Effects of test conditions on the outcome of place conditioning with morphine and naltrexone in mice

 Drug administration during test trials can increase the expression of place conditioning, offering an opportunity to determine the specificity of this enhanced response. Prior to training, Swiss-Webster mice spent similar durations in each of the distinctive compartments of a two-compartment box during three 900-s tests. During a 4-day conditioning period, daily injections of morphine (5–20 mg/kg, SC) or vehicle were differentially paired with one of two compartments of the box using an unbiased place conditioning procedure. Post-conditioning tests were conducted 2 and 3 days after the last conditioning day. Mice pre-treated during post-conditioning tests with vehicle did not show significant preference for the morphine-paired compartment when conditioned with morphine. Pretreatment with morphine (2.5–30 mg/kg, SC) led to a dose-dependent increase in time spent in the morphine-paired compartment. Post-conditioning tests in other groups of mice were conducted with heroin (0.1–3 mg/kg), fentanyl (0.01–0.3 mg/kg), cocaine (10–30 mg/kg) and pentobarbital (10–30 mg/kg), and results suggested that none of the tested drugs facilitated the expression of the morphine-conditioned place preference. In another experiment, naltrexone (0.1–10 mg/kg, SC) was administered as the conditioning drug. When tested with naltrexone (0.1–10 mg/kg), there was a dose-dependent avoidance of the naltrexone-paired compartment. Overall, the present data indicated that: (1) failure to exhibit place preference or place aversion when tested in a drug-free state does not imply the failure of conditioning procedure; and (2) effects of the morphine cue reinstatement during the post-conditioning tests appeared to be related to the unique pharmacological profile of the morphine stimulus. Received: 28 November 1997 / Final version: 23 July 1998     

Spatial learning and morphine-rewarded place preference negatively correlates in mice

Accumulating evidence has indicated that there might exist some correlation between opiate reward and certain kinds of learning and memory processes. The present study attempted to investigate the correlation between individual differences in morphine reward and capacities in spatial learning and spontaneous alternation. In the present studies, good-response (GR) and poor-response (PR) mice were respectively selected according to their performance in a spatial learning test involving the Morris water maze or in a spontaneous alternation task using the Y-maze. In a place preference conditioning procedure, morphine (3.0 mg/kg) produced significant conditioned place preference (CPP) in both GR and PR mice selected by using either the Morris water maze or the Y-maze. The PR mice selected with the Morris water maze showed significantly more CPP induced by morphine than the GR mice. However, no detectable difference was observed in morphine-induced CPP between the GR and PR mice selected with the Y-maze. These results suggested that the variation in morphine-induced CPP in mice is somehow differentially related to that of spatial learning but unlikely to that of spontaneous alternation.     

Morphine conditioned reward is inhibited by MPEP,the mGluR5 antagonist

In the present study we examined the effect of MPEP [2-methyl-6-(phenylethynyl)-pyridine] a potent, selective and systemically active metabotropic glutamate receptor (mGluR) type I (subtype mGluR5) antagonist on conditioned morphine reward in mice. In an unbiased version of conditioned place preference (CPP) paradigm, single conditioning with 10 mg/kg of morphine produced reliable place preference. MPEP at 30, but not 10 mg/kg significantly inhibited the acquisition as well as expression of morphine-induced CPP, but it neither produced place preference or aversion, nor affected locomotor activity of mice. Effects of MPEP on learning and memory were studied in the elevated plus maze model of spatial learning. In contrast to 0.1 mg/kg of MK-801, which inhibited the acquisition of this task, 30 mg/kg of MPEP affected neither learning nor memory retrieval. These data suggest that mGluR5 may be involved in conditioned morphine reward.     

Effect of social isolation on the metabolism of morphine and its passage through the blood-brain barrier and on consumption of sucrose solutions

  Rationale: We have previously shown that place preference conditioning to morphine was observed in social mice at the dose of 8 mg/kg, whereas 4 weeks of isolation impairs the place preference conditioning to morphine (8–100 mg/kg). Objective: The present study, aimed at explaining this phenomenon, tested three hypotheses: firstly, a reduced sensitivity to reinforcers induced by isolation; secondly, a difference in morphine disposition in isolated and social mice; thirdly, an altered blood-brain barrier transport of morphine in isolated mice. Methods: In the sucrose experiments, mice had the choice (for 24 h) between a bottle containing tap water and a bottle containing a sucrose solution. Three sucrose concentrations were used: 0.5, 1 and 2% (weight/weight). In the morphine disposition experiments, the plasma levels of morphine and of morphine-3-glucuronide (M3G) were measured for 240 min. The brain concentrations of morphine was measured at 15 and 30 min. The passage of morphine through the blood-brain barrier was measured using a method modified from that of Takasato (1984). Results: The preference for the sucrose solutions was significantly greater in isolated than in social mice for the concentration of 2%. Isolation reduced the plasma levels of morphine and of M3G, but did not alter the brain concentration of morphine. The passage of morphine through the blood-brain barrier was altered by isolation in neither of the eight structures examined. Conclusions: We conclude that the behavioural effect of isolation observed in the conditioned place preference to morphine may depend on changes both in morphine disposition and in the sensitivity to reinforcers in isolated mice. Received: 31 January 1998 / Final version: 11 January 1999     

The disruptive effects of the CB<Subscript>1</Subscript> receptor antagonist rimonabant on extinction learning in mice are task-specific

Rationale Disruption of CB₁ receptor signaling through the use of CB₁ (−/−) mice or the CB₁ receptor antagonist rimonabant (SR141716) has been demonstrated to impair extinction of learned responses in conditioned fear and Morris water maze tasks. In contrast, CB₁ (−/−) mice exhibited normal extinction rates in an appetitively motivated operant conditioning task. Objectives The purpose of this study was to test whether rimonabant would differentially disrupt extinction learning between fear-motivated and food-motivated tasks. Materials and methods Separate groups of C57BL/6J mice were trained in two aversively motivated tasks, conditioned freezing and passive avoidance, and an appetitively motivated operant conditioning task at a fixed ratio (FR-5) schedule of food reinforcement. After acquisition, the respective reinforcers in each task were withheld, and an intraperitoneal injection of vehicle or rimonabant was given 30 min before each extinction session. Results Rimonabant (3 mg/kg) treatment significantly disrupted extinction in both the conditioned freezing and passive avoidance tasks but failed to affect extinction rates in the operant conditioning task, whether using daily or weekly extinction sessions. Interestingly, rimonabant (3 mg/kg) prevented the significant increases in lever pressing (i.e., extinction burst) that occurred during the first extinction session of the operant conditioning task. Conclusions These results support the hypothesis that the CB₁ receptor plays a vital role in the extinction of aversive memories but is not essential for extinction of learned responses in appetitively motivated tasks.     

The effects of daidzin and its aglycon,daidzein, on the scopolamineinduced memory impairment in male mice

In this study, the effect of daidzin or daidzein isolated from Pueraria lobata on the memory impairments induced by scopolamine was assessed in male mice using the passive avoidance and the Morris water maze tasks. Administration of daidzin (5 mg/kg) or daidzein (5 mg/kg) significantly reversed the scopolamine (1 mg/kg)-induced cognitive impairments in male mice as evidenced by the passive avoidance test (p < 0.05) and on the Morris water maze test (p < 0.05). Moreover, the ameliorating effects of daidzin or daidzein were antagonized by tamoxifen (1 mg/kg), the nonspecific estrogen receptor antagonist. These results indicate that daidzin or daidzein may be useful in cognitive impairment induced by cholinergic dysfunction, and this beneficial effect is mediated, in part, via estrogen receptor.     

Mecamylamine- or scopolamine-induced learning impairment: ameliorated by nefiracetam

Nefiracetam is undergoing preclinical and clinical tests as a cognition-enhancing drug in Alzheimer’s disease (AD). Nicotinic cholinergic receptors are lost in AD, and nicotinic as well as muscarinic cholinergic receptors are involved in the modulation of eyeblink conditioning. Experiments were carried out using young rabbits to examine the effect of nefiracetam on cholinergic antagonists to nicotinic (mecamylamine) and muscarinic (scopolamine) receptors. Rabbits were tested for 15 days in the 750 ms delay eyeblink classical conditioning paradigm in paired and explicitly unpaired conditions. Nefiracetam at a dose of 15 mg/kg significantly ameliorated the effects of 0.5 mg/kg mecamylamine, and nefiracetam at a dose of 10 mg/kg significantly ameliorated the effect of 1.5 mg/kg scopolamine. The vehicle alone and nefiracetam alone groups performed similarly to the groups treated with mecamylamine or scopolamine and nefiracetam. Reversal by nefiracetam of a nicotinic as well as a muscarinic cholinergic antagonist indicates that the drug may affect deficits specific to AD. Received: 16 July 1996 /Final version: 16 December 1996     

Conditioned drug reward enhances subsequent spatial learning and memory in rats

Rationale Chronic exposure to drugs of abuse alters neural processes that normally promote learning and memory. A context that is repeatedly paired with reinforcing drugs will acquire secondary reinforcing properties (conditioned reward). However, the effects of conditioned reward on spatial learning are unknown. Objective Using the conditioned place preference procedure and Morris water maze task, we examined the role of conditioned reward or aversion in spatial learning. Materials and methods Groups of rats acquired morphine (10 mg/kg), cocaine (10 mg/kg), or oral sucrose (15%) conditioned place preference (CPP). Another group of morphine-dependent rats acquired conditioned place aversion (CPA) to a context paired with precipitated opiate withdrawal induced by naloxone injections (1 mg/kg). To examine the role of conditioned reward or aversion in spatial learning, rats were then exposed to the previously morphine-, cocaine-, sucrose- or naloxone-paired context for 10 min before training of spatial learning in the Morris water maze. Results Exposure to the morphine- or cocaine-paired but not the sucrose- or the naloxone-paired context decreased the latency to find the platform in the Morris water maze test. Conclusions Our results provide the first evidence that conditioned drug reward promotes spatial learning. We speculate that this enhancement of spatial learning by the drug-paired context may promote contextual-cue-induced relapse to drug taking by facilitating exploratory drug-seeking behaviors.     

Pharmacological dissociation between the spatial learning deficits produced by morphine and diazepam

This study sought to determine whether the place learning deficits produced by diazepam are a secondary result of opioid release. Rats pretreated with diazepam (3 mg/kg) or morphine (15 mg/kg) were trained in the Morris water maze. Diazepam impaired place learning-slowing acquisition and preventing the formation of a quadrant preference. Morphine also slowed acquisition, but did not prevent place learning, and impaired escape to a visible platform. Flumazenil blocked the deficits produced by diazepam, but not morphine. Naloxone (2 mg/kg) blocked the deficits produced by morphine, but not diazepam. A high dose of naloxone (10 mg/kg) slowed acquisition, and exacerbated the deficit produced by diazepam. These results demonstrate that diazepam interferes with mnemonic processes through endogenous benzodiazepine receptors, independently of opioidergic systems. Further, they suggest that morphine interferes with motivational processes through opioidergic systems, independently of endogenous benzodiazepine systems.     

N-Methyl-D-aspartate (NMDA) and α-amino-3-hydroxy-5-methyl-4- isoxazoleproprionate (AMPA) glutamate-receptor antagonists have different interactions with the discriminative stimuli of abused drugs

The effects of the AMPA-receptor antagonists NBQX and GYKI 52466 were compared with those of the NMDA-receptor channel blocker dizocilpine in two drug discrimination tests. In the first, rats were trained to discriminate morphine (2 mg/kg) from saline and in the second, to discriminate ketamine (7 mg/kg) from saline, using a two-lever food reinforced method. NBQX (1–6 mg/kg) did not substitute for either morphine or ketamine, even at a dose which reduced response rates (6 mg/kg). Likewise, the non-competitive antagonist GYKI 52466 (5 and 10 mg/kg) produced only saline lever responding in the ketamine trained rats. When tested in combination with the training drug, NBQX (4.5 mg/kg) did not alter the morphine generalisation gradient, and similarly, neither NBQX (3 mg/kg) nor GYKI 52466 (5 and 10 mg/kg) interacted with the ketamine cue. In contrast, dizocilpine (0.05 mg/kg) significantly disrupted discrimination of morphine and produced clear drug lever responding (0.0125–0.1 mg/kg) in ketamine trained rats. These results suggest that AMPA-receptor antagonists and non-competitive NMDA-antagonists have different stimulus properties. Received: 24 May 1996/Final version: 28 July 1996     

Learning impairment following acute administration of the calcium channel antagonist nimodipine in mice

The effects of acute systemic administration of the Ca(2+) channel antagonist nimodipine were examined on learning capacities of adult Swiss mice. Tests included spontaneous alternation behaviour, for spatial working memory; and step-down passive avoidance and place learning in a water maze, for long-term memory. Nimodipine markedly impaired spontaneous alternation at doses of 0.3-1mg/kg i.p., and passive avoidance at doses of 0.3-3mg/kg i.p., as compared to the vehicle-treated animals. At 0.3mg/kg i.p., the drug did not alter motility in an open field, but significantly decreased performances in training trials and retention in the water maze. Subchronic nimodipine 0.3 and 1mg/kg once a day i.p. for 10 days) did not affect performances in the Y-maze and passive avoidance tests. These results show that acute nimodipine administration alters learning in adult mice, and argue for an involvement of voltage-dependent Ca(2+) channels in learning.     

Combined stimulation of the glycine and polyamine sites of the NMDA receptor attenuates NMDA blockade-induced learning deficits of rats in a 14-unit T-maze

 The present study examined the effects of multi-site activation of the glycine and polyamine sites of the NMDA receptor on memory formation in rats learning a 14-unit T-maze task. The competitive NMDA receptor antagonist, (±)-3-(2-carboxypiperazine-4-yl)-propyl-1-phosphonic acid (CPP, 9 mg/kg), was used to impair learning. The objectives were two-fold: (1) to investigate the effects of independent stimulation of the strychnine-insensitive glycine site or the polyamine site; (2) to investigate the effects of simultaneous activation of these two sites. Male, Fischer-344 rats were pretrained to a criterion of 13 out of 15 shock avoidances in a straight runway, and 24 h later were trained in a 14-unit T-maze that also required shock avoidance. Prior to maze training, rats received intraperitoneal (IP) injections of saline, saline plus CPP, CPP plus the glycine agonist, D-cycloserine (DCS, 30 or 40 mg/kg), CPP plus the polyamine agonist, spermine (SPM, 2.5 or 5 mg/kg), or CPP plus a combination of DCS (7.5 mg/kg) and SPM (0.625 mg/kg). Individual administration of either DCS or SPM attenuated the CPP-induced maze learning impairment in a dose-dependent manner. However, the combined treatment with both DCS and SPM completely reversed the learning deficit at doses five-fold less than either drug given alone. These findings provide additional evidence that the glycine and polyamine modulatory sites of the NMDA receptor are involved in memory formation. Furthermore, the potent synergistic effect resulting from combined activation of the glycine and polyamine sites would suggest a stronger interaction between these two sites than previously considered, and might provide new therapeutic approaches for enhancing glutamatergic function. Received: 9 May 1997/Final version: 13 August 1997     

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     

Effects of E-2078, a stable dynorphin A(1–8) analog, on sedation and serum prolactin levels in rhesus monkeys

Rationale: In previous comparisons with C57BL/6J mice, DBA/2J mice have been characterized as ”hyporesponsive” to cocaine’s rewarding effect in the conditioned place-preference paradigm. This finding contrasts with other studies showing greater sensitivity of DBA/2J mice to the rewarding effects of ethanol and morphine in the place conditioning task. Objectives: The purpose of the present study was to examine cocaine- induced place conditioning in both strains using apparatus and procedures similar to those used previously to assess ethanol and morphine preference conditioning. Methods: Mice from both strains were exposed to an unbiased place-conditioning procedure using 1, 10, or 30 mg/kg cocaine. Conditioning trial duration was 15, 30, or 60 min. Results: In general, C57BL/6J mice displayed a significant conditioned place preference that was relatively unaffected by cocaine dose or trial duration. In contrast, DBA/2J mice showed no place conditioning at the shortest trial duration, but an increasing level of preference as trial duration increased. At the longest trial duration, both strains showed similar levels of place preference. Conclusions: Genetic differences in sensitivity to cocaine’s rewarding effect depend critically on temporal parameters of the place-conditioning procedure. One possible interpretation of these findings is that short trial durations produce conditioned activity responses that interfere more with expression of conditioned place preference in DBA/2J mice than in C57BL/6J mice. More generally, these findings underscore the need for caution when drawing conclusions about genetic differences in place conditioning, especially when using this paradigm to evaluate the effects of gene knockouts or insertions on drug reward. Received: 31 December 1998 / Final version: 15 April 1999     

Stimulant activities of dimethocaine in mice: reinforcing and anxiogenic effects

The present study evaluated the effects of dimethocaine and procaine, esteratic local anesthetics, on locomotor activity, conditioned place preference and on the elevated plus-maze test of anxiety in mice, behavioral tests believed to be sensitive to cocaine action. Acute administration of dimethocaine (10–40 mg/kg, IP) significantly increased locomotor activity and time spent on the drug-paired side and reduced the relative number of entries and time spent on the open arms of the plus-maze in mice. Procaine (20–50 mg/kg, IP) failed to affect these responses. These data demonstrate the locomotor stimulant, reinforcing and anxiogenic actions of dimethocaine similar to those reported for cocaine in animals. In addition, these findings support a role for dopaminergic activity, rather than local anesthetic action, in the behavioral effects caused by dimethocaine. Received: 17 November 1995/Final version: 15 May 1996     

The effects of dopamine D2 and D3 antagonists on spontaneous motor activity and morphine-induced hyperactivity in male mice

Rationale: Dopaminergic neurotransmission, in particular the mesolimbic pathway, is involved in spontaneous locomotor activity and in morphine-induced hyperactivity, since the drugs acting on DA receptors can modify the action of morphine and this effect could be dependent on the type of DA receptor affected. Objective: In this study, the action of U-99194A maleate, haloperidol, sulpiride and morphine (5, 10, 20, 40 mg/kg) on locomotor activity in male mice was evaluated. Likewise, the effects of these dopaminergic antagonists on morphine-induced hyperactivity were studied. Methods: Animals treated with U-99194A maleate (2.5, 5, 10, 20 mg/kg), haloperidol (0.075, 0.1 mg/kg), sulpiride (20, 40 mg/kg), or morphine (5, 10, 20, 40 mg/kg), and animals treated with these neuroleptics plus morphine were tested in an actimetre at different time points. Results: It was found that an increase in locomotor activity was produced between 0 and 30 min after the administration of 20 mg/kg U-99194A maleate and between 30 and 60 min after the administration of 20 and 40 mg/kg morphine. This dose of U-99194A maleate and the high dose of sulpiride reverts the hyperactivity induced by 20 mg/kg morphine. Haloperidol reversed the hyperactivity induced by all doses of morphine. Conclusions: Our results confirm that the action of DA D₂ and D₃ receptors could be dependent on the dopaminergic state, in this case modified by the action of morphine. Received: 19 June 1998/Final version: 17 October 1998     

Theophylline inhibits tolerance and sensitization induced by morphine: a conditioned place preference paradigm study in female mice

The effect of theophylline on reward properties of morphine was examined in the present study. A biased conditioned place preference paradigm was used to study the effects of theophylline on the development of conditioned place preference by morphine in sensitized and tolerant female mice. Subcutaneous injection of morphine (0.5-10 mg/kg) induced conditioned place preference in mice, while intraperitoneal administration of theophylline (2.5-100 mg/kg) did not induce conditioned place preference or conditioned place aversion. Theophylline (2.5-100 mg/kg) in combination with morphine (5 mg/kg), during conditioning sessions, decreased the acquisition of morphine conditioned place preference dose independently. Administration of theophylline (2.5-100 mg/kg) before testing also caused a significant reduction of the expression of morphine-induced conditioned place preference in a dose-independent manner. Administration of morphine (12.5, 25 or 50 mg/kg) daily, for 3 days, produced tolerance to conditioned place preference induced by the drug (5 mg/kg). Administration of theophylline (2.5 and 10 mg/kg) 1 h before morphine (12.5, 25 mg/kg), during development of tolerance, abolished morphine tolerance. A higher dose of theophylline (100 mg/kg), however, did not alter morphine tolerance. In addition, theophylline (2.5, 10 and 100 mg/kg) failed to reduce tolerance to a higher dose of morphine (50 mg/kg). Daily administration of morphine (5 mg/kg) for 3 days followed by a 5-day interval caused sensitization to morphine place conditioning. When theophylline was administered (2.5, 10 and 100 mg/kg) 1 h before morphine (5 mg/kg), during development of sensitization, inhibition of morphine-induced sensitization was demonstrated. The effect of theophylline was dose independent. It is concluded that while theophylline has no effect by itself, it reduced both the acquisition and expression of morphine conditioned place preference. In addition, theophylline reduced the acquisition of morphine conditioned place preference in morphine-sensitized and morphine-tolerant mice.     

Involvement of central cannabinoid (CB1) receptors in the establishment of place conditioning in rats

The involvement of cannabinoid processes in positive reinforcement was studied using an unbiased, one-compartment, conditioned place preference (CPP) procedure in rats. This was achieved by examining the ability of the selective antagonist of the CB₁ cannabinoid receptor subtype, SR 141716, to counteract the CPP supported by classical reinforcers. The acquisition of CPP induced by cocaine (2 mg/kg), morphine (4 mg/kg) and food (standard chow and sucrose pellets) was dose-dependently blocked by pre-pairing administration of SR 141716 (0.03–3 mg/kg). However, SR 141716 (up to 10 mg/kg) did not significantly counteract the expression of cocaine-induced CPP. On the other hand, the synthetic CB receptor agonist, WIN 55212-2 (0.3–1 mg/kg), established a robust place aversion (CPA), as already described with other agonists, and CPP was never observed, even at 100-fold lower doses. The aversive effect of WIN 55212-2 was reversed by SR 141716 (0.3–1 mg/kg), suggesting that it was accounted for by the stimulation of CB₁ receptors. These findings indicate that, on their own, CB receptor agonists are unable to generate the processes necessary to induce a pleasurable state in animals, as assessed in place conditioning procedures. Nevertheless, a cannabinoid link may be involved in the neurobiological events, allowing the perception of the rewarding value of various kinds of reinforcers. However, a permanent endogenous cannabinoid tone seems unlikely to be necessary to ensure the organism a basal hedonic level since, given alone, SR 141716 supported neither CPP nor CPA. Received: 14 March 1997 / Final version: 28 July 1997     

The role of beta-endorphin in the acute motor stimulatory and rewarding actions of cocaine in mice

Rationale Opioid receptor antagonists have been shown to attenuate the rewarding and addictive effects of cocaine. Furthermore, cocaine has been shown to cause the release of beta-endorphin, an endogenous opioid peptide. Objective We assessed whether this neuropeptide would play a functional role in cocaine-induced motor stimulation and conditioned place preference (CPP). Materials and methods Mice lacking beta-endorphin and their wild-type littermates were habituated to motor activity chambers for 1 h, then injected with cocaine (0, 15, 30, or 60 mg/kg, intraperitoneally) or morphine (0, 5, or 10 mg/kg, subcutaneously), and motor activity was recorded for 1 h. In the CPP paradigm, mice were tested for baseline place preference on day 1. On days 2 and 3, mice received an alternate-day saline/cocaine (15, 30, or 60 mg/kg) or saline/morphine (10 mg/kg) conditioning session and then tested for postconditioning place preference on day 4. Results Cocaine-induced motor stimulation and CPP were both reduced in mice lacking beta-endorphin. On the other hand, motor stimulation and CPP induced by morphine were not altered in mutant mice. Conclusion The present results demonstrate that the endogenous opioid peptide beta-endorphin plays a modulatory role in the motor stimulatory and rewarding actions of acute cocaine.     

Involvement of glucose and ATP-sensitive potassium (K+) channels on morphine-induced conditioned place preference

In the present study, the effects of glucose and ATP-sensitive K+ channel compounds on the acquisition of morphine-induced place preference in male mice were investigated. Subcutaneous administration of different doses of morphine (2.5-7.5 mg/kg) produced a dose-dependent conditioned place preference. With a 3-day conditioning schedule, it was found that glucose (100, 200, 500 and 1000 mg/kg), diazoxide (15, 30 and 60 mg/kg) or glibenclamide (3, 6 and 12 mg/kg) did not produce significant place preference or place aversion. Intraperitoneal administration of the glucose (1000 mg/kg) or glibenclamide (6 and 12 mg/kg) with a lower dose of morphine (0.5 mg/kg) elicited the significant conditioned place preference. The response of glibenclamide (6 mg/kg) was reversed by diazoxide (15, 30 and 60 mg/kg). Drug injections had no effects on locomotor activity during the test sessions. It is concluded that glucose and the ATP-sensitive K+ channel may play an active role in morphine reward.