produced an increase in the amount of time per entry in the drug-associated environment. The results suggest that naloxone may enhance morphine-induced CPP by decreasing locomotor activity that may otherwise compete with expression of CPP.     

The effect of neurotoxic doses of methamphetamine on methamphetamine-conditioned place preference in rats

Rationale. Methamphetamine has been shown to produce neurotoxicity demonstrated by depletions of dopamine and serotonin in the striatum and nucleus accumbens. Objective. The current study examined the effects of neurotoxic doses of methamphetamine on the rewarding effect of subsequent administration of methamphetamine assessed by the conditioned place preference (CPP) procedure. Methods. Male and female rats were treated with a neurotoxic regimen of methamphetamine (4×10 mg/kg, s.c., once every 2 h) or saline, and concentrations of dopamine, 3,4-dihydroxyphenylacetic acid, serotonin, and 5-hydroxyindoleacetic acid were measured 15 days later in the striatum, nucleus accumbens, and prefrontal cortex (PFC). In another experiment, male rats were given methamphetamine neurotoxic treatment or saline and were then conditioned 7 days later with methamphetamine (0.1, 0.3, or 1.0 mg/kg, s.c.) or saline using a four-trial CPP procedure. Locomotor activity was also measured during the conditioning sessions to investigate whether or not the neurotoxic methamphetamine treatment altered locomotor activity following a subsequent methamphetamine challenge. Results. Males and females did not differ significantly in the amount of neurochemical depletion produced by methamphetamine in any brain region. Collapsed across sex, dopamine was significantly depleted in nucleus accumbens (25%) and striatum (51%); serotonin was significantly depleted in nucleus accumbens (35%), striatum (34%) and PFC (33%). The methamphetamine challenge dose dependently increased locomotor activity, but the increase was not affected by treatment with neurotoxic doses of methamphetamine. In contrast, treatment with neurotoxic doses of methamphetamine enhanced CPP at the intermediate conditioning dose (0.3 mg/kg). Conclusions. These results indicate that the rewarding effect of methamphetamine is enhanced by prior treatment with neurotoxic doses of methamphetamine, suggesting either a compensatory hyperfunctioning of spared dopamine neurons or a loss of inhibitory control from serotonergic input. Electronic Publication     

Locomotion and conditioned place preference produced by acute intravenous amphetamine: role of dopamine receptors and individual differences in amphetamine self-administration

 Although previous studies have shown that dopamine (DA) antagonists block amphetamine reward, these studies have utilized animal models that involve repeated exposures to amphetamine. The present investigation examined the effect of DA antagonists on single-trial conditioned place preference (CPP) produced by acute intravenous (IV) amphetamine in rats. In the first experiment, rats were prepared with a jugular catheter and then received an acute IV injection of amphetamine (0.1–3 mg/kg) paired with one compartment of a CPP apparatus. Relative to sham controls (no IV catheter), amphetamine produced a dose-dependent increase in locomotor activity and CPP. Two further experiments demonstrated that both effects of amphetamine were completely blocked by pretreating rats with the D₁ DA antagonist SCH-23390 (0.025 and 0.25 mg/kg) or the D₂ DA antagonist eticlopride (0.2 and 2 mg/kg) on the conditioning trial. In a final experiment, single-trial amphetamine CPP did not predict subsequent self-administration of IV amphetamine (10–50 μg/infusion) using either a fixed ratio (FR) 1 or progressive ratio (PR) schedule of reinforcement. Thus, while sharing a similar DA receptor mechanism, the present results indicate that single-trial CPP and self-administration are dissociable effects of IV amphetamine. Received: 22 April 1998 / Final version: 8 October 1998     

Nicotine-induced conditioned place preference in adolescent rats

A number of clinical reports have noted that women are more vulnerable to tobacco abuse than men, and adolescent females are especially vulnerable to nicotine addiction. Conditioned place preference (CPP) is a widely used technique for determining the rewarding effects of drugs with abuse potential in animal models. Several studies have reported that nicotine was ineffective in eliciting CPP in rats; while others have observed conditioned place aversion (CPA) rather than preference for nicotine. One recent investigation established CPP in adolescent female rats, however at a reasonably high dose; while a second reported dose dependence of nicotine-induced CPP in male but not female rats. The present study was designed to determine the lowest dose necessary to induce CPP to nicotine in adolescent female rats. Nicotine-induced CPP was obtained at a subcutaneous dose of 0.03 mg/kg (salt content) using a biased conditioning paradigm. Higher doses produced aversion and lower doses provided no rewarding or aversive effects. CPP persisted for at least 3 weeks following conditioning in the absence of further nicotine treatment. In contrast with results from adolescent human females and males, age-matched male rats also evidenced CPP at this very low dose of nicotine. These results indicate that even a low dose of nicotine is reinforcing and addicting in both adolescent male and female rats and brings into question the suggestion that nicotine induces greater addicting capacity in adolescent girls than boys.     

Failure to establish a conditioned place preference with ethanol in rats

Previous studies have demonstrated that many drugs of abuse are able to produce a conditioned place preference in rats. We sought to determine if ethanol, injected in a wide range of doses, could also produce a conditioned place preference. Statistical analysis of our results indicated that the IP administration of the drug (50, 100, 150, 300, 600, 800, or 1000 mg/kg) failed to produce either a conditioned place preference or aversion compared to vehicle injected control rats. Under similar testing conditions a conditioned place preference was obtained with amphetamine (2 mg/kg) and this preference was not secondary to conditioned hyperactivity. In another experiment, rats were injected with ethanol through indwelling jugular cannulae at doses similar to those reported [24,26] to support (1, 2 mg/kg) or not to support (8 mg/kg) self-administration by rats. We also failed to obtain a conditioned place preference using these doses. Blood and brain ethanol levels, determined 1, 2 or 5 minutes after the administration of 2 mg/kg (IV) indicated very low ethanol levels. These results may suggest that rats do not self-administer ethanol for its intoxicating properties, and that the affective state produced by ethanol administration per se is not readily conditionable to environmental cues.     

Independence of amphetamine reward from locomotor stimulation demonstrated by conditioned place preference

The conditioned place preference (CPP) paradigm is used widely as a measure of a drug's rewarding properties. The present study examined whether the CPP produced by amphetamine is dependent on the locomotor stimulation that is produced by the drug. An earlier study (Swerdlow and Koob 1984) found that interfering with loomotor stimulation using restraint during the drug treatment blocked CPP. The present study examined whether this effect of restraint was indeed due to restriction of locomotion or was due to restraint maintaining the stimulus novelty of the CPP apparatus. The first experiment showed that novelty of the apparatus itself was a potent factor in the CPP paradigm and was capable of producing a place preference. The second experiment showed that restraint alone could produce a CPP, as would be expected if it maintained stimulus novelty of the apparatus. It also showed that although a CPP to amphetamine could be blocked by restraining the animals during drug treatment, prior habituation to the apparatus to reduce stimulus novelty before treatment negated the effect of restraint on amphetamine CPP. These results indicate that rats can demonstrate a CPP produced by amphetamine even when their activity is restrained. This suggests that the drug's rewarding properties are not dependent on locomotor stimulation. Offprint requests to: G.D. Carr     

Conditioned locomotor activity but not conditioned place preference following intra-accumbens infusions of cocaine

In the first experiment, the conditioned place preference (CPP) paradigm was used to examine the rewarding properties of bilateral microinfusions of cocaine HCl into the nucleus accumbens (0, 12.5, 25, 50, or 100 µg). No dose of intra-accumbens cocaine induced a significant CPP. However, bilateral intra-accumbens infusions ofd-amphetamine sulfate (10 µg) or intraperitoneal administration of cocaine HCl (5 or 10 mg/kg) both produced a significant preference for the drug-paired compartment. In the second experiment, the ability of bilateral intra-accumbens infusions of cocaine HCl (50 µg) to elicit conditioned locomotor activity (CLA) was examined. During the conditioning trials, intra-accumbens cocaine significantly increased locomotor activity. On the test day, when no drug was administered, the group that had previously received cocaine in the activity chamber showed significantly greater locomotor activity than the vehicle control group. This demonstration of CLA indicates that rats are able to associate the effects of intra-accumbens infusions of cocaine with environmental stimuli; however, these infusions are not rewarding as measured by the CPP paradigm. In addition, these results may indicate important differences between the neural substrates for cocaine and amphetamine reward and reveal a dissociation between CPP and CLA.     

Enhancement of conditioned preference for a place paired with amphetamine produced by blocking the association between place and amphetamine-induced sickness

Rats learn to prefer a place that has been paired with the rewarding effect of amphetamine. Since amphetamine is also known to produce an aversive effect, called here sickness, pairings of a place with amphetamine should produce a place-sickness association as well as the place-reward association that underlies the conditioned place preference. The purpose of the present experiments was to enhance the conditioned place preference produced by place-amphetamine pairings by blocking the place-sickness association. In Experiments 1 and 2, the taste of saccharin was paired with sickness induced by amphetamine or by lithium, respectively. The saccharin taste was presented prior to each pairing of a white chamber with amphetamine to block the place-sickness association. In Experiment 3, a brief placement in a distinctive cage that had previously been paired with lithium-induced sickness preceded each pairing of the white chamber with amphetamine. Blocking of the place-sickness association occurred as evidenced by the reliable enhancement of conditioned place preference obtained in each of the three experiments.     

Clonidine produces a conditioned place preference in rats

The possibility that the -adrenergic agonist clonidine can act as a reinforcing agent was investigated using the conditioned place preference paradigm. Using two different variants of this method we were able to demonstrate reinforcing properties of clonidine at doses of 200 and 400 g/kg. These results are consistent with those obtained by other investigators using the self-administration technique, and support the view that adrenergic mechanisms may be involved in reinforcement.     

Concurrent choice for social interaction and amphetamine using conditioned place preference in rats: Effects of age and housing condition

Background

Social interaction can serve as a natural reward that attenuates drug reward in rats; however, it is unknown if age or housing conditions alter the choice between social interaction and drug.

Methods

Individually- and pair-housed adolescent and adult male rats were tested using conditioned place preference (CPP) in separate experiments in which: (1) social interaction was conditioned against no social interaction; (2) amphetamine (AMPH; 1 mg/kg, s.c.) was conditioned against saline; or (3) social interaction was conditioned against AMPH.

Results

Social interaction CPP was obtained only in individually-housed adolescents, whereas AMPH CPP was obtained in both individually-housed adolescents and adults; however, the effect of AMPH was not statistically significant in pair-housed adults. When allowed to choose concurrently between compartments paired with either social interaction or AMPH, individually-housed adolescents preferred the compartment paired with social interaction, whereas pair-housed adolescents preferred the compartment paired with AMPH. Regardless of housing condition, adults showed a similar preference for the compartments paired with either social interaction or AMPH.

Conclusions

Although some caution is needed in interpreting cross-experiment comparisons, the overall results suggest that individually-housed adolescents were most sensitive to the rewarding effect of social interaction, and this hypersensitivity to social reward effectively competed with AMPH reward.     

Effects of diazepam on conditioned place preference induced by morphine or amphetamine in the rat

RATIONALE: The drug-abuse literature suggests that benzodiazepines may be preferentially abused in conjunction with opioids rather than stimulants. OBJECTIVE: To investigate possible effects of diazepam on the reinforcing effects of morphine and amphetamine. METHODS: The effects of diazepam (0.5, 1 or 2 mg/kg) on the formation and expression of conditioned place preferences (CPP) induced by morphine sulphate (0.3, 0.8, 2 and 8 mg/kg) or D-amphetamine (0.4, 0.8, 2 or 2.5 mg/kg) were studied in an unbiased CPP paradigm. The action of diazepam (1 mg/kg) on conditioned and unconditioned locomotion induced by morphine (2 mg/kg) or amphetamine (2 mg/kg) was assessed. RESULTS: Rats that received conditioning injections of morphine in one environment displayed a preference for this environment. Pre-testing injections of diazepam did not alter the magnitude of this CPP. When diazepam was given with morphine during training, rats displayed a CPP for the environment paired with the two drugs. Injections of amphetamine in one environment also induced a preference for this environment. However, pre-testing injections of diazepam blocked the expression of amphetamine-induced CPP, and co-injections of diazepam blocked the formation of amphetamine CPP. Diazepam itself did not produce a CPP nor did it alter spontaneous place preferences. Diazepam equally blocked both morphine and amphetamine unconditioned and conditioned locomotor hyperactivity. This indicates that its effects on morphine and amphetamine CPP were not due to a differential effect on locomotion. CONCLUSIONS: Diazepam interferes with the reinforcing properties of amphetamines but not of morphine. The reinforcing effects of morphine and amphetamine are pharmacologically dissociable.     

Food-deprivation increases cocaine-induced conditioned place preference and locomotor activity in rats

 Food-deprivation increases the reinforcing efficacy of cocaine and other drugs within self-administration experiments. In this study, the effects of food-deprivation on cocaine-induced conditioned place preference were investigated. Male Sprague-Dawley rats were assigned to one of two feeding conditions: satiated (with ad libitum food) or deprived (maintained at 80% of free-feeding body weights). During conditioning trials, on alternate days, rats received IP injections of cocaine (0.0, 2.5, 5.0, or 10.0 mg/kg; n=12 per dose group) and were confined for 30 min in one of two distinct environments. On intervening days, the same rats were injected with saline and confined for 30 min in the opposite environment. After four cocaine and four saline trials, a 15-min choice test (with no injections) was given. During this time, the rats were able to move freely through a passageway between both environments. Relative to the food-satiated rats, the food-deprived rats showed a greater conditioned preference for the cocaine-paired environment during the choice test, greater cocaine-induced locomotor activity during conditioning trials, and a greater degree of sensitization to the activating effects of cocaine across conditioning trials. This study extends the general findings of food deprivation-induced increases in the reinforcing efficacy of cocaine to include the conditioned place preference paradigm. Received: 23 January 1996 / Final version: 4 December 1996     

Stress-induced reinstatement of amphetamine-conditioned place preference and changes in tyrosine hydroxylase in the nucleus accumbens in adolescent rats

Drug abuse among humans often begins during adolescence. Exposure to psychostimulants during this age period may have long-term consequences which can render the organism more susceptible to drug abuse and relapse later in life. It has been demonstrated that exposure to stress can promote relapse to drug use even after long periods of withdrawal. The reinstatement of conditioned place preference (CPP) is a useful animal model for studying relapse. In humans and animals, changes in tyrosine hydroxylase (TH) have been related to drug addiction. Our study examined whether amphetamine-induced CPP during adolescence could be reinstated by exposure to stress 1 (adolescence) and 30 (adulthood) days after the extinction test. We also investigated TH levels following the reinstatement of CPP. Our results showed that amphetamine-induced CPP during adolescence can be reinstated by stress exposure 1 day (P42, end of adolescence) but not 30 days after extinction (P71, adulthood). Moreover the reinstatement of AMPH-induced CPP by stress exposure occurred in the presence of decreased TH in the nucleus accumbens. In conclusion, our data add new evidence that neuroadaptations on TH may mediate relapse to drug-seeking behavior induced by stress within adolescence.     

The mu opioid receptor is involved in buprenorphine-induced locomotor stimulation and conditioned place preference

The analgesic effect of buprenorphine is mediated via the mu opioid receptor (MOP). In the present study, using mice lacking the MOP and their wild-type littermates, we determined the role of the MOP in buprenorphine-induced locomotor stimulation and conditioned place preference (CPP). Buprenorphine (3 mg/kg) increased motor activity in wild-type but not in MOP knockout mice, showing the motor stimulatory action of buprenorphine is mediated via the MOP. When the mice were given the same treatment once daily for 5 consecutive days and challenged with buprenorphine on day 11, the motor stimulatory action of buprenorphine was enhanced in wild-type but not in MOP knockout mice, showing sensitization developed to the motor stimulatory action of buprenorphine and this phenomenon was mediated via the MOP. Likewise, buprenorphine induced CPP in wild-type mice after four alternate-day saline/buprenorphine (3 mg/kg) injections paired with olfactory and visual cues. However, buprenorphine failed to induce CPP in MOP knockout mice. In contrast, amphetamine (1 mg/kg) induced a comparable CPP in wild-type and MOP knockout mice. Together, the present results suggest that the ability of buprenorphine to increase motor activity and induce locomotor sensitization and CPP is mediated via the MOP.     

The effect of novelty on amphetamine self-administration in rats classified as high and low responders

Rationale Rats categorized as high responders (HR) based on their activity in an inescapable novel environment self-administer more amphetamine than low responder (LR) rats. Previous research has also demonstrated that novel stimuli presented during the amphetamine self-administration session decreases the number of infusions earned.Objectives This study determined whether individual differences in response to inescapable or free-choice novelty differentially predict the ability of novel stimuli to decrease amphetamine self-administration. Further, this study determined whether novel stimuli maintained the ability to reduce self-administration with repeated presentations, and whether the effect of novel stimuli varied as a function of the unit dose of amphetamine tested.Methods Male rats were screened for their response in inescapable and free-choice novelty tests. Following initial training using a high unit dose of amphetamine (0.1 mg/kg per infusion), the dose was reduced (0.03 mg/kg per infusion), and novel stimuli were presented in the operant conditioning chamber on four separate sessions. In experiment 2, novel stimuli were presented during several sessions at a variety of amphetamine doses (0.003, 0.01, 0.03, and 0.056 mg/kg per infusion).Results Four repeated presentations of novel stimuli reduced amphetamine self-administration with no significant loss in the effect of novel stimuli across repeated presentations. In experiment 2, novel stimuli reduced amphetamine self-administration at low unit doses (0.003 mg/kg and 0.01 mg/kg per infusion), and rats classified as HR based on their activity in inescapable novel stimuli were more disrupted by novel stimuli than LR rats.Conclusions These results suggest that repeated presentation of novel stimuli can reduce amphetamine self-administration at low unit doses and that HR rats are more sensitive than LR rats to non-drug stimuli that compete with responding for amphetamine.     

Haloperidol reduces ethanol-induced motor activity stimulation but not conditioned place preference

This experiment examined the impact of a dopamine receptor blocker on ethanol's rewarding effect in a place conditioning paradigm. DBA/2J mice received four pairings of a tactile stimulus with ethanol (2 g/kg, IP), haloperidol (0.1 mg/kg, IP) + ethanol, or haloperidol alone. A different stimulus was paired with saline. Ethanol produced increases in locomotor activity that were reduced by haloperidol. However, conditioned preference for the ethanol-paired stimulus was not affected by haloperidol. Haloperidol alone decreased locomotor activity during conditioning and produced a place aversion. These results indicate a dissociation of ethanol's activating and rewarding effects. Moreover, they suggest that ethanol's ability to induce conditioned place preference is mediated by nondopaminergic mechanisms.     

东莨菪碱对吗啡依赖大鼠条件位置性偏爱激活的抑制作用

目的:观察东莨菪碱(Scopolamine,Sco)对吗啡(Morphine,Mor)依赖大鼠条件位置性偏爱激活的抑制作用。方法:以剂量递增连续皮下(SC)给吗啡6天建立吗啡诱导大鼠条件位置性偏爱(CPP)模型,第7天用生理盐水替代吗啡训练大鼠10天,使形成的CPP逐渐消退,单次SC4mg/kg吗啡激发消退的CPP。部分大鼠在注射吗啡前30分钟分别腹腔注射(ip)Sco(1mg/kg、2mg/kg、3mg/kg)。观察东莨菪碱对吗啡依赖大鼠在伴药箱停留时间的变化。结果:与Mor依赖组相比在SC4mg/kgMor引燃刺激前30min应用Sco1mg/kg、2mg/kg、3mg/kg均可以使大鼠在伴药箱停留时间缩短(P<0.05)。结论:Sco一定程度上抑制Mor引燃的Mor依赖大鼠的条件位置性偏爱激活。     

东茛菪碱对吗啡依赖大鼠条件位置性偏爱激活的抑制作用

目的：观察东莨菪碱（Scopolamine，Sco）对吗啡（Morphine，Mor）依赖大鼠条件位置性偏爱激活的抑制作用。方法：以剂量递增连续皮下（SC）给吗啡6天建立吗啡诱导大鼠条件位置性偏爱（CPP）模型，第7天用生理盐水替代吗啡训练大鼠10天，使形成的CPP逐渐消退，单次SC4mg／kg吗啡激发消退的CPP。部分大鼠在注射吗啡前30分钟分别腹腔注射（ip）Sco（1mg／kg、2mg／kg、3mg／kg）。观察东莨菪碱对吗啡依赖大鼠在伴药箱停留时间的变化。结果：与Mor依赖组相比在SC4mg／kgMor引燃刺激前30min应用Sco 1mg／kg、2mg／kg、3mg／kg均可以使大鼠在伴药箱停留时间缩短（P〈0．05）。结论：Sco一定程度上抑制Mor引燃的Mor依赖大鼠的条件位置性偏爱激活。