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Rational: Morphine is one of the most well-known and potent analgesic agents; however, it can also induce various side effects. Thus, finding drugs and mechanisms which can potentiate the analgesic effects of low doses of morphine will be a good strategy for pain management. Objective: The involvement of μ-opioid receptors and ventral tegmental area (VTA) glutamatergic system in harmaline and morphine combination on the nociceptive response were investigated. Also, we examined reward efficacy and tolerance expression following the drugs. Methods: Animals were bilaterally cannulated in the VTA by stereotaxic instrument. A tail-flick (TF) apparatus and conditioned place preference (CPP) paradigm were used to measure nociceptive response and rewarding effects in male NMRI mice respectively. Results: Morphine (2 mg/kg, i.p.) had no effect in TF test. Also, harmaline (1.25 and 5 mg/kg, i.p.) could not change pain threshold. Combination of a non-effective dose of harmaline (5 mg/kg) and morphine (2 mg/kg) produced antinociception and also prevented morphine tolerance but had no effect on the acquisition of CPP. Systemic administration of naloxone (0.5 and 1 mg/kg) and intra-VTA microinjection of NMDA (0.06 and 0.1 μg/mouse) before harmaline (5 mg/kg) plus morphine (2 mg/kg) prevented antinociception induced by the drugs. D-AP5 (0.5 and 1 μg/mouse, intra-VTA) potentiated the effect of low-dose harmaline (1.25 mg/kg) and morphine (2 mg/kg) and induced antinociception. Microinjection of the same doses of NMDA or D-AP5 into the VTA alone had no effect on pain threshold. Conclusion: The findings showed that harmaline potentiated the analgesic effect of morphine and reduced morphine tolerance. Glutamatergic and μ-opioidergic system interactions in the VTA seem to have a modulatory role in harmaline plus morphine-induced analgesia. [ABSTRACT FROM AUTHOR]

Rationale: Females are considered more susceptible to the reinforcing effects of drugs and subsequently at increased risk for drug abuse and relapse after treatment. Estrogen is known to facilitate drug effects in females. However, other factors which contribute to the incidence of drug abuse are important to identify in order to recognize early risk factors and develop effective prevention and treatment schemes. Cue-directed behavior (aka sign tracking) has been implicated as a behavioral phenotype which identifies populations susceptible to drug abuse, partly due to its association with impulsivity and heightened dopamine function. Objectives and Methods: In this study, we investigate the viability of conditioned orienting (a form of cue-directed behavior) as a potential phenotype which predicts drug proclivity in female rats. In addition, we examine any influence endogenous female hormones across the estrous cycle may have on conditioned orienting and drug proclivity. Results and Conclusions: Utilizing an amphetamine-conditioned place preference task, results suggest that the orienting phenotype is an effective predictor of drug proclivity in females. Rats exhibiting enhanced orienting behavior show more robust preference for an amphetamine-associated context and are more resistant to extinction of this preference than nonorienting counterparts. Furthermore, both conditioned orienting behavior and conditioned place preference are minimally influenced by the estrous cycle. [ABSTRACT FROM AUTHOR]

Rationale Systemic estradiol (E2) increases the behavioral and neural response to cocaine. Where in the brain E2 acts to modulate cocaine response is not entirely clear. Evidence supports a role in this modulation for several candidate regions, including the medial preoptic area (mPOA). Objectives This study examined whether manipulation of E2 in the mPOA modulates differing behavioral responses to cocaine and whether this is reflected in differing levels of c-Fos in the NAc following cocaine administration. Methods Female rats received ovariectomies and bilateral cannulations of the mPOA. They then received either artificial cerebrospinal fluid (aCSF) or E2 microinjections into the mPOA the day before receiving systemic injections of saline or cocaine (5 or 10 mg/kg). Conditioned-place preference (CPP) to cocaine and locomotor activation were then obtained. Results Animals receiving 10 mg/kg, but not 5 mg/kg, cocaine developed significant CPP, and those receiving E2 into the mPOA expressed greater CPP than those receiving microinjections of only aCSF at both doses (p < 0.05, d > 0.80). Cocaine also caused significant psychomotor activation, but this was not dependent on microinjection of E2 in the mPOA. Finally, animals that received cocaine had increased NAc core and shell c-Fos relative to animals that received saline, with animals receiving both E2 microinjections and systemic cocaine expressing the highest activation in the caudal NAc, compared to rats receiving aCSF microinjections and systemic cocaine (p = 0.05, d = 0.70). Conclusions These results indicate that E2 in the mPOA facilitates the behavioral response and neural activation that follows cocaine administration. Furthermore, they confirm the close relationship between the mPOA and cocaine response. [ABSTRACT FROM AUTHOR]

Rationale: Previous studies have shown that repeated exposure to drugs of abuse is associated with changes in clock genes expression and that mice strains with various mutations in clock genes show alterations in drug-induced behaviors. Objective: The objective of this study is to characterize the role of the clock gene mPer1 in the development of morphine-induced behaviors and a possible link to histone deacetylase (HDAC) activity. Methods: In Per1 null mutant mice and wild-type (WT) littermates, we examined whether there were any differences in the development of morphine antinociception, tolerance to antinociception, withdrawal, sensitization to locomotion, and conditioned place preference (CPP). Results: Per1 mutant mice did not show any difference in morphine antinociception, tolerance development, nor in physical withdrawal signs precipitated by naloxone administration compared to WT. However, morphine-induced locomotor sensitization and CPP were significantly impaired in Per1 mutant mice. Because a very similar dissociation between tolerance and dependence vs. sensitization and CPP was recently observed after the co-administration of morphine and the HDAC inhibitor sodium butyrate (NaBut), we studied a possible link between mPer1 and HDAC activity. As opposed to WT controls, Per1 mutant mice showed significantly enhanced striatal global HDAC activity within the striatum when exposed to a locomotor-sensitizing morphine administration regimen. Furthermore, the administration of the HDAC inhibitor NaBut restored the ability of morphine to promote locomotor sensitization and reward in Per1 mutant mice. Conclusions: Our results reveal that although the mPer1 gene does not alter morphine-induced antinociception nor withdrawal, it plays a prominent role in the development of morphine-induced behavioral sensitization and reward via inhibitory modulation of striatal HDAC activity. These data suggest that PER1 inhibits deacetylation to promote drug-induced neuroplastic changes. [ABSTRACT FROM AUTHOR]

Rationale: Topiramate is an anticonvulsant drug which has been evaluated as a therapeutic option for the treatment of cocaine addiction during the last decade. Objectives: The purpose of this study was to evaluate the effects of topiramate on the reinforcing actions of cocaine. To this aim, the topiramate-mediated regulation of acquisition and extinction phases of the cocaine conditioned place preference (CPP) was assessed in young-adult mice using three experimental designs. Methods: Topiramate (50 mg/kg, p.o.) was given as follows: (1) during cocaine (1 and 25 mg/kg, i.p.) conditioning sessions (4 days) and cocaine (25 mg/kg) post-conditioning session; (2) 2 weeks before and during cocaine conditioning (25 mg/kg); and (3) during extinction of CPP induced by cocaine (25 mg/kg). In the first experimental design, changes in tyrosine hydroxylase (TH) and dopamine transporter (DAT) gene expressions were measured in the ventral tegmental area (VTA). Results: Topiramate significantly increased cocaine-induced CPP and delayed or failed to produce extinction after the first cocaine reinstatement extinction in the first and second experiments. Furthermore, treatment with topiramate after place conditioning blocked the extinction of cocaine-induced CPP. TH and DAT gene expression in the VTA was significantly lower both with topiramate alone and in combination with cocaine compared with animals receiving only cocaine. Conclusions: These findings suggest that topiramate increases the rewarding properties of cocaine, at least in part, by regulating dopaminergic signaling in the mesolimbic circuit. Consequently, the results of this study do not support the use of topiramate for the treatment of problems related to cocaine dependence. Highlights: • Topiramate increases the rewarding properties of cocaine in CPP • Topiramate alters dopaminergic signaling in the mesolimbic circuit • Topiramate delays the extinction of cocaine-induced CPP • TH and DAT gene expression in the VTA decreases with topiramate and/or with cocaine • Results show that it should limit the use of topiramate in cocaine-dependent subjects [ABSTRACT FROM AUTHOR]

Rationale: The practice of binge drinking is very common among adolescents of both sexes. It can have long-term consequences with respect to drug consumption during adulthood, but knowledge on these effects in females is limited. Objectives: The long-lasting effects of intermittent exposure to ethanol (EtOH) during adolescence on different cocaine-elicited behaviours, including locomotor reactivity, conditioned place preference (CPP) and intravenous self-administration, were evaluated in male and female adult mice. It was hypothesized that an EtOH binge during adolescence would increase sensitivity to the effects of a sub-threshold dose of cocaine and has a differential impact on the drug's effects in males and females. Methods: Adolescent OF1 mice (postnatal day (PND) 26) underwent a 2-week pre-treatment schedule consisting of 16 doses of EtOH (2.5 g/kg) or saline (twice daily administrations separated by a 4-h interval i.p.) administered on two consecutive days separated by an interval of 2 days. Three weeks later (PND > 60), we assessed locomotor activity responses induced by an acute injection of different doses of cocaine in experiment 1 and the rewarding effects of cocaine on the CPP (1 mg/kg) and intravenous self-administration (1 mg/kg/infusion) paradigms in experiment 2. Results: Pre-exposure to EtOH during adolescence altered motor reactivity to cocaine in a dose- and sex-dependent manner, increased sensitivity to cocaine in CPP and enhanced self-administration in adult mice. Conclusions: The effects of intermittent exposure to ethanol during adolescence are evident in adulthood, during which greater sensitivity and intake of cocaine is observed and differ in each sex. [ABSTRACT FROM AUTHOR]

Rationale: Brain histaminergic system is involved in the regulation of the dopaminergic circuitry. The role of histamine H3 receptor (H3R) in behaviors linked to amphetamine addiction and other behaviors induced by dopaminergic compounds has remained unclear. Objective: Our aim was to study whether H3R antagonist JNJ-39220675 inhibits amphetamine-induced stimulation and reward. The effects of JNJ-39220675 on dopamine D2-like receptor (D2R-like) agonist quinpirole-induced behaviors were also investigated in order to clarify whether the possible effects of H3R antagonists are D2R-like dependent. Methods: The effects of JNJ-39220675 on amphetamine and quinpirole-induced behavioral responses in mice were studied assessing the locomotor activation after both acute and repeated administrations of amphetamine and quinpirole. The place conditioning paradigm was also used as a measure of reward or aversion. Results: JNJ-39220675 inhibited amphetamine-induced stimulation acutely but not after repeated administrations. Amphetamine (2 mg/kg) induced conditioned place preference that was not affected by either of the tested doses of JNJ-39220675 (1 and 10 mg/kg). Quinpirole (0.5 mg/kg) induced conditioned place aversion to which the pretreatment by JNJ-39220675 (10 mg/kg) had no effect. In repeated administration, JNJ-39220675 did, however, inhibit quinpirole-induced tolerance to hypokinesia. Conclusions: Our results show that although H3R antagonists inhibit ethanol reward, they may not possess the same ability on psychostimulants, such as amphetamine. However, if H3R antagonists will become clinically available, it is of importance that these compounds potentiate neither the rewarding nor aversive effects of other drugs. [ABSTRACT FROM AUTHOR]

Rationale: Exposure to drugs during adolescence can induce alterations in the central nervous system. The novelty-seeking personality trait influences differences observed among individuals exposed to drugs of abuse. Objectives: Long-term effects of intensive pre-treatment with cocaine during adolescence or adulthood were evaluated in High- and Low-Novelty Seeker (HNS and LNS) mice. It was hypothesized that a cocaine binge during adolescence would increase sensitivity to the rewarding effects of cocaine and MDMA, especially in HNS animals, and modify the spontaneous behaviour of adult animals. Methods: Adolescent (PND 33) and adult (PND 60) mice were identified as HNS or LNS according to their performance in the hole-board test. Subsequently, they received pre-treatment with cocaine (three injections per day of an increasing dose for 10 days) or saline. Three weeks later, the mice performed the hole-board, elevated plus maze, spontaneous locomotor activity and cocaine- (1 mg/kg) or MDMA- (1.25 mg/kg) induced conditioning place preference (CPP) tests. In another set of mice, the effects of pre-treatment of cocaine during adulthood on MDMA- or cocaine-induced CPP were also evaluated 3 weeks later. Results: Only HNS mice treated with cocaine during adolescence acquired MDMA- or cocaine-induced CPP in adulthood. Moreover, pre-exposure to cocaine during adolescence caused subsequent behavioural alterations, including reduced exploratory behaviour and increased locomotor reactivity. Conclusions: Cocaine binge administration during adolescence induces a higher sensitivity to the rewarding effects of MDMA and cocaine in HNS mice in adulthood. This may explain the greater vulnerability often seen among individuals exposed early in life to drugs of abuse. [ABSTRACT FROM AUTHOR]

Rationale: We have shown previously, using an animal model of voluntary ethanol intake and ethanol-conditioned place preference (EtOH-CPP), that exposure to chronic psychosocial stress induces increased ethanol intake and EtOH-CPP acquisition in mice. Objective: Here, we examined the impact of chronic subordinate colony (CSC) exposure on EtOH-CPP extinction, as well as ethanol-induced reinstatement of CPP. Methods: Mice were conditioned with saline or 1.5 g/kg ethanol and were tested in the EtOH-CPP model. In the first experiment, the mice were subjected to 19 days of chronic stress, and EtOH-CPP extinction was assessed during seven daily trials without ethanol injection. In the second experiment and after the EtOH-CPP test, the mice were subjected to 7 days of extinction trials before the 19 days of chronic stress. Drug-induced EtOH-CPP reinstatement was induced by a priming injection of 0.5 g/kg ethanol. Results: Compared to the single-housed colony mice, CSC mice exhibited increased anxiety-like behavior in the elevated plus maze (EPM) and the open field tests. Interestingly, the CSC mice showed delayed EtOH-CPP extinction. More importantly, CSC mice showed increased alcohol-induced reinstatement of the EtOH-CPP behavior. Conclusion: Taken together, this study indicates that chronic psychosocial stress can have long-term effects on EtOH-CPP extinction as well as drug-induced reinstatement behavior and may provide a suitable model to study the latent effects of chronic psychosocial stress on extinction and relapse to drug abuse. [ABSTRACT FROM AUTHOR]

Rationale: Rats develop preferences for places associated with the immediate rewarding effects of cocaine and aversions for places paired with the drug's delayed negative effects. The motivation to seek cocaine should therefore depend upon the relative magnitude of these two opposing effects of the drug. Objective: The current study tested this notion by assessing the relative persistence of the positive and negative associations formed between environmental cues and the immediate or delayed effects of cocaine. Methods: Rats were administered 1.0 mg/kg intravenous cocaine and placed into a distinctive environment either immediately or 15-min after injection, alternating daily with pairings of a second environment with saline. After four drug-place and four saline-place pairings, rats were returned to their home cages for 1, 7, or 21 days after which a 15-min place preference test was conducted. In a second experiment, the effectiveness of a single reconditioning session (one drug-place and one saline-place pairing) to reactivate learned cocaine-place associations was assessed after 1 or 3 weeks of drug abstinence. Results: Places associated with the immediate effects of cocaine were preferred (CPP), while places associated with the delayed effects of cocaine were avoided (CPA). The persistence of these effects differed with CPP remaining viable at 3 weeks of withdrawal, while CPA was no longer present after 1 week. Reconditioning with an additional cocaine-place pairing failed to reinstate the CPA. Conclusions: Cue-induced 'relapse' of cocaine-seeking behavior may be fueled in part by an increased persistence of positive relative to negative associations with drug-paired stimuli. [ABSTRACT FROM AUTHOR]

Rationale: Disruption of acquired drug-cue associations can effectively decrease relapse. The benefits of extinction training as opposed to abstinence have been reported. Timing of extinction trials is an important variable. Finding an effective extinction regimen can optimize addiction therapies. Objective: To determine the effects of different drug-free periods on cocaine-conditioned place preference (CPP) in rats that either did or did not receive non-reinforced exposure to drug-associated stimuli. Materials and methods: Male adolescent rats were trained for cocaine-CPP (5, 10, or 15 mg/kg, i.p.) in a biased manner for 8 days and then tested following different intervals. Results: Rats treated with 15 mg/kg cocaine displayed high and equal CPP on the first test, performed 1, 4, 7, or 14 days following conditioning. Expression of CPP during the test performed 1 day after conditioning was equal in the groups conditioned with 5, 10, or 15 mg/kg cocaine. When the interval before the first test was extended to 14 days, the group treated with 5 mg/kg did not show CPP. Rats treated with the three doses and tested repeatedly at 1, 7, and 14 days did not display CPP on the third test. CPP after treatment with 10 or 15 mg/kg cocaine was already extinguished in the second test but only for an interval of 1-14 days. Conclusions: Maintenance of CPP was evident at least 2 weeks after forced abstinence. Extinguished CPP can be obtained after a single extinction trial, performed close to original training and followed by prolonged abstinence. However, with low doses of cocaine, abstinence alone may be sufficient to disrupt drug-cue associations. [ABSTRACT FROM AUTHOR]

Rationale: Chemical mutagenesis in the mouse is a forward genetics approach that introduces random mutations into the genome, thereby providing an opportunity to annotate gene function and characterize phenotypes that have not been previously linked to a given gene. Objectives: We report on the behavioral characterization of Highper, an N-ethyl- N-nitrosourea (ENU)-induced mutant mouse line. Methods: Highper and B6 control mice were assessed for locomotor activity in the open field and home cage environments. Basal and acute restraint stress-induced corticosterone levels were measured. Mice were tested for locomotor response to cocaine (5, 20, 30, and 45 mg/kg), methylphenidate (30 mg/kg), and ethanol (0.75, 1.25, and 1.75 g/kg). The rewarding and reinforcing effects of cocaine were assessed using conditioned place preference and self-administration paradigms. Results: Highper mice are hyperactive during behavioral tests but show normal home cage locomotor behavior. Highper mice also exhibit a twofold increase in locomotor response to cocaine, methylphenidate, and ethanol and prolonged activation of the hypothalamic-pituitary-adrenal axis in response to acute stress. Highper mice are more sensitive to the rewarding and reinforcing effects of cocaine, although place preference in Highper mice appears to be significantly influenced by the environment in which the drug is administered. Conclusions: Altogether, our findings indicate that Highper mice may provide important insights into the genetic, molecular, and biological mechanisms underlying stress and the drug reward pathway. [ABSTRACT FROM AUTHOR]

Rationale: Previous research suggests that the vesicular monoamine transporter-2 (VMAT2) is a novel target for the treatment of methamphetamine (METH) abuse. Objective: The effects GZ-793A, a novel, selective, and potent lobelane analog, on the rewarding effects of METH, cocaine, and palatable food in rats were determined. Method: GZ-793A (3-30 mg/kg, s.c.) was administered 20 min prior to each session in which the groups of rats pressed a lever for infusions of METH (0.03 mg/kg/infusion), cocaine (0.3 mg/kg/infusion), or food pellets. Tolerance to repeated GZ-793A (15 mg/kg, s.c. for 7 days) on METH self-administration and food-maintained responding was determined. The ability of increasing doses of METH (0.001-0.56 mg/kg, i.v.) to surmount inhibition produced by GZ-793A (15 mg/kg, s.c.) was determined. Self-administration of GZ-793A (0.01-0.3 mg/kg/infusion, i.v.) was tested as a substitute for METH infusion. GZ-793A (15 mg/kg, s.c.) was administered 20 min prior to METH or saline conditioning in a place preference test. Results: GZ-793A specifically decreased METH self-administration, without the development of tolerance. Increasing the unit dose of METH did not surmount the inhibition produced by GZ-793A on METH self-administration. GZ-793A did not serve as a substitute for self-administered METH. GZ-793A blocked METH-induced conditioned place preference (CPP) and did not induce CPP alone. Conclusions: These results indicate that VMAT2 is a viable target for pharmacological inhibition of METH reward and that GZ-793A represents a new lead in the discovery of a treatment for METH abuse. [ABSTRACT FROM AUTHOR]

Brain-derived neurotrophic factor (BDNF) is involved in the survival and function of midbrain DA neurons. BDNF action is mediated by the TrkB receptor–tyrosine kinase, and both BDNF and TrkB transcripts are widely expressed in the rat mesolimbic pathway, including the nucleus accumbens (NAc) and the ventral tegmentum area (VTA). BDNF was previously shown to be involved in cocaine reward and relapse, as assessed in rat models. The goal of this study is to explore the role of BDNF and TrkB in the rat nucleus accumbens (NAc) in cocaine-induced psychomotor sensitization and in conditioned-place preference acquisition, expression, and reinstatement. In vivo genetic manipulations of BDNF and TrkB were performed using a lentiviral gene delivery approach to over-express these genes in the NAc and siRNA-based technology to locally knockdown gene expression. Behavioral experiments consisted of locomotor activity monitoring or cocaine-induced conditioned-place preference (CPP). BDNF and/or its receptor TrkB in the NAc enhance drug-induced locomotor activity and induce sensitization in rats. Furthermore, LV-BDNF- and LV-TrkB-treated rats display enhanced cocaine-induced CPP, delayed CPP-extinction upon repeated measurements, and increased CPP reinstatement. In contrast, expression of TrkT1 (truncated form of TrkB, acting as a dominant negative) inhibits these behavioral changes. This inhibition is also observed when rats are fed doxycycline (to block lentivirus-mediated gene expression) or when injected with siRNAs-expressing lentiviruses against TrkB. In addition, we investigate the establishment, maintenance, extinction, and reinstatement of cocaine-induced CPP. We show that BDNF and TrkB-induced CPP takes place during the learning period (conditioning), whereas extinction leads to the loss of CPP. Extinction is delayed when rats are injected LV-BDNF or LV-TrkB, and in turn, priming injections of 2 mg/kg of cocaine reinstates it. These results demonstrate the crucial function of BDNF—through its receptor TrkB—in the enhancement of locomotor activity, sensitization, conditioned-place preference, CPP-reinstatement, and rewarding effects of cocaine in the mesolimbic dopaminergic pathway. [ABSTRACT FROM AUTHOR]

Cannabis is the most widely consumed drug associated with 3,4-methylenedioxymethamphetamine (MDMA) use. This study examines whether low doses of MDMA and delta-9-tetrahydrocannabinol (THC) produce synergistic rewarding/reinforcing effects in mice using the conditioned place preference (CPP) and operant self-administration paradigms. Changes in dopamine (DA) outflow were monitored in the nucleus accumbens (NAC) after single or combined administration of these compounds. MDMA induced a significant CPP at the dose of 10 mg/kg but not at the dose of 3 mg/kg. THC (0.3 mg/kg) by itself was also ineffective in this paradigm. The combined administration of the low dose of MDMA (3 mg/kg) and THC (0.3 mg/kg) produced CPP, whereas the combination of MDMA (10 mg/kg) and THC (0.3 mg/kg) significantly decreased CPP. Animals treated with THC self-administered a sub-threshold dose of MDMA (0.06 mg/kg per infusion), while animals receiving vehicle did not. However, THC did not modify the self-administration of an effective dose of MDMA (0.125 mg/kg per infusion). In microdialysis studies, a low dose of THC significantly increased DA outflow in the NAC, while a low dose of MDMA did not. When MDMA was administered before THC, DA levels decreased with respect to THC. However, when THC was administered before MDMA, DA levels were not significantly modified with respect to THC. These results demonstrate that a low dose of THC modifies in different ways (increases and decreases) the sensitivity of animals to the behavioural effects of MDMA and that THC and MDMA converge at a common mechanism modulating DA outflow in the NAC of mice. [ABSTRACT FROM AUTHOR]

Acute stress has been shown to facilitate the rewarding effects of a number of commonly abused drugs, although the stressor typically must be administered either immediately before or during drug administration and often in the same environment. We have previously reported that a single session of an uncontrollable (inescapable tailshock, IS), but not controllable (escapable tailshock, ES), stressor can enhance the conditioned place preference (CPP) response to morphine, even when stressor and drug administration are separated temporally and spatially. However, this persistent, trans-situational enhancement did not occur to amphetamine CPP. The following experiments were conducted to determine whether the long-term effects of IS on drug reward are specific to opioids. Adult, male Sprague–Dawley rats were exposed to a single session of IS or remained in their home cages (HC). Twenty-four hours later, using an unbiased procedure, CPP conditioning was conducted with either oxycodone (0, 2, or 5 mg/kg, sc), cocaine (0, 1, 5, or 10 mg/kg, ip), or ethanol (0.3, 1, or 2 g/kg, ip). Another group of rats were exposed to IS, ES, or HC treatment and conditioned with oxycodone (5 mg/kg, sc) 24 h later. IS enhanced the subsequent CPP response to oxycodone, but not cocaine or ethanol. This enhancement was dependent on the controllability of the stressor, as ES did not affect oxycodone CPP. These results indicate that the long-term, trans-situational enhancing effect of uncontrollable stress on drug reward is specific to opioids. [ABSTRACT FROM AUTHOR]

Provides information on a study which examined the effects of various NMDA receptor antagonists on a developed rat model of Parkinson's disease. Sensitive measure of akinesia in unilateral 6-OHDA-lesioned rats; Characteristics of the disease; Type of transmission associated with the disease.

The effects of the competitive NMDA antagonist CPP and the non-competitive NMDA antagonist MK 801 (dizolcipine) on short term working memory in the rat were investigated. The behavioural paradigm used was discrete trial, operant delayed matching to position, as originally described by Dunnett (1985), with delays of 0, 5, 15 and 30 s. These delays generated an orderly 'forgetting' curve in control rats, with matching accuracy decreasing from approximately 100% at 0-s delay to approximately 75% at 30-s delay. Intraperitoneal (IP) administration of CPP (10 mg/kg) produced a marked delay dependent impairment in performance, suggesting a specific effect on short term working memory. This effect was accompanied by a minor decrease in the speed of responding, and a slight increase in the number of missed trials. Lower doses of CPP had no significant effects on either matching accuracy or sedation. In contrast, IP administration of MK 801 (0.1 and 0.2 mg/kg) caused a marked delay independent impairment in the accuracy of delayed matching performance, suggesting a non-specific disruption of performance. A lower dose (0.05 mg/kg) of MK 801 had no significant effect on matching accuracy. The two lower doses of MK 801 increased the number of nose pokes made during the delays and tended to increase the speed of responding, suggesting a stimulant-like action. The highest dose of MK 801 had the opposite effects and also decreased the number of trials completed. The results with CPP therefore support the hypothesized role of NMDA receptors in learning and memory, and the contrasting effects of these two NMDA antagonists support previous suggestions of different behavioural effects resulting from administration of competitive and non-competitive NMDA antagonists. [ABSTRACT FROM AUTHOR]

C57BL/6Ibg mice were treated with the N-methyl- d-aspartate (NMDA) receptor antagonist 3-(2-carboxypiperazin-4-yl) propyl-1-phosphonic acid (CPP) and tested for selective deficits in spatial learning ability in the Morris water task. Two types of training protocols were used during the initial exposure to the training environment. In protocol 1, animals were given four massed trials before being returned to their home cages. In protocol 2, animals were returned to their home cages after each of the first four trials. Following the initial four trials, both sets of animals were given massed trials in blocks of four. CPP had minor effects on nonspatial learning, with greater impairment seen in animals trained according to protocol 1 than in animals trained according to protocol 2. The drug increased latency to find the platform in the spatial learning form of the task, with no effect of training protocol on latency. When spatial learning ability was measured in terms of the search behavior exhibited by the animals after the platform was removed from the pool, animals trained according to protocol 1 showed a severe CPP-induced impairment in search accuracy. Animals trained according to protocol 2 showed no effect of drug treatment. The results suggest that CPP does not have a reliable effect on place learning and that factors other than the type of learning being tested may contribute to performance deficits following CPP treatment. [ABSTRACT FROM AUTHOR]

The discriminative stimulus effects of the N-methyl- d-aspartate (NMDA) antagonists 3-([+/-]-2-carboxypiperazin-4-yl)propyl-1-phosphonic acid (CPP) and phencyclidine were assessed in a drug discrimination based on the competitive NMDA antagonist 2-amino-4,5-(1,2-cyclohexyl)-7-phosphonoheptanoic acid (NPC 12626). Adult male Sprague-Dawley rats were trained to discriminate NPC 12626 from saline using a standard two-lever fixed ratio 32 schedule of food reinforcement. NPC 12626 dose-dependently substituted for the training dose (20 mg/kg IP) with an ED of 9.5 mg/kg. The competitive NMDA antagonist CPP completely substituted for NPC 12626 (ED=1.4 mg/kg IP). The non-competitive NMDA antagonist phencyclidine, as well as pentobarbital and NMDA, failed to substitute completely for NPC 12626, even at doses of these drugs that reduced response rates. These data indicate that the discriminative stimulus properties of NPC 12626 are selective and shared by CPP but not by phencyclidine, pentobarbital or NMDA. The emerging evidence for differences in the discriminative stimulus effects of competitive NMDA antagonists and phencyclidine suggests that competitive antagonists such as NPC 12626 and CPP may not have phencyclidine-like abuse liability. [ABSTRACT FROM AUTHOR]

N-methyl- D-aspartate (NMDA) receptor/channel antagonists have previously been shown to impair spatial working memory and hippocampal long-term potentiation. The present experiment investigated the effects of a variety of doses of NMDA antagonists on a working memory task in rats involving an auditory delayed conditional discrimination. Signal detection analysis and an exponential memory decay model were used to extract independent measures of stimulus discriminability and rate of forgetting. A competitive NMDA antagonist, (CPP, 0.33, 1.0, 10.0 mg/kg, IP) produced a reduction in discriminability which was linearly related to log dose, but which was only clear at the 10 mg/kg dose. Rate of forgetting was not increased by any dose. Similar results were obtained with a non-competitive antagonist (MK-801, 0.1, 0.33 mg/kg, IP). These data suggest that doses of NMDA receptor channel antagonists sufficient to disrupt hippocampal long-term potentiation and radial arm maze performance will also disrupt delayed conditional discrimination. The effect on delayed conditional discrimination is due to a disruption of stimulus discriminability and not to an increased rate of forgetting. The extent to which these effects relate to the reported changes in hippocampal long-term potentiation and radial arm maze performance remains to be determined. [ABSTRACT FROM AUTHOR]

Rats were trained to discriminate phencyclidine (PCP) from saline at doses of 2 and 4 mg/kg, using a two-lever food reinforced operant technique. ±N-allylnormetazocine (±SKF 10047), +5-methyl-10,11-dihydro-5H-dibenzo[A,D]cyclohepten-5,10-imine (MK 801), 3-(2-carboxypiperazin-4-yl) propyl-1-phosphonic acid (CPP) and ifenprodil, which have been shown to antagonise the effects of N-methyl- d-aspartate (NMDA), were tested for their ability to give rise to PCP-appropriate responding. In rats trained at both doses of PCP, ±SKF 10047 (2-12 mg/kg) and MK 801 (0.0125-0.2 mg/kg) produced dose-related responding on the lever associated with PCP injection. The relative potency of these two compounds was the same in the two groups of animals, but their absolute potencies to produce a PCP-like discriminative stimulus were dependent on the training dose of PCP. In contrast, neither the competitive NMDA antagonist CPP (4-20 mg/kg) nor the non-competitive antagonist ifenprodil (2-12 mg/kg) produced PCP-appropriate responding and ifenprodil (4-mg/kg) neither potentiated nor antagonised PCP. These findings are discussed in the light of the hypothesis that the behavioural effects of PCP are mediated via a reduction of neurotransmission at the NMDA-subtype of glutamate receptors. [ABSTRACT FROM AUTHOR]

Post-training administration of the N-methyl- d-aspartate (NMDA) antagonists CPP (0.5 and 1.0 mg/kg) and MK-801 (0.25 and 0.5 mg/kg) impaired, in a dose dependent fashion, the one-trial inhibitory avoidance response in NMRI mice. The D dopamine (DA) agonist SKF 38393 (10 and 20 mg/kg) and the D agonist quinpirole (0.5 and 1.0 mg/kg) instead facilitate the response in the same behavioral paradigm. Sub-chronic blockade of NMDA receptors with MK-801 (0.25 mg/kg once a day for 14 days) did not change the response to both competitive (CPP) and non-competitive (MK-801) NMDA antagonists. The same chronic treatment with MK-801 induced an increased response to both SKF 38393 and quinpirole. These data suggest that repeated administration of MK-801 induce an upregulation of both D and D DA receptors without affecting NMDA receptors. [ABSTRACT FROM AUTHOR]

The ability of kappa opioid agonists to modulate dopamine-mediated behavior and Fos immunore-activity was assessed in adult rats. It was predicted that kappa agonist treatment would block the unconditioned and conditioned behaviors produced by cocaine (an indirect dopamine agonist). In the initial experiments, cocaine-induced locomotor activity was assessed after either acute or chronic injections of the kappa receptor agonist U-50,488 (5 mg/kg, SC). As expected, U-50,488 decreased cocaine-induced activity, while leaving baseline activity levels unaffected. Interestingly, chronic treatment with U-50,488 did not induce behavioral tolerance. The conditioned effects of cocaine (20 mg/kg, IP) were assessed using the conditioned place preference (CPP) paradigm. As expected, rats showed a preference for the cocaine-paired compartment, an effect blocked by U-50,488 (5 mg/kg, SC). One hour after CPP testing, rats were killed and Fos immunoreactivity was assessed. Rats conditioned with cocaine, but not U-50,488, showed increased Fos activity in the anterior cingulate cortex, piriform cortex, lateral septal area, and olfactory tubercles. When considered together, these results suggest that U-50,488 was effective at blocking the unconditioned and conditioned effects of cocaine, as well as cocaine-induced neuronal activity (as measured by Fos induction). [ABSTRACT FROM AUTHOR]