Inactive Lever Research Articles

Differential effects of clozapine, metoclopramide, haloperidol and risperidone on acquisition and performance of operant responding in rats.

Prior research has not systematically investigated the effects of systemic antipsychotic drugs on operant response acquisition, specifically their behavioural microstructure, reinforcement blunting and relative potency in acquisition compared to performance once operant responding has stabilized. This study aims to systematically investigate the effects of systemically administered clozapine, metoclopramide, haloperidol and risperidone during free operant response acquisition and performance. Following magazine training, food-restricted male Wistar rats lever pressed for food reward in 15 min daily operant conditioning sessions. All drugs suppressed operant response acquisition and performance. Risperidone and metoclopramide, but not clozapine or haloperidol, suppressed operant responding more potently during acquisition than performance. The dopamine D2-like receptor antagonists haloperidol and metoclopramide that affect the ventral and dorsal striatum blunted reinforcement and decreased inactive lever presses in acquisition. In contrast, the atypical antipsychotics clozapine and risperidone that affect the ventral striatum and prefrontal cortex failed to decrease inactive lever presses during acquisition, suggesting a possible decision-making deficit. Haloperidol decreased active lever pressing over performance days. The drugs did not appear to affect rats' sensitivity to active lever press outcome, even though they suppressed active lever pressing. Results suggest that reinforcement impact during operant acquisition is dependent on dopamine D2 receptors while drugs affecting, among other areas, the prefrontal cortex produce a deficit in ability to suppress inactive lever press responses.

Varied behavioral responses induced by morphine in the tree shrew: a possible model for human opiate addiction.

Tree shrews represent a suitable animal model to study the pathogenesis of human diseases as they are phylogenetically close to primates and have a well-developed central nervous system that possesses many homologies with primates. Therefore, in our study, we investigated whether tree shrews can be used to explore the addictive behaviors induced by morphine. Firstly, to investigate the psychoactive effect of morphine on tree shrews’ behavior, the number of jumping and shuttling, which represent the vertical and horizontal locomotor activity respectively, was examined following the injection of different dosage of morphine. Our results showed intramuscular (IM) injection of morphine (5 or 10 mg/kg) significantly increased the locomotor activity of tree shrews 30–60 min post-injection. Then, using the conditioned place preference/aversion (CPP/CPA) paradigm, we found morphine-conditioned tree shrews exhibited place preference in the morphine-paired chamber on the test day. In addition, naloxone-precipitated withdrawal induced place aversion in the chronic morphine-dependent tree shrews. We evaluated the craving for morphine drinking by assessing the break point that reflects the maximum effort animals will expend to get the drug. Our data showed the break point was significantly increased when compared to the baseline on the 1st, 7th and 14th day after the abstinence. Moreover, in the intravenous morphine self-administration experiment, tree shrews conditioned with morphine responded on the active lever significantly more frequently than on the inactive lever after training. These results suggest that tree shrew may be a potential candidate for study the addictive behaviors and the underling neurological mechanisms.

Behavioural and neurochemical assessment of salvinorin A abuse potential in the rat

Salvinorin A is a recreational drug derived from Salvia divinorum, a sage species long used as an entheogen. While salvinorin A has potent hallucinogenic properties, its abuse potential has not been assessed consistently in controlled behavioural and neurochemical studies in rodents. This study aimed to assess salvinorin A abuse potential by measuring its capacity to establish and maintain self-administration behaviour and to modify dopamine (DA) levels in the nucleus accumbens (NAcc) of rats. Male Lister Hooded (LH) and Sprague-Dawley (SD) rats were allowed to self-administer salvinorin A (0.5 or 1.0 μg/kg/infusion) intravenously 2 h/day for 20 days under a continuous schedule of reinforcement and lever pressing as operandum. LH rats discriminated between the active and inactive levers but did not reach the acquisition criterion for stable self-administration (≥12 active responses vs ≤5 inactive responses for at least 5 consecutive days). SD rats discriminated between the two levers at the lower dose only but, like LH rats, never acquired stable self-administration behaviour. Systemic salvinorin A increased extracellular DA in the NAcc shell of both LH (at ≥40 μg/kg) and SD rats (at ≥5 μg/kg), but injection into the ventral tegmental area (VTA) induced no significant change in NAcc DA concentration in LH rats and only brief elevations in SD rats. Salvinorin A differs from other commonly abused compounds since although it affects accumbal dopamine transmission, yet it is unable, at least at the tested doses, to sustain stable intravenous self-administration behaviour.

Exposure to nicotine enhances its subsequent self-administration: Contribution of nicotine-associated contextual stimuli

Contextual stimuli present during nicotine exposure can come to act as conditioned stimuli and have been shown to play an important role in ongoing nicotine self-administration. In the present study, we characterized the effects of contextual stimuli previously paired with non-contingent nicotine exposure injections on subsequent nicotine self-administration. Rats were exposed to five injections of either saline or nicotine (0.4mg/kg, i.p.) in either their home cage or a self-administration chamber with the levers retracted. Two weeks later, they were allowed to self-administer nicotine (30μg/kg/infusion, IV) under fixed ratio (FR) schedules of reinforcement across 12 consecutive sessions. Lastly, responding under a progressive ratio (PR) schedule was assessed. Rats exposed to nicotine in the self-administration chamber subsequently increased their intake of nicotine across the FR test days, obtaining more infusions on average by days 7–12 compared to their saline exposed controls. This increase was not due to nicotine exposure alone as rats exposed to nicotine in the home cage did not show this effect. It was also not due to differences in the final ratio achieved between nicotine and saline exposed rats. Although rats exposed to nicotine in the self-administration chambers displayed reduced discrimination between the active and inactive levers during FR testing, they showed increased motivation to self-administer nicotine under the PR schedule. These results indicate that exposure to nicotine can enhance its subsequent self-administration and highlight the contribution of nicotine-associated contextual stimuli to the work output rats ultimately emit to obtain the drug.

Mu-opioid stimulation in rat prefrontal cortex engages hypothalamic orexin/hypocretin-containing neurons, and reveals dissociable roles of nucleus accumbens and hypothalamus in cortically driven feeding.

Mu-opioid receptor (μOR) stimulation within ventral medial prefrontal cortex (vmPFC) induces feeding and hyperactivity, resulting possibly from recruitment of glutamate signaling in multiple vmPFC projection targets. We tested this hypothesis by analyzing Fos expression in vmPFC terminal fields after intra-vmPFC μOR stimulation, and by examining of the impact of glutamate receptor blockade in two feeding-related targets of vmPFC, the lateral-perifornical hypothalamic area (LH-PeF) and nucleus accumbens shell (Acb shell), upon behavioral effects elicited by intra-vmPFC μOR stimulation in rats. Intra-vmPFC infusion of the μOR agonist, DAMGO, provoked Fos expression in the dorsomedial sector of tuberal hypothalamus (including the perifornical area) and increased the percentage of Fos-expressing hypocretin/orexin-immunoreactive neurons in these zones. NMDA receptor blockade in the LH-PeF nearly eliminated intra-vmPFC DAMGO-induced food intake without altering DAMGO-induced hyperactivity. In contrast, blocking AMPA-type glutamate receptors within the Acb shell (the feeding-relevant subtype in this structure) antagonized intra-vmPFC DAMGO-induced hyperlocomotion but enhanced food intake. Intra-vmPFC DAMGO also elevated the breakpoint for sucrose-reinforced progressive-ratio responding; this effect was significantly enhanced by concomitant AMPA blockade in the Acb shell. Conversely, intra-Acb shell AMPA stimulation reduced breakpoint and increased nonspecific responding on the inactive lever. These data indicate intra-vmPFC μOR signaling jointly modulates appetitive motivation and generalized motoric activation through functionally dissociable vmPFC projection targets. These findings may shed light on the circuitry underlying disorganized appetitive responses in psychopathology; e.g., binge eating and opiate or alcohol abuse, disorders in which μORs and aberrant cortical activation have been implicated.

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

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. Rats were trained to self-administer heroin (0.05mgkg(-1)injection(-1)) or cocaine (0.5mgkg(-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. 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. 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.

Cocaine self-administration in rats lacking a functional trpc4 gene

The canonical transient receptor potential (TRPC) family of Ca 2+ permeable, non-selective cation channels is abundantly expressed throughout the brain, and plays a pivotal role in modulating cellular excitability. Unlike other TRPC channels, TRPC4 subtype expression in the adult rodent brain is restricted to a network of structures that receive dopaminergic innervation, suggesting an association with motivation- and reward-related behaviors. We hypothesized that these channels may play a critical role in dopamine-dependent drug-seeking behaviors. Here, we gathered data testing trpc4 knockout (KO) rats and wild-type (WT) littermates in the acquisition of a natural sucrose reward (10 days), and cocaine self-administration (13 days) at 0.5 mg/kg/infusion. Rats lacking the trpc4 gene ( trpc4-KO) learned to lever press for sucrose to a similar degree as their WT controls. However, when they were switched to cocaine, the trpc4-KO rats had substantially reduced cocaine-paired lever pressing compared to WT controls. No obvious group differences in inactive lever pressing were observed, for any time, during cocaine self-administration.

Efficacy of buspirone for attenuating cocaine and methamphetamine reinstatement in rats

BackgroundThere are no approved pharmacotherapies for preventing psychomotor stimulant relapse. The operant reinstatement model has been suggested as a screen for identifying candidate medications. The present study examined if the anxiolytic buspirone could attenuate reinstatement of extinguished responding in Long–Evans rats that previously self-administered intravenous cocaine or methamphetamine. MethodsRats were trained in 2-h daily sessions to self-administer 0.5mg/kg cocaine or 0.1mg/kg methamphetamine infusions followed by 12 days of instrumental extinction. Reinstatement was evoked by 17mg/kg i.p. cocaine primes or response-contingent cocaine-paired cues in cocaine-reinforced rats, and by 1mg/kg i.p. methamphetamine primes or response-contingent methamphetamine-paired cues in methamphetamine-reinforced rats. ResultsBuspirone (1 and 3mg/kg) significantly (p<0.05) attenuated cocaine cue but not cocaine prime reinstatement. Buspirone (1 and 3mg/kg) also significantly attenuated methamphetamine cue reinstatement. Buspirone (3mg/kg) significantly attenuated methamphetamine prime reinstatement. During all reinstatement tests, 3mg/kg buspirone reduced levels of inactive lever pressing relative to those of vehicle, significantly so during the cocaine cue-induced reinstatement tests. ConclusionsGiven the complexity of buspirone's neuropharmacology consisting of serotonin 5-HT1A receptor partial agonist activity, and dopamine D2, D3 and D4 receptor antagonist effects, it is uncertain which of these activities or their combination is responsible for the present results. Overall, these results suggest that buspirone may reduce the likelihood of relapse to cocaine and methamphetamine use under some conditions, although this speculation must be interpreted with caution given buspirone's similar potency to attenuate inactive-lever responding.

Enhanced cognitive function and antidepressant-like effects after krill oil supplementation in rats

BackgroundThe purpose of the study was to evaluate the effects of krill oil (KO) on cognition and depression-like behaviour in rats.MethodsCognition was assessed using the Aversive Light Stimulus Avoidance Test (ALSAT). The Unavoidable Aversive Light Stimulus (UALST) and the Forced Swimming Test (FST) were used to evaluate the antidepressant-like effects of KO. Imipramine (IMIP) was used as the antidepressant reference substance.ResultsAfter 7 weeks of KO intake, both males and females treated with KO were significantly better in discriminating between the active and the inactive levers in the ALSAT from day 1 of training (p<0.01). Both KO and IMIP prevented resignation/depression on the third day in the UALST. Similarly, a shorter immobility time was observed for the KO and IMIP groups compared to the control in the FST (p<0.001). These data support a robust antidepressant-like potential and beneficial cognitive effect of KO. Changes in expression of synaptic plasticity-related genes in the prefrontal cortex and hippocampus were also investigated. mRNA for brain-derived neurotrophic factor (Bdnf) was specifically upregulated in the hippocampus of female rats receiving 7 weeks of KO supplementation (p=0.04) and a similar trend was observed in males (p=0.08). Males also exhibited an increase in prefrontal cortex expression of Arc mRNA, a key protein in long-term synaptic plasticity (p=0.05). IMIP induced clear effects on several plasticity related genes including Bdnf and Arc.ConclusionsThese results indicate that active components (eicosapentaenoic acid, docosahexaenoic acid and astaxanthin) in KO facilitate learning processes and provide antidepressant-like effects. Our findings also suggest that KO might work through different physiological mechanisms than IMIP.

Cocaine potentiates excitatory drive in the perifornical/lateral hypothalamus

The hypothalamus is a critical controller of homeostatic responses and plays a fundamental role in reward-seeking behaviour. Recently, hypothalamic neurones in the perifornical/lateral hypothalamic area (PF/LHA) have also been implicated in drug-seeking behaviour through projections to extra-hypothalamic sites such as the ventral tegmental area. For example, a population of neurones that expresses the peptide orexin has been strongly implicated in addiction-relevant behaviours. To date, the effect of addictive drugs on synaptic properties in the hypothalamus remains largely unexplored. Previous studies focusing on the PF/LHA neurones, however, have shown that the orexin system exhibits significant plasticity in response to food or sleep restriction. This neuroadaptive ability suggests that PF/LHA neurones could be highly susceptible to modifications by drug exposure. Here, we sought to determine whether cocaine produces synaptic plasticity in PF/LHA neurones. Whole-cell patch-clamp techniques were used to examine the effects of experimenter-administered (passive) or self-administered (SA) cocaine on glutamatergic synaptic transmission in PF/LHA neurones. These experiments demonstrate that both passive and SA cocaine exposure increases miniature excitatory postsynaptic current (mEPSC) frequency in PF/LHA neurones. In addition, SA cocaine reduced the paired-pulse ratio but the AMPA/NMDA ratio of evoked excitatory inputs was unchanged, indicative of a presynaptic locus for synaptic plasticity. Dual-labelling for orexin and excitatory inputs using the vesicular glutamate transporter (VGLUT2), showed that passive cocaine exposure increased VGLUT2-positive appositions onto orexin neurones. Further, a population of recorded neurones that were filled with neurobiotin and immunolabelled for orexin confirmed that increased excitatory drive occurs in this PF/LHA population. Given the importance of the PF/LHA and the orexin system in modulating drug addiction, we suggest that these cocaine-induced excitatory synapse-remodelling events within the hypothalamus may contribute to persistence in drug-seeking behaviour and relapse.

Stress history increases alcohol intake in relapse: relation to phosphodiesterase 10A

Stressful experiences can result in elevated alcohol drinking, as exemplified in many individuals with post-traumatic stress disorder. However, how stress history, rather than acute stressors, influences alcohol intake remains uncertain. To model the protracted effects of past stress, male Wistar rats were subjected to light-cued footshock (stress history) or light cues alone (control) prior to acquisition of alcohol self-administration (1-hour sessions, fixed ratio 1-3, 100 µl of 10% v/v alcohol as reinforcer). Stress history did not alter mean alcohol intake during acquisition of self-administration, but it increased preference for the alcohol-paired lever over the inactive lever. Following an extinction period, rats with a history of stress exposure and low baseline alcohol intake showed a twofold elevation in alcohol self-administration, as compared with low-drinking rats with no stress history. Similar effects were not seen in rats self-administering 0.1% sucrose. Analysis of mRNA levels of phosphodiesterase 10A (PDE10A), a dual-specificity cyclic adenosine monophosphate and cyclic guanosine monophosphate hydrolyzing enzyme, showed that stress history increased Pde10a mRNA levels in the basolateral amygdala and, in low-drinking rats, the prelimbic prefrontal cortex (plPFC). Pde10a mRNA levels in the plPFC correlated directly with greater alcohol self-administration during the relapse-like phase, and greater BLA Pde10a mRNA levels correlated with increased ethanol preference after acquisition. The data demonstrate that stress history sensitizes otherwise low alcohol drinkers to consume more alcohol in a relapse-like situation and identify stress-induced neuroadaptations in amygdala and prefrontal cortical Pde10a expression as changes that may drive heightened alcohol intake and preference in susceptible individuals.

A new criterion for acquisition of nicotine self-administration in rats

BackgroundAcquisition of nicotine self-administration in rodents is relatively difficult to establish and measures of acquisition rate are sometimes confounded by manipulations used to facilitate the process. This study examined acquisition of nicotine self-administration without such manipulations and used mathematical modeling to define the criterion for acquisition. MethodsRats were given 20 daily 2-h sessions occurring 6 days/week in chambers equipped with active and inactive levers. Each active lever press resulted in nicotine reinforcement (0–0.06mg/kg, IV) and retraction of both levers for a 20-s time out, whereas inactive lever presses had no consequences. Acquisition was defined for individual rats by the higher likelihood of reinforcers obtained across sessions fitting a logistic over a constant function according to the corrected Akaike Information Criterion (AICc). ResultsFor rats that acquired self-administration, an AICc-based multi-model comparison demonstrated that the asymptote (highest number of reinforcers/session) and mid-point of the acquisition curve (h; the number of sessions necessary to reach half the asymptote) varied by nicotine dose, with both exhibiting a negative relationship (the higher the dose, the lower number of reinforcers and the lower h). ConclusionsThe modeling approach used in this study provides a way of defining acquisition of nicotine self-administration that takes advantage of all data from individual subjects and the procedure used is sensitive to dose differences in the absence of manipulations that influence acquisition (e.g., food restriction, prior food reinforcement, conditioned reinforcers).

Cues Paired with either Rapid or Slower Self-Administered Cocaine Injections Acquire Similar Conditioned Rewarding Properties

The faster drugs of abuse reach the brain, the more addictive they can be. It is not known why this is. Environmental stimuli associated with drugs can promote the development and persistence of addiction by invigorating and precipitating drug-seeking behaviour. We determined, therefore, whether cues associated with the self-administration of rapidly delivered cocaine (injected intravenously over 5 versus 90 seconds) would acquire greater conditioned rewarding properties, as assessed by the performance of an operant response reinforced solely by the cues. Rats nose-poked for intravenous cocaine infusions delivered either over 5 or 90 seconds. Discrete visual cues accompanied each infusion. The rats could then press a lever to obtain the cues—now a conditioned reward—or an inactive lever. Rats in both the 5- and 90-second groups pressed more on the active versus inactive lever following extensive (24 sessions) but not following limited (3 sessions) self-administration training. There were no group differences in this behaviour. Following withdrawal from cocaine self-administration, lever discrimination progressively abated in both groups and was lost by withdrawal day 30. However, the rewarding properties of the cues were not “forgotten” because on withdrawal days 32–33, amphetamine selectively enhanced active-lever pressing, and did so to a similar extent in both groups. Thus, cues paired with rapid or slower cocaine delivery acquire similar conditioned rewarding properties. We conclude, therefore, that the rapid delivery of cocaine to the brain promotes addiction by mechanisms that might not involve a greater ability of drug cues to control behaviour.

Nicotine self-administered directly into the VTA by rats is weakly reinforcing but has strong reinforcement enhancing properties

Rats will lever press to deliver nanolitre quantities of nicotine or the muscarinic agonist carbachol directly into the ventral tegmental area (VTA). The purpose of these experiments was to investigate further the characteristics of nicotine self-administration directly into the VTA. This study aimed to confirm previous data relating to intra-VTA self-administration of nicotine and carbachol and then test two hypotheses: (a) that pre-sensitisation of nicotinic receptors is needed for robust intra-VTA self administration and (b) that rats will lever press for intra-VTA nicotine if pre-trained to associate lever pressing with a rewarding outcome. Rats were equipped with cannulae aimed at posterior VTA and allowed five sessions to self-administer nicotine or carbachol. In different experiments, rats were either pre-sensitised to nicotine by subcutaneous (s.c.) injections or pre-trained to lever press for food and a simultaneous conditioned stimulus light. We confirmed that carbachol had strong activating effects when self-administered into the VTA; selective responding for nicotine developed over five sessions by reduction in the amount of pressing on an inactive lever. Prior sensitisation did not improve responding for intra-VTA nicotine but training rats to lever press before putting them on the drug regime did potentiate pressing. The action of nicotine in the VTA might be better considered as reinforcement enhancing and that its intrinsic rewarding property here is at best weak. Identification of the VTA as a target for the reinforcement enhancing effects of nicotine is compatible with the reinforcement-related functions of VTA dopamine neurons and their cholinergic inputs.

Testosterone as a discriminative stimulus in male rats

Testosterone and other anabolic–androgenic steroids (AAS) are reinforcing in animals, as determined by conditioned place preference or self-administration. Most drugs of abuse produce subjective effects on mood and perception that initiate and maintain drug taking. Whether AAS have similar effects is not known. Food-restricted male Sprague–Dawley rats (n=9) were tested for their ability to discriminate an injection of testosterone from the β-cyclodextrin vehicle using a standard two-lever operant paradigm. In drug discrimination, animals use the subjective effects of drug or vehicle to select the appropriate lever to obtain food pellets under an FR10 schedule of reinforcement. All rats demonstrated vigorous responding for food (1415.1±76.1 responses/20min) with 94.9% of responses on the active lever. For the first 30days, rats received 1mg/kg testosterone sc 30min before testing. On Day 14, one rat achieved the discrimination criteria of 9/10 consecutive days with >90% responses on the active lever and ≤5 responses on the inactive lever before the first reinforcement. Subsequently, rats were tested with testosterone at different doses (2, 7.5, 15mg/kg at 30min before testing) and times (2mg/kg at 30 or 60min before testing), each for 20days. One additional rat demonstrated successful discrimination at Day 54 with 2mg/kg testosterone 60min before testing. The remaining 7 rats failed to discriminate testosterone within 110days. When analyzed according to less-stringent standards, 4 additional rats met criteria for testosterone discrimination. However, continued performance was not stable. Thus, testosterone was unable to consistently support drug discrimination. We conclude that testosterone does not produce rapid interoceptive effects (NIH DA12843 to RIW).

Environmental enrichment, administered after establishment of cocaine self-administration, reduces lever pressing in extinction and during a cocaine context renewal test

The objective of this study was to test the hypothesis that environmental enrichment (EE) administered to rats previously trained to self-administer cocaine would reduce responding in extinction and in a cocaine-context renewal test. Long-Evans male rats were trained to press an active lever reinforced by cocaine (1.0 mg/kg/injection) under a fixed-ratio 1 schedule of reinforcement (inactive lever presses produced no consequences). After stable responding was established, all rats were given a 10-day break from the operant chambers followed by random assignment to EE (larger cages equipped with visual and auditory stimuli) or control (standard housing) group conditions in which they lived for the remainder of the experiment. Ten days after this move, rats were exposed to 10 extinction-responding sessions in a context different from the one in which self-administration occurred, followed by a context-renewal session occurring in the original self-administration context. The EE group responded significantly less in both the extinction and context-renewal sessions compared with the control group. These results suggest that EE reduces the ability of cocaine-associated stimuli to control cocaine-related responding.

MGluR5 positive allosteric modulation enhances extinction learning following cocaine self-administration.

Extinction of classically and instrumentally conditioned behaviors, such as conditioned fear and drug-seeking behavior, is a process of active learning, and recent studies indicate that potentiation of glutamatergic transmission facilitates extinction learning. In this study, the authors investigated the effects of the Type-5 metabotropic glutamate receptors (mGluR5) positive allosteric modulator 3-cyano-N-(1,3-diphenyl-1H-pyrazol-5-yl)benzamide (CDPPB) on the extinction of cocaine-seeking behavior in rats with a history of intravenous cocaine self-administration. To assess its effects on acquisition and consolidation of extinction learning, CDPPB (60 mg/kg) or vehicle was administered either 20 min prior to, or immediately following, each of 10 extinction sessions, respectively. When administered prior to each extinction session, CDPPB produced a significant reduction in the number of active lever presses on all 10 days of extinction training as compared to vehicle-treated animals. When administered following each extinction session, a significant reduction in the number of active lever presses was observed on the 2nd through 10th day of extinction. Both treatment regimens also reduced the number of extinction-training sessions required to meet extinction criteria. Pre- or postextinction-training administration of CDPPB did not alter responding on the inactive lever and had no effects on open field locomotor activity. These data indicate that positive allosteric modulation of mGluR5 receptors facilitates the acquisition and consolidation of extinction learning following cocaine self-administration and may provide a novel pharmacological approach to enhancing extinction learning when combined with cue exposure therapy for the treatment of cocaine addiction.

Behavioral Activating Effects of Selective AMPA Receptor Antagonism in the Ventral Tegmental Area

In recent years, the role of glutamate in drug seeking has received increasing attention. The current study tested the hypothesis that NBQX (a selective AMPA receptor antagonist) in the ventral tegmental area (VTA) would reduce cocaine seeking. Rats were trained to lever-press for intravenous cocaine (1.0 mg/kg/injection). Two test conditions were used, each preceded by bilateral intra-VTA microinjections of vehicle, 0.5, 1.0 or 2.0 µg/0.5 µl of NBQX. In the without-conditioned-stimulus (without-CS) condition, neither active (cocaine-associated) nor inactive levers produced any consequences. In the with-CS condition, the active lever turned on the stimulus light (as during training) and the infusion pump, which delivered an injection of saline. NBQX produced 2 effects: (1) an overall increase in responding, and (2) an increase in active lever-pressing at the 0.5-µg dose in the with-CS condition. A separate group of rats was allowed to press 2 levers without reinforcement, and the 0.5-µg NBQX dose enhanced responding on both levers. These results failed to support the hypothesis that AMPA receptor antagonism in VTA would reduce cocaine seeking and suggest that such antagonism causes general activating effects and may enhance the capacity of cocaine-CSs to function as conditioned reinforcers.

Nicotinic acetylcholine receptors are required for the conditioned reinforcing properties of sucrose-associated cues

We recently demonstrated that blocking specific nicotinic acetylcholine receptors (nAChRs) abolishes the conditioned reinforcing properties of ethanol-associated cues in rat, suggesting nAChRs as promising pharmacological targets for prevention of cue-induced relapse. The present study investigated the involvement of nAChR subtypes in the conditioned reinforcing properties of stimuli associated with a natural reward (sucrose). Water-deprived rats were trained to associate a tone + light stimulus (CS) with the presentation of a 0.1M sucrose solution for 10 consecutive days. On the subsequent day, the animals were tested on the stringent acquisition of a new instrumental response with conditioned reinforcement, following a systemic injection of the nonselective nAChR antagonist mecamylamine (MEC) or the selective α7 and α6/α3β2β3* nAChR antagonist methyllycaconitine (MLA). At testing, the rats were presented with two novel levers. Responding on the lever assigned as active (CR lever) resulted in a presentation of the CS alone, while pressing the inactive lever (NCR lever) had no programmed consequences. Control animals pressed the CR lever significantly more than the NCR lever, demonstrating that the CR had acquired conditioned reinforcing properties. Systemic MEC as well as MLA reduced the CR lever responses to the same level as for the NCR lever. These results demonstrate a role for the α7 and/or α6/α3β2β3* nAChRs in conditioned reinforcement to a natural reward and suggest neuronal nAChRs as common mediators of the impact of cues on incentive processes.

Exercise is Associated with Increased Drug‐Taking in Rats that Self‐Administer Methamphetamine at Low Levels

ObjectiveAbout 1% of young adults in the U.S. report using methamphetamine (METH) within the past year. Although METH is commonly used at dance parties, little is known about how physical activity influences use. Experiments were conducted to determine the relationship between voluntary exercise and METH self‐administration.MethodsRats were trained to self‐administer METH in chambers that contained both drug self‐administration apparatus and a running wheel. Rats were initially trained to self‐administer METH without wheel access. Once performance stabilized, rats were permitted access to the running wheel and the METH‐reinforced response lever concurrently.ResultsRats self‐administered METH at low levels prior to wheel access and the mean number of drug infusions taken during each session more than tripled after wheel‐access was permitted. Wheel running was stable within individual across sessions. The number of responses on the inactive lever was not significantly related to the dose of METH.ConclusionsIn these experiments, voluntary exercise was associated with increased METH self‐administration in rats that had previously demonstrated low levels of drug self‐administration. These results suggest that reinforcer competition is not the sole factor mediating effects of exercise on drug self‐administration. Research supported by National Institute of Drug Abuse grant R01 DA024705.