Baclofen blocks the development of sensitization to the locomotor stimulant effect of amphetamine.

The GABAB agonist baclofen (BCF) has recently been reported to block the expression of sensitization to the locomotor effect of amphetamine (AMPH), and to reverse it after repeated administration. The present study was undertaken to investigate whether baclofen could also prevent the development of sensitization to the psychostimulant. Chronic AMPH treatment (1.5 mg/kg i.p. for 10 days) led to an increased locomotor response to AMPH (1.5 mg/kg) when the animals were challenged 3 and 30 days after the end of repeated treatment. Chronic co-administration of BCF (2 mg/kg, i.p.) and AMPH blocked the development of sensitization to the stimulant effect of AMPH. An ancillary experiment excluded that a 'state-dependency' hypothesis could account for the effect of baclofen. Furthermore, a previous repeated treatment with baclofen alone had no influence either on the acute AMPH effect or on the subsequent development of sensitization to AMPH. In conclusion, the results confirm that GABAB receptors play an important role in the acquisition of AMPH behavioural sensitization and further support a potential use of GABAB agonists in the treatment of psychostimulant addiction.

The GABAB agonist baclofen blocks the expression of sensitisation to the locomotor stimulant effect of amphetamine.

The purpose of the present study was to test the possible influence of baclofen, a GABAB agonist, on the long-term sensitisation to amphetamine in rats. As expected, chronic amphetamine treatment (1.5 mg/kg i.p. daily for 10 days) led to an increased locomotor response to amphetamine (0.75 mg/kg i.p.), when the animals were challenged 20 days after the end of repeated treatment. Baclofen (2 mg/kg i.p.), administered before the test session, did not significantly modify the spontaneous locomotor activity of rats, but decreased the normal and, to a greater extent, the sensitised locomotor response to amphetamine; thus baclofen prevented the expression of sensitisation to amphetamine. Moreover a previous chronic treatment with baclofen (2 mg/kg i.p. daily for 10 days) attenuated the amphetamine-induced locomotor activity in sensitised, but not in control animals. This effect was observed 20 days after the last baclofen administration. In conclusion, the present results demonstrate that GABAB receptors play an important role in the expression of the sensitised behavioural response to amphetamine and further support a potential role of GABAB agonists in the treatment of psychostimulant addiction.

Effects of N-methyl-D-aspartate agonists and antagonists in rats discriminating amphetamine.

The present study assessed the interactions between N-methyl-D-aspartate (NMDA) agonists or antagonists and the discriminative stimulus effects of amphetamine. Adult male Sprague-Dawley rats were trained to discriminate 0.5 mg/kg (i.p.) of amphetamine from saline under a two-lever fixed-ratio schedule of food reinforcement. During test sessions, i.p. injections of the glycine site agonist D-cycloserine, the ion-channel blocker dizocilpine and the competitive antagonist CGP 43487 were coadministered with i.p. saline or with a full range of doses of amphetamine. D-Cycloserine did not substitute for amphetamine and attenuated the cueing effects of the drug. Both dizocilpine and CGP 43487 engendered intermediate levels of amphetamine-appropriate responses and potentiated the stimulus properties of amphetamine; however, the effects of CGP 43487 were very small and not dose-dependent. In an ancillary experiment, the training dose of amphetamine was reduced to 0.25mg/kg; under these conditions dizocilpine, but not CGP 43487, produced full substitution for the discriminative stimulus effects of amphetamine. These results show that drugs affecting NMDA receptor-based neurotransmission can modulate the discriminative stimulus effects of amphetamine.

Sensitization to the morphine-like discriminative stimulus effects of buprenorphine in rats.

An experiment was performed to determine whether chronic non-contingent administration of morphine would produce cross-sensitization to the cueing properties of buprenorphine or D-amphetamine. To this end the sensitivity to the discriminative stimulus effects of morphine, buprenorphine and D-amphetamine was determined in rats trained to discriminate 10 mg kg(-1)morphine from saline in a food-reinforced operant task. Seven rats were given repeated non-contingent treatments with morphine (20 mg kg(-1)on saline or no-test days and 10 mg kg(-1)on drug days) starting 20 days before the beginning of discrimination training; another six animals received injections of saline. Chronic administration of morphine resulted in sensitization to the discriminative stimulus effect of this drug and in cross-sensitization to the discriminative stimulus effect of buprenorphine. D-Amphetamine produced only saline lever selection in all rats. In conclusion, the present results confirm that the stimulus properties of opioid drugs may be enhanced, rather than decreased, in animals with a history of repeated non-contingent treatment with morphine. Sensitization to central-acting drugs is thought to play a role in the psychopathology of drug abuse. Hence, the present results point out the necessity of considering the effects of drugs which show tolerance, and those which show sensitization, under any particular drug regimen.

Effects of buprenorphine on motility in morphine post-dependent rats.

The effects of buprenorphine (0.0125-0.2 mg kg(-1)) on the locomotor activity of rats were determined 1-2 months after ceasing a chronic treatment with morphine (20 mg kg(-1)for 28 days). In control animals buprenorphine exhibited both depressive and stimulatory actions, as repeatedly described for morphine. In post-dependent animals buprenorphine showed a depressive effect similar to that observed in naive ones. On the contrary, a persistent sensitization to the excitatory effect was observed; the degree of cross-sensitization was similar to that of morphine itself (20 mg kg(-1)). The results are discussed in terms of persistent changes in the locomotor response to opioids, possibly correlated to both drug craving and relapse.

Facilitatory and inhibitory actions of morphine on the discriminative stimulus properties of D-amphetamine.

Facilitatory and inhibitory actions of morphine on the discriminative stimulus properties of D-amphetamine were examined in rats trained to discriminate D-amphetamine (1 mg kg-1) from saline in a two-lever food reinforced operant task. Morphine (0.625-2.5 mg kg-1) did not itself generalize to amphetamine. When the percentages of rats selecting the drug-appropriate lever were plotted as a function of the individual lowest generalized dose (LGD), a log-linear model fitted to cell frequency indicated a rising single quote, left (low)morphinexamphetaminexlever selection' interaction. Subsequent comparisons indicated that morphine significantly increased or decreased drug lever selection in rats receiving one-half LGD or LGD, respectively. In both cases no difference was found among morphine doses. The present study confirms that the discriminative stimulus properties of amphetamine can be both potentiated and attenuated by morphine. The direction to which morphine modulates the interoceptive effects of 1 mg kg-1 amphetamine seems to be dependent on the individual sensitivity of animals to amphetamine rather than on the overall effect of the test dose of amphetamine alone. (c) 1998 The Italian Pharmacological Society.

Taste conditioning effects of buprenorphine in morphine-naive and morphine-experienced rats.

Male Sprague-Dawley rats were injected daily with saline (morphine-naive rats) or 20 mg kg-1 morphine (morphine-experienced rats), starting 15 days before the experiment. Subsequent taste conditioning indicated that 0.1 mg kg-1 buprenorphine significantly decreased 0.025% saccharin consumption in morphine-naive, but not in morphine-experienced rats. A 10 mg kg-1 dose of morphine gave similar results, while d-amphetamine (0.75 mg kg-1) was consistently aversive. It was concluded that morphine experience selectively blocks the aversive effects of buprenorphine in rats; thus it possibly increases the potential for buprenorphine abuse.

Modulation of the stimulus effects of morphine by d-amphetamine.

The stimulus effects of morphine and d-amphetamine coadministration were studied in rats. Place conditioning, drug discrimination, and taste conditioning were employed to assess the rewarding, discriminative, and aversive stimulus properties of both drugs. d-Amphetamine increased the rewarding and morphine-like discriminative stimulus effects of 1.25 mg/kg morphine. d-Amphetamine did not, however, change the aversive effects of 1.25 mg/kg morphine, or any effect of higher (5-20 mg/kg) morphine doses. Because the rewarding/discriminative properties and the aversive properties of a drug are considered the main attributes that regulate (facilitate and weaken, respectively) drug-seeking behavior, the present data are in keeping with clinical reports indicating that amphetamines are sometimes used by opiate abusers in an attempt to increase the effect obtained from poor-quality heroin.

Motivational properties of buprenorphine as assessed by place and taste conditioning in rats.

Buprenorphine, a mixed agonist-antagonist opioid with considerable analgesic activity, is currently indicated as a therapeutic agent with low abuse potential. Nevertheless, buprenorphine abuse has been recently reported from some countries. Thus the present experiments were performed to characterize further the motivational properties of buprenorphine in rats. Rewarding and aversive effects were assessed by place preference and taste aversion conditioning, respectively. It was found that buprenorphine (0.025, 0.050, 0.100 mg/kg s.c.) causes a significant increase in the amount of time spent on the conditioned side, but no significant decrease in saccharin consumption. Therefore buprenorphine data are not consistent with the general finding that psychoactive drugs cause rewarding and aversive effects within a similar dose range.

Food deprivation and motor activity in rats: differences between morphine and clonidine.

The effects of various doses of morphine (0, 1.25, 2.5, 5 mg/kg) and clonidine (0, 1.67, 15, 45 micrograms/kg) on motility were determined in food satiated and in food deprived rats. Food deprivation failed to change the general activity of rats after saline injections. Nevertheless, food-deprived animals tested under morphine were more active than food satiated ones. Clonidine exhibited slight psychomotor stimulant properties that were not increased by food deprivation. The results are discussed in terms of possible mechanisms of deprivation-related hypermotility.

Effects of buprenorphine on motility in chronically morphine treated rats.

The effects of buprenorphine (0.01-0.1 mg/kg) on the activity of nondependent and morphine dependent rats (a 20 mg/kg dose for 28 days) were determined. In naive animals buprenorphine exhibited both depressive and stimulatory actions upon the motility of rats, as repeatedly described for morphine. When buprenorphine was administered to rats chronically treated with morphine, the depressive effect disappeared (cross-tolerance to the inhibitory action); on the contrary the excitatory effect was enhanced (cross-sensitization). The results are discussed in terms of cross-sensitization to the excitatory effects in morphine dependent animals as predictor of morphine-like addictive properties in humans.

Role of repeated exposure to morphine in determining its affective properties: place and taste conditioning studies in rats.

Male Sprague Dawley rats were injected daily with saline (morphine naive rats) or 20 mg/kg morphine (morphine experienced rats), starting at least 12 days before training. Subsequent place and taste conditioning indicated that 2.5 mg/kg morphine caused a significant increase in the amount of time spent on the least preferred side by morphine experienced but not by morphine naive rats; furthermore, saccharin consumption was markedly decreased and slightly increased by 10-20 mg/kg morphine in naive and experienced rats, respectively. It was concluded that morphine experience enhances the reinforcing efficacy of morphine and broadens the conditions under which the drug is reinforcing; thus it possibly increases morphine abuse potential.

Morphine attenuation of a conditioned emotional response in post-dependent rats.

Rats placed in a test chamber where they had received repetitive shocks the previous day significantly reduced their motor activity; this was taken as indicator of a conditioned emotional response. Morphine attenuated this conditioned suppression of motility, possibly due to a reduction of the anxiety associated with the expectation of the noxious stimuli. Previous morphine dependence (20 mg/kg daily for 26 days) did not modify the effect of the opioid on the conditioned suppression of motility. This fact suggests that the action of morphine on pain anticipatory anxiety is similar in non-dependent and in post-dependent rats. Opioids are considered to produce pain relief in part by decreasing the anticipatory anxiety. The present results thus indicate that this important component of the analgesic action of morphine is unchanged in post-addicts.

Cross-tolerance between morphine and clonidine: a study on motility in rats.

The effects of clonidine on motility were determined in non-dependent, morphine-dependent (a 20 mg/kg dose i.p. for 26 days) and post-dependent rats. In naive animals, clonidine (30-100 micrograms/kg) produced a dose-related suppression of motility. However, when the drug was administered in morphine-dependent rats, it induced slight hyperactivity at small doses and a decrease of activity only at the largest dose (100 micrograms/kg). Thus, tolerance to morphine conferred cross-tolerance to clonidine. On the contrary, the effects of clonidine on motility in post-dependent animals did not differ from those observed in control animals. The results are discussed in terms of similarities and differences between the depressant and excitatory effects of morphine and clonidine.

Time-dependent generalization of morphine stimulus properties to meperidine: antagonism by naloxone.

The time course of the stimulus generalization to morphine by meperidine (20 mg/kg) was determined in rats trained to discriminate morphine (10 mg/kg) from saline in a standard two-lever procedure with food reinforcement. It was found that morphine lever selection following meperidine was a strictly time-dependent phenomenon. Naloxone (0.3 mg/kg) antagonized the stimulus properties of both morphine and meperidine; however, the antagonism was significantly more pronounced against morphine. The results suggest that there may be certain differences in the neuropharmacology of the stimulus properties of morphine and meperidine.

Increased sensitivity to the stimulus properties of morphine in food deprived rats.

Recent research has shown that food deprivation increases opiate self-administration; in this line a first purpose of the present experiments was to determine whether the food deprivation effect could be replicated by the use of place conditioning, an alternative procedure for the study of drug reinforcement. It was found that the conditioned reinforcing properties of morphine (2.5 mg/kg IP) paired cues are greater in food deprived rats both after 1 and 3 conditioning sessions. A second objective of the work was to examine the possibility that food deprivation could also influence the discriminative stimulus properties of opiates. To this end rats trained to discriminate 10 mg/kg IP of morphine from saline were submitted to morphine generalization tests when food deprived or after 15 min supplemental feeding in the home cages. The ED50 value was significantly lower for food deprived (6.09 mg/kg) than for partially satiated (7.79 mg/kg) rats. It was concluded that food deprived rats are mores sensitive to both the reinforcing and the discriminative stimulus properties of morphine.

Previous treatment with morphine and sensitization to the excitatory actions of opiates: dose-effect relationship.

The stimulatory effect of morphine on locomotor activity has been shown to be largely modified in rats that have been formerly dependent on this drug. In the present study, the relationship between the chronic dose of morphine and the degree of sensitization to the excitatory effect of opiates was investigated. To this end, four groups of rats were treated daily for 30 days with 1.25, 5, 20 and 80 mg/kg of morphine (i.p.) and challenged with morphine (1.25 and 2.5 mg/kg) or fentanyl (40 and 80 micrograms/kg) 1-4 months after ceasing the treatment. Drug-induced hypermotility in post-dependent rats appeared to be linearly related to the dose of the preceding chronic treatment after test doses of both morphine and fentanyl. The results are discussed in terms of a persistent dose-related modification of the neuronal mechanism subserving the excitatory component of the action of opiates; such a modification might offer a neurobiological basis for the fact that "relapse tendencies" for opiates persist for a long time after withdrawal.

Sensitivity to the narcotic cue in non-dependent, morphine-dependent and post-dependent rats.

Using a food-reinforced two-lever operant procedure, 12 rats were trained to discriminate 10 mg/kg (i.p.) of morphine from saline. Five animals were given daily non-contingent exposure to morphine (20 mg/kg on saline, or no-test days, and 10 mg/kg on drug days) from the beginning of the experiment; the others received injections of saline. In the morphine generalization tests, the dependent rats showed an increased sensitivity to the narcotic cue as compared with non-dependent animals (ratio of the ED50 values: 2.30). This increased sensitivity was still present 3 months after discontinuing the non-contingent treatment with morphine (ratio of the ED50 values: 1.98). The results of the present study, together with other results reported in the literature, suggest that the experimental procedure plays a role in determining whether tolerance, no tolerance or enhanced sensitivity to the discriminative stimulus properties of narcotics, is observed.

Cross-sensitization to the excitatory effect of morphine in post-dependent rats.

Time-effects of morphine, methadone, meperidine and pentazocine upon locomotor activity were investigated in naive and in post-dependent rats. Dependence was induced by daily injection of 20 mg/kg (i.p.) of morphine for 30 days. Tests were run starting from 1 month after withdrawal from morphine. Morphine produced a greater increase in activity in post-dependent than in naive rats. Marked cross-sensitization to the excitatory effect occurred with methadone but not with pentazocine. The motility pattern of meperidine was similar in naive and in post-dependent animals. The findings presented here suggest that: different mechanisms underlie the excitatory actions of opiates; the narcotic character of a drug can be detected by challenging this drug in rats previously dependent on morphine.