The journal of pharmacology and experimental therapeutics/The Journal of pharmacology and experimental therapeutics, Mar 15, 2024
This issue of the Journal of Pharmacology and Experimental Therapeutics includes an article by Wi... more This issue of the Journal of Pharmacology and Experimental Therapeutics includes an article by Withey et al. that addresses an important challenge in the seemingly unending quest for effective and safe pharmacological approaches to the treatment of opioid use disorders (OUDs). One focus of the article is on the use of chronic naltrexone, a l-opioid receptor antagonist, to block "reinstatement" of a number of full and partial l-opioid receptor agonists in squirrel monkeys. An additional objective of the research was to examine the effects of chronic naltrexone administration on the antinociceptive effects of the same drugs used in the reinstatement experiments. The rationale behind this portion of the publication is related to naltrexone's ability to block l-opioid receptor-mediated effects that include antinociception. Opioid pain management may be challenging in patients undergoing treatment with extended-release naltrexone. The article serving as the basis for this Viewpoint could be viewed as a companion publication to Withey et al. (2019), who studied the effects of chronic buprenorphine under similar conditions and with comparable drugs. Together, they provide valuable information on issues surrounding both reinstatement and antinociception with chronic administration of naltrexone and buprenorphine. The study of reinstatement of drug-seeking behavior in laboratory animals has become standard as one of the experimental approaches to aid in guiding the development of potential medications to treat relapse to drug use. Susceptibility to relapse is, among other variables, frequently believed to be related to craving, which has emerged as an important indicator of drug seeking and relapse. Gauld et al. (2023), following an extensive network analysis of opioids and other drugs, concluded that craving is a potential central marker of addiction, connecting to the entire symptom network regardless of the specific substance, and can be used to aid and facilitate the understanding and treatment of SUDs.
Journal of the Experimental Analysis of Behavior, Sep 1, 1991
Key pecking of 4 pigeons was maintained under a multiple 3-min fixed-interval, 30-response fixedr... more Key pecking of 4 pigeons was maintained under a multiple 3-min fixed-interval, 30-response fixedratio schedule of food presentation. Only one schedule was in effect during an experimental session, and each was correlated with a different keylight stimulus and location (left vs. right). The different schedule components alternated across days or weeks. Cerebrospinal fluid was collected from chronically implanted intracerebroventricular cannulae following sessions with the different schedules, as well as following sessions in which reinforcement was withheld (extinction), when response-independent food was delivered, and when the experimental chamber was dark and there were no scheduled events. Metabolites of the neurotransmitters serotonin, norepinephrine, and dopamine were assayed in cerebrospinal fluid using high-performance liquid chromatography with electrochemical detection. Compared to the fixed-ratio condition, responding maintained under the fixed-interval schedule resulted in consistently higher levels of the serotonin metabolite 5-hydroxyindoleacetic acid and of the dopamine metabolite homovanillic acid in all pigeons. Levels of 3-methoxy-4-hydroxyphenylethylene glycol, a metabolite of norepinephrine, and dihydroxyphenylacetic acid, another dopamine metabolite, were also higher in 3 of the 4 pigeons following exposure to the fixed-interval schedules when compared to levels of these metabolites after exposure to the fixed-ratio schedule. Extinction of fixed-ratio responding resulted in large increases in 5-hydroxyindoleacetic acid compared to levels of this metabolite under the fixed-ratio schedule, whereas this serotonin metabolite decreased during extinction of responding under the fixed-interval schedule. Control procedures suggested that the neurochemical changes were not related to the rate of responding but were a function of the specific experimental conditions. Distinctive neurochemical changes that accompany schedule-controlled responding show the sensitivity of the neurochemical environment to behavioral contingencies and demonstrate further the profound impact that such contingencies have on biobehavioral processes.
Journal of the Experimental Analysis of Behavior, Jul 1, 1975
Responding of three pigeons was maintained under conjunctive fixed-ratio, fixed-interval schedule... more Responding of three pigeons was maintained under conjunctive fixed-ratio, fixed-interval schedules where a key peck produced food after both schedule requirements were completed. The individual schedule requirements were then successively removed and reinstated with responding maintained under the following conditions: conjunctive fixedratio, fixed-time; fixed-time; and fixed-interval schedules. Patterns of responding changed in accord with the successive removal of the schedule requirements. Compared to the conjunctive fixed-ratio, fixed-interval schedule, pause duration increased and response rate decreased under conjunctive fixed-ratio, fixed-time schedules and under fixed-time schedules alone. Overall mean rates of responding were highest and pause duration lowest under fixed-interval schedules. When changes in the keylight colors were correlated with completion of the fixed-ratio, the end of the fixed-interval, or both of these conditions, the pattern of responding was modified and indicated a greater degree of control by the individual schedules. Although two birds showed large increases in interreinforcement time when they were initially exposed to the conjunctive schedule, when responding stabilized this measure was largely invariant for all birds across most schedule conditions.
Journal of the Experimental Analysis of Behavior, Mar 1, 1976
Key pecking of three pigeons was studied under a conjunctive schedule that specified both a fixed... more Key pecking of three pigeons was studied under a conjunctive schedule that specified both a fixed-interval and an adjusting fixed-ratio requirement. The fixed-interval schedule was 6 min for one pigeon and 3 min for the other two. The size of the ratio requirement was determined within each cycle of the fixed interval by the duration of the pause before responding began. The fixed-ratio value was at maximum at the start of each fixed interval and decreased linearly until the first response occurred (adjusting fixed-ratio schedule). A peck produced food when the number of responses remaining on the fixed-ratio schedule was completed and when the fixed interval had elapsed. If no response occurred during the interval, the fixed-ratio requirement decreased to one and a single response after the interval elapsed produced food. The initial value of the adjusting fixed-ratio schedule was studied over a range of 0 to 900. Increases in the adjusting fixed-ratio schedule to about 300 responses increased both pause duration and running response rate and also modified the pattern of responding from that obtained under the fixed-interval schedule. Higher values of the adjusting fixed ratio generally decreased pause duration and running response rate and also disrupted responding. Interreinforcement time under the conjunctive schedule was increased substantially when the adjusting fixed-ratio size exceeded 300 responses.
Journal of the Experimental Analysis of Behavior, Jul 1, 1980
A chain-pulling response was initially developed under a shock-postponement (avoidance) schedule ... more A chain-pulling response was initially developed under a shock-postponement (avoidance) schedule with two squirrel monkeys. Few responses occurred on a lever where responding initially had no scheduled consequence or, subsequently, when a 3-minute fixed-interval shock-presentation schedule was concurrently arranged for lever responses. Appropriate rates and patterns of lever responding developed and were later maintained under the fixed-interval 3-minute shock-presentation schedule alone when the chain and shock-postponement schedule were removed. When both the shock-postponement and shock-presentation schedules were again simultaneously in effect, steady rates of chain pulling were maintained by the shock-postponement schedule and positively accelerated rates and patterns were maintained on the lever by the shock-presentation schedule. Response rates under both schedules were directly related to shock intensity. A history of exposure to a shock-postponement schedule, even though with a topographically different response and manipulandum, was sufficient for the development and eventual maintenance of responding by the presentation of shock. Further, differential performances can be maintained simultaneously by the presentation and postponement of electric shock.
Oxycodone, a semi-synthetic derivative of naturally occurring thebaine, an opioid alkaloid, has b... more Oxycodone, a semi-synthetic derivative of naturally occurring thebaine, an opioid alkaloid, has been available for over 100 years. Although thebaine cannot be used therapeutically due to the occurrence of convulsions at higher doses, it has been converted to a number of other widely used compounds that include naloxone, naltrexone, buprenorphine, and oxycodone. Despite the early identification of oxycodone, it was not until the 1990s that clinical studies began to explore its analgesic efficacy. These studies were followed by the pursuit of several preclinical studies to examine the analgesic effects and abuse liability of oxycodone in laboratory animals and the subjective effects in human volunteers. For a number of years oxycodone was at the forefront of the opioid crisis, playing a significant role in contributing to opioid misuse and abuse, with suggestions that it led to transitioning to other opioids. Several concerns were expressed as early as the 1940s that oxycodone had significant abuse potential similar to heroin and morphine. Both animal and human abuse liability studies have confirmed, and in some cases amplified, these early warnings. Despite sharing a similar structure with morphine and pharmacological actions also mediated by the μ-opioid receptor, there are several differences in the pharmacology and neurobiology of oxycodone. The data that have emerged from the many efforts to analyze the pharmacological and molecular mechanism of oxycodone have generated considerable insight into its many actions, reviewed here which, in turn, have provided new information on opioid receptor pharmacology.
Journal of the Experimental Analysis of Behavior, Nov 1, 2006
Peter B. Dews played a significant role in shaping the distinctive characteristics and defining t... more Peter B. Dews played a significant role in shaping the distinctive characteristics and defining the underlying principles of the discipline of behavioral pharmacology. His early and sophisticated use of schedules of reinforcement in the 1950s, incorporated from research in the experimental analysis of behavior and integrated into the discipline of pharmacology, provided tremendous insight, inspiration, and impetus to the newly emerging field of behavioral pharmacology. The experimental findings generated by Dews' research, blending the sophisticated use of behavior and pharmacological principles together with the elegant manner of their presentation and far-reaching implications, provided the force and momentum to establish and direct behavioral pharmacology for several decades. This article attempts to capture some of Dews' research that integrated and inspired the blending of sophisticated behavioral work with that of pharmacology.
Interactions of the nonbenzodiazepine anxiolytic, buspirone, with serotonin (5-HT) were studied u... more Interactions of the nonbenzodiazepine anxiolytic, buspirone, with serotonin (5-HT) were studied using behavioral and neurochemical procedures. Punished responding was studied in pigeons as this behavior is a generally acknowledged preclinical predictor of anxiolytic activity and because buspirone increases punished responding of pigeons with greater potency and efficacy than in other species. Keypeck responses were maintained under either fixed-interval or fixed-ratio schedules of food presentation; every 30th response produced a brief electric shock and suppressed responding (punishment). Buspirone (0.1-5.6 mg/kg i.m.) produced dose-related increases in punished responding which reached a maximum at 1 mg/kg. A serotonin agonist, MK-212 (0.01 mg/kg), antagonized whereas the 5-HT antagonist, cyproheptadine (0.01 mg/kg), potentiated the effects of buspirone without having behavioral effects of their own. The characteristics of [3H]-5-HT binding in pigeon brain membranes were similar to results reported in mammalian brain. Neither buspirone, MJ-13805 (gepirone, a related analog), nor MJ-13653 (a buspirone metabolite), significantly affected [3H]-5-HT binding and none of the compounds appreciably inhibited uptake of [3H]-5-HT into pigeon cerebral synaptosomes. Hill coefficients significantly less than unity for all drugs except 5-HT suggested multiple serotonergic binding sites for buspirone and analogs. Buspirone and MJ-13805 (1 nM) inhibited [3H]ketanserin binding (a measure of 5-HT2 binding sites) in pigeon cerebrum with Ki values above 10(-6) M. The number of [3H]ketanserin binding sites was estimated to be 109 fmol/mg of protein in pigeon cerebrum compared to 400 fmol/mg of protein in rat cerebrum.(ABSTRACT TRUNCATED AT 250 WORDS)
Background: Therapeutic plasma exchange (PE) or plasmapheresis is an extracorporeal procedure emp... more Background: Therapeutic plasma exchange (PE) or plasmapheresis is an extracorporeal procedure employed to treat immunological disorders. Exosomes, nanosized vesicles of endosomal origin, mediate intercellular communication by transferring cargo proteins and nucleic acids and regulate many pathophysiological processes. Exosomal miRNAs are potential biomarkers due to their stability and dysregulation in diseases including complex regional pain syndrome (CRPS), a chronic pain disorder with persistent inflammation. A previous study showed that a subset of CRPS patients responded to PE. Methods: As a proof-of-concept, we investigated the PE-induced exosomal miRNA changes in six CRPS patients. Plasma cytokine levels were measured by HPLC and correlated with miRNA expression. Luciferase assay following cotransfection of HEK293 cells with target 3′UTR constructs and miRNA mimics was used to evaluate miRNA mediated gene regulation of target mRNA. Transient transfection of THP-1 cells with miRNA mimics followed by estimation of target gene and protein expression was used to validate the findings. Results: Comparison of miRNAs in exosomes from the serum of three responders and three poor-responders showed that 17 miRNAs differed significantly before and after therapy. Of these, poor responders had lower exosomal hsa-miR-338-5p. We show that miR-338-5p can bind to the interleukin 6 (IL-6) 3′ untranslated region and can regulate IL-6 mRNA and protein levels in vitro. PE resulted in a significant reduction of IL-6 in CRPS patients. Conclusions: We propose that lower pretreatment levels of miR-338-5p in poor responders are linked to IL-6 levels and inflammation in CRPS. Our data suggests the feasibility of exploring exosomal miRNAs as a strategy in patient stratification for maximizing therapeutic outcome of PE.
Calcium release-activated calcium (CRAC) channels are unique among ion channels that are activate... more Calcium release-activated calcium (CRAC) channels are unique among ion channels that are activated in response to depletion of intracellular calcium stores and are highly permeable to Ca 2+ compared to other cations. CRAC channels mediate an important calcium signal for a wide variety of cell types and are well studied in the immune system. They have been implicated in a number of disorders such as immunodeficiency, musculosketal disorders and cancer. There is growing evidence showing that CRAC channels are expressed in the nervous system and are involved in pathological conditions including pain. This review summarizes the expression, distribution, and function of the CRAC channel family in the dorsal root ganglion, spinal cord and some brain regions, and discusses their functional significance in neurons and glial cells and involvement in nociception and chronic pain. Although further studies are needed to understand how these channels are activated under physiological conditions, the recent findings indicate that the CRAC channel Orai1 is an important player in pain modulation and could represent a new target for pathological pain.
AB Numerous experiments have examined the effects on food-maintained responding of presenting sti... more AB Numerous experiments have examined the effects on food-maintained responding of presenting stimuli terminated with response-independent shock (W. K. Estes and B. F. Skinner 1941 procedure). Under a wide range of conditions, responding is suppressed during presentations of the preshock stimulus. Often these studies have purported to be concerned with the experimental induction of fear or anxiety. Such interpretations are shown to be misleading by experiments demonstrating that stimuli preceding responseindependent food also produce a reduction of responding maintained by either shock or food presentation. The behavioral effects of environmental stimuli reside not in t h e p r o p e r t i e s o f s t i m u l i b u t d e p e n d o n manipulable relationships between those events and behavior.
Recent studies have shown that histone deacetylase (HDAC) inhibitors can alleviate inflammatory a... more Recent studies have shown that histone deacetylase (HDAC) inhibitors can alleviate inflammatory and neuropathic pain. We investigated the effects of JNJ-26481585, a pan-HDAC inhibitor on basal mechanical sensitivity. Unlike previous reports for HDAC inhibitors, JNJ-26481585 induced mechanical hypersensitivity in mice. This effect was reversible with gabapentin. Voltage-dependent calcium channel subunit alpha-2/delta-1, one of the putative targets for gabapentin, was upregulated in the spinal cord from JNJ-26481585treated mice. Transcriptional profiling of spinal cord from JNJ-26481585-treated mice showed significant alterations in pathways involved in axon guidance, suggesting overlap in mechanisms underlying neurotoxicity caused by other known chemotherapeutic agents. To investigate the mechanisms underlying the development of pain, RAW 264.7 mouse macrophage cells were treated with JNJ-26481585. There was a dose-and time-dependent activation of nuclear factor-kappaB and interleukin-1β increase. Thus, alterations in the axon guidance pathway, increase in voltage-dependent calcium channel alpha(2)delta-1 subunit, and the induction of proinflammatory mediators by JNJ-26481585 could all contribute to increased mechanical sensitivity. Our data indicate that the effect of HDAC inhibitors may be unique to the compound studied and highlights the potential to develop chemotherapy-induced peripheral neuropathy with the use of a pan-HDAC inhibitor for cancer treatment, and this pain may be alleviated by gabapentin.
to the dorsal raphe. The fibers were quantified by stereology and analyzed by two-way ANOVA. UCN1... more to the dorsal raphe. The fibers were quantified by stereology and analyzed by two-way ANOVA. UCN1 cell bodies were counted in the supraoculomotor area near the Edinger-Westphal nucleus. Results: S-citalopram significantly decreased the CRF fiber density in SS animals, but not in HSR animals. SS monkeys had a significantly lower UCN1 fiber density compared to HSR monkeys, but S-citalopram treatment did not alter the UCN1 fiber density. SS animals treated with S-citalopram tended to have a higher number of UCN1positive cell bodies than the other groups. Conclusion: Scitalopram decreased CRF fiber density and appears to increase the production of UCN1 in SS individuals, indicating the likelihood that serotonin is involved in regulating CRF and UCN1 in individuals who are sensitive to the effects of serotonin.
White Carneau pigeons were trained to discriminate 1.0 mg/kg buspirone from saline when key pecki... more White Carneau pigeons were trained to discriminate 1.0 mg/kg buspirone from saline when key pecking was maintained under a fixed-ratio 30 schedule of food presentation. Buspirone (0.3–10.0 mg/kg), the serotonin 1A (5-HT1A) agonist 8-OH-DPAT (0.1–1.0mg/kg), the buspirone analog BMY 7378 (3.0–5.6mg/kg), the mixed 5-HT1A/1B agonist RU 24969 (3.0–10.0mg/kg) and the 5-HT1A agonist spiroxatrine (0.1–1.0mg/kg) occasioned at least 80% buspirone-appropriate responding in all subjects tested. Administration of the 5-HT1B agonist (TFMPP 0.1–10.0mg/kg) or the 5-HT3 antagonist (MDL 72222 (3.0–17.0mg/kg) resulted in primarily saline-key responding. The dopamine receptor antagonist chlorpromazine (1.0–17.0mg/kg), the specific D-2 receptor antagonist eticlopride (0.03–0.56mg/kg), the noradrenergic alpha-2 antagonist yohimbine (0.1–1.0mg/kg), the alpha-2 agonist clonidine (0.003–0.10mg/kg) and (±) and (-) propranolol (3.0–30.0mg/kg) all produced primarily saline-appropriate responding. Coadministration of the β-adrenergic agonist isoproterenol (1.0–5.6mg/kg) or the 5-HT1A partial agonist BMY 7378 (0.01–10.0mg/kg) with 1.0mg/kg buspirone did not block the discriminative stimulus effects of buspirone. However, 3.0–10.0mg/kg BMY 7378, in combination with a lower dose of buspirone (0.3mg/kg) decreased drug-key responding to approximately 50%. Results from the present study suggest that (1) the discriminative stimulus effects of buspirone, 8-OH-DPAT, BMY 7378, RU 24969 and spiroxatrine are mediated through the 5-HT1A receptor; (2) buspirone's discriminative stimulus effects do not interact with the noradrenergic or dopaminergic system; and 3) under this procedure BMY 7378 was a partial agonist at 5-HT1A receptors.
Background and PurposeStore‐operated calcium (SOC) channels are thought to play a critical role i... more Background and PurposeStore‐operated calcium (SOC) channels are thought to play a critical role in immune responses, inflammatory diseases and chronic pain. The aim of this study was to explore the potential role and mechanisms of SOC channels in collagen‐induced arthritis (CIA).Experimental ApproachThe CIA mouse model was used to examine the effects of the SOC channel inhibitor YM‐58483 on CIA and arthritic pain. Hargreaves' and von Frey hair tests were conducted to measure thermal and mechanical sensitivities of hind paws. elisa was performed to measure cytokine production, and haematoxylin and eosin staining was used to assess knee histological changes. Western blot analysis was performed to examine protein levels.Key ResultsPretreatment with 5 or 10 mg·kg−1 of YM‐58483 reduced the incidence of CIA, prevented the development of inflammation and pain hypersensitivity and other signs and features of arthritis disease. Similarly, treatment with YM‐58483 after the onset of CIA: (...
Buspirone, a clinically effective anxiolytic, has not shown robust effects consistently in proced... more Buspirone, a clinically effective anxiolytic, has not shown robust effects consistently in procedures used traditionally with rodents and nonhuman primates to evaluate potential antianxiety activity. When key pecking by pigeons was maintained by food and was punished alternately under one component of a multiple schedule by the presentation of electric shock (conflict procedure), buspirone (0.03-10.0 mg/kg i.m.) produced increases in punished responding that were up to 30 times those of the control response rate. These doses did not affect or decreased unpunished responding. A buspirone analog, MJ 13805 (gepirone) produced effects similar to buspirone, although unpunished responding was slightly more sensitive to the rate-decreasing effects of MJ 13805 than to those of buspirone. A metabolite of buspirone, 1-pyrimidinyl piperazine (1-PP; MJ 13653), did not affect key pecking across a wide dose range (0.01-3.0 mg/kg i.m.), although slight decreases in both punished and unpunished responding occurred at the highest dose. Increases in punished responding with buspirone were not affected by the benzodiazepine receptor antagonist Ro 15-1788 (0.01-0.1 mg/kg i.m.). [3H]Diazepam binding to pigeon cerebrum or cerebellum in vivo was not altered by buspirone, or did buspirone, MJ 13805, or 1-pyrimidinyl piperazine displace [3H]flunitrazepam binding in vitro at pharmacologically relevant concentrations. These findings confirm previous work demonstrating marked rate-increasing effects of buspirone on punished responding in the pigeon, extend such effects to the buspirone analog MJ 13805 and indicate that the effects of buspirone are not mediated through the benzodiazepine receptor complex.
The journal of pharmacology and experimental therapeutics/The Journal of pharmacology and experimental therapeutics, Mar 15, 2024
This issue of the Journal of Pharmacology and Experimental Therapeutics includes an article by Wi... more This issue of the Journal of Pharmacology and Experimental Therapeutics includes an article by Withey et al. that addresses an important challenge in the seemingly unending quest for effective and safe pharmacological approaches to the treatment of opioid use disorders (OUDs). One focus of the article is on the use of chronic naltrexone, a l-opioid receptor antagonist, to block "reinstatement" of a number of full and partial l-opioid receptor agonists in squirrel monkeys. An additional objective of the research was to examine the effects of chronic naltrexone administration on the antinociceptive effects of the same drugs used in the reinstatement experiments. The rationale behind this portion of the publication is related to naltrexone's ability to block l-opioid receptor-mediated effects that include antinociception. Opioid pain management may be challenging in patients undergoing treatment with extended-release naltrexone. The article serving as the basis for this Viewpoint could be viewed as a companion publication to Withey et al. (2019), who studied the effects of chronic buprenorphine under similar conditions and with comparable drugs. Together, they provide valuable information on issues surrounding both reinstatement and antinociception with chronic administration of naltrexone and buprenorphine. The study of reinstatement of drug-seeking behavior in laboratory animals has become standard as one of the experimental approaches to aid in guiding the development of potential medications to treat relapse to drug use. Susceptibility to relapse is, among other variables, frequently believed to be related to craving, which has emerged as an important indicator of drug seeking and relapse. Gauld et al. (2023), following an extensive network analysis of opioids and other drugs, concluded that craving is a potential central marker of addiction, connecting to the entire symptom network regardless of the specific substance, and can be used to aid and facilitate the understanding and treatment of SUDs.
Journal of the Experimental Analysis of Behavior, Sep 1, 1991
Key pecking of 4 pigeons was maintained under a multiple 3-min fixed-interval, 30-response fixedr... more Key pecking of 4 pigeons was maintained under a multiple 3-min fixed-interval, 30-response fixedratio schedule of food presentation. Only one schedule was in effect during an experimental session, and each was correlated with a different keylight stimulus and location (left vs. right). The different schedule components alternated across days or weeks. Cerebrospinal fluid was collected from chronically implanted intracerebroventricular cannulae following sessions with the different schedules, as well as following sessions in which reinforcement was withheld (extinction), when response-independent food was delivered, and when the experimental chamber was dark and there were no scheduled events. Metabolites of the neurotransmitters serotonin, norepinephrine, and dopamine were assayed in cerebrospinal fluid using high-performance liquid chromatography with electrochemical detection. Compared to the fixed-ratio condition, responding maintained under the fixed-interval schedule resulted in consistently higher levels of the serotonin metabolite 5-hydroxyindoleacetic acid and of the dopamine metabolite homovanillic acid in all pigeons. Levels of 3-methoxy-4-hydroxyphenylethylene glycol, a metabolite of norepinephrine, and dihydroxyphenylacetic acid, another dopamine metabolite, were also higher in 3 of the 4 pigeons following exposure to the fixed-interval schedules when compared to levels of these metabolites after exposure to the fixed-ratio schedule. Extinction of fixed-ratio responding resulted in large increases in 5-hydroxyindoleacetic acid compared to levels of this metabolite under the fixed-ratio schedule, whereas this serotonin metabolite decreased during extinction of responding under the fixed-interval schedule. Control procedures suggested that the neurochemical changes were not related to the rate of responding but were a function of the specific experimental conditions. Distinctive neurochemical changes that accompany schedule-controlled responding show the sensitivity of the neurochemical environment to behavioral contingencies and demonstrate further the profound impact that such contingencies have on biobehavioral processes.
Journal of the Experimental Analysis of Behavior, Jul 1, 1975
Responding of three pigeons was maintained under conjunctive fixed-ratio, fixed-interval schedule... more Responding of three pigeons was maintained under conjunctive fixed-ratio, fixed-interval schedules where a key peck produced food after both schedule requirements were completed. The individual schedule requirements were then successively removed and reinstated with responding maintained under the following conditions: conjunctive fixedratio, fixed-time; fixed-time; and fixed-interval schedules. Patterns of responding changed in accord with the successive removal of the schedule requirements. Compared to the conjunctive fixed-ratio, fixed-interval schedule, pause duration increased and response rate decreased under conjunctive fixed-ratio, fixed-time schedules and under fixed-time schedules alone. Overall mean rates of responding were highest and pause duration lowest under fixed-interval schedules. When changes in the keylight colors were correlated with completion of the fixed-ratio, the end of the fixed-interval, or both of these conditions, the pattern of responding was modified and indicated a greater degree of control by the individual schedules. Although two birds showed large increases in interreinforcement time when they were initially exposed to the conjunctive schedule, when responding stabilized this measure was largely invariant for all birds across most schedule conditions.
Journal of the Experimental Analysis of Behavior, Mar 1, 1976
Key pecking of three pigeons was studied under a conjunctive schedule that specified both a fixed... more Key pecking of three pigeons was studied under a conjunctive schedule that specified both a fixed-interval and an adjusting fixed-ratio requirement. The fixed-interval schedule was 6 min for one pigeon and 3 min for the other two. The size of the ratio requirement was determined within each cycle of the fixed interval by the duration of the pause before responding began. The fixed-ratio value was at maximum at the start of each fixed interval and decreased linearly until the first response occurred (adjusting fixed-ratio schedule). A peck produced food when the number of responses remaining on the fixed-ratio schedule was completed and when the fixed interval had elapsed. If no response occurred during the interval, the fixed-ratio requirement decreased to one and a single response after the interval elapsed produced food. The initial value of the adjusting fixed-ratio schedule was studied over a range of 0 to 900. Increases in the adjusting fixed-ratio schedule to about 300 responses increased both pause duration and running response rate and also modified the pattern of responding from that obtained under the fixed-interval schedule. Higher values of the adjusting fixed ratio generally decreased pause duration and running response rate and also disrupted responding. Interreinforcement time under the conjunctive schedule was increased substantially when the adjusting fixed-ratio size exceeded 300 responses.
Journal of the Experimental Analysis of Behavior, Jul 1, 1980
A chain-pulling response was initially developed under a shock-postponement (avoidance) schedule ... more A chain-pulling response was initially developed under a shock-postponement (avoidance) schedule with two squirrel monkeys. Few responses occurred on a lever where responding initially had no scheduled consequence or, subsequently, when a 3-minute fixed-interval shock-presentation schedule was concurrently arranged for lever responses. Appropriate rates and patterns of lever responding developed and were later maintained under the fixed-interval 3-minute shock-presentation schedule alone when the chain and shock-postponement schedule were removed. When both the shock-postponement and shock-presentation schedules were again simultaneously in effect, steady rates of chain pulling were maintained by the shock-postponement schedule and positively accelerated rates and patterns were maintained on the lever by the shock-presentation schedule. Response rates under both schedules were directly related to shock intensity. A history of exposure to a shock-postponement schedule, even though with a topographically different response and manipulandum, was sufficient for the development and eventual maintenance of responding by the presentation of shock. Further, differential performances can be maintained simultaneously by the presentation and postponement of electric shock.
Oxycodone, a semi-synthetic derivative of naturally occurring thebaine, an opioid alkaloid, has b... more Oxycodone, a semi-synthetic derivative of naturally occurring thebaine, an opioid alkaloid, has been available for over 100 years. Although thebaine cannot be used therapeutically due to the occurrence of convulsions at higher doses, it has been converted to a number of other widely used compounds that include naloxone, naltrexone, buprenorphine, and oxycodone. Despite the early identification of oxycodone, it was not until the 1990s that clinical studies began to explore its analgesic efficacy. These studies were followed by the pursuit of several preclinical studies to examine the analgesic effects and abuse liability of oxycodone in laboratory animals and the subjective effects in human volunteers. For a number of years oxycodone was at the forefront of the opioid crisis, playing a significant role in contributing to opioid misuse and abuse, with suggestions that it led to transitioning to other opioids. Several concerns were expressed as early as the 1940s that oxycodone had significant abuse potential similar to heroin and morphine. Both animal and human abuse liability studies have confirmed, and in some cases amplified, these early warnings. Despite sharing a similar structure with morphine and pharmacological actions also mediated by the μ-opioid receptor, there are several differences in the pharmacology and neurobiology of oxycodone. The data that have emerged from the many efforts to analyze the pharmacological and molecular mechanism of oxycodone have generated considerable insight into its many actions, reviewed here which, in turn, have provided new information on opioid receptor pharmacology.
Journal of the Experimental Analysis of Behavior, Nov 1, 2006
Peter B. Dews played a significant role in shaping the distinctive characteristics and defining t... more Peter B. Dews played a significant role in shaping the distinctive characteristics and defining the underlying principles of the discipline of behavioral pharmacology. His early and sophisticated use of schedules of reinforcement in the 1950s, incorporated from research in the experimental analysis of behavior and integrated into the discipline of pharmacology, provided tremendous insight, inspiration, and impetus to the newly emerging field of behavioral pharmacology. The experimental findings generated by Dews' research, blending the sophisticated use of behavior and pharmacological principles together with the elegant manner of their presentation and far-reaching implications, provided the force and momentum to establish and direct behavioral pharmacology for several decades. This article attempts to capture some of Dews' research that integrated and inspired the blending of sophisticated behavioral work with that of pharmacology.
Interactions of the nonbenzodiazepine anxiolytic, buspirone, with serotonin (5-HT) were studied u... more Interactions of the nonbenzodiazepine anxiolytic, buspirone, with serotonin (5-HT) were studied using behavioral and neurochemical procedures. Punished responding was studied in pigeons as this behavior is a generally acknowledged preclinical predictor of anxiolytic activity and because buspirone increases punished responding of pigeons with greater potency and efficacy than in other species. Keypeck responses were maintained under either fixed-interval or fixed-ratio schedules of food presentation; every 30th response produced a brief electric shock and suppressed responding (punishment). Buspirone (0.1-5.6 mg/kg i.m.) produced dose-related increases in punished responding which reached a maximum at 1 mg/kg. A serotonin agonist, MK-212 (0.01 mg/kg), antagonized whereas the 5-HT antagonist, cyproheptadine (0.01 mg/kg), potentiated the effects of buspirone without having behavioral effects of their own. The characteristics of [3H]-5-HT binding in pigeon brain membranes were similar to results reported in mammalian brain. Neither buspirone, MJ-13805 (gepirone, a related analog), nor MJ-13653 (a buspirone metabolite), significantly affected [3H]-5-HT binding and none of the compounds appreciably inhibited uptake of [3H]-5-HT into pigeon cerebral synaptosomes. Hill coefficients significantly less than unity for all drugs except 5-HT suggested multiple serotonergic binding sites for buspirone and analogs. Buspirone and MJ-13805 (1 nM) inhibited [3H]ketanserin binding (a measure of 5-HT2 binding sites) in pigeon cerebrum with Ki values above 10(-6) M. The number of [3H]ketanserin binding sites was estimated to be 109 fmol/mg of protein in pigeon cerebrum compared to 400 fmol/mg of protein in rat cerebrum.(ABSTRACT TRUNCATED AT 250 WORDS)
Background: Therapeutic plasma exchange (PE) or plasmapheresis is an extracorporeal procedure emp... more Background: Therapeutic plasma exchange (PE) or plasmapheresis is an extracorporeal procedure employed to treat immunological disorders. Exosomes, nanosized vesicles of endosomal origin, mediate intercellular communication by transferring cargo proteins and nucleic acids and regulate many pathophysiological processes. Exosomal miRNAs are potential biomarkers due to their stability and dysregulation in diseases including complex regional pain syndrome (CRPS), a chronic pain disorder with persistent inflammation. A previous study showed that a subset of CRPS patients responded to PE. Methods: As a proof-of-concept, we investigated the PE-induced exosomal miRNA changes in six CRPS patients. Plasma cytokine levels were measured by HPLC and correlated with miRNA expression. Luciferase assay following cotransfection of HEK293 cells with target 3′UTR constructs and miRNA mimics was used to evaluate miRNA mediated gene regulation of target mRNA. Transient transfection of THP-1 cells with miRNA mimics followed by estimation of target gene and protein expression was used to validate the findings. Results: Comparison of miRNAs in exosomes from the serum of three responders and three poor-responders showed that 17 miRNAs differed significantly before and after therapy. Of these, poor responders had lower exosomal hsa-miR-338-5p. We show that miR-338-5p can bind to the interleukin 6 (IL-6) 3′ untranslated region and can regulate IL-6 mRNA and protein levels in vitro. PE resulted in a significant reduction of IL-6 in CRPS patients. Conclusions: We propose that lower pretreatment levels of miR-338-5p in poor responders are linked to IL-6 levels and inflammation in CRPS. Our data suggests the feasibility of exploring exosomal miRNAs as a strategy in patient stratification for maximizing therapeutic outcome of PE.
Calcium release-activated calcium (CRAC) channels are unique among ion channels that are activate... more Calcium release-activated calcium (CRAC) channels are unique among ion channels that are activated in response to depletion of intracellular calcium stores and are highly permeable to Ca 2+ compared to other cations. CRAC channels mediate an important calcium signal for a wide variety of cell types and are well studied in the immune system. They have been implicated in a number of disorders such as immunodeficiency, musculosketal disorders and cancer. There is growing evidence showing that CRAC channels are expressed in the nervous system and are involved in pathological conditions including pain. This review summarizes the expression, distribution, and function of the CRAC channel family in the dorsal root ganglion, spinal cord and some brain regions, and discusses their functional significance in neurons and glial cells and involvement in nociception and chronic pain. Although further studies are needed to understand how these channels are activated under physiological conditions, the recent findings indicate that the CRAC channel Orai1 is an important player in pain modulation and could represent a new target for pathological pain.
AB Numerous experiments have examined the effects on food-maintained responding of presenting sti... more AB Numerous experiments have examined the effects on food-maintained responding of presenting stimuli terminated with response-independent shock (W. K. Estes and B. F. Skinner 1941 procedure). Under a wide range of conditions, responding is suppressed during presentations of the preshock stimulus. Often these studies have purported to be concerned with the experimental induction of fear or anxiety. Such interpretations are shown to be misleading by experiments demonstrating that stimuli preceding responseindependent food also produce a reduction of responding maintained by either shock or food presentation. The behavioral effects of environmental stimuli reside not in t h e p r o p e r t i e s o f s t i m u l i b u t d e p e n d o n manipulable relationships between those events and behavior.
Recent studies have shown that histone deacetylase (HDAC) inhibitors can alleviate inflammatory a... more Recent studies have shown that histone deacetylase (HDAC) inhibitors can alleviate inflammatory and neuropathic pain. We investigated the effects of JNJ-26481585, a pan-HDAC inhibitor on basal mechanical sensitivity. Unlike previous reports for HDAC inhibitors, JNJ-26481585 induced mechanical hypersensitivity in mice. This effect was reversible with gabapentin. Voltage-dependent calcium channel subunit alpha-2/delta-1, one of the putative targets for gabapentin, was upregulated in the spinal cord from JNJ-26481585treated mice. Transcriptional profiling of spinal cord from JNJ-26481585-treated mice showed significant alterations in pathways involved in axon guidance, suggesting overlap in mechanisms underlying neurotoxicity caused by other known chemotherapeutic agents. To investigate the mechanisms underlying the development of pain, RAW 264.7 mouse macrophage cells were treated with JNJ-26481585. There was a dose-and time-dependent activation of nuclear factor-kappaB and interleukin-1β increase. Thus, alterations in the axon guidance pathway, increase in voltage-dependent calcium channel alpha(2)delta-1 subunit, and the induction of proinflammatory mediators by JNJ-26481585 could all contribute to increased mechanical sensitivity. Our data indicate that the effect of HDAC inhibitors may be unique to the compound studied and highlights the potential to develop chemotherapy-induced peripheral neuropathy with the use of a pan-HDAC inhibitor for cancer treatment, and this pain may be alleviated by gabapentin.
to the dorsal raphe. The fibers were quantified by stereology and analyzed by two-way ANOVA. UCN1... more to the dorsal raphe. The fibers were quantified by stereology and analyzed by two-way ANOVA. UCN1 cell bodies were counted in the supraoculomotor area near the Edinger-Westphal nucleus. Results: S-citalopram significantly decreased the CRF fiber density in SS animals, but not in HSR animals. SS monkeys had a significantly lower UCN1 fiber density compared to HSR monkeys, but S-citalopram treatment did not alter the UCN1 fiber density. SS animals treated with S-citalopram tended to have a higher number of UCN1positive cell bodies than the other groups. Conclusion: Scitalopram decreased CRF fiber density and appears to increase the production of UCN1 in SS individuals, indicating the likelihood that serotonin is involved in regulating CRF and UCN1 in individuals who are sensitive to the effects of serotonin.
White Carneau pigeons were trained to discriminate 1.0 mg/kg buspirone from saline when key pecki... more White Carneau pigeons were trained to discriminate 1.0 mg/kg buspirone from saline when key pecking was maintained under a fixed-ratio 30 schedule of food presentation. Buspirone (0.3–10.0 mg/kg), the serotonin 1A (5-HT1A) agonist 8-OH-DPAT (0.1–1.0mg/kg), the buspirone analog BMY 7378 (3.0–5.6mg/kg), the mixed 5-HT1A/1B agonist RU 24969 (3.0–10.0mg/kg) and the 5-HT1A agonist spiroxatrine (0.1–1.0mg/kg) occasioned at least 80% buspirone-appropriate responding in all subjects tested. Administration of the 5-HT1B agonist (TFMPP 0.1–10.0mg/kg) or the 5-HT3 antagonist (MDL 72222 (3.0–17.0mg/kg) resulted in primarily saline-key responding. The dopamine receptor antagonist chlorpromazine (1.0–17.0mg/kg), the specific D-2 receptor antagonist eticlopride (0.03–0.56mg/kg), the noradrenergic alpha-2 antagonist yohimbine (0.1–1.0mg/kg), the alpha-2 agonist clonidine (0.003–0.10mg/kg) and (±) and (-) propranolol (3.0–30.0mg/kg) all produced primarily saline-appropriate responding. Coadministration of the β-adrenergic agonist isoproterenol (1.0–5.6mg/kg) or the 5-HT1A partial agonist BMY 7378 (0.01–10.0mg/kg) with 1.0mg/kg buspirone did not block the discriminative stimulus effects of buspirone. However, 3.0–10.0mg/kg BMY 7378, in combination with a lower dose of buspirone (0.3mg/kg) decreased drug-key responding to approximately 50%. Results from the present study suggest that (1) the discriminative stimulus effects of buspirone, 8-OH-DPAT, BMY 7378, RU 24969 and spiroxatrine are mediated through the 5-HT1A receptor; (2) buspirone's discriminative stimulus effects do not interact with the noradrenergic or dopaminergic system; and 3) under this procedure BMY 7378 was a partial agonist at 5-HT1A receptors.
Background and PurposeStore‐operated calcium (SOC) channels are thought to play a critical role i... more Background and PurposeStore‐operated calcium (SOC) channels are thought to play a critical role in immune responses, inflammatory diseases and chronic pain. The aim of this study was to explore the potential role and mechanisms of SOC channels in collagen‐induced arthritis (CIA).Experimental ApproachThe CIA mouse model was used to examine the effects of the SOC channel inhibitor YM‐58483 on CIA and arthritic pain. Hargreaves' and von Frey hair tests were conducted to measure thermal and mechanical sensitivities of hind paws. elisa was performed to measure cytokine production, and haematoxylin and eosin staining was used to assess knee histological changes. Western blot analysis was performed to examine protein levels.Key ResultsPretreatment with 5 or 10 mg·kg−1 of YM‐58483 reduced the incidence of CIA, prevented the development of inflammation and pain hypersensitivity and other signs and features of arthritis disease. Similarly, treatment with YM‐58483 after the onset of CIA: (...
Buspirone, a clinically effective anxiolytic, has not shown robust effects consistently in proced... more Buspirone, a clinically effective anxiolytic, has not shown robust effects consistently in procedures used traditionally with rodents and nonhuman primates to evaluate potential antianxiety activity. When key pecking by pigeons was maintained by food and was punished alternately under one component of a multiple schedule by the presentation of electric shock (conflict procedure), buspirone (0.03-10.0 mg/kg i.m.) produced increases in punished responding that were up to 30 times those of the control response rate. These doses did not affect or decreased unpunished responding. A buspirone analog, MJ 13805 (gepirone) produced effects similar to buspirone, although unpunished responding was slightly more sensitive to the rate-decreasing effects of MJ 13805 than to those of buspirone. A metabolite of buspirone, 1-pyrimidinyl piperazine (1-PP; MJ 13653), did not affect key pecking across a wide dose range (0.01-3.0 mg/kg i.m.), although slight decreases in both punished and unpunished responding occurred at the highest dose. Increases in punished responding with buspirone were not affected by the benzodiazepine receptor antagonist Ro 15-1788 (0.01-0.1 mg/kg i.m.). [3H]Diazepam binding to pigeon cerebrum or cerebellum in vivo was not altered by buspirone, or did buspirone, MJ 13805, or 1-pyrimidinyl piperazine displace [3H]flunitrazepam binding in vitro at pharmacologically relevant concentrations. These findings confirm previous work demonstrating marked rate-increasing effects of buspirone on punished responding in the pigeon, extend such effects to the buspirone analog MJ 13805 and indicate that the effects of buspirone are not mediated through the benzodiazepine receptor complex.
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Papers by James Barrett