Modulatory effects of low-dose MDMA on cocaine-induced locomotor activity and place conditioning in rats

Methylenedioxymethamphetamine (MDMA; “Ecstasy”) is commonly abused by humans in environments such as nightclubs and rave parties where other drugs of abuse are readily available. Despite the popularity of polysubstance abuse among recreational MDMA users, relatively few controlled experimental studies have documented the neurobehavioral effects of MDMA in combination with other abused substances. This study employed conditioned place preference procedures (CPP) to assess the locomotor activating and place conditioning effects of acute concurrent administration of MDMA (1.5 or 3.0 mg/kg) and cocaine (10 or 20 mg/kg) in rats. Results indicate that low dose MDMA can enhance the locomotor and conditioned rewarding effects of cocaine. These findings may have important implications for understanding the contribution of serotonergic-dopaminergic interactions in the abuse liability of MDMA when used in combination with cocaine or other psychostimulant drugs.     

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.     

Long-term changes in social interaction and reward following repeated MDMA administration to adolescent rats without accompanying serotonergic neurotoxicity

RATIONALE: MDMA is a popular drug of abuse in adolescents which causes serotonergic neurotoxicity in adult but not young rodents. However, few studies have examined the long-term behavioural consequence of MDMA and it is unclear whether such changes occur in the absence of neurotoxicity. OBJECTIVES: The present study examined whether treatment of young rats with MDMA produced long-term behavioural alterations without accompanying serotonergic neurotoxicity. METHOD: Male Lister hooded rats ( n=36, postnatal day (PND) 39) received MDMA (7.5 mg/kg i.p., twice daily for 3 days) or saline (l ml/kg i.p.) and the acute effect on open field behaviour and body temperature was monitored. Following drug withdrawal, social interaction in pre-treatment- and weight-matched rat pairs, cortical [(3)H]paroxetine binding and hippocampal and frontal cortical serotonin and dopamine levels (PND 53, n=12) and conditioned place preference (PND 70, n=24) to cocaine (5 mg/kg IP) were analysed. RESULTS: MDMA elicited the expected immediate serotonin syndrome with significant hyperlocomotion, decreased rearing and hypothermia. Twelve to 29 days after the last MDMA injection social interaction was significantly attenuated (by 41%) and the sub-threshold conditioned place preference to cocaine was significantly enhanced compared with that in saline controls, although no significant side preference to cocaine occurred in the latter. MDMA pre-treatment did not alter 5-HT levels or cortical [(3)H]paroxetine binding. CONCLUSION: MDMA administration to adolescent rats reduced social interaction and enhanced the sub-threshold rewarding effect of cocaine at adulthood, despite an absence of accompanying serotonergic and dopaminergic neurotoxicity.     

Multiple 5-HT receptors are involved in the effects of acute MDMA treatment: studies on locomotor activity and responding for conditioned reinforcement

RATIONALE: Responding for conditioned reinforcement is increased by the dopamine releasing agent amphetamine, but reduced by drugs that enhance serotonin (5-HT) function. The amphetamine derivative 3,4-methylenedioxymethamphetamine (MDMA, Ecstasy) releases both monoamines. OBJECTIVES: The primary purpose of this study was to examine the effects of MDMA on responding for conditioned reinforcement as well as on locomotor activity. The roles of several 5-HT receptor sub-types in mediating these behavioural effects of MDMA were also examined. METHODS: Locomotion was measured in photocell activity monitors. For conditioned reinforcement experiments thirsty rats learned to associate a conditioned stimulus (CS) with water in operant chambers. Subsequently, two response levers were available; responding on one lever delivered the CS, while responding on the second lever had no consequences. Drug effects on this operant response were measured. RESULTS: MDMA dose-dependently increased locomotion but reduced responding for conditioned reinforcement. This latter effect differs from that induced by amphetamine, which potentiates conditioned reinforcement responding. The stimulant effect of MDMA was attenuated by GR127935 and ketanserin, indicating facilitatory roles of 5-HT(1B) and 5-HT(2A) receptors in mediating this effect. The 5-HT(2C) antagonist SB242084 enhanced the stimulant effect of MDMA. Only SB242084 attenuated the suppressant effect of MDMA on responding for conditioned reinforcement. CONCLUSIONS: The results show that 5-HT(2A) and 5-HT(1B/1D) receptors play a facilitatory role in mediating the stimulant effect of MDMA, whereas 5-HT(2C) receptors are inhibitory. Activation of 5-HT(2C) receptors also contributes to the deficit in operant responding. Multiple 5-HT receptor sub-types appear to contribute to the behavioural effects of MDMA.     

Effects of MDMA exposure on the conditioned place preference produced by other drugs of abuse

Rationale. MDMA is a serotonergic neurotoxin but few pre-clinical studies have found long-term behavioural consequences. As human users of MDMA are polydrug users, it is important to investigate whether the behavioural effects of other drugs are modulated by prior exposure to MDMA. Objectives. This study investigated whether pretreatment with a multiple high dose regimen of MDMA altered the rewarding effects of other drugs of abuse. Methods. Adult male Lister Hooded rats (n=10/group) were pretreated with 10 mg/kg MDMA or 1 ml/kg saline vehicle IP every 2 h for 6 h. Fourteen days later, conditioned place preference (CPP) to d-amphetamine (3 mg/kg), cocaine (20 mg/kg), ethanol (2.0 g/kg), heroin (0.5 mg/kg), or MDMA (10 mg/kg) was assessed. Results. In general, MDMA pretreatment had no effect on drug reward or habituation to the place conditioning apparatus. However, in contrast to saline pretreated rats, those animals receiving MDMA failed to show CPP after ethanol. Conclusion. MDMA pretreatment reduced the rewarding properties of ethanol. This finding may represent a functional consequence of MDMA-induced neurotoxicity. By extrapolation, human users of MDMA may be exposed to an increase in risks associated with alcohol abuse. Electronic Publication     

Differential effects of excitotoxic lesions of the amygdala on cocaine-induced conditioned locomotion and conditioned place preference

The reinforcing properties of cocaine can readily become associated with salient environmental stimuli that acquire secondary reinforcing properties. This type of classical conditioning is of considerable clinical relevance, as intense drug craving can be evoked by the presentation of stimuli previously associated with the effects of cocaine. Given the large body of evidence that implicates the amygdaloid complex in the learning of stimulus-reward associations, the present experiments examined the effects of quinolinic acid lesions of the amygdala on cocaine-induced conditional locomotion and conditioned place preference (CPP). Destruction of the amygdala did not affect basal or cocaine-induced locomotion, suggesting that the amygdala does not mediate the unconditioned psychomotor stimulant effects of this drug. Preconditioning lesions also failed to affect cocaine-induced conditional locomotion. Specifically, exposure of both lesioned and non-lesioned rats to a cocaine-paired environment produced significant conditional increases in locomotion. This lack of effect was contrasted by a complete blockade of cocaine-induced CPP by the amygdaloid lesions. These data demonstrate that cocaine-induced stimulus-reward conditioning can be differentially affected by lesions of the amygdala.     

Metrazol produces conditioned taste aversion in rats

Employing a two bottle drinking procedure where an animal's preference is measured between plain water and a novel fluid, it was found that the convulsant drug Metrazol produced a conditioned taste aversion to saccharin. This finding is contrary to that of previous reports and highlights the sensitivity of the two bottle method in detecting a taste aversion.     

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     

Chronic intermittent heroin produces locomotor sensitization and long-lasting enhancement of conditioned reinforcement

In a previous study we showed that chronic intermittent heroin in rats enhanced responding with conditioned reinforcement and reversal learning of a conditioned magazine approach task when tested three days after the heroin treatment. Whether or not this enhanced appetitive learning persists after a protracted withdrawal period remains unknown and constitutes the aim of the present study. Forty-eight male Long Evans rats were each exposed to positive pairings of a light stimulus and food for 4 consecutive daily sessions. Then, two groups of rats received saline and two groups received heroin (2 mg/kg) injections before placement in activity monitors for 9 consecutive daily sessions. This was followed by testing in operant conditioning chambers where one lever produced the light stimulus previously paired with food and another no stimulus. For one saline and one heroin group this testing occurred after 2 days of withdrawal while for the other saline and heroin groups it occurred after 30 days of withdrawal. The results indicate that animals treated with heroin displayed progressively and significantly greater locomotor activity across sessions while animals treated with saline displayed locomotor activity that remained low and stable across sessions. In addition, the heroin groups in each withdrawal condition displayed significantly enhanced responding with conditioned reinforcement compared to their respective saline control groups. These results demonstrate that chronic intermittent heroin enhances appetitive learning for natural reinforcers and motivational processes and that this effect persists even after 30-days of withdrawal.     

Relevance of MDMA ("ecstasy")-induced neurotoxicity to long-lasting psychomotor stimulation in mice

Rationale. Although many studies have focused on the mechanisms underlying MDMA-induced neurotoxicity, little is known about the subsequent long-term response to psychostimulants following exposure to a neurotoxic dose of MDMA. Objectives. We investigated the effect of pre-exposure to neurotoxic and non-neurotoxic doses of MDMA on the response of mice to the psychomotor stimulating effects of MDMA and cocaine. Methods. To investigate MDMA-induced neurotoxicity, male Swiss Webster mice were subjected to three regimens of MDMA: i) 40 mg/kg×2, ii) 30 mg/kg×2, and iii) 15 mg/kg×2 for 2 days. On day 5 following the last exposure to MDMA, the levels of dopaminergic and serotonergic markers were determined. For the behavioral experiments, mice received either a single injection of 10 mg/kg MDMA [MDMA(L)] or one of the following doses of MDMA: 30 mg/kg×2 or 15 mg/kg×2 for 2 days [MDMA (H)]. A third group received saline as a control. On day 5 after the last pretreatment injection, the first MDMA (10 mg/kg) challenge was given, and on day 12, cocaine (20 mg/kg) was administered. Subsequently, mice were re-challenged with MDMA on days 35, 50 and 80, after which locomotor activity was monitored by infrared beam-interrupts. On day 83, mice were killed to detect the levels of dopaminergic and serotonergic markers. Results. MDMA-induced mortality and depletion of dopaminergic and serotonergic markers were dose-dependent. MDMA (H) mice endured a sensitized response to MDMA challenge from days 5 through 80, e.g. a persistent 3-fold increase in locomotor activity compared to the response of mice that were not pretreated with a neurotoxic dose of MDMA. The depletion of DAT and 5-HTT binding sites was sustained throughout this time period (64–68% of control). The MDMA (L) mice showed a sensitized response to MDMA only on day 5. Both MDMA (L) and MDMA (H) mice were sensitized to the cocaine challenge. Conclusions. The induction of sensitization to the locomotor stimulating effects of MDMA and cocaine was independent of MDMA-induced neurotoxicity. However, the long-lasting maintenance of the sensitized response to MDMA may be related to the enduring neurotoxicity caused by MDMA. Electronic Publication     

Age-dependent effects of nicotine on locomotor activity and conditioned place preference in rats

Rationale Most adult smokers start smoking during their adolescence. This adolescent initiation may be due to multiple factors, but little evidence is available regarding whether their brains are differentially sensitive to the addictive effects of nicotine during adolescence.Objective To test the hypothesis that adolescents are more sensitive than adults to nicotines rewarding actions.Methods An unbiased, counterbalanced, place-conditioning procedure was used to examine drug-induced reward and locomotor activity. Early adolescent (postnatal day 28), late adolescent (P38) and adult (P90) rats received either saline or nicotine (0.125, 0.25 or 0.5 mg/kg, s.c.) and were tested for place conditioning.Results During early adolescence, a single nicotine injection (0.5 mg/kg) induced significant conditioned place preference (CPP). In contrast, during late adolescence or adulthood, nicotine did not induce CPP after either one or four conditioning trials. Initial locomotor responses to acute nicotine administration during the first conditioning trial also differed with age, with no effect at P28, but substantial inhibitory responses at all doses studied (0.125–0.5 mg/kg) at later ages. Although not differing in their initial locomotor response to nicotine, there was a significantly greater tolerance/sensitization during the second and subsequent drug exposures in late adolescents than in adults.Conclusions These findings provide evidence that adolescent brain is differentially sensitive to both the acute and repeated effects of nicotine relative to adult brain. Furthermore, there are significant differences in nicotine sensitivity between early and late phases of adolescence.     

Extinction training following cocaine or MDMA self-administration produces discrete changes in D2-like and mGlu5 receptor density in the rat brain

BackgroundSeveral studies strongly support the role of the dopamine D₂-like and glutamate mGlu₅ receptors in psychostimulant reward and relapse.MethodsThe present study employed cocaine or MDMA self-administration with yoked-triad procedure in rats to explore whether extinction training affects the drug-seeking behavior and the D₂-like and mGlu₅ receptor B_max and K_d values in several regions of the animal brain.ResultsBoth cocaine and MDMA rats developed maintenance of self-administration, but MDMA evoked lower response rates and speed of self-administration acquisition. During reinstatement tests, cocaine or MDMA seeking behavior was produced by either exposure to the drug-associated cues or drug-priming injections. The extinction training after cocaine self-administration did not alter significantly D₂-like receptor expression the in the limbic and subcortical brain areas, while MDMA yoked rats showed a decrease of the D_2-like binding density in the nucleus accumbens and increase in the hippocampus and a rise of affinity in the striatum and hippocampus. Interestingly, in the prefrontal cortex a reduction in the mGlu₅ receptor density in cocaine- or MDMA-abstinent rats was demonstrated, with significant effects being observed after previous MDMA exposure. Moreover, rats self-administered cocaine showed a rise in the density of mGlu₅ receptor for the nucleus accumbens.ConclusionThis study first time shows that abstinence followed extinction training after cocaine or MDMA self- or passive-injections changes the D₂-like and mGlu₅ density and affinity. The observed changes in the expression of both receptors are brain-region specific and related to either pharmacological and/or motivational features of cocaine or MDMA.     

Influence of a conditioned light stimulus on cocaine self-administration in rats

RATIONALE: A number of studies have suggested that the continued presentation of stimuli associated with cocaine may contribute to drug-seeking and drug-taking. The influence of conditioned stimuli on the maintenance of self-administration has not, however, been systematically investigated. OBJECTIVES: This study was designed to determine whether omission of a stimulus that had been paired with self-administered cocaine would influence the maintenance of cocaine self-administration and whether the effect was dependent on cocaine dose or session length. METHODS: During self-administration training, self-administered cocaine infusions were always paired with the illumination of a light. On test days, self-administered cocaine was delivered either with or without the cocaine-associated cue. For one group of rats, responding maintained by cocaine (0.50 mg/kg per infusion) was measured during daily 18-h sessions. For other groups, responding maintained by additional doses of cocaine (0.125, 0.25, or 1.0 mg/kg per infusion) was measured during daily 8-h sessions. For a final group, daily test sessions (4-5 h) produced the dose-effect curve (0.015-1.0 mg/kg per infusion) by repeatedly reducing the cocaine dose from a starting dose of 1.0 mg/kg per infusion. RESULTS: Removal of the light cue decreased cocaine self-administration. The magnitude of this effect was dependent on the dose of self-administered cocaine and on the test session duration. Greater decrements in responding were produced as session length increased or when low doses of cocaine were self-administered. CONCLUSIONS: These findings demonstrate that in the absence of a cocaine-associated stimulus, cocaine self-administration is attenuated and that maintenance of cocaine self-administration is maximally affected by the presence or absence of the conditioned stimulus when the self-administered dose is low and/or when session duration is long.     

Stimulation of serotonin1B receptors induces conditioned place aversion and facilitates cocaine place conditioning in rats

RATIONALE: Changes in serotonin(1B) (5-HT(1B)) receptor function appear to modify the reinforcing properties of cocaine, but the direction of this effect is not completely clear. Pharmacological stimulation of 5-HT(1B) enhanced the rewarding properties of self-administered cocaine while attenuating the threshold-reducing effect of cocaine in the intracerebral brain stimulation procedure. OBJECTIVE: The present study investigates how pharmacological modification of 5-HT(1B) receptor-mediated neurotransmission influence cocaine motivational properties in the conditioned place preference paradigm in rats. METHODS: In separate groups of rats the motivational properties of CP 94,253, a selective 5-HT(1B) agonist, or GR 127935, a 5-HT(1B/D) receptor partial agonist, given alone or in combination, were determined. To evaluate their influence on cocaine-induced place conditioning, CP 94,253, that was found to be aversive, was given every day before each conditioning session, while GR 127935, which given alone had no effect, was administered only before cocaine conditioning sessions. RESULTS: CP 94,253, injected IP at 2.5 and 10 (but not 0.5) mg/kg produced place aversion in the place conditioning paradigm. The aversive effect of 2.5 mg/kg CP 94,253 was completely reversed by 10 mg/kg SC GR 127935. Given before every conditioning session, CP 94,253 did not modify place conditioning by four injections of 10 mg/kg cocaine but at 2.5 mg/kg it potentiated a sub-threshold dose of cocaine. The place preference caused by these two drugs was completely reversed by 10 mg/kg GR 127935. The antagonism by GR 127935 of CP 94,253's effects was shown not to be due to the induction of state-dependent effects. CONCLUSION: The results suggest that stimulation of 5-HT(1B) receptors causes place aversion, and enhances the effect of low doses of cocaine in the conditioned place preference paradigm.     

Cocaine-induced conditioned taste aversions in rats

In two separate studies cocaine hydrochloride at doses between 10--36 mg/kg was found to induce a dose-related conditioned taste aversion (C.T.A.) to saccharin, and to be an effective conditioning agent even when injections of the drug were delayed 90 min after saccharin intake. These data contrast with conditioning agent when unjectuons of the drug were delayed 90 min after saccharin intake. These data contrast with an earlier report [3] which suggested that cocaine was totally devoid of aversive properties. However, they do indicate that cocaine is only a weak aversion-inducing agent. In contrast to other drugs, the doses of cocaine which are required to induce a C.T.A. are very large relative to those commonly employed in behavioural studies. The weak potency of cocaine in inducing C.T.A. may be related to the drug's marked potency in the self-administration paradigm. Some possible determinants of cocaine's weak effects are discussed.     

Interactions between ethanol and cocaine,amphetamine, or MDMA in the rat: thermoregulatory and locomotor effects

Rationale (±)-3,4-methylenedioxymethamphetamine (MDMA, ecstasy) is often taken recreationally with ethanol (EtOH). In rats, EtOH may potentiate MDMA-induced hyperactivity, but attenuate hyperthermia. Objective Experiment 1 compared the interactions between EtOH (1.5 g/kg) and MDMA (6.6 mg/kg) with EtOH + cocaine (COCA; 10 mg/kg) and EtOH + amphetamine (AMPH; 1 mg/kg) on locomotor activity and thermoregulation. Experiment 2 used a weaker dose of MDMA (3.3 mg/kg) and larger doses of COCA (20 mg/kg) and AMPH (2 mg/kg). Materials and methods Drug treatments were administered on four occasions (2, 5, and 2 days apart, respectively; experiment 1) or two (2 days apart; experiment 2). Results All psychostimulants increased activity, and EtOH markedly increased the effect of MDMA. AMPH alone-related hyperactivity showed modest sensitization across treatment days, while MDMA + EtOH activity showed marked sensitization. AMPH, COCA, and MDMA induced hyperthermia of comparable amplitude (+1 to +1.5°C). Co-treatment with EtOH and AMPH (1 mg/kg) or COCA (10 mg/kg) produced hypothermia greater than that produced by EtOH alone. Conversely, EtOH attenuated MDMA-related hyperthermia, an effect increasing across treatment days. These results demonstrate that the interaction between MDMA and EtOH may be different from the interaction between EtOH and AMPH or COCA. Conclusion Because of potential health-related consequences of such polydrug misuse, it is worth identifying the mechanisms underlying these interactions, especially between EtOH and MDMA. Given the different affinity profiles of the three drugs for serotonin, dopamine, and norepinephrine transporters, our results appear compatible with the possibility of an important role of serotonin in at least the EtOH-induced potentiation of MDMA-induced hyperlocomotion.     

Prenatal cocaine exposure: effects on locomotor activity in rat offspring

This study examines the developmental effects of prenatal exposure to cocaine in the rat, evaluated during the first month of life through open-field behavior. The offspring of Wistar dams that received 60 mg/kg of cocaine, from gestational day 8 to 22, were examined in the open-field during the second, third and fourth weeks of postnatal life in three consecutive 15-min daily sessions, starting on postnatal day (PND) 14, (PND 14–16), PND 21 (PND 21–23) and PND 28 (PND 28–30). Results show that prenatal exposure to cocaine increased total activity and rearing behavior on PND 22 and PND 29. Also, on PND 14, cocaine-exposed animals reared significantly more than control rats. There were no significant differences in the frequency of center and peripheral ambulation, nor in the defecation rate. The present results evidence alterations in the emotional behavior of rats prenatally exposed to cocaine. The delayed onset of exploration in the open-field observed in cocaine-exposed animals suggests that they take more time to become habituated to a novel and open environment.     

Effects of priming injections of MDMA and cocaine on reinstatement of MDMA- and cocaine-seeking in rats

Exposure to self-administered drugs is sufficient to produce drug-seeking in animal models. In many cases priming injections of drugs that share discriminative stimulus properties with the self-administered drug also can lead to drug-seeking, suggesting that exposure might precipitate relapse. The present investigation examined the ability of MDMA or cocaine priming injections to reinstate extinguished drug-seeking in rats. Priming injections of cocaine (0-20.0 mg/kg) and MDMA (0.0-10.0 mg/kg) reinstated extinguished drug-taking for both the cocaine- and MDMA-trained rats. In a separate group of cocaine-trained rats that received repeated exposure to 10.0 mg/kg MDMA, the initial exposure to MDMA (10.0 mg/kg, i.p.) failed to reinstate extinguished responding but MDMA became an effective prime for reinstatement of extinguished cocaine-taking behavior with repeated exposure. Effects of MDMA in MDMA-trained rats was greater than the effect in cocaine-trained rats suggesting that extensive experience with MDMA self-administration might have sensitized rats to this effect. These findings show that extinguished MDMA self-administration, like self-administration of other drugs of abuse, can be reinstated by exposure to psychostimulants thereby precipitating relapse.     

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.     

Cocaine-seeking behavior after extended cocaine-free periods in rats: role of conditioned stimuli

Rationale. Cocaine abstinence symptoms and conditioned stimuli (CSs) previously associated with cocaine administration are postulated to contribute to relapse to drug taking in humans. Objective. The present study assessed the role of both non-contingent CS presentation and experimenter-imposed extended cocaine-free periods on cocaine-seeking behavior in rats. Methods. A fixed interval (FI) second-order schedule of intravenous cocaine (0.5 mg/infusion) reinforcement of the type FI 15 min (fixed ratio 8:S) was used. Results. Non-contingent CS presentation before exposure to a cocaine binge had no effect on responding under the second-order schedule of reinforcement for cocaine after 23 h of no access to cocaine. By contrast, six non-contingent presentations of the CS during a 1-min period before the test session increased the number of responses in both no-binge (daily 2-h sessions, five infusions) and binge (two 12-h overnight sessions; maximum 48 infusions) exposed rats on day 7 of the cocaine-free period compared to no-binge- and binge-exposed rats that were not presented with the CSs. On day 30 of the cocaine-free period, only binge-exposed rats presented with the CSs exhibited a tendency for increased level of responding. Conclusions. The results indicated that non-contingent CS presentation had no effect after 23 h of no access to cocaine, increased drug-seeking behavior on day 7 of the cocaine-free period independent of binge exposure, and a strong tendency to increase drug-seeking behavior only in binge-exposed rats, on day 30 of the cocaine-free period, illustrating the interactive effects of conditioned stimuli with the extended cocaine-free period.