Drug Self-administration Studies Research Articles

High quality, high throughput, and low-cost simultaneous video recording of 60 animals in operant chambers using PiRATeMC

BackgroundThe development of Raspberry Pi-based recording devices for video analyses of drug self-administration studies has been shown to be promising in terms of affordability, customizability, and capacity to extract in-depth behavioral patterns. Yet, most video recording systems are limited to a few cameras making them incompatible with large-scale studies. New MethodWe expanded the PiRATeMC (Pi-based Remote Acquisition Technology for Motion Capture) recording system by increasing its scale, modifying its code, and adding equipment to accommodate large-scale video acquisition, accompanied by data on throughput capabilities, video fidelity, synchronicity of devices, and comparisons between Raspberry Pi 3B+ and 4B models. ResultsUsing PiRATeMC default recording parameters resulted in minimal storage (~350MB/h), high throughput (< ~120seconds/Pi), high video fidelity, and synchronicity within ~0.02seconds, affording the ability to simultaneously record 60 animals in individual self-administration chambers for various session lengths at a fraction of commercial costs. No consequential differences were found between Raspberry Pi models. Comparison with Existing Method(s)This system allows greater acquisition of video data simultaneously than other video recording systems by an order of magnitude with less storage needs and lower costs. Additionally, we report in-depth quantitative assessments of throughput, fidelity, and synchronicity, displaying real-time system capabilities. ConclusionsThe system presented is able to be fully installed in a month’s time by a single technician and provides a scalable, low cost, and quality-assured procedure with a high-degree of customization and synchronicity between recording devices, capable of recording a large number of subjects and timeframes with high turnover in a variety of species and settings.

Nucleus accumbens shell neurons’ early sensitivity to cocaine is associated with future increases in drug intake

The striatum, both dorsal and ventral, is strongly implicated in substance use disorder. Chronic consumption of abused substances, such as cocaine, can cause an oversaturation of mesostriatal dopamine, which results in alterations in the firing of striatal neurons. While most preclinical studies of drug self-administration (S-A) are focused on these alterations, individual differences in a subject's early responses to drugs can also account for substantial differences in addiction susceptibility. In this study, we modeled longitudinal pharmacokinetics using data from a previous longitudinal study (Coffey et al., 2015) and aimed to determine if firing in specific dorsal and ventral striatal subregions was subject to changes across chronic cocaine S-A, and if individual animal differences in striatal firing in response to early drug exposure correlated with increases in drug intake. We observed that the firing patterns of nucleus accumbens (NAc) core and shell neurons exhibited increasing sensitivity to cocaine over the first 6 S-A sessions and maintained a strong negative correlation between drug intake and neuronal firing rates across chronic S-A. Moreover, we observed that the early sensitivity of NAc shell neurons to cocaine correlated with future increases in drug intake. Specifically, rats whose NAc shell neurons were most inhibited by increasing levels of cocaine upon first exposure exhibited the strongest increases in cocaine intake over time. If this difference can be linked to a genetic difference, or druggable targets, it may be possible to screen for similar addiction susceptibility in humans or develop novel preemptive pharmacotherapies.

Expression of stable and reliable preference and aversion phenotypes following place conditioning with psychostimulants.

Drug-seeking behavior occurs more readily in some individuals than others. This phenomenon is considered in studies of drug self-administration in which high drug-seeking/taking individuals can be identified. In contrast, studies of conditioned place preference (CPP) often involve a random sample of drug-naïve rodents that includes phenotypes not considered relevant to addiction. The main objective of the current studies was to determine if a priori identification of different conditioning phenotypes could improve the validity and sensitivity of CPP expression as a preclinical test for vulnerability to addiction. Analysis of cocaine place conditioning data from 443 Swiss-Webster mice revealed a trimodal distribution with peaks corresponding to means of k = 3 clusters. The cluster means occurred at high, low, or negative preference scores, the latter suggesting a phenotype acquiring conditioned place aversion (CPA). The same clusters were identified in mice conditioned with methamphetamine, MDPV, or amphetamine, and these clusters remained stable and reliable during three additional expression tests spaced at 24h. A meta-analysis of effect sizes obtained from CPP literature revealed a positively skewed distribution affected by sample size, consistent with the existence of a CPA phenotype within the populations tested. A dopamine receptor antagonist, flupentixol, blocked cocaine CPP expression in a group containing all phenotypes, but sensitivity improved markedly when CPA phenotypes were excluded from the dataset. These studies suggest that taking phenotype into consideration when designing place conditioning studies will improve their application as a preclinical tool in addiction biology and drug discovery.

Environmental influence on the preclinical evaluation of substance use disorder therapeutics.

Substance use disorders (SUD) develop as a result of complex interactions between the environment, the subject, and the drug of abuse. Preclinical basic research investigating each of these tripartite components of SUD individually has resulted in advancements in our fundamental knowledge regarding the progression from drug abuse to SUD and severe drug addiction and the underlying behavioral and neurobiological mechanisms. How these complex interactions between the environment, the subject, and the drug of abuse impact the effectiveness of candidate or clinically used medications for SUD has not been as extensively investigated. The focus of this chapter will address the current state of our knowledge how these environmental, subject, and pharmacological variables have been shown to impact candidate or clinical SUD medication evaluation in preclinical research using drug self-administration procedures as the primary dependent measure. The results discussed in this chapter highlight the importance of considering environmental variables such as the schedule of reinforcement, concurrent availability of alternative nondrug reinforcers, and experimental housing conditions in the context of SUD therapeutic evaluation. The thesis of this chapter is that improved understanding of environmental variables in the context of SUD research will facilitate the utility of preclinical drug self-administration studies in the evaluation and development of candidate SUD therapeutics.

Rate of Onset as a Determinant of Abuse Potential Assessment Using Intracranial Self‐Stimulation in Rats

Background Intracranial self-stimulation (ICSS) is one procedure that has been used to evaluate abuse potential of drugs, and as with more commonly used drug self-administration procedures, ICSS is especially sensitive to drugs that activate the mesolimbic dopamine system. Drug self-administration studies have shown that abuse potential can also be influenced by temporal parameters, and especially rate of onset; however, the degree to which rate of onset influences abuse-potential metrics in ICSS procedures has not been systematically examined. To address this issue, this study evaluated three dopamine transporter (DAT) inhibitors that have different onset rates and were shown previously to maintain different peak break points in rhesus monkeys responding under a progressive-ratio schedule (cocaine > WIN35428 > RTI-31 for both rate of onset and break point). In ICSS, abuse potential is generally indicated when a drug increases low rates of responding maintained by low levels of brain stimulation, a phenomenon called “ICSS facilitation”. We hypothesized that these three DAT inhibitors would facilitate ICSS different time courses, but the degree to which rate of onset might influence peak facilitation was unknown. Methods Adult male and female Sprague-Dawley rats (n = 5-7 per drug) were surgically implanted with permanent stainless-steel electrodes targeting the medial forebrain bundle and trained to respond on a lever to receive electrical brain stimulation. Behavioral sessions were organized in components consisting of ten one-minute frequency trials over a range of brain-stimulation frequencies (56-158 Hz), such that a full curve relating brain-stimulation frequency to response rate could be determined every 10 min. On test days, three baseline ICSS components were followed first by intraperitoneal drug injection and then immediately by 12 consecutive test components (120 min). Additional pairs of test components were initiated at 300 and 1440 minutes post-injection. The drugs and dose ranges tested were as follows: cocaine HCl (1.0 - 10 mg/kg), WIN35428 (0.10 – 0.32 mg/kg), and RTI-31 (0.032 – 0.10 mg/kg). All drugs were tested up to doses that produced peak levels of ICSS facilitation; higher doses disrupted responding and produced stereotypies. Results Under baseline conditions, brain stimulation maintained a frequency-dependent increase in reinforcement rates. All three drugs dose-dependently and robustly facilitated ICSS, shifting ICSS frequency-rate curves to the left and increasing the total number of stimulations per component when data were collapsed across all frequencies. Consistent with previous studies, the rate of onset for ICSS facilitation was fastest for cocaine, slower for WIN35428, and slowest for RTI-31. Cocaine also had the shortest duration of action and the lowest potency, whereas RTI-31 had the longest duration of action and highest potency. However, despite these differences in time course and potency, peak ICSS facilitation was not statistically different across drugs. Conclusions These results suggest that ICSS studies should evaluate rate of onset as well as peak ICSS facilitation in reaching conclusions about overall abuse potential of a test drug.

Associative processes in addiction relapse models: A review of their Pavlovian and instrumental mechanisms, history, and terminology

Animal models of relapse to drug-seeking have borrowed heavily from associative learning approaches. In studies of relapse-like behaviour, animals learn to self-administer drugs then receive a period of extinction during which they learn to inhibit the operant response. Several triggers can produce a recovery of responding which form the basis of a variety of models. These include the passage of time (spontaneous recovery), drug availability (rapid reacquisition), extinction of an alternative response (resurgence), context change (renewal), drug priming, stress, and cues (reinstatement). In most cases, the behavioural processes driving extinction and recovery in operant drug self-administration studies are similar to those in the Pavlovian and behavioural literature, such as context effects. However, reinstatement in addiction studies have several differences with Pavlovian reinstatement, which have emerged over several decades, in experimental procedures, associative mechanisms, and terminology. Interestingly, in cue-induced reinstatement, drug-paired cues that are present during acquisition are omitted during lever extinction. The unextinguished drug-paired cue may limit the model’s translational relevance to cue exposure therapy and renders its underlying associative mechanisms ambiguous. We review major behavioural theories that explain recovery phenomena, with a particular focus on cue-induced reinstatement because it is a widely used model in addiction. We argue that cue-induced reinstatement may be explained by a combination of behavioural processes, including reacquisition of conditioned reinforcement and Pavlovian to Instrumental Transfer. While there are important differences between addiction studies and the behavioural literature in terminology and procedures, it is clear that understanding associative learning processes is essential for studying relapse.

Δ9-tetrahydrocannabinol: Drug discrimination abuse liability testing in female Lister Hooded rats: Trials, tribulations and triumphs

IntroductionThe assessment of the abuse potential of CNS-active drugs is a regulatory requirement. Drug discrimination is one of the nonclinical tests that contribute to this assessment by providing information on a drug's potential to induce a discriminative stimulus comparable to that of a known drug of abuse. AimThe objective was to validate drug discrimination in the rat for the purpose of supporting regulatory submissions for novel drugs with potential cannabinoid-like activity. MethodsTen female Lister hooded rats were trained to discriminate no-drug from Δ9-THC (1.5 mg/kg, IP) under a FR10 schedule of reinforcement. Once trained, a Δ9-THC dose-response curve was obtained using doses of 0.25, 0.75, 1.5, and 3 mg/kg, IP. This was followed by evaluation of amphetamine (0.3 mg/kg, SC); morphine (3 mg/kg, IP); midazolam (2.5 mg/kg, PO); and the synthetic cannabinoids WIN55,212–2 (0.75 to 2 mg/kg, IP), CP-47,497 (0.5 to 2 mg/kg, IP), and JWH-018 (1 mg/kg, IP) for their discriminative stimulus similarity to Δ9-THC. ResultsPharmacological specificity was demonstrated by achieving the anticipated dose-response curve for Δ9-THC, and a vehicle-like response for the non-cannabinoid drugs. Although full generalisation was obtained for JWH-018, in contrast to published literature, WIN55,212–2 and CP-47,497 failed to generalise to Δ9-THC. DiscussionBased on the literature review performed in light of the results obtained, contrasting and unpredictable behavioural responses produced by cannabinoids in animals and humans raises the question of the reliability and relevance of including drug discrimination and self-administration studies within an abuse potential assessment for novel cannabinoid-like drugs.

Establishing performance characteristics for positive control article selection in drug self-administration studies

The selection of a controlled substance (CS) for use as the positive control article in a nonclinical drug abuse liability (DAL) assessment study should be contemplated carefully and with full understanding of the stated intent of the study design. Any CS that can maintain day-to-day stable baseline responding of voluntary intravenous intakes in animals may be selected under the current guidelines. Schedule I – IV CNS stimulants, depressants, and sedative/hypnotics can serve as maintenance drugs in these protocols, but not all of these compounds will provide comparatively efficient, robust, and stable daily intakes. Each Sponsor is directed to select a positive control article and training dose that will provide the most balanced, predictive, and scientifically-sound comparison consistent with the mechanism of action or therapeutic target of the test article. The SA study design is not a “one-size-fits-all” assay. This is a discussion of the critical design factors to be considered in selecting the most appropriate positive control article to use for a SA study.

The Rise and Fall of Kappa-Opioid Receptors in Drug Abuse Research.

Substance use disorders represent a global public health issue. This mental health disorder is hypothesized to result from neurobiological changes as a result of chronic drug exposure and clinically manifests as inappropriate behavioral allocation toward the procurement and use of the abused substance and away from other behaviors maintained by more adaptive nondrug reinforcers (e.g., social relationships, work). The dynorphin/kappa-opioid receptor (KOR) is one receptor system that has been altered following chronic exposure to drugs of abuse (e.g., cocaine, opioids, alcohol) in both laboratory animals and humans, implicating the dynorphin/KOR system in the expression, mechanisms, and treatment of substance use disorders. KOR antagonists have reduced drug self-administration in laboratory animals under certain experimental conditions, but not others. Recently, several human laboratory and clinical trials have evaluated the effectiveness of KOR antagonists as candidate pharmacotherapies for cocaine or tobacco use disorder to test hypotheses generated from preclinical studies. KOR antagonists failed to significantly alter drug use metrics in humans suggesting translational discordance between some preclinical drug self-administration studies and consistent with other preclinical drug self-administration studies that provide concurrent access to an alternative nondrug reinforcer (e.g., food). The implications of this translational discordance and future directions for examining the therapeutic potential of KOR agonists or antagonists as candidate substance use disorder pharmacotherapies are discussed.

9 Neurobiology of addiction

Trevor is Professor of Cognitive Neuroscience, being elected to the Chair of Expt. Psychology (and Head of Department) at the University of Cambridge, from October 2002. He is a Fellow of the British Psychological Society (1990), the Academy of Medical Sciences (2000), and the Royal Society (2005). He received the Distinguished Scientific Contribution Award for 2011 from the American Psychological Association. He has published about 750 full papers, with an H index of about 167. He has co-edited eight books, most recently Translational Neuropsychopharmacology (Springer, 2016). Trevor directs the University of Cambridge ‘Behavioural and Clinical Neuroscience Institute’, the mission of which is to enhance translation from basic to clinical neuroscience. His interest in translation began with his co-invention of the CANTAB computerised neuropsychological battery, which is currently used in over 700 institutes and clinical centres world-wide. He stepped down as President of the British Neuroscience Association in 2011 and was made a CBE in the New Year’s Honours list of the U.K. in 2012. In 2014, he shared the ‘Brain Prize’ of the Grete Lundbeck European Brain Research Foundation, the most valuable in neuroscience, and in 2015 he received the “Lifetime Achievement Award” of the British Association for Psychopharmacology’. Much evidence, based on experimental studies of intravenous drug self-administration in experimental animals and neuroimaging studies in humans now supports the view that drug addiction results in part from aberrant learning mediated by dopamine-dependent processes of the limbic-striatal interface, including the amygdala and nucleus accumbens. The neural systems of this interface and other frontostriatal networks mediate several relevant forms of learning, including Pavlovian conditioning, goal-directed, action-outcome learning, and stimulus-response habit learning (which is not controlled by outcomes or goals). Hypothetically, drug addiction involves an imbalance between instrumental behaviour controlled by outcomes and habitual responding mediated by stimulus-response associations, corresponding hypothetically to a devolution of neurobehavioural control from (i) the prefrontal cortex to the striatum, and (ii) from the ventral to the dorsal striatum (Everitt and Robbins 2016). I will consider the experimental evidence relevant to these predictions from studies of both experimental animals and humans with substance use disorders. I will focus especially on stimulant drugs, but will consider other substance use disorders, as well the latter as part of a ‘impulse-compulsive’ spectrum of mental health disorders. For human drug abuse, it is difficult to unravel predispositions or causal neurobehavioural factors contributing to addiction, from potential neurotoxic effects of the drugs themselves. I will thus describe strategies for determining the aetiological role of these factors, based on evidence from (i) experimental animals, using several techniques and (ii) human drug abusers or vulnerable adolescents, based on functional neuroimaging methods, employing both longitudinal and endophenotype designs. I will conclude that both types of influence contribute to the drive to addiction. Finally, I will consider implications of this evidence for possible new therapeutic approaches to drug addiction, whether pharmacological or behavioural. Reference . Everitt BJ, Robbins TW. Drug addiction: updating actions to habits to compulsions ten years on. annual review of psychology2016;67:23–50.

Utility of Nonhuman Primates in Substance Use Disorders Research.

Substance use disorders (i.e., drug addiction) constitute a global and insidious public health issue. Preclinical biomedical research has been invaluable in elucidating the environmental, biological, and pharmacological determinants of drug abuse and in the process of developing innovative pharmacological and behavioral treatment strategies. For more than 70 years, nonhuman primates have been utilized as research subjects in biomedical research related to drug addiction. There are already several excellent published reviews highlighting species differences in both pharmacodynamics and pharmacokinetics between rodents and nonhuman primates in preclinical substance abuse research. Therefore, the aim of this review is to highlight three advantages of nonhuman primates as preclinical substance abuse research subjects. First, nonhuman primates offer technical advantages in experimental design compared to other laboratory animals that afford unique opportunities to promote preclinical-to-clinical translational research. Second, these technical advantages, coupled with the relatively long lifespan of nonhuman primates, allows for pairing longitudinal drug self-administration studies and noninvasive imaging technologies to elucidate the biological consequences of chronic drug exposure. Lastly, nonhuman primates offer advantages in the patterns of intravenous drug self-administration that have potential theoretical implications for both the neurobiological mechanisms of substance use disorder etiology and in the drug development process of pharmacotherapies for substance use disorders. We conclude with potential future research directions in which nonhuman primates would provide unique and valuable insights into the abuse of and addiction to novel psychoactive substances.

Abuse-related effects of subtype-selective GABAA receptor positive allosteric modulators in an assay of intracranial self-stimulation in rats.

GABAA positive allosteric modulators (GABAA PAMs), such as diazepam and zolpidem, are used clinically for anxiety and insomnia, but abuse liability is a concern. Novel GABAA PAMS may have lower abuse liability while retaining clinical utility. The present study compared abuse-related effects of the non-selective GABAA PAM diazepam, the α1-selective GABAA PAM zolpidem, and three novel GABAA PAMs (JY-XHe-053, XHe-II-053, and HZ-166) using intracranial self-stimulation (ICSS) in rats. These novel compounds have relatively low efficacy at α1-, α2-, and α3-containing GABAA receptors, putative in vivo selectivity at α2/α3-containing GABAA receptors, and produce anxiolytic-like effects with limited sedation in non-human primates. Adult, male Sprague-Dawley rats (n=17) were each implanted with a bipolar electrode in the medial forebrain bundle and trained to respond under a fixed-ratio 1 schedule of reinforcement for electrical brain stimulation. The potency and time course of effects were compared for diazepam (0.1-10mg/kg), zolpidem (0.032-3.2mg/kg), and the three novel compounds (JY-XHe-053, XHe-II-053, and HZ-166; all 3.2-32mg/kg). Zolpidem and diazepam produced transient facilitation of ICSS at small doses and more sustained rate-decreasing effects at larger doses. JY-XHe-053 and HZ-166 produced weak and inconsistent ICSS facilitation, whereas XHe-II-053 had no effect on ICSS. These results support a key role for α1-containing GABAA receptors in mediating GABAA PAM-induced ICSS facilitation. These results are concordant with drug self-administration studies in monkeys in suggesting that GABAA PAMs with low α1 efficacy and putative α2/α3 selectivity have lower abuse liability than high-efficacy non-selective or α1-selective GABAA PAMs.

Nicotine self-administration research: the legacy of Steven R. Goldberg and implications for regulation, health policy, and research.

Steven R. Goldberg was a pioneering behavioral pharmacologist whose intravenous drug self-administration studies advanced the understanding of conditioned stimuli and schedules of reinforcement as determinants of pattern and persistence of drug-seeking behavior, and in particular, the importance of nicotine in tobacco use. His passing in 2014 led to invitations to contribute articles to psychopharmacology dedicated to his work. The objectives of this review are to summarize and put into historical perspective Goldberg's contributions to elucidate the reinforcing effects of nicotine and to summarize the implications of his research for medication development, tobacco regulation, and potential tobacco control policy options. This includes a review of intravenous nicotine self-administration research from the 1960s to 2016. Goldberg's application of behavioral pharmacology methods to investigate nicotine reinforcement and the influence of schedule of reinforcement and conditioned stimuli on nicotine administration contributed to the conclusions of the US National Institute on Drug Abuse, and the Surgeon General, that nicotine met the criteria as a dependence-producing drug and cigarette smoking as a prototypic drug dependency or "addiction." Equally important, this work has been systematically extended to other species and applied to address a range of factors relevant to tobacco use, medication development, regulation, and public health policy. Steven R. Goldberg was a pioneering scientist whose systematic application of the science of behavioral pharmacology advanced the understanding of tobacco and nicotine use and contributed to the scientific foundation for tobacco product regulation and potential public health tobacco control policy development.

Animal models of social contact and drug self-administration

Social learning theories of drug abuse propose that individuals imitate drug use behaviors modeled by social peers, and that these behaviors are selectively reinforced and/or punished depending on group norms. Historically, animal models of social influence have focused on distal factors (i.e., those factors outside the drug-taking context) in drug self-administration studies. Recently, several investigators have developed novel models, or significantly modified existing models, to examine the role of proximal factors (i.e., those factors that are immediately present at the time of drug taking) on measures of drug self-administration. Studies using these newer models have revealed several important conclusions regarding the effects of social learning on drug abuse: 1) the presence of a social partner influences drug self-administration, 2) the behavior of a social partner determines whether social contact will increase or decrease drug intake, and 3) social partners can model and imitate specific patterns of drug self-administration. These findings are congruent with those obtained in the human laboratory, providing support for the cross-species generality and validity of these preclinical models. This mini-review describes in detail some of the preclinical animal models used to study social contact and drug self-administration to guide future research on social learning and drug abuse.

Nicotine-like behavioral effects of the minor tobacco alkaloids nornicotine, anabasine, and anatabine in male rodents.

Tobacco use is associated with lethal diseases in an estimated 440,000 persons in the United States each year (Centers for Disease Control and Prevention, 2005). Successful smoking quit-rates are estimated at 5%-8%, even though a quarter of those attempts included use of smoking-cessation aids (Messer et al., 2008; Henningfield et al., 2009). Current projections are that 16% of the U.S. population-35 million people-will still smoke in 2025, thus more effective smoking-cessation aids are urgently needed (Pollock et al., 2009). The minor tobacco alkaloids may be promising candidates, but further research is necessary (Hoffman & Evans, 2013). Accordingly, we systematically evaluated the minor tobacco alkaloids nornicotine, anabasine, and anatabine using assays of behavioral tolerability, nicotine withdrawal, nicotine discrimination, and nicotine self-administration in male rodents. At doses that were well tolerated, all 3 minor alkaloids dose-dependently engendered robust substitution for a nicotine discriminative stimulus in mice (0.32 mg/kg, IP), and anabasine attenuated nicotine withdrawal. When the ED50 dose of each alkaloid was administered in combination with nicotine, the discriminative stimulus effects of nicotine were not enhanced by any of the alkaloids, and anatabine blunted nicotine's effects. In drug self-administration studies, only nornicotine was self-administered by rats that self-administered nicotine intravenously; anabasine and anatabine had no reinforcing effects. Moreover, prior administration of each of the minor tobacco alkaloids dose-dependently decreased nicotine self-administration. Collectively these results suggest that the minor tobacco alkaloids may substitute for the subjective effects of nicotine and attenuate withdrawal and craving without the abuse liability of nicotine.

Effects of methcathinone and 3-Cl-methcathinone (PAL-434) in cocaine discrimination or self-administration in rhesus monkeys

Monoamine releasers with varying selectivity for dopamine (DA)/norepinephrine and serotonin (5-HT) release are potential treatment medications for cocaine abuse. Although DA-selective monoamine releasers effectively reduce cocaine abuse, their clinical usefulness is limited by abuse liability. It is hypothesized that increasing 5-HT neurotransmission may reduce the abuse-related effects of DA releasers, but the optimal DA:5-HT release ratio remains to be determined. This study in rhesus monkeys compared the effects of two compounds with differing potency for 5-HT release. Methcathinone and 3-Cl-methcathinone (PAL-434) have equal potency for DA release, but PAL-434 has 10-fold higher potency for 5-HT release. In drug discrimination studies, monkeys were trained to discriminate cocaine (0.4 mg/kg i.m.) from saline in a two-key, food-reinforced procedure. In drug self-administration studies, a separate group of monkeys was trained to respond for cocaine [0.01 mg/kg/injection (inj)] and food (1 g pellets) under a second order schedule of reinforcement [FR2(VR16:S)]. When responding was stable, methcathinone (0.1–0.56 mg/kg.h i.v.) or PAL-434 (0.32–1.8 mg/kg.h i.v.) was administered chronically (one injection every 20 min for 23 h/d) for 7–10 d. In discrimination studies, both compounds dose-dependently increased cocaine-like responding but with different potencies (cocaine=methcathinone >PAL-434). Chronic treatment with methcathinone or PAL-434 dose-dependently and selectively reduced cocaine self-administration. PAL-434 was about 4-fold and methcathinone about 1.6-fold more potent at decreasing cocaine- over food-maintained responding. These data suggest that compounds with moderate selectivity for DA vs. 5-HT release (8–15-fold) may be effective for the treatment of cocaine dependence.

Drug self-administration studies

Relative reinforcing effects of different ethanol and different cocaine doses were studied under concurrent independent fixed-ratio (FR) schedules and concurrent nonindependent FR schedules with rhesus monkeys. Nonindependent FR schedules differed from independent FR schedules in that responses on either side counted towards the FR requirements of two concurrently presented choices. Thus, responses on the right operandum counted toward completion of both right and left FR schedules and, symmetrically, responses on the left did the same. Nonindependent schedules allow the number of responses per drug delivery to vary considerably, unlike independent schedules, thereby making the number of responses per delivery a sensitive dependent variable. In contrast, standard independent schedules do not allow responses per drug delivery to vary; the required number of responses is an independent variable. Three rhesus monkeys were subjects, and choices between different doses of ethanol or cocaine were studied. Larger doses maintained higher response rates than smaller doses - consistent with previous choice studies. By using nonindependent schedules, however, graded responses per drug delivery and increased switching between sides were obtained, providing additional data and useful measures of choice.

Ethanol Self‐Administration in Free‐Flying Honeybees (Apis mellifera L.) in an Operant Conditioning Protocol

This study examines the effect of ethanol (EtOH) on continuous reinforcement schedules in the free-flying honeybee (Apis mellifera L.). As fermented nectars may be encountered naturally in the environment, we designed an experiment combining the tools of laboratory research with minimal disturbance to the natural life of honeybees. Twenty-five honeybees were trained to fly from their colonies to a fully automated operant chamber with head poking as the operant response. Load size, intervisit interval, and interresponse times (IRTs) served as the dependent variables and were monitored over the course of a daily training session consisting of many visits. Experimental bees were tested using an ABA design in which sucrose only was administered during condition A and a 5% EtOH sucrose solution was administered during condition B. Control bees received sucrose solution only. Most bees continued to forage after EtOH introduction. EtOH significantly reduced the load size and the intervisit interval with no significant effect on IRTs. However, a look on individual data shows large individual differences suggesting the existence of different kinds of behavioral phenotypes linked to EtOH consumption and effects. Our results contribute to the study of EtOH consumption as a normal phenomenon in an ecological context and open the door to schedule-controlled drug self-administration studies in honeybees.

Pavlovian-to-instrumental transfer in cocaine seeking rats.

Drug-associated cues are believed to be important mediators of addiction and drug relapse. Although such cues may influence drug-seeking behavior through multiple routes, it is their putative incentive motivational properties-their ability to elicit "craving"-that interests many addiction researchers. The Pavlovian-to-instrumental transfer paradigm is commonly used to assay cue-evoked incentive motivation in situations involving natural rewards, but has not been widely applied to the study of drug self-administration. We used this paradigm to determine whether cues paired with intravenous cocaine could promote performance of an independently trained task in which rats self-administered cocaine by completing a chain of two different lever press actions, a procedure used to parse behavior into cocaine seeking (first action) and cocaine taking (second action). Rats showed significant transfer, increasing task performance during cocaine-paired cues. This effect was observed for both seeking and taking actions, although a trend toward greater cocaine taking was observed, a result that is consistent with studies using natural rewards. Our results demonstrate that cocaine-paired cues can provoke the pursuit of cocaine through a Pavlovian motivational process. This phenomenon may provide a useful new tool for modeling drug relapse, particularly as a method for targeting the response-invigorating effects of stimulus-drug learning.

Computer-controlled drug doses for IV drug self-administration.

This report describes a novel procedure for computer-controlled drug-dose determination for IV drug self-administration studies. By modifying the duration of each infusion of a single concentration of a drug solution, five or more unit doses (mg/kg/inj) can be dispensed from the same syringe. The advantages of this procedure include the following: (a) it is not necessary to prepare a new syringe for each dose change, (b) the sterility of the IV catheter line is broken less often and, (c) the confounding effect of flushing through the catheter line with the previous drug dose is avoided. This procedure is accurate and reliable and can be applied to multiple sessions of any duration across days or weeks.