20 results on '"Banks, Matthew L."'
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2. Effects of pharmacological and environmental manipulations on choice between fentanyl and shock avoidance/escape in male and female rats under mutually exclusive and non-exclusive choice conditions.
- Author
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Marcus MM, Marsh SA, Arriaga M, Negus SS, and Banks ML
- Abstract
Substance use disorders are defined by persistent drug consumption despite adverse consequences. Accordingly, we developed two fentanyl-vs-shock avoidance/escape choice procedures in which male and female rats responded under a fixed-ratio (FR)1:FR1 concurrent schedule of shock avoidance/escape and IV fentanyl under either mutually exclusive or non-exclusive choice conditions. Initial experiments using a discrete-trial procedure determined behavioral allocation between mutually exclusive shock avoidance/escape and different fentanyl doses (0.32-18 μg/kg/infusion; Experiment 1). Shock intensity (0.1-0.7 mA) and shock avoidance/escape response requirement (FR1-16) were also manipulated (Experiment 2). Next, we used a free-operant procedure in which shock avoidance/escape and fentanyl were continuously available under non-exclusive conditions, and response-shock (R-S) interval (30-1000 s) was manipulated (Experiment 3). Finally, we tested the hypothesis that extended-access fentanyl self-administration would produce fentanyl dependence, establish fentanyl withdrawal as an endogenous negative reinforcer, and increase fentanyl choice in both procedures (Experiments 4 and 5). The shock avoidance/escape contingency decreased fentanyl self-administration, and rats consistently chose shock avoidance/escape over fentanyl in both choice conditions. Decreasing shock intensity or increasing shock avoidance/escape response requirement failed to increase fentanyl choice, suggesting that fentanyl and shock avoidance/escape are independent economic commodities. Increasing the R-S interval increased fentanyl choice but failed to increase shock delivery. Extended fentanyl access engendered high fentanyl intake and opioid withdrawal signs but failed to increase fentanyl choice under either choice condition. These results suggest that neither positive fentanyl reinforcement nor negative reinforcement by fentanyl withdrawal is sufficient to reduce shock avoidance/escape-maintained responding and increase foot shock as an adverse consequence., (© 2024. The Author(s).)
- Published
- 2024
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3. Effects of selective dopamine D3 receptor partial agonist/antagonists on oxycodone self-administration and antinociception in monkeys.
- Author
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Woodlief K, Allen MI, Cornelissen JC, Banks ML, Newman AH, and Nader MA
- Subjects
- Animals, Female, Male, Analgesics, Opioid pharmacology, Dopamine Agonists pharmacology, Dopamine Antagonists pharmacology, Dose-Response Relationship, Drug, Naltrexone pharmacology, Self Administration, Macaca fascicularis, Opioid-Related Disorders, Oxycodone administration & dosage, Receptors, Dopamine D3 drug effects
- Abstract
Recent studies suggest that dopamine D3 receptors (D3R) may be a therapeutic target for opioid use disorders (OUD). This study examined the effects of the D3R partial agonist (±)VK4-40 and the D3R-selective antagonist (±)VK4-116, compared to the mu-opioid receptor antagonist naltrexone (NTX), in nonhuman primate models of OUD and antinociception. Adult male and female (N = 4/sex) cynomolgus monkeys were trained to self-administer oxycodone (0.003-0.1 mg/kg/injection) first under a fixed-ratio (FR) and then a progressive-ratio (PR) schedule of reinforcement during daily 1- and 4-hr sessions, respectively. Under the FR schedule, intravenous NTX (0.01-0.1 mg/kg), (±)VK4-116 (1.0-10 mg/kg), and (±)VK4-40 (1.0-10 mg/kg) were studied in combination with the peak oxycodone dose and a dose on the descending limb of the dose-effect curve; NTX and (±)VK4-40 were also studied at the peak of the PR dose-response curve (N = 4). Following saline extinction, each compound was examined on oxycodone-induced reinstatement. Finally, these compounds were assessed in adult male rhesus monkeys (N = 3) in a warm-water (38 °C, 50 °C, 54 °C) tail withdrawal assay. NTX decreased responding on the peak of the FR oxycodone dose-response curve, but increased responding on the descending limb. (±)VK4-40, but not (±)VK4-116, significantly decreased peak oxycodone self-administration; (±)VK4-40 did not increase responding on the descending limb. NTX and (±)VK4-40, but not (±)VK4-116, attenuated oxycodone-induced reinstatement. Under PR responding, NTX and (±)VK4-40 decreased breakpoints. Oxycodone-induced antinociception was attenuated by NTX, but not by (±)VK4-40 or (±)VK4-116. Together, these results suggest that further research evaluating the effects of (±)VK4-40 as a novel pharmacotherapy for OUD is warranted., (© 2023. The Author(s), under exclusive licence to American College of Neuropsychopharmacology.)
- Published
- 2023
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4. Effect of TRV130 and methadone on fentanyl-vs.-food choice and somatic withdrawal signs in opioid-dependent and post-opioid-dependent rats.
- Author
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Townsend EA, Blough BE, Epstein DH, Negus SS, Shaham Y, and Banks ML
- Subjects
- Analgesics, Opioid, Animals, Fentanyl pharmacology, Male, Methadone pharmacology, Methadone therapeutic use, Narcotics, Rats, Receptors, Opioid, Spiro Compounds, Thiophenes, Buprenorphine pharmacology, Opioid-Related Disorders drug therapy, Substance Withdrawal Syndrome drug therapy
- Abstract
The high efficacy mu-opioid receptor (MOR) agonist methadone is an effective opioid use disorder (OUD) medication used exclusively in opioid-dependent patients. However, methadone has undesirable effects that limit its clinical efficacy. Intermediate efficacy MOR agonists may treat OUD with fewer undesirable effects. We compared the effects of methadone with the intermediate efficacy MOR agonist TRV130 (oliceridine) on fentanyl-vs.-food choice and somatic withdrawal signs in opioid-dependent and post-opioid-dependent rats. Male rats (n = 20) were trained under a fentanyl-vs.-food choice procedure. Rats were then provided extended fentanyl (3.2 µg/kg/infusion) access (6 p.m.-6 a.m.) for 10 days to produce opioid dependence/withdrawal. Rats were treated with vehicle (n = 7), TRV130 (3.2 mg/kg; n = 8), or methadone (3.2 mg/kg; n = 5) three times per day after each extended-access session (8:30 a.m., 11 a.m., 1:30 p.m.). Withdrawal sign scoring (1:55 p.m.) and choice tests (2-4 p.m.) were conducted daily. Vehicle, TRV130, and methadone effects on fentanyl choice were redetermined in post-opioid-dependent rats. Vehicle-, TRV130-, and methadone-treated rats had similar fentanyl intakes during extended access. Vehicle-treated rats exhibited increased withdrawal signs and decreased bodyweights. Both methadone and TRV130 decreased these withdrawal signs. TRV130 was less effective than methadone to decrease fentanyl choice and increase food choice in opioid-dependent rats. Neither methadone nor TRV130 decreased fentanyl choice in post-opioid-dependent rats. Results suggest that higher MOR activation is required to reduce fentanyl choice than withdrawal signs in fentanyl-dependent rats. Additionally, given that TRV130 did not precipitate withdrawal in opioid-dependent rats, intermediate efficacy MOR agonists like TRV130 may facilitate the transition of patients with OUD from methadone to lower efficacy treatments like buprenorphine., (© 2022. The Author(s), under exclusive licence to American College of Neuropsychopharmacology.)
- Published
- 2022
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5. Adding dopamine to the complexity of sex differences in opioid reinforcement.
- Author
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Robinson HL and Banks ML
- Subjects
- Female, Humans, Male, Reinforcement, Psychology, Sex Characteristics, Analgesics, Opioid, Dopamine
- Published
- 2021
- Full Text
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6. Learning from lorcaserin: lessons from the negative clinical trial of lorcaserin to treat cocaine use disorder.
- Author
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Negus SS and Banks ML
- Subjects
- Clinical Trials as Topic, Humans, Serotonin 5-HT2 Receptor Agonists, Benzazepines therapeutic use, Cocaine
- Published
- 2020
- Full Text
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7. Experimental design and analysis for consideration of sex as a biological variable.
- Author
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Diester CM, Banks ML, Neigh GN, and Negus SS
- Subjects
- Animals, Data Interpretation, Statistical, Female, Humans, Male, Sex Factors, Biomedical Research methods, Research Design, Sex Characteristics
- Published
- 2019
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8. Sex differences in opioid reinforcement under a fentanyl vs. food choice procedure in rats.
- Author
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Townsend EA, Negus SS, Caine SB, Thomsen M, and Banks ML
- Subjects
- Animals, Dietary Sucrose administration & dosage, Female, Food, Formulated, Male, Rats, Sprague-Dawley, Reinforcement Schedule, Analgesics, Opioid administration & dosage, Choice Behavior drug effects, Fentanyl administration & dosage, Food Preferences drug effects, Reinforcement, Psychology, Sex Characteristics
- Abstract
Clinical evidence suggest that men are more sensitive than women to the abuse-related effects of mu-opioid agonists. In contrast, preclinical studies suggest the opposite sex difference. The aim of the present study was to clarify this discrepancy using a fentanyl vs. diluted Ensure
® choice procedure to assess sex differences in opioid reinforcement. Sex differences in intravenous (IV) fentanyl self-administration were examined under a fixed-ratio (FR5) schedule, a multi-day progressive-ratio (PR) schedule for behavioral economic analysis, and a concurrent (choice) schedule of fentanyl and diluted Ensure® reinforcement in Sprague-Dawley male and female rats. The fentanyl dose-effect function under the FR5 schedule was significantly shifted upward in females compared to males. Similarly, the reinforcing effectiveness of both fentanyl (3.2 and 10 µg/kg per injection, IV) and diluted Ensure® (18 and 56%) were greater in females than in males as assessed using behavioral economic analysis, irrespective of dose or concentration. However, under a fentanyl vs. foodchoice procedure, males chose 3.2 µg/kg per injection fentanyl injections over 18%, but not 56%, diluted Ensure® at a higher percentage compared to females. Overall, these results suggest that the expression of sex differences in opioid reinforcement depends upon the schedule of reinforcement and that preclinical opioid vs. food choice procedures provide a translationally relevant measure (i.e., behavioral allocation) consistent with the direction of sex differences reported in the clinical literature.- Published
- 2019
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9. Conjugate vaccine produces long-lasting attenuation of fentanyl vs. food choice and blocks expression of opioid withdrawal-induced increases in fentanyl choice in rats.
- Author
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Townsend EA, Blake S, Faunce KE, Hwang CS, Natori Y, Zhou B, Bremer PT, Janda KD, and Banks ML
- Subjects
- Adrenergic alpha-2 Receptor Agonists pharmacology, Animals, Clonidine pharmacology, Feeding Behavior drug effects, Female, Food, Male, Naltrexone pharmacology, Narcotic Antagonists pharmacology, Opioid-Related Disorders, Rats, Reinforcement, Psychology, Self Administration, Substance Withdrawal Syndrome physiopathology, Tetanus Toxoid, Analgesics, Opioid administration & dosage, Analgesics, Opioid immunology, Behavior, Animal drug effects, Choice Behavior drug effects, Drug-Seeking Behavior drug effects, Fentanyl administration & dosage, Fentanyl immunology, Vaccines, Conjugate pharmacology
- Abstract
The current opioid crisis remains a significant public health issue and there is a critical need for biomedical research to develop effective and easily deployable candidate treatments. One emerging treatment strategy for opioid use disorder includes immunopharmacotherapies or opioid-targeted vaccines. The present study determined the effectiveness of a fentanyl-tetanus toxoid conjugate vaccine to alter fentanyl self-administration using a fentanyl-vs.-food choice procedure in male and female rats under three experimental conditions. For comparison, continuous 7-day naltrexone (0.01-0.1 mg/kg/h) and 7-day clonidine (3.2-10 μg/kg/h) treatment effects were also determined on fentanyl-vs.-food choice. Male and female rats responded for concurrently available 18% diluted Ensure® (liquid food) and fentanyl (0-10 μg/kg/infusion) infusions during daily sessions. Under baseline and saline treatment conditions, fentanyl maintained a dose-dependent increase in fentanyl-vs.-food choice. First, fentanyl vaccine administration significantly blunted fentanyl reinforcement and increased food reinforcement for 15 weeks in non-opioid dependent rats. Second, surmountability experiments by increasing the unit fentanyl dose available during the self-administration session 10-fold empirically determined that the fentanyl vaccine produced an approximate 22-fold potency shift in fentanyl-vs.-food choice that was as effective as the clinically approved treatment naltrexone. Clonidine treatment significantly increased fentanyl-vs.-food choice. Lastly, fentanyl vaccine administration prevented the expression of withdrawal-associated increases in fentanyl-vs.-food choice following introduction of extended 12 h fentanyl access sessions. Overall, these results support the potential and further consideration of immunopharmacotherapies as candidate treatments to address the current opioid crisis.
- Published
- 2019
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10. Testing the 10 most wanted: a preclinical algorithm to screen candidate opioid use disorder medications.
- Author
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Banks ML, Townsend EA, and Negus SS
- Subjects
- Animals, Algorithms, Drug Evaluation, Preclinical standards, Narcotics, Opioid-Related Disorders drug therapy
- Published
- 2019
- Full Text
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11. Impaired cognitive behavioral flexibility following methamphetamine or high caloric diet consumption: a common 5-HT 2C mechanism?
- Author
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Banks ML
- Subjects
- Animals, Cognition, Diet, Female, Macaca mulatta, Receptor, Serotonin, 5-HT2C, Reversal Learning, Serotonin, Methamphetamine
- Published
- 2019
- Full Text
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12. Amphetamine maintenance differentially modulates effects of cocaine, methylenedioxypyrovalerone (MDPV), and methamphetamine on intracranial self-stimulation and nucleus accumbens dopamine in rats.
- Author
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Johnson AR, Banks ML, Selley DE, and Negus SS
- Subjects
- Animals, Dopamine metabolism, Male, Nucleus Accumbens metabolism, Rats, Sprague-Dawley, Self Stimulation, Serotonin metabolism, Synthetic Cathinone, Amphetamine pharmacology, Benzodioxoles pharmacology, Central Nervous System Agents pharmacology, Cocaine pharmacology, Methamphetamine pharmacology, Nucleus Accumbens drug effects, Pyrrolidines pharmacology
- Abstract
Amphetamine maintenance is effective clinically to reduce the consumption of the monoamine uptake inhibitor cocaine but not of the monoamine releaser methamphetamine, and its effectiveness in treating the abuse of other psychostimulants is not known. The mechanisms for differential amphetamine-maintenance effectiveness to treat different types of psychostimulant abuse are also not known. Accordingly, the present study compared the effects of amphetamine maintenance on abuse-related behavioral and neurochemical effects of cocaine, methamphetamine, and the "bath salts" constituent 3,4-methylenedioxypyrovalerone (MDPV) in rats. In behavioral studies, rats were trained to lever press for electrical brain stimulation in an intracranial self-stimulation (ICSS) procedure. In neurochemical studies, nucleus accumbens (NAc) levels of dopamine (DA) and serotonin (5-HT) were monitored by in vivo microdialysis. Cocaine, methamphetamine, and MDPV each produced dose-dependent ICSS facilitation and increases in NAc DA; cocaine and methamphetamine also increased NAc 5-HT. Amphetamine maintenance (0.32 mg/kg/h × 7 days) produced (1) sustained increases in basal ICSS and NAc DA with no change in NAc 5-HT, (2) blockade of cocaine but not methamphetamine effects on ICSS and NAc DA, and (3) no blockade of cocaine- or methamphetamine-induced increases in NAc 5-HT. Amphetamine maintenance blocked the increases in NAc DA produced by the selective DA uptake inhibitor MDPV, but it did not block MDPV-induced ICSS facilitation. These results show different effects of amphetamine maintenance on behavioral and neurochemical effects of different psychostimulants. The selective effectiveness of amphetamine maintenance to treat cocaine abuse may reflect attenuation of cocaine-induced increases in NAc DA while preserving cocaine-induced increases in NAc 5-HT.
- Published
- 2018
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13. Repeated 7-Day Treatment with the 5-HT 2C Agonist Lorcaserin or the 5-HT 2A Antagonist Pimavanserin Alone or in Combination Fails to Reduce Cocaine vs Food Choice in Male Rhesus Monkeys.
- Author
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Banks ML and Negus SS
- Subjects
- Animals, Cocaine-Related Disorders drug therapy, Dose-Response Relationship, Drug, Macaca mulatta, Male, Reinforcement Schedule, Urea administration & dosage, Benzazepines administration & dosage, Choice Behavior drug effects, Cocaine administration & dosage, Feeding Behavior drug effects, Piperidines administration & dosage, Serotonin 5-HT2 Receptor Agonists administration & dosage, Serotonin 5-HT2 Receptor Antagonists administration & dosage, Urea analogs & derivatives
- Abstract
Cocaine use disorder is a global public health problem for which there are no Food and Drug Administration-approved pharmacotherapies. Emerging preclinical evidence has implicated both serotonin (5-HT) 2C and 2A receptors as potential mechanisms for mediating serotonergic attenuation of cocaine abuse-related neurochemical and behavioral effects. Therefore, the present study aim was to determine whether repeated 7-day treatment with the 5-HT
2C agonist lorcaserin (0.1-1.0 mg/kg per day, intramuscular; 0.032-0.1 mg/kg/h, intravenous) or the 5-HT2A inverse agonist/antagonist pimavanserin (0.32-10 mg/kg per day, intramuscular) attenuated cocaine reinforcement under a concurrent 'choice' schedule of cocaine and food availability in rhesus monkeys. During saline treatment, cocaine maintained a dose-dependent increase in cocaine vs food choice. Repeated pimavanserin (3.2 mg/kg per day) treatments significantly increased small unit cocaine dose choice. Larger lorcaserin (1.0 mg/kg per day and 0.1 mg/kg/h) and pimavanserin (10 mg/kg per day) doses primarily decreased rates of operant behavior. Coadministration of ineffective lorcaserin (0.1 mg/kg per day) and pimavanserin (0.32 mg/kg per day) doses also failed to significantly alter cocaine choice. These results suggest that neither 5-HT2C receptor activation nor 5-HT2A receptor blockade are sufficient to produce a therapeutic-like decrease in cocaine choice and a complementary increase in food choice. Overall, these results do not support the clinical utility of 5-HT2C agonists and 5-HT2A inverse agonists/antagonists alone or in combination as candidate anti-cocaine use disorder pharmacotherapies.- Published
- 2017
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14. Dissociable effects of the prodrug phendimetrazine and its metabolite phenmetrazine at dopamine transporters.
- Author
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Solis E Jr, Suyama JA, Lazenka MF, DeFelice LJ, Negus SS, Blough BE, and Banks ML
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- Animals, Dopamine metabolism, Down-Regulation, Male, Molecular Structure, Morpholines chemistry, Morpholines pharmacology, Nucleus Accumbens metabolism, Oocytes metabolism, Phenmetrazine chemistry, Phenmetrazine pharmacology, Rats, Xenopus, Dopamine Plasma Membrane Transport Proteins metabolism, Morpholines administration & dosage, Oocytes drug effects, Phenmetrazine administration & dosage
- Abstract
Phendimetrazine (PDM) is a clinically available anorectic and a candidate pharmacotherapy for cocaine addiction. PDM has been hypothesized to function as a prodrug that requires metabolism to the amphetamine-like monoamine transporter substrate phenmetrazine (PM) to produce its pharmacological effects; however, whether PDM functions as an inactive prodrug or has pharmacological activity on its own remains unclear. The study aim was to determine PDM pharmacological mechanisms using electrophysiological, neurochemical, and behavioral procedures. PDM blocked the endogenous basal hDAT (human dopamine transporter) current in voltage-clamped (-60 mV) oocytes consistent with a DAT inhibitor profile, whereas its metabolite PM induced an inward hDAT current consistent with a DAT substrate profile. PDM also attenuated the PM-induced inward current during co-application, providing further evidence that PDM functions as a DAT inhibitor. PDM increased nucleus accumbens dopamine levels and facilitated electrical brain stimulation reinforcement within 10 min in rats, providing in vivo evidence supporting PDM pharmacological activity. These results demonstrate that PDM functions as a DAT inhibitor that may also interact with the pharmacological effects of its metabolite PM. Overall, these results suggest a novel mechanism for PDM therapeutic effects via initial PDM DAT inhibition followed by PM DAT substrate-induced dopamine release.
- Published
- 2016
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15. Effects of Environmental Manipulations and Treatment with Bupropion and Risperidone on Choice between Methamphetamine and Food in Rhesus Monkeys.
- Author
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Banks ML and Blough BE
- Subjects
- Animals, Conditioning, Operant drug effects, Macaca mulatta, Male, Self Administration, Bupropion pharmacology, Choice Behavior drug effects, Dopamine Agents pharmacology, Environment, Food, Methamphetamine administration & dosage, Risperidone pharmacology
- Abstract
Preclinical and human laboratory choice procedures have been invaluable in improving our knowledge of the neurobiological mechanisms of drug reinforcement and in the drug development process for candidate medications to treat drug addiction. However, little is known about the neuropharmacological mechanisms of methamphetamine vs food choice. The aims of this study were to develop a methamphetamine vs food choice procedure and determine treatment effects with two clinically relevant compounds: the monoamine uptake inhibitor bupropion and the dopamine antagonist risperidone. Rhesus monkeys (n=6) responded under a concurrent schedule of food delivery (1-g pellets, fixed-ratio (FR) 100 schedule) and intravenous methamphetamine injections (0-0.32 mg/kg/injection, FR10 schedule) during 7-day bupropion (0.32-1.8 mg/kg/h) and risperidone (0.001-0.0056 mg/kg/h) treatment periods. For comparison, effects of removing food pellets or methamphetamine injections and FR response requirement manipulations were also examined. Under saline treatment conditions, food was preferred over no methamphetamine or small unit methamphetamine doses (0.01-0.032 mg/kg/injection). Larger methamphetamine doses resulted in greater methamphetamine preference and 0.32 mg/kg/injection methamphetamine maintained near exclusive preference. Removing food availability increased methamphetamine choice, whereas removing methamphetamine availability decreased methamphetamine choice. Methamphetamine choice was not significantly altered when the FR response requirements for food and drug were the same (FR100:FR100 or FR10:FR10). Risperidone treatment increased methamphetamine choice, whereas bupropion treatment did not alter methamphetamine choice up to doses that decreased rates of operant behavior. Overall, these negative results with bupropion and risperidone are concordant with previous human laboratory and clinical trials and support the potential validity of this preclinical methamphetamine vs food choice model.
- Published
- 2015
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16. Pain-related depression of the mesolimbic dopamine system in rats: expression, blockade by analgesics, and role of endogenous κ-opioids.
- Author
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Leitl MD, Onvani S, Bowers MS, Cheng K, Rice KC, Carlezon WA Jr, Banks ML, and Negus SS
- Subjects
- Analgesics, Opioid pharmacology, Animals, Benzeneacetamides pharmacology, Depression etiology, Depression pathology, Disease Models, Animal, Ketoprofen pharmacology, Lactic Acid pharmacology, Male, Medial Forebrain Bundle drug effects, Medial Forebrain Bundle physiology, Morphine pharmacology, Naltrexone analogs & derivatives, Naltrexone pharmacology, Narcotic Antagonists pharmacology, Nucleus Accumbens drug effects, Pain drug therapy, Pyrrolidines pharmacology, Rats, Rats, Sprague-Dawley, Receptors, Opioid, kappa genetics, Self Stimulation, Time Factors, Depression metabolism, Dopamine metabolism, Gene Expression Regulation drug effects, Nucleus Accumbens metabolism, Pain complications, Receptors, Opioid, kappa metabolism
- Abstract
Pain is often associated with depression of behavior and mood, and relief of pain-related depression is a common goal of treatment. This study tested the hypothesis that pain-related behavioral depression is mediated by activation of endogenous κ-opioid systems and subsequent depression of mesolimbic dopamine release. Adult male Sprague-Dawley rats were implanted with electrodes targeting the medial forebrain bundle (for behavior studies of intracranial self-stimulation (ICSS)) or with cannulae for microdialysis measures of nucleus accumbens dopamine (NAc DA). Changes in ICSS and NAc DA were examined after treatment with a visceral noxious stimulus (intraperitoneal injection of dilute lactic acid) or an exogenous κ-agonist (U69593). Additional studies examined the sensitivity of acid and U69593 effects to blockade by two analgesics (the nonsteroidal antiinflammatory drug ketoprofen and the μ-opioid agonist morphine) or by the κ-antagonist norbinaltorphimine (norBNI). The effects of acid were also examined on mRNA expression for prodynorphin (PDYN) and κ-opioid receptors (KORs) in mesocorticolimbic brain regions. Both acid and U69593 depressed ICSS and extracellular levels of NAc DA. Pain-related acid effects were blocked by ketoprofen and morphine but not by norBNI. The U69593 effects were blocked by norBNI but not by ketoprofen, and were only attenuated by morphine. Acid did not significantly alter PDYN or KOR in NAc, but it produced a delayed increase in PDYN in prefrontal cortex. These results support a key role for the mesolimbic DA system, but a more nuanced role for endogenous κ-opioid systems, in mediating acute pain-related behavioral depression in rats.
- Published
- 2014
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17. Effects of phendimetrazine treatment on cocaine vs food choice and extended-access cocaine consumption in rhesus monkeys.
- Author
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Banks ML, Blough BE, Fennell TR, Snyder RW, and Negus SS
- Subjects
- Analysis of Variance, Animals, Central Nervous System Stimulants blood, Conditioning, Operant drug effects, Dose-Response Relationship, Drug, Macaca mulatta, Male, Morpholines blood, Reinforcement, Psychology, Self Administration, Time Factors, Central Nervous System Stimulants pharmacology, Choice Behavior drug effects, Cocaine administration & dosage, Dopamine Uptake Inhibitors administration & dosage, Food, Morpholines pharmacology
- Abstract
There is currently no Food and Drug Administration-approved pharmacotherapy for cocaine addiction. Monoamine releasers such as d-amphetamine constitute one class of candidate medications, but clinical use and acceptance are hindered by their own high-abuse liability. Phendimetrazine (PDM) is a schedule III anorectic agent that functions as both a low-potency monoamine-uptake inhibitor and as a prodrug for the monoamine-releaser phenmetrazine (PM), and it may serve as a clinically available, effective, and safer alternative to d-amphetamine. This study determined efficacy of chronic PDM to reduce cocaine self-administration by rhesus monkeys (N=4) using a novel procedure that featured both daily assessments of cocaine vs food choice (to assess medication efficacy to reallocate behavior away from cocaine choice and toward choice of an alternative reinforcer) and 20 h/day cocaine access (to allow high-cocaine intake). Continuous 21-day treatment with ramping PDM doses (days 1-7: 0.32 mg/kg/h; days 8-21: 1.0 mg/kg/h) reduced cocaine choices, increased food choices, and nearly eliminated extended-access cocaine self-administration without affecting body weight. There was a trend for plasma PDM and PM levels to correlate with efficacy to decrease cocaine choice such that the monkey with the highest plasma PDM and PM levels also demonstrated the greatest reductions in cocaine choice. These results support further consideration of PDM as a candidate anti-cocaine addiction pharmacotherapy. Moreover, PDM may represent a novel pharmacotherapeutic approach for cocaine addiction because it may simultaneously function as both a monoamine-uptake inhibitor (via the parent drug PDM) and as a monoamine releaser (via the active metabolite PM).
- Published
- 2013
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18. Interaction between behavioral and pharmacological treatment strategies to decrease cocaine choice in rhesus monkeys.
- Author
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Banks ML, Blough BE, and Negus SS
- Subjects
- Animals, Appetite Depressants administration & dosage, Choice Behavior physiology, Dose-Response Relationship, Drug, Eating physiology, Macaca mulatta, Male, Self Administration, Treatment Outcome, Choice Behavior drug effects, Cocaine administration & dosage, Eating drug effects, Eating psychology, Phenmetrazine administration & dosage, Reinforcement Schedule
- Abstract
Behavioral and pharmacotherapeutic approaches constitute two prominent strategies for treating cocaine dependence. This study investigated interactions between behavioral and pharmacological strategies in a preclinical model of cocaine vs food choice. Six rhesus monkeys, implanted with a chronic indwelling double-lumen venous catheter, initially responded under a concurrent schedule of food delivery (1-g pellets, fixed-ratio (FR) 100 schedule) and cocaine injections (0-0.1 mg/kg/injection, FR 10 schedule) during continuous 7-day treatment periods with saline or the agonist medication phenmetrazine (0.032-0.1 mg/kg/h). Subsequently, the FR response requirement for cocaine or food was varied (food, FR 100; cocaine, FR 1-100; cocaine, FR 10; food, FR 10-300), and effects of phenmetrazine on cocaine vs food choice were redetermined. Decreases in the cocaine FR or increases in the food FR resulted in leftward shifts in the cocaine choice dose-effect curve, whereas increases in the cocaine FR or decreases in the food FR resulted in rightward shifts in the cocaine choice dose-effect curve. The efficacy of phenmetrazine to decrease cocaine choice varied systematically as a function of the prevailing response requirements, such that phenmetrazine efficacy was greatest when cocaine choice was maintained by relatively low unit cocaine doses. These results suggest that efficacy of pharmacotherapies to modulate cocaine use can be influenced by behavioral contingencies of cocaine availability. Agonist medications may be most effective under contingencies that engender choice of relatively low cocaine doses.
- Published
- 2013
- Full Text
- View/download PDF
19. Effects of extended cocaine access and cocaine withdrawal on choice between cocaine and food in rhesus monkeys.
- Author
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Banks ML and Negus SS
- Subjects
- Animals, Cocaine administration & dosage, Disease Models, Animal, Dopamine Uptake Inhibitors administration & dosage, Dose-Response Relationship, Drug, Drug Administration Schedule, Food Preferences drug effects, Macaca mulatta, Male, Reinforcement Schedule, Self Administration, Time Factors, Choice Behavior drug effects, Cocaine adverse effects, Conditioning, Operant drug effects, Dopamine Uptake Inhibitors adverse effects, Food, Substance Withdrawal Syndrome psychology
- Abstract
Chronic drug use may lead to sufficient drug intake to produce dependence and the emergence of abstinence signs during withdrawal. Although withdrawal can increase the reinforcing effects of some drugs (eg opioids), the impact of withdrawal on the reinforcing effects of stimulants like cocaine is less clear. This study used a novel cocaine vs food choice procedure to examine the relative reinforcing strength of cocaine before, during, and after exposure to graded levels of extended cocaine access. Responding in four rhesus monkeys was maintained by cocaine (0-0.1 mg/kg/injection) and food delivery under a concurrent-choice schedule during daily 2-h sessions. Under baseline conditions, cocaine maintained a dose-dependent increase in cocaine choice. Subsequently, subjects were exposed to and withdrawn from periods of extended cocaine access, which was accomplished by implementing daily 21-h supplemental sessions of cocaine self-administration in addition to daily choice sessions. During supplemental sessions, cocaine (0.1 mg/kg/injection) was available under a fixed-ratio 10/time-out X schedule, and the duration of the time-out was varied from 30 to 7.5 min. Cocaine intake increased 10-fold to >11 mg/kg/day during exposure to supplemental sessions with the shortest post-injection time-out. However, parameters of cocaine choice were not significantly affected either during or after extended cocaine access. These results do not support the hypothesis that cocaine withdrawal increases the reinforcing strength of cocaine. This differs from results with the opioid agonist heroin and suggests that withdrawal may have different functions in the maintenance of opioid and stimulant abuse.
- Published
- 2010
- Full Text
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20. Effects of cocaine and MDMA self-administration on serotonin transporter availability in monkeys.
- Author
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Banks ML, Czoty PW, Gage HD, Bounds MC, Garg PK, Garg S, and Nader MA
- Subjects
- Animals, Caudate Nucleus diagnostic imaging, Caudate Nucleus drug effects, Cocaine administration & dosage, Gyrus Cinguli diagnostic imaging, Gyrus Cinguli drug effects, Macaca mulatta, Magnetic Resonance Imaging, Male, N-Methyl-3,4-methylenedioxyamphetamine administration & dosage, Positron-Emission Tomography, Putamen diagnostic imaging, Putamen drug effects, Radiography, Self Administration, Serotonin metabolism, Serotonin Plasma Membrane Transport Proteins drug effects, Caudate Nucleus metabolism, Cocaine pharmacology, Gyrus Cinguli metabolism, N-Methyl-3,4-methylenedioxyamphetamine pharmacology, Putamen metabolism, Serotonin Plasma Membrane Transport Proteins metabolism
- Abstract
Although serotonin (5-HT) can interact with dopamine (DA) systems to modulate the subjective and reinforcing effects of psychostimulants such as cocaine and 3,4-methyldioxymethamphetamine (MDMA, ecstasy), the long-term effects of exposure to psychostimulants on brain 5-HT systems are not well characterized. The present study assessed 5-HT transporter (SERT) availability using positron emission tomography (PET) in rhesus monkeys with the SERT-specific radioligand [(11)C]3-amino-4-(2-dimethylaminomethyl-phenylsulfanyl)-benzonitrile (DASB). SERT availability was assessed in regions of interest including the caudate nucleus, putamen, anterior cingulate cortex, and cerebellum. [(11)C]DASB distribution volume ratios (DVRs) were calculated using the cerebellum as the reference region. DVRs were calculated in control monkeys and in cocaine or MDMA self-administering monkeys approximately 24 h after the last self-administration (SA) session. SERT availability did not differ between monkeys with a history of MDMA SA and control monkeys in any region examined. In contrast, monkeys with a history of cocaine SA showed significantly higher levels of SERT availability in the caudate nucleus and putamen compared to control subjects. These results suggest that chronic SA of cocaine, but not MDMA, leads to alterations in serotonergic function in brain areas relevant to drug abuse. The higher level of SERT availability in cocaine-experienced monkeys may lead to a reduced inhibitory tone of 5-HT on the DA system, which may explain, in part, differences in the abuse liability between cocaine and MDMA.
- Published
- 2008
- Full Text
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