Facilitation of extinction of operant behaviour in C57Bl/6 mice by chlordiazepoxide and d-cycloserine

Rationale and objective

Effects on the extinction of GABAergic drug, chlordiazepoxide (CDP), and glutamatergic drug, d-cycloserine (DCS), in C57BL/6 mice were compared.

Materials and methods

Following a palatability test (Experiment 1), Experiments 2–6 involved food-reinforced lever press training followed by extinction sessions at 1- or 4-day intervals. The effects of drugs were examined. Experiment 7 involved a two-lever task.

Results

CDP did not affect food palatability (Experiment 1), but facilitated extinction when administered prior to extinction sessions via intracerebral (Experiment 2) or peripheral administration at 1-day (Experiments 3–7) or 4-day intervals (Experiment 6). Reducing the amount of training prior to extinction reduced the delay in the effect of CDP typically seen, and CDP had a larger effect in early sessions on mice that had received less training (Experiment 3). There was some evidence that CDP could be blocked by flumazenil (Experiment 4), and CDP withdrawal reversed extinction facilitation (Experiments 5 and 7). With 4-day intervals, DCS administered immediately following extinction sessions, or pre-session CDP, facilitated extinction with 48-trial sessions (experiment 6B). With six-trial sessions, the co-administration of post-session DCS enhanced facilitation produced by pre-session CDP (experiment 6A). Finally, CDP facilitated extinction in a dose-related fashion following training on a two-lever food-reinforced task (Experiment 7).

Conclusions

The findings are consistent with the hypotheses that two neurotransmitter systems have different roles in operant extinction and that glutamatergic systems are involved in extinction learning and GABAergic systems involved in the expression of that learning. This parallels findings with extinction following Pavlovian conditioning, which has been more extensively investigated.     

Sensory reinforcement as a predictor of cocaine and water self-administration in rats

Rationale

The ability of locomotor activity in a novel environment (Loco) and visual stimulus reinforcement (VSR) to predict acquisition of responding for cocaine and water reinforcers in the absence of explicit audiovisual signals was evaluated.

Methods

In Experiment 1 (Exp 1), rats (n?=?60) were tested for VSR, followed by Loco, and finally acquisition of responding for cocaine (0.3 mg/kg/inf). In Experiment 2 (Exp 2), rats (n?=?32) were tested for VSR, followed by Loco, and finally acquisition of responding for water (0.01 mL/reinforcer).

Results

There were three main findings. First, Loco and VSR were significantly associated (Exp 1: r?=?0.49, p?<?0.00; Exp 2: r?=?0.35, p?<?0.05). Second, neither Loco (r?=?.00, p?=?0.998) nor VSR (r?=??0.12, p?=?0.352) predicted acquisition of cocaine SA. Third, in the subgroup of animals that acquired cocaine SA, VSR (r?=?0.41, p?<?0.01) but not Loco (r?=?0.28, p?=?0.10) was positively associated with operant responding for cocaine. Both Loco and VSR (Loco: r?=?0.37, p?<?0.04; VSR: r?=?0.51, p?<?0.00) were positively associated with operant responding for water reinforcers.

Conclusions

The results indicate that VSR is at least as good a predictor of cocaine reinforced responding as Loco. VSR was predictive of operant responding for both drug and water reinforcers, while Loco was found to be predictive of responding only for water reinforcers. In studies that present visual stimuli in association with drug delivery, Loco may be predicting acquisition of responding for VSR rather than drug.     

Random-ratio schedules produce greater demand for i.v. drug administration than fixed-ratio schedules in rhesus monkeys

Rationale

Organisms emit more responses when food is provided according to random as compared with fixed schedules of reinforcement. Similarly, many human behaviors deemed compulsive are maintained on variable schedules (e.g., gambling). If greater amounts of behavior are maintained by drugs of abuse when earned according to variably reinforced schedules, this would suggest that excessive drug-taking behavior may be due in part to the nature of drug availability.

Objectives

The aim was to determine whether random schedules of contingent intravenous drug delivery would produce more responding than similarly priced fixed schedules.

Methods

Six rhesus macaque subjects responded to produce cocaine (0.003–0.03 mg/kg/inj), remifentanil (0.01–1.0 μg/kg/inj), or ketamine (0.01–0.1 mg/kg/inj) according to either fixed or random ratio requirements that increased systematically across sessions. Demand curves were generated with the most effective dose of each drug and compared across drug and schedule type.

Results

Cocaine and remifentanil maintained higher levels and rates of responding when earned according to random-ratio schedules as compared with fixed-ratio schedules. This difference was most pronounced when drugs were available at high unit prices. Differences in responding across the schedule types generated by ketamine—a lesser-valued reinforcer—were qualitatively similar but smaller in magnitude.

Conclusions

The current study provides a systematic replication across reinforcer type demonstrating that drugs delivered after a random number of responses generate more behavior than those delivered according to a fixed schedule. The variable nature of the availability of drugs of abuse—particularly those that are scarce or expensive—may be a contributing factor to excessive drug intake by humans. This effect is most likely to be observed when more highly demanded (reinforcing) drugs are being consumed.     

A within-subject assessment of the discriminative stimulus and reinforcing effects of self-administered cocaine in rhesus monkeys

Rationale

Drug discrimination (DD) and drug self-administration (SA) are frequently used preclinical assays. All preclinical studies with cocaine have examined the discriminative stimulus (S^D) and reinforcing (S^R) effects in separate groups of subjects.

Objective

The objective of the study is to train drug-naïve rhesus macaques to discriminate self-administered cocaine from saline and to assess S^D and S^R effects using a within-subjects design.

Materials and methods

Adult male rhesus monkeys (n?=?4) were trained to self-administer cocaine (0.1 mg/kg per injection) under a progressive-ratio (PR) reinforcement schedule. Next, they were trained to discriminate self-administered cocaine (0.45 or 0.56 mg/kg) or saline under a fixed-ratio (FR) 50 schedule of food presentation. The final schedule combined DD and SA into a multiple [chained FR 50 SA (cocaine or saline), food-reinforced DD] and PR SA schedule.

Results

Each subject acquired SA under a PR schedule with significant differences in breakpoint between saline and cocaine evident by session 5. Self-administered cocaine was established as an S^D, such that 80% of responding before delivery of the first reinforcer and 90% of all responding occurred on the injection-appropriate lever. In all monkeys, there was at least one cocaine dose that did not engender cocaine-appropriate responding during DD (i.e., <20% cocaine-appropriate responding) yet functioned as a reinforcer during PR SA, suggesting that cocaine-like S^D effects are not necessary for cocaine reinforcement.

Conclusions

This within-subject model may provide new information related to the behavioral mechanisms of action leading to the high abuse potential of cocaine; such information may lead to novel pharmacological treatment strategies for addiction.     

Cocaine self-administration reinforced on a progressive ratio schedule decreases with continuous d-amphetamine treatment in rats

Rationale

To date, there is no medication specifically approved for cocaine addiction. Agonist medications are used clinically in the treatment of other addictions, which suggests that this method of drug therapy could potentially be successful in treating cocaine addiction as well.

Objective

The objective of this study was to determine the effect of extended d-amphetamine treatment on responding on a progressive ratio (PR) schedule reinforced by cocaine.

Materials and methods

Rats were trained to self-administer cocaine (0.19, 0.38, 0.75, or 1.5 mg/kg/injection) or food on a PR schedule. After stable baseline breakpoints (the number of reinforcers earned in one session) were established over 3 days, animals were implanted with osmotic mini-pumps that continuously delivered d-amphetamine (5 mg/kg/day) for a duration of either 7 or 14 days. Breakpoints were then determined during and/or after this treatment period.

Results

Rats demonstrated dose-dependent decreases in cocaine-reinforced responding over the d-amphetamine treatment period. Breakpoints for doses of 0.75 mg/kg/injection and below decreased significantly when compared to baseline and remained decreased for up to 14 days after mini-pump removal, whereas those for the highest dose of cocaine remained unchanged. Additionally, d-amphetamine treatment during a 14-day abstinence period from cocaine self-administration had no effect on breakpoints when tested the day after mini-pump removal.

Conclusions

These data suggest that the reduction in cocaine-reinforced responding after continuous d-amphetamine treatment cannot be accounted for by tolerance alone. Instead, the roles of learning and the interaction between cocaine and d-amphetamine must be considered and examined in future studies.     

The effects of the novel DA D3 receptor antagonist SR 21502 on cocaine reward, cocaine seeking and cocaine-induced locomotor activity in rats

Rationale

There is a focus on developing D3 receptor antagonists as cocaine addiction treatments.

Objective

We investigated the effects of a novel selective D3 receptor antagonist, SR 21502, on cocaine reward, cocaine-seeking, food reward, spontaneous locomotor activity and cocaine-induced locomotor activity in rats.

Methods

In Experiment 1, rats were trained to self-administer cocaine under a progressive ratio (PR) schedule of reinforcement and tested with vehicle or one of three doses of SR 21502. In Experiment 2, animals were trained to self-administer cocaine under a fixed ratio schedule of reinforcement followed by extinction of the response. Then, animals were tested with vehicle or one of the SR 21502 doses on cue-induced reinstatement of responding. In Experiment 3, animals were trained to lever press for food under a PR schedule and tested with vehicle or one dose of the compound. In Experiments 4 and 5, in separate groups of animals, the vehicle and three doses of SR 21502 were tested on spontaneous or cocaine (10 mg/kg, IP)-induced locomotor activity, respectively.

Results

SR 21502 produced significant, dose-related (3.75, 7.5 and 15 mg/kg) reductions in breakpoint for cocaine self-administration, cue-induced reinstatement (3.75, 7.5 and 15 mg/kg) and cocaine-induced locomotor activity (3.75, 7.5 and 15 mg/kg) but failed to reduce food self-administration and spontaneous locomotor activity.

Conclusions

SR 21502 decreases cocaine reward, cocaine-seeking and locomotor activity at doses that have no effect on food reward or spontaneous locomotor activity. These data suggest SR 21502 may selectively inhibit cocaine’s rewarding, incentive motivational and stimulant effects.     

Disrupted social development enhances the motivation for cocaine in rats

Rationale

Early social experiences are of major importance for behavioural development. In particular, social play behaviour during post-weaning development is thought to facilitate the attainment of social, emotional and cognitive capacities. Conversely, social insults during development can cause long-lasting behavioural impairments and increase the vulnerability for psychiatric disorders, such as drug addiction.

Objectives

The aim of this study was to investigate whether a lack of social experiences during the juvenile and early adolescent stage, when social play behaviour is highly abundant, alters cocaine self-administration in rats.

Methods

Rats were socially isolated from postnatal days 21 to 42 followed by re-socialization until adulthood. Cocaine self-administration was then assessed under a fixed ratio and progressive ratio schedule of reinforcement. Next, cue, cocaine and stress-induced reinstatement of cocaine seeking was determined following extinction of self-administration.

Results

Early social isolation resulted in an enhanced acquisition of self-administration of a low dose (0.083 mg/infusion) of cocaine, but the sensitivity to cocaine reinforcement, assessed using a dose–response analysis, was not altered in isolated rats. Moreover, isolated rats displayed an increased motivation for cocaine under a progressive ratio schedule of reinforcement. Extinction and reinstatement of cocaine seeking was not affected by early social isolation.

Conclusions

Early social isolation causes a long-lasting increase in the motivation to self-administer cocaine. Thus, aberrations in post-weaning social development, such as the absence of social play, enhance the vulnerability for drug addiction later in life.     

Interactions of cocaine with dopamine D2-like antagonists in squirrel monkeys

Rationale

Studies investigating dopamine D₂ receptor antagonism of cocaine's discriminative stimulus effects have resulted in varied effects possibly due to the use of different antagonists, species, and procedures.

Objectives

The present study sought to further investigate D₂ antagonism of cocaine's discriminative stimulus effects using a variety of D₂ antagonists and multiple doses of the antagonists in combination with cocaine.

Methods

The benzamide D₂ antagonists, eticlopride, raclopride, and sulpiride, and the butyrophenone D₂ antagonists haloperidol and spiperone were administered alone and in combination with cocaine in squirrel monkeys trained to discriminate cocaine from saline under a fixed-ratio food reinforcement procedure.

Results

All the D₂ antagonists, except haloperidol, antagonized the discriminative stimulus effects of the cocaine training dose. However, only the benzamide D₂ antagonists produced significant rightward shifts in the cocaine discriminative stimulus dose–effect curve and they only did so within a narrow dose range and time after administration. In contrast, the D₂ antagonists failed to antagonize the rate-suppressant effects of cocaine, and in some cases, cocaine appeared to antagonize the rate-suppressant effects of the antagonists.

Conclusions

The present results suggest (1) that D₂ antagonism of cocaine's discriminative stimulus effects depends critically on the selected antagonist, antagonist dose, and time of administration, as well as how antagonism is assessed (i.e., in terms of effects on training dose or on the cocaine dose–effect curve), (2) that the maximal shift in cocaine's discriminative stimulus dose–effect curve possible with D₂ antagonists under these procedures is ~two- to threefold, and (3) that different effects of cocaine are differentially sensitive to dopamine receptor antagonism.     

Cue-induced resumption of heroin and cocaine seeking in rats using a conflict model of abstinence and relapse

Rationale and objectives

Most animal research on drug relapse involves the reinstatement model where abstinence is a result of drug removal (extinction). However, abstinence in humans often results from the aversive consequences that accompany drug seeking (conflict situation). This study was aimed at using a conflict-based animal model of abstinence/relapse in rats self-administering heroin or cocaine.

Methods

Rats were trained to self-administer heroin (0.05 mg kg^?1 injection^?1) or cocaine (0.5 mg kg^?1 injection^?1) with each injection paired with a light cue. After stable responding was demonstrated, the floor near the levers was electrified, creating a barrier, in order to model the negative consequences of continued drug seeking. Shock intensities were increased over sessions until no responses occurred for three consecutive sessions. During a relapse test, where shock was maintained,the capacity of noncontingent drug cue presentations to induce active lever pressing was assessed.

Results

Ten of ten heroin animals and three of eight cocaine animals exposed to noncontingent cue presentations resumed responding. During the relapse test, for both drug groups, active lever pressing was significantly higher than during abstinence but only in the heroin group was it significantly higher than inactive lever pressing.

Conclusions

The implementation of negative consequences for drug seeking can result in its cessation just as they might in human addicts. Similarly, exposure to drug cues can lead to resumption of drug seeking. This model may be useful for studying the mechanisms underlying abstinence and relapse and for developing strategies to prevent relapse.     

Cariprazine (RGH-188), a D3-preferring dopamine D3/D2 receptor partial agonist antipsychotic candidate demonstrates anti-abuse potential in rats

Rationale

Cariprazine (RGH-188) is a D₃-preferring dopamine D₃/D₂ receptor partial agonist antipsychotic candidate for the treatment of schizophrenia and bipolar mania. Substance abuse is a frequent comorbidity of both disorders and is associated with serious health issues. Based on preclinical efficacy, dopamine D₂ and D₃ receptor partial agonists and antagonists are assumed to have relapse-preventing potential in human cocaine addiction.

Objectives

We investigated the anti-abuse potential of cariprazine in cocaine self-administration paradigms. Aripiprazole and bifeprunox were used as comparators because of their pharmacological similarity to cariprazine.

Methods

The effects of compounds on cocaine's rewarding effect were investigated in a continuous self-administration regimen. The relapse-preventing potential of drugs was studied in rats with a history of cocaine self-administration after a period of complete abstinence in a relapse to cocaine-seeking paradigm.

Results

Cariprazine, as well as aripiprazole and bifeprunox, were able to reduce the rewarding effect of cocaine (minimum effective doses were 0.17, 1, and 0.1 mg/kg, respectively) and attenuated relapse to cocaine seeking with half maximal effective dose [ED₅₀] values of 0.2, 4.2, and 0.17 mg/kg, respectively.

Conclusions

These results may predict a relapse-preventing action for cariprazine in humans in addition to its already established antipsychotic and antimanic efficacy.     

On the persistence of cocaine-induced place preferences and aversions in rats

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.     

Cortical activation during cocaine use and extinction in rhesus monkeys

Rationale

Acute re-exposure to cocaine or drug cues associated with cocaine use can elicit drug craving and relapse. Neuroimaging studies have begun to define neurobiological substrates underlying the acute effects of cocaine or cocaine cues in cocaine-dependent subjects.

Objective

The present study was the first to use functional brain imaging to document acute cocaine-induced changes in brain activity during active drug use in nonhuman primates.

Materials and methods

Positron emission tomography imaging with O15-labeled water was used to measure drug-induced changes in cerebral blood flow. The acute effects of cocaine administered noncontingently were characterized in four drug-naïve rhesus monkeys. The same subjects were trained to self-administer cocaine under a fixed ratio schedule during image acquisition. Subsequently, three subjects with an extensive history of cocaine use were trained to self-administer cocaine under a second-order schedule. The same subjects also underwent extinction sessions during which saline was substituted for cocaine under the second-order schedule.

Results

Noncontingent administration of cocaine in drug-naïve subjects induced robust activation of prefrontal cortex localized primarily to the dorsolateral regions. In contrast, the pattern of brain activation induced by self-administered cocaine differed qualitatively and included anterior cingulate cortex. Moreover, drug-associated stimuli during extinction also induced robust activation of prefrontal cortex.

Conclusions

The effects of cocaine and associated cues extend beyond the limbic system to engage brain areas involved in cognitive processes. The identification of neural circuits underlying the direct pharmacological and conditioned stimulus effects of cocaine may be highly relevant toward efforts to develop treatments for cocaine addiction.     

Assessment of the impact of pattern of cocaine dosing schedule during conditioning and reconditioning on magnitude of cocaine CPP, extinction, and reinstatement

Rationale and objective

We sought to examine the impact of differing cocaine administration schedules and dosing on the magnitude of cocaine conditioned place preference (CPP), extinction, and stress- and cocaine-induced reinstatement of CPP.

Methods

First, in C57Bl/6J mice, we investigated whether total cocaine administration or pattern of drug exposure could influence the magnitude of cocaine CPP by conditioning mice with a fixed-low dose (F_L; 7.5 mg/kg; total of 30 mg/kg), a fixed-high dose (F_H; 16 mg/kg; total of 64 mg/kg), or an ascending dosing schedule (Asc; 2, 4, 8, and 16 mg/kg; total of 30 mg/kg). Next, we investigated if cocaine or saline is more effective at extinguishing preference by reconditioning mice with either a descending dosing schedule (Desc; 8, 4, 2, and 1 mg/kg) or saline. Finally, we examined if prior conditioning and reconditioning history alters stress (~2–3-min forced swim test) or cocaine-induced (3.5 mg/kg) reinstatement.

Results

We replicated and extended findings by Itzhak and Anderson (Addict. Biol. 17(4): 706–16, 2011) demonstrating that Asc conditioning produces a greater CPP than either the F_L or F_H conditioning schedules. The magnitude of extinction expressed was similar in the Desc reconditioned and saline groups. Moreover, only the saline, and not the Desc reconditioned mice, showed stress and cocaine-induced reinstatement of CPP.

Conclusions

Our results suggest that the schedule of cocaine administration during conditioning and reconditioning can have a significant influence on the magnitude of CPP and extinction of preference and the ability of cocaine or a stressor to reinstate CPP.     

Individual differences in the effects of environmental stimuli on cocaine choice in socially housed male cynomolgus monkeys

Rationale

Studies in laboratory animals have demonstrated an influence of environmentally derived stress and enrichment on the reinforcing effects of stimulants.

Objective

To characterize the effects of acute exposure to ethologically valid environmental stimuli on the reinforcing strength of cocaine relative to food in socially housed monkeys.

Materials and methods

Choice between cocaine and food was assessed in subsets of 16 socially housed (4/pen) male cynomolgus monkeys immediately after the following manipulations: (1) treats placed in home cage, (2) a 10-min exposure to a rubber snake, or (3) 3 to 7 days of living in a larger environment without cage mates.

Results

Placing treats in the home cage shifted the cocaine dose–response curve to the left in five monkeys tested and to the right in 4 of 12 animals. The rubber snake significantly shifted the cocaine choice curve to the left in dominant monkeys. Exposure to an enlarged environment decreased cocaine choice in 9 of 15 monkeys; this effect was transient and not related to social rank. Repeated testing did not affect cocaine choice.

Conclusions

Brief exposure to environmental events hypothesized to be stressors or enrichment altered cocaine choice, although not all individuals were affected and the effects were transient. Importantly, the data suggest that implementing positive changes in the environment produced effects that are clinically desirable. Understanding the behavioral and neurobiological mechanisms mediating sensitivity to environmental events in socially housed animals will lead to better treatment strategies for drug addiction.     

Assessment of the abuse liability of ABT-288, a novel histamine H3 receptor antagonist

Rationale

Histamine H₃ receptor antagonists, such as ABT-288, have been shown to possess cognitive-enhancing and wakefulness-promoting effects. On the surface, this might suggest that H₃ antagonists possess psychomotor stimulant-like effects and, as such, may have the potential for abuse.

Objectives

The aim of the present study was to further characterize whether ABT-288 possesses stimulant-like properties and whether its pharmacology gives rise to abuse liability.

Methods

The locomotor-stimulant effects of ABT-288 were measured in mice and rats, and potential development of sensitization was addressed. Drug discrimination was used to assess amphetamine-like stimulus properties, and drug self-administration was used to evaluate reinforcing effects of ABT-288. The potential development of physical dependence was also studied.

Results

ABT-288 lacked locomotor-stimulant effects in both rats and mice. Repeated administration of ABT-288 did not result in cross-sensitization to the stimulant effects of d-amphetamine in mice, suggesting that there is little overlap in circuitries upon which the two drugs interact for motor activity. ABT-288 did not produce amphetamine-like discriminative stimulus effects in drug discrimination studies nor was it self-administered by rats trained to self-administer cocaine. There were no signs of physical dependence upon termination of repeated administration of ABT-288 for 30 days.

Conclusions

The sum of these preclinical data, the first of their kind applied to H₃ antagonists, indicates that ABT-288 is unlikely to possess a high potential for abuse in the human population and suggests that H₃ antagonists, as a class, are similar in this regard.     

Facilitation of intravenous nicotine self-administration in rats by a motivationally neutral sensory stimulus

Rationale and objective

Intravenous infusions of nicotine appear to exert little primary reinforcing effects in adult rats but, instead, maintain self-administration behavior at least, in part, by increasing the intrinsic reinforcing effects of drug-paired sensory stimuli. The present study examined instead the impact of a motivationally neutral cue on self-administration.

Methods

Adult male Long-Evans rats were permitted to self-administer nicotine (0.015 mg/kg IV given over 30 s, 2 h/day) or saline presented with or without a sensory stimulus (light, white noise). Fixed and progressive ratio reinforcement schedules of nicotine reinforcement were tested. Experiment 2 determined whether noncontingent nicotine or mecamylamine (nicotinic antagonist) would induce lever pressing for either sensory stimulus. Experiment 3 tested whether the white noise stimulus alone could maintain responding after repeated pairing with self-administered nicotine. Finally, the sensory stimuli were assessed for possible aversive properties.

Results

Nicotine infusions alone were at best weakly reinforcing. The white noise stimulus, presented alone, was neither reinforcing nor aversive, whereas the white light appeared marginally reinforcing. Both stimuli, however, facilitated intravenous nicotine self-administration. Neither nicotine nor mecamylamine challenge rendered the white noise reinforcing. The white noise, after being self-administered with nicotine, failed to maintain self-administration behavior on its own.

Conclusions

Even a motivationally neutral sensory stimulus, lacking detectable primary or secondary reinforcing properties, can facilitate self-administration of nicotine. Possibly, drug-paired stimuli provide a "response marker" or serve as a temporal bridge between the operant response and drug effect. Motivationally neutral stimuli may therefore serve to isolate primary reinforcing effects of nicotine.     

The self-administration of rapidly delivered cocaine promotes increased motivation to take the drug: contributions of prior levels of operant responding and cocaine intake

Rationale

Rapid drug delivery to the brain might increase the risk for developing addiction. In rats, increasing the speed of intravenous cocaine delivery (5 vs. 90 s) increases drug intake and the subsequent motivation to self-administer cocaine. Increased motivation for cocaine could result not only from more extensive prior drug intake and operant responding for drug, but also from neuroplasticity evoked by rapid drug uptake.

Objective

We determined the contributions of prior drug intake and operant responding to the increased motivation for cocaine evoked by rapid delivery. We also investigated the effects of cocaine delivery speed on corticostriatal expression of brain-derived neurotrophic factor (BDNF) and tropomyosin receptor kinase B (TrkB) mRNA.

Methods

Rats self-administered cocaine (0.25 mg/kg/infusion) delivered over 5 or 90 s during short-access (1 h/session; ShA) or long-access (6 h; LgA) sessions. Motivation for cocaine was then assessed by measuring responding under a progressive ratio schedule of reinforcement. Next, BDNF and TrkB mRNA levels were measured in 5- and 90-s rats.

Results

Five-second ShA and 5-s-LgA rats were more motivated for cocaine than their 90-s counterparts. This effect was dissociable from previous levels of drug intake or of operant responding for cocaine. In parallel, only rats self-administering rapid cocaine injections had altered BDNF and TrkB mRNA levels in corticostriatal regions.

Conclusions

Rapid drug delivery augments the motivation for cocaine independently of effects on the levels of drug intake or operant responding for drug. We suggest that rapid delivery might increase the motivation for drug by promoting neuroplasticity within reward pathways. This neuroplasticity could involve increased regulation of BDNF/TrkB.     

Characterization of Highper, an ENU-induced mouse mutant with abnormal psychostimulant and stress responses

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.     

Examination of behavioral strategies regulating cocaine intake in rats

Rationale

It has long been observed that rats self-administer psychostimulants in a highly regular pattern. The inverse relationship between dose and rate of drug intake has been interpreted as a titration phenomenon wherein brain-cocaine levels are maintained within a range. Most studies examining this phenomenon have used fixed, unit doses in which case the only titration strategy available to the animal is to adjust inter-infusion intervals.

Objectives

In this study, we examined whether selection of dose size could also be a factor in regulation of intake. We used a schedule of reinforcement, under which the dose can vary through a wide range and is determined by the behavior of the animal.

Methods

Rats self-administered cocaine using a behaviorally dependent dosing schedule of reinforcement, under which the size of each dose was determined by the length of time the lever was held down. The concentration of cocaine was changed across sessions.

Results

Total pump-time self-administered decreased by 56 % following each doubling of the concentration, which led to an average 11 % increase in total intake. Similarly, estimated brain levels of cocaine increased by 12 % for each doubling of concentration. These adjustments were the result of manipulation of both the size and spacing of infusions.

Conclusions

In agreement with previous studies, the regular pattern of intake appears to be the result of a titration mechanism in which animals maintain brain levels of cocaine above some threshold. Compensatory regulation appeared to involve both the selection of dose size and inter-infusion intervals.