David C S Roberts

Wake Forest University, Winston-Salem, North Carolina, United States

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Publications (108)385.85 Total impact

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    ABSTRACT: How much, how often and how fast a drug reaches the brain determine the behavioural and neuroplastic changes associated with the addiction process. Despite the critical nature of these variables, the drug addiction field often ignores pharmacokinetic issues, which we argue can lead to false conclusions. First, we review the clinical data demonstrating the importance of the speed of drug onset and of intermittent patterns of drug intake in psychostimulant drug addiction. This is followed by a review of the preclinical literature demonstrating that pharmacokinetic variables play a decisive role in determining behavioural and neurobiological outcomes in animal models of addiction. This literature includes recent data highlighting the importance of intermittent, 'spiking' brain levels of drug in producing an increase in the motivation to take drug over time. Rapid drug onset and intermittent drug exposure both appear to push the addiction process forward most effectively. This has significant implications for refining animal models of addiction and for better understanding the neuroadaptations that are critical for the disorder. Copyright © 2015. Published by Elsevier Ltd.
    Neuroscience & Biobehavioral Reviews 06/2015; 56. DOI:10.1016/j.neubiorev.2015.06.012 · 8.80 Impact Factor
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    ABSTRACT: Relapse is a widely recognized and difficult to treat feature of the addictions. Substantial evidence implicates cue-triggered activation of the mesolimbic dopamine system as an important contributing factor. Even drug cues presented outside of conscious awareness (i.e., subliminally) produce robust activation within this circuitry, indicating the sensitivity and vulnerability of the brain to potentially problematic reward signals. Because pharmacological agents that prevent these early cue-induced responses could play an important role in relapse prevention, we examined whether baclofen-a GABAB receptor agonist that reduces mesolimbic dopamine release and conditioned drug responses in laboratory animals-could inhibit mesolimbic activation elicited by subliminal cocaine cues in cocaine-dependent individuals. Twenty cocaine-dependent participants were randomized to receive baclofen (60 mg/d; 20 mg t.i.d.) or placebo. Event-related BOLD fMRI and a backward-masking paradigm were used to examine the effects of baclofen on subliminal cocaine (vs neutral) cues. Sexual and aversive cues were included to examine specificity. We observed that baclofen-treated participants displayed significantly less activation in response to subliminal cocaine (vs neutral) cues, but not sexual or aversive (vs neutral) cues, than placebo-treated participants in a large interconnected bilateral cluster spanning the ventral striatum, ventral pallidum, amygdala, midbrain, and orbitofrontal cortex (voxel threshold p < 0.005; cluster corrected at p < 0.05). These results suggest that baclofen may inhibit the earliest type of drug cue-induced motivational processing-that which occurs outside of awareness-before it evolves into a less manageable state.
    The Journal of Neuroscience : The Official Journal of the Society for Neuroscience 04/2014; 34(14):5038-43. DOI:10.1523/JNEUROSCI.4977-13.2014 · 6.34 Impact Factor
  • Benjamin A Zimmer · Keri A Chiodo · David C S Roberts ·
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    ABSTRACT: Continuous administration of D-amphetamine has shown promise as a treatment for psychostimulant addiction. In rodent studies, constant infusion of D-amphetamine (5 mg/kg/day) has been shown to reduce cocaine-reinforced responding in the dose range of 0.19-0.75 mg/kg/inf. The present study tested whether these effects were a reflection of pharmacological interactions between D-amphetamine and cocaine or if they resulted from associative learning mechanisms METHODS: After stable progressive ratio (PR) baselines were established, rats were implanted with subcutaneous osmotic minipumps filled with either D-amphetamine (5 mg/kg/day-groups 1 and 2) or saline (group 3). During the treatment period, groups 1 and 3 self-administered cocaine at a dose that was previously shown to produce the most robust effects in combination with D-amphetamine treatment (0.19 mg/kg/inf), while group 2 received passive cocaine infusions. In replication of previous studies, D-amphetamine treatment resulted in a significant (35 %) decrease in breakpoints relative to saline controls. By contrast, no reductions in breakpoints were observed in animals that received passive cocaine infusions during the treatment period (group 2). Active self-administration of cocaine during the treatment period appears to be an important factor in reducing cocaine-reinforced breakpoints. These findings suggest learning mechanisms are involved in the therapeutic effects of continuous D-amphetamine, and pharmacological interaction mechanisms such as cross-tolerance cannot completely account for the observed decreases in cocaine seeking.
    Psychopharmacology 10/2013; 231(5). DOI:10.1007/s00213-013-3305-4 · 3.88 Impact Factor
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    Jordan T Crawford · David C S Roberts · Thomas J R Beveridge ·
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    ABSTRACT: Given the problems associated with the escalation in methamphetamine (METH) use, the identification of more effective treatment strategies is essential. Group II metabotropic glutamate receptors (mGluRs) have been suggested to be a novel therapeutic target for psychostimulant addiction. We sought to test the ability of the selective group II mGluR agonist LY379268 to reduce METH self-administration in rats. Rats were trained to self-administer METH on a progressive ratio (PR) schedule. Animals were then switched to fixed ratio responding and given daily extended access (6h/day) to METH self-administration for 14 days. Rats were then re-tested on the PR schedule. The effect of LY379268 on METH-reinforced PR responding was determined before and after 14 days of extended access. To test for non-specific effects, a separate group of animals received LY379268 prior to a sucrose pellet-reinforced PR schedule. Animals escalated their daily intake of METH during extended access. PR responding did not change as a function of extended access. LY379268 significantly attenuated METH reinforced responding, both before and after extended access. The degree of attenuation did not change as a function of extended access. LY379268 had no effect on sucrose pellet-reinforced responding at any dose. LY379268 selectively reduced the motivation to self-administer METH. In contrast to data with other compounds, the sensitivity to the effects of LY379268 did not change following extended access to METH self-administration. Group II mGluR agonists, therefore, may represent a relatively new class of compounds for the development of pharmacotherapies for METH addiction.
    Drug and alcohol dependence 08/2013; 132(3). DOI:10.1016/j.drugalcdep.2013.07.024 · 3.42 Impact Factor
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    ABSTRACT: There is great interest in outlining biological factors and behavioral characteristics that either predispose or predict vulnerability to substance use disorders. Response to an inescapable novel environment has been shown to predict a "drug-use-prone" phenotype that is defined by rapid acquisition of cocaine self-administration. Here, we showed that response to novelty can also predict the neurochemical and behavioral effects of acute and repeated cocaine in rats. We used cocaine self-administration under a fixed-ratio 1 schedule followed by fast-scan cyclic voltammetry in brain slices to measure subsecond dopamine (DA) release and uptake parameters in drug-use-prone and -resistant phenotypes. Despite no significant differences in stimulated release and uptake, animals with high responses to a novel environment had DA transporters that were more sensitive to cocaine-induced uptake inhibition, which corresponded to greater locomotor activating effects of cocaine. These animals also acquired cocaine self-administration more rapidly and, after 5 days of extended access cocaine self-administration, high-responding animals showed robust tolerance to DA uptake inhibition by cocaine. The effects of cocaine remained unchanged in animals with low novelty responses. Similarly, the rate of acquisition was negatively correlated with DA uptake inhibition by cocaine after self-administration. Thus, we showed that tolerance to the cocaine-induced inhibition of DA uptake coexists with a behavioral phenotype that is defined by increased preoccupation with cocaine as measured by rapid acquisition and early high intake.
    European Journal of Neuroscience 06/2013; 38(4). DOI:10.1111/ejn.12266 · 3.18 Impact Factor
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    Erin S Calipari · Mark J Ferris · Benjamin A Zimmer · David C S Roberts · Sara R Jones ·
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    ABSTRACT: The dopamine transporter (DAT) is responsible for terminating dopamine (DA) signaling and is the primary site of cocaine's reinforcing actions. Cocaine self-administration has been shown previously to result in changes in cocaine potency at the DAT. To determine whether the DAT changes associated with self-administration are due to differences in intake levels or temporal patterns of cocaine-induced DAT inhibition, we manipulated cocaine access to produce either continuous or intermittent elevations in cocaine brain levels. Long-access (LgA, 6 h) and short-access (ShA, 2 h) continuous self-administration produced similar temporal profiles of cocaine intake that were sustained throughout the session; however, LgA had greater intake. ShA and Intermittent-access (IntA, 6 h) produced the same intake, but different temporal profiles, with 'spiking' brain levels in IntA compared to constant levels in ShA. IntA consisted of 5 min access periods alternating with 25 min time-outs, which resulted in bursts of high responding followed by periods of no responding. DA release and uptake, as well as the potency of cocaine for DAT inhibition, were assessed by voltammetry in nucleus accumbens slices following control, IntA, ShA, and LgA self-administration. Continuous access protocols (LgA and ShA) did not change DA parameters, but the 'spiking' protocol (IntA) increased both release and uptake of DA. In addition, high continuous intake (LgA) produced tolerance, while 'spiking' (IntA) produced sensitization, relative to ShA and naïve controls. Thus, intake and pattern can both influence cocaine potency, and tolerance seems to be produced by high intake, while sensitization is produced by intermittent temporal patterns of intake.Neuropsychopharmacology accepted article preview online, 30 May 2013; doi:10.1038/npp.2013.136.
    Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 05/2013; 38(12). DOI:10.1038/npp.2013.136 · 7.05 Impact Factor
  • David C S Roberts · Amanda Gabriele · Benjamin A Zimmer ·
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    ABSTRACT: IV drug self-administration is a special case of an operant task. In most operant experiments, the instrumental response that completes the schedule requirement is separate and distinct from the consumptive response (e.g. eating or drinking) that follows the delivery of the reinforcing stimulus. In most IV self-administration studies drug seeking and drug taking responses are conflated. The instrumental lever press or nose poke is also a consumptive response. The conflation of these two response classes has important implications for interpretation of the data as they are differentially regulated by dose and price. The types of pharmacological pretreatments that affect appetitive responses are not necessarily the same as those that affect consumptive responses suggesting that the neurobiology of the two response classes are to some extent controlled by different mechanisms. This review discusses how schedules of reinforcement and behavioral economic analyses can be used to assess the regulation of drug seeking and drug taking separately. New methods are described that allow the examination of appetitive or consumptive responding in isolation and provide subjects with greater control over the self-administered dose. These procedures provide novel insights into the regulation of drug intake. Cocaine intake patterns that result in large, intermittent spikes in cocaine levels are shown to produce increases in appetitive responding (i.e. drug seeking). The mechanisms that control drug intake should be considered distinct from appetitive and motivational processes and should be taken into consideration in future IV self-administration studies.
    Neuroscience & Biobehavioral Reviews 05/2013; 37(9). DOI:10.1016/j.neubiorev.2013.04.017 · 8.80 Impact Factor
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    ABSTRACT: Although biochemical and physiological evidence suggests a strong interaction between striatal CB(1) cannabinoid (CB(1) R) and D(2) dopamine (D(2) R) receptors, the mechanisms are poorly understood. We targeted medium spiny neurons (MSNs) of the indirect pathway using shRNA to knockdown either CB(1) R or D(2) R. Chronic reduction in either receptor resulted in deficits in gene and protein expression for the alternative receptor and concomitantly increased expression of the cannabinoid receptor interacting protein 1a (CRIP1a), suggesting a novel role for CRIP1a in dopaminergic systems. Both CB(1) R and D(2) R knockdown reduced striatal dopaminergic-stimulated [(35) S]GTPγS binding, and D(2) R knockdown reduced pallidal WIN55212-2-stimulated [(35) S]GTPγS binding. Decreased D(2) R and CB(1) R activity was associated with decreased striatal phosphoERK. A decrease in mRNA for opioid peptide precursors pDYN and pENK accompanied knockdown of CB(1) Rs or D(2) Rs, and over-expression of CRIP1a. Down-regulation in opioid peptide mRNAs was followed in time by increased DOR1 but not MOR expression, leading to increased DPDPE-stimulated [(35) S]GTPγS binding in the striatum. We conclude that mechanisms intrinsic to striatal MSNs or extrinsic via the indirect pathway adjust for changes in CB(1) R or D(2) R levels by modifying the expression and signaling capabilities of the alternative receptor as well as CRIP1a and the opioid system. © 2013 International Society for Neurochemistry, J. Neurochem. (2013) 10.1111/jnc.12139.
    Journal of Neurochemistry 01/2013; 124(6). DOI:10.1111/jnc.12139 · 4.28 Impact Factor
  • Benjamin A Zimmer · Carson V Dobrin · David C S Roberts ·
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    ABSTRACT: 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.
    Psychopharmacology 09/2012; 225(4). DOI:10.1007/s00213-012-2877-8 · 3.88 Impact Factor
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    ABSTRACT: Methylphenidate (MPH) is a commonly abused psychostimulant prescribed for the treatment of attention deficit hyperactivity disorder. MPH has a mechanism of action similar to cocaine (COC) and is commonly characterized as a dopamine transporter (DAT) blocker. While there has been extensive work aimed at understanding dopamine (DA) nerve terminal changes following COC self-administration, very little is known about the effects of MPH self-administration on the DA system. We used fast scan cyclic voltammetry in nucleus accumbens core slices from animals with a 5-day self-administration history of 40 injections/day of either MPH (0.56 mg/kg) or COC (1.5 mg/kg) to explore alterations in baseline DA release and uptake kinetics as well as alterations in the interaction of each compound with the DAT. Although MPH and COC have similar behavioral effects, the consequences of self-administration on DA system parameters were found to be divergent. We show that COC self-administration reduced DAT levels and maximal rates of DA uptake, as well as reducing electrically stimulated release, suggesting decreased DA terminal function. In contrast, MPH self-administration increased DAT levels, DA uptake rates and DA release, suggesting enhanced terminal function, which was supported by findings of increased metabolite/DA tissue content ratios. Tyrosine hydroxylase messenger RNA, protein and phosphorylation levels were also assessed in both groups. Additionally, COC self-administration reduced COC-induced DAT inhibition, while MPH self-administration increased MPH-induced DAT inhibition, suggesting opposite pharmacodynamic effects of these two drugs. These findings suggest that the factors governing DA system adaptations are more complicated than simple DA uptake blockade.
    Addiction Biology 03/2012; 19(2). DOI:10.1111/j.1369-1600.2012.00456.x · 5.36 Impact Factor
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    ABSTRACT: The dopamine transporter (DAT) is the primary site of action for psychostimulant drugs such as cocaine, methylphenidate, and amphetamine. Our previous work demonstrated a reduced ability of cocaine to inhibit the DAT following high-dose cocaine self-administration (SA), corresponding to a reduced ability of cocaine to increase extracellular dopamine. However, this effect had only been demonstrated for cocaine. Thus, the current investigations sought to understand the extent to which cocaine SA (1.5 mg/kg/inf × 40 inf/day × 5 days) altered the ability of different dopamine uptake blockers and releasers to inhibit dopamine uptake, measured using fast-scan cyclic voltammetry in rat brain slices. We demonstrated that, similar to cocaine, the DAT blockers nomifensine and bupropion were less effective at inhibiting dopamine uptake following cocaine SA. The potencies of amphetamine-like dopamine releasers such as 3,4-methylenedioxymethamphetamine, methamphetamine, amphetamine, and phentermine, as well as a non-amphetamine releaser, 4-benzylpiperidine, were all unaffected. Finally, methylphenidate, which blocks dopamine uptake like cocaine while being structurally similar to amphetamine, shared characteristics of both, resembling an uptake blocker at low concentrations and a releaser at high concentrations. Combined, these experiments demonstrate that after high-dose cocaine SA, there is cross-tolerance of the DAT to other uptake blockers, but not releasers. The reduced ability of psychostimulants to inhibit dopamine uptake following cocaine SA appears to be contingent upon their functional interaction with the DAT as a pure blocker or releaser rather than their structural similarity to cocaine. Further, methylphenidate's interaction with the DAT is unique and concentration-dependent.
    Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 03/2012; 37(7):1708-16. DOI:10.1038/npp.2012.17 · 7.05 Impact Factor
  • Benjamin A Zimmer · David C S Roberts ·
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    ABSTRACT: For decades, researchers have used animal self-administration models to examine the effects drugs of abuse have on physiology and behavior. Sophisticated self-administration procedures have been developed to model many different aspects of drug addiction. The hold-down procedure provides animals with control over the amount of each injection. Holding the lever down turns the syringe pump on and subsequently releasing the lever turns the pump off. In this way, animals can hold the lever down for any duration of time thereby self-administering any dose on a continuous spectrum. This procedure eliminates some of the ambiguity in translating results from effects only observed at one unit dose and allows examination of which dose the animal "prefers" at different times.
    Methods in molecular biology (Clifton, N.J.) 01/2012; 829:279-90. DOI:10.1007/978-1-61779-458-2_18 · 1.29 Impact Factor
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    Erik B Oleson · David C S Roberts ·
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    ABSTRACT: Cocaine self-administration provides a methodology allowing researchers to study changes in distinct aspects of drug-taking behavior that model behaviors observed in drug addicts. Traditionally, self-administration schedules were designed to independently study changes in drug-taking behaviors (e.g., rate of responding, reinforcing efficacy, etc.). The threshold self-administration procedure was developed to measure two distinct dependent measures within the same experimental session that are important in the study of drug addiction: the maximal price an animal expends to self-administer cocaine and an animal's preferred level of cocaine consumption when available at a low behavioral cost.
    Methods in molecular biology (Clifton, N.J.) 01/2012; 829:303-19. DOI:10.1007/978-1-61779-458-2_20 · 1.29 Impact Factor
  • Carson V Dobrin · David C S Roberts ·
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    ABSTRACT: A discrete trials procedure involves splitting up a self-administration session so that there are multiple distinct trials and inter-trial-intervals. This schedule is well suited to be used over 24 h periods which allows insight into diurnal variability in self-administration behavior. DT is also well suited for investigations using pretreatments for increasing or decreasing both high and low probability behavior.
    Methods in molecular biology (Clifton, N.J.) 01/2012; 829:291-302. DOI:10.1007/978-1-61779-458-2_19 · 1.29 Impact Factor
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    Paul W Czoty · David C S Roberts ·
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    ABSTRACT: Neuropsychopharmacology, the official publication of the American College of Neuropsychopharmacology, publishing the highest quality original research and advancing our understanding of the brain and behavior.
    Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 11/2011; 37(5):1079-80. DOI:10.1038/npp.2011.269 · 7.05 Impact Factor
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    Benjamin A Zimmer · Carson V Dobrin · David C S Roberts ·
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    ABSTRACT: A novel behaviorally dependent dosing (BDD) schedule was used to examine the relationship between doses of cocaine self-administered by rats and brain drug levels within a session. The BDD schedule used a hold-down response to activate a syringe pump. The length of time the lever was held down determined the duration that the syringe pump was activated. In the first experiment, rats self-administered cocaine for daily 3 h sessions and brain levels of cocaine were modeled using well-established parameters. Although analysis revealed that rats self-administered doses within a predicted range, one extremely large dose was consistently observed at the beginning of each session when brain levels of cocaine were low. In the second experiment, we introduced a range of timeout periods (10-25 min) in order to produce variability in brain-cocaine concentrations. Animals self-administered larger doses immediately following each timeout period and the dose size was inversely correlated with the length of the timeout. These results show that the dose of cocaine that rats self-administer within a session is inversely related to the amount of drug on board.
    Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 08/2011; 36(13):2741-9. DOI:10.1038/npp.2011.165 · 7.05 Impact Factor
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    Mark J Ferris · Yolanda Mateo · David C.S. Roberts · Sara R Jones ·
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    ABSTRACT: Psychomotor stimulant drugs such as cocaine and amphetamine activate brain dopamine (DA) neurotransmission and support self-administration in humans and laboratory animals. Cocaine amplifies DA signaling by blocking the DA transporter (DAT), and this has been described as the most important mechanism underlying cocaine's reinforcing effects. Amphetamine has the added mechanism of reverse transport of intracellular DA through the DAT. We used cocaine and amphetamine self-administration under a fixed-ratio 1 schedule followed by microdialysis in freely moving rats to measure extracellular DA levels and fast scan cyclic voltammetry in brain slices to measure subsecond DA release and uptake parameters. Following a high dose (1.5 mg/kg intravenous) cocaine self-administration paradigm (40 injections/day × 5 days), the DAT was markedly less sensitive to cocaine, as measured by microdialysis and voltammetry in the nucleus accumbens core. In contrast, the DAT substrate amphetamine retained the same efficacy at the DAT in cocaine self-administering animals, and amphetamine did not mimic cocaine's effect on the DAT when self-administered. A single session of cocaine self-administration caused a significant decrease in the ability of cocaine to inhibit the DAT, a finding that may provide a neurochemical basis for rapid tolerance. The effects of cocaine returned to normal within a few weeks following cessation of self-administration. Here, we, for the first time, demonstrate an in vivo, pharmacologically induced alteration in the sensitivity of the DAT to cocaine that is specific to cocaine, spares DAT and substrate/releaser interactions, and is independent of maximal rate of DA uptake (V(max)).
    Biological psychiatry 02/2011; 69(3):201-7. DOI:10.1016/j.biopsych.2010.06.026 · 10.26 Impact Factor
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    Erik B Oleson · Jasmine M Richardson · David C S Roberts ·
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    ABSTRACT: Behavior occurring during cocaine self-administration can be classified as either consummatory or appetitive. These two concepts are usually addressed independently using separate reinforcement schedules. For example, appetitive behavior can be assessed with a progressive ratio schedule, whereas consummatory behavior is typically measured using a fixed ratio schedule. Depending on the schedule used, it is often difficult to determine whether a particular drug pretreatment is affecting self-administration through an effect on appetitive responding, consummatory responding, or perhaps both. In the present study, we tested the effect of pretreating rats with four different drugs on appetitive and consummatory behaviors. We recently developed a technique that provides an independent assessment of both behavioral concepts within the same experimental session. In this threshold procedure, rats are offered a descending series of 11 unit doses (422-1.3 μg/injection) during consecutive timed intervals under a fixed-ratio schedule. Consummatory behavior can be analyzed by assessing intake at high unit doses; an estimate of appetitive responding can be determined from responding occurring at the threshold dose. Applying behavioral economics to these data provides dependent measures of consumption when minimally constrained by price and the maximal price paid (P (max)) for cocaine. Haloperidol increased cocaine consumption when minimally constrained by price but decreased P (max). In contrast, D: -amphetamine increased P (max). Fluoxetine decreased P (max) and consumption when minimally constrained by price. Baclofen selectively decreased P (max). These data suggest that drug pretreatments can alter consummatory and appetitive behavior differently because each concept involves distinct neural mechanisms.
    Psychopharmacology 11/2010; 214(2):567-77. DOI:10.1007/s00213-010-2058-6 · 3.88 Impact Factor
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    Rodrigo A España · James R Melchior · David C S Roberts · Sara R Jones ·
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    ABSTRACT: Recent evidence indicates that the hypocretin/orexin system participates in the regulation of reinforcement and addiction processes. For example, manipulations that decrease hypocretin neurotransmission result in disruptions of neurochemical and behavioral responses to cocaine. To further assess the relationship between the hypocretin system and cocaine reinforcement, the current studies used microdialysis and in vivo voltammetry to examine the effects of hypocretin 1 on cocaine-induced enhancement of dopamine signaling in the nucleus accumbens core. Fixed ratio, discrete trials, and progressive ratio self-administration procedures were also used to assess whether hypocretin 1 promotes cocaine self-administration behavior. Infusions of hypocretin 1 into the ventral tegmental area increased the effects of cocaine on tonic and phasic dopamine signaling and increased the motivation to self-administer cocaine on the discrete trials and progressive ratio schedules. Together with previous observations demonstrating that a hypocretin 1 receptor antagonist disrupts dopamine signaling and reduces self-administration of cocaine, the current observations further indicate that the hypocretin system participates in reinforcement processes likely through modulation of the mesolimbic dopamine system.
    Psychopharmacology 10/2010; 214(2):415-26. DOI:10.1007/s00213-010-2048-8 · 3.88 Impact Factor
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    Caroline E Bass · Heiko T Jansen · David C S Roberts ·
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    ABSTRACT: Using a discrete trials (DT) procedure, we have previously shown that rats exhibit variations in their pattern of cocaine self-administration relative to the time-of-day, often producing a daily rhythm of intake in which the majority of infusions occur during the dark phase of the 24 h light-dark cycle. We have sought to determine if cocaine self-administration demonstrates free-running circadian characteristics under constant-lighting conditions in the absence of external environmental cues. Rats self-administering cocaine (1.5 mg/kg/infusion) under a DT3 procedure (three trials/h) were kept in constant-dim (<2 lux, DIM) conditions, and the pattern of intake was analyzed for free-running behavior. We show that cocaine self-administration has a period length (tau) of 24.14 +/- 0.07 h in standard 12 h light:12 h dark conditions, which is maintained for at least five days in constant-dim conditions. With longer duration DIM exposure, cocaine self-administration free-runs with a tau of approximately 24.92 +/- 0.16 h. Exposure to constant-light conditions (1000 lux, LL) lengthened tau to 26.46 +/- 0.23 h; this was accompanied by a significant decrease in total cocaine self-administered during each period. The pattern of cocaine self-administration, at the dose and availability used in this experiment, is circadian and is likely generated by an endogenous central oscillator. The DT procedure is therefore a useful model to examine the substrates underlying the relationship between circadian rhythms and cocaine intake.
    Chronobiology International 05/2010; 27(3):535-48. DOI:10.3109/07420521003664221 · 3.34 Impact Factor

Publication Stats

6k Citations
385.85 Total Impact Points


  • 2003-2014
    • Wake Forest University
      • Department of Physiology and Pharmacology
      Winston-Salem, North Carolina, United States
  • 2000-2013
    • Wake Forest School of Medicine
      • Department of Physiology and Pharmacology
      Winston-Salem, North Carolina, United States
  • 1982-2008
    • Carleton University
      • • Department of Psychology
      • • Institute of Biochemistry
      Ottawa, Ontario, Canada
  • 2005
    • Champalimaud Neuroscience Program
      Lisboa, Lisbon, Portugal
  • 1988-2003
    • University of Ottawa
      • • Department of Biochemistry, Microbiology and Immunology
      • • School of Psychology
      Ottawa, Ontario, Canada
  • 1977-2002
    • University of British Columbia - Vancouver
      • Department of Psychiatry
      Vancouver, British Columbia, Canada
  • 1993
    • University of South Carolina School of Medicine - Greenville
      Гринвилл, South Carolina, United States
  • 1985
    • University of Toronto
      • Division of Anatomy
      Toronto, Ontario, Canada