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  1. Article: Antinociceptive Effects of Kappa-Opioid Receptor Agonists.

    Lazenka, Matthew F

    Handbook of experimental pharmacology

    2021  Volume 271, Page(s) 293–313

    Abstract: Preclinical models that assess "pain" in rodents typically measure increases in behaviors produced by a "pain stimulus." A large literature exists showing that kappa opioid receptor (KOR) agonists can decrease these "pain-stimulated behaviors" following ... ...

    Abstract Preclinical models that assess "pain" in rodents typically measure increases in behaviors produced by a "pain stimulus." A large literature exists showing that kappa opioid receptor (KOR) agonists can decrease these "pain-stimulated behaviors" following many different pain stimuli. Despite showing apparent antinociceptive properties in these preclinical models, KOR agonists failed as analgesics in clinical trials. Recent studies that assessed decreases in behavior due to a pain stimulus show that KOR agonists are not effective in restoring these "pain-depressed behaviors" to normal levels, which agrees with the lack of effectiveness for KOR agonists in clinical trials. One current explanation for the failure of previous KOR agonists in clinical trials is that those agonists activated beta-arrestin signaling and that KOR agonists with a greater bias for G protein signaling will be more successful. However, neither G protein-biased agonists nor beta-arrestin-biased agonists are very effective in assays of pain-depressed behavior, which suggests that novel biased agonists may still not be effective analgesics. This review provides a concise account of the effectiveness of KOR agonists in preclinical models of pain-stimulated and pain-depressed behaviors following the administration of different pain stimuli. Based on the previous results, it may be appropriate to include both behaviors when testing the analgesic potential of KOR agonists.
    MeSH term(s) Analgesics, Opioid/pharmacology ; GTP-Binding Proteins/metabolism ; Humans ; Pain/drug therapy ; Receptors, Opioid, kappa ; Signal Transduction ; beta-Arrestins/pharmacology
    Chemical Substances Analgesics, Opioid ; Receptors, Opioid, kappa ; beta-Arrestins ; GTP-Binding Proteins (EC 3.6.1.-)
    Language English
    Publishing date 2021-01-02
    Publishing country Germany
    Document type Journal Article ; Review
    ISSN 0171-2004
    ISSN 0171-2004
    DOI 10.1007/164_2020_430
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  2. Article ; Online: Oral modafinil facilitates intracranial self-stimulation in rats: comparison with methylphenidate.

    Lazenka, Matthew F / Negus, S Stevens

    Behavioural pharmacology

    2017  Volume 28, Issue 4, Page(s) 318–322

    Abstract: Modafinil is a low-potency inhibitor of dopamine transporters (DAT) approved clinically to promote wakefulness. In most procedures used for abuse-liability assessment, modafinil produces effects similar to those of abused DAT inhibitors such as cocaine ... ...

    Abstract Modafinil is a low-potency inhibitor of dopamine transporters (DAT) approved clinically to promote wakefulness. In most procedures used for abuse-liability assessment, modafinil produces effects similar to those of abused DAT inhibitors such as cocaine and methylphenidate, although modafinil often shows lower effectiveness. However, modafinil has failed to maintain drug self-administration or produce conditioned place preferences in rats. The low potency and poor solubility of modafinil complicate its delivery by parenteral routes of administration commonly used in rats, and this may contribute toward negative results. This study evaluated the effects of orally administered modafinil in rats using an assay of intracranial self-stimulation (ICSS) that has been used to examine the effects of other DAT inhibitors. Adult male Sprague-Dawley rats equipped with electrodes in the medial forebrain bundle responded for pulses of brain stimulation that varied across a range of frequencies (158-56 Hz) during daily behavioral sessions. Modafinil (20-600 mg/kg, orally) and methylphenidate (1.0-10 mg/kg, intraperitoneally; 3.2-32 mg/kg, orally) produced dose-dependent and time-dependent facilitation of ICSS, an effect produced by abused DAT inhibitors and other classes of abused drugs. These results are in agreement with other evidence for stimulant-like abuse liability of modafinil and show the sensitivity of ICSS to orally administered drug.
    MeSH term(s) Administration, Oral ; Animals ; Benzhydryl Compounds/administration & dosage ; Benzhydryl Compounds/pharmacology ; Central Nervous System Stimulants/administration & dosage ; Central Nervous System Stimulants/pharmacology ; Dopamine Plasma Membrane Transport Proteins/metabolism ; Dose-Response Relationship, Drug ; Male ; Medial Forebrain Bundle/drug effects ; Methylphenidate/administration & dosage ; Methylphenidate/pharmacology ; Rats ; Rats, Sprague-Dawley ; Self Administration ; Self Stimulation/drug effects ; Time Factors ; Wakefulness-Promoting Agents/administration & dosage ; Wakefulness-Promoting Agents/pharmacology
    Chemical Substances Benzhydryl Compounds ; Central Nervous System Stimulants ; Dopamine Plasma Membrane Transport Proteins ; Wakefulness-Promoting Agents ; Methylphenidate (207ZZ9QZ49) ; modafinil (R3UK8X3U3D)
    Language English
    Publishing date 2017-01-25
    Publishing country England
    Document type Comparative Study ; Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 1027374-8
    ISSN 1473-5849 ; 0955-8810
    ISSN (online) 1473-5849
    ISSN 0955-8810
    DOI 10.1097/FBP.0000000000000288
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    Zs.A 2883: Show issues Location:
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  3. Article ; Online: Preclinical Abuse Potential Assessment of Flibanserin: Effects on Intracranial Self-Stimulation in Female and Male Rats.

    Lazenka, Matthew F / Blough, Bruce E / Negus, S Stevens

    The journal of sexual medicine

    2016  Volume 13, Issue 3, Page(s) 338–349

    Abstract: Introduction: Flibanserin is a serotonin receptor subtype 1A agonist and 2A antagonist that has been approved by the Food and Drug Administration for treating female sexual interest and arousal disorder. Little is known about the abuse potential of ... ...

    Abstract Introduction: Flibanserin is a serotonin receptor subtype 1A agonist and 2A antagonist that has been approved by the Food and Drug Administration for treating female sexual interest and arousal disorder. Little is known about the abuse potential of flibanserin.
    Aim: To examine abuse-related effects of flibanserin in rats using an intracranial self-stimulation (ICSS) procedure previously used to evaluate the abuse potential of other drugs.
    Methods: Adult female and male Sprague-Dawley rats with electrodes implanted in the medial forebrain bundle were trained to press a lever for electrical brain stimulation under a "frequency-rate" ICSS procedure. In this procedure, increasing frequencies of brain stimulation maintain increasing rates of responding. Drugs of abuse typically increase (or "facilitate") ICSS rates and produce leftward and upward shifts in ICSS frequency-rate curves, whereas drugs that lack abuse potential typically do not alter or only decrease ICSS rates. Initial studies determined the potency and time course of effects on ICSS produced by acute flibanserin administration (1.0, 3.2 and 10.0 mg/kg). Subsequent studies determined the effects of flibanserin (3.2-18 mg/kg) before and after a regimen of repeated flibanserin administration (5.6 mg/kg/d for 5 days). Effects of the abused stimulant amphetamine (1.0 mg/kg) were examined as a positive control.
    Main outcome measures: Flibanserin effects on ICSS frequency-rate curves in female and male rats were examined and compared with the effects of amphetamine.
    Results: Baseline ICSS frequency-rate curves were similar in female and male rats. Acute and repeated administrations of flibanserin produced only decreases in ICSS rates, and rate-decreasing effects of the highest flibanserin dose (10 mg/kg) were greater in female than in male rats. In contrast to flibanserin, amphetamine produced an abuse-related increase in ICSS rates that did not differ between female and male rats.
    Conclusion: These results suggest that flibanserin has low abuse potential. In addition, this study suggests that female rats might be more sensitive than male rats to the rate-decreasing effects of high flibanserin doses.
    MeSH term(s) Animals ; Benzimidazoles/pharmacology ; Brain/drug effects ; Brain/pathology ; Conditioning, Operant/drug effects ; Electric Stimulation ; Female ; Male ; Medial Forebrain Bundle/drug effects ; Medial Forebrain Bundle/pathology ; Rats ; Rats, Sprague-Dawley ; Self Stimulation/drug effects ; Serotonin 5-HT2 Receptor Agonists/pharmacology ; Serotonin 5-HT2 Receptor Antagonists/pharmacology ; Substance-Related Disorders/pathology ; United States
    Chemical Substances Benzimidazoles ; Serotonin 5-HT2 Receptor Agonists ; Serotonin 5-HT2 Receptor Antagonists ; flibanserin (37JK4STR6Z)
    Language English
    Publishing date 2016-01-28
    Publishing country Netherlands
    Document type Journal Article
    ZDB-ID 2251959-2
    ISSN 1743-6109 ; 1743-6095
    ISSN (online) 1743-6109
    ISSN 1743-6095
    DOI 10.1016/j.jsxm.2015.12.031
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    Zs.A 6417: Show issues Location:
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    Zs.MO 505: Show issues

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  4. Article ; Online: Opposing effects of dopamine D1- and D2-like agonists on intracranial self-stimulation in male rats.

    Lazenka, Matthew F / Legakis, Luke P / Negus, S Stevens

    Experimental and clinical psychopharmacology

    2016  Volume 24, Issue 3, Page(s) 193–205

    Abstract: Dopamine acts through dopamine Type I receptors (comprising D1 and D5 subtypes) and dopamine Type II receptors (comprising D2, D3, and D4 subtypes). Intracranial self-stimulation (ICSS) is 1 experimental procedure that can be used to evaluate abuse- ... ...

    Abstract Dopamine acts through dopamine Type I receptors (comprising D1 and D5 subtypes) and dopamine Type II receptors (comprising D2, D3, and D4 subtypes). Intracranial self-stimulation (ICSS) is 1 experimental procedure that can be used to evaluate abuse-related effects of drugs targeting dopamine receptors. This study evaluated effects of dopamine receptor ligands on ICSS in rats using experimental procedures that have been used previously to examine abused indirect dopamine agonists such as cocaine and amphetamine. Male Sprague-Dawley rats responded under a fixed-ratio 1 schedule for electrical stimulation of the medial forebrain bundle, and frequency of stimulation varied from 56-158 Hz in 0.05 log increments during each experimental session. Drug potency and time course were determined for the D1 ligands A77636, SKF82958, SKF38393, fenoldopam, and SCH39166 and the D2/3 ligands sumanirole, apomorphine, quinpirole, PD128907, pramipexole, aripiprazole, eticlopride, and PG01037. The high-efficacy D1 agonists A77636 and SKF82958 produced dose-dependent, time-dependent, and abuse-related facilitation of ICSS. Lower efficacy D1 ligands and all D2/3 ligands failed to facilitate ICSS at any dose or pretreatment time. A mixture of SKF82958 and quinpirole produced a mixture of effects produced by each drug alone. Quinpirole also failed to facilitate ICSS after regimens of repeated treatment with either quinpirole or cocaine. These studies provide more evidence for divergent effects of dopamine D1- and D2-family agonists on ICSS procedure in rats and suggest that ICSS may be a useful complement to other approaches for preclinical abuse potential assessment, in part because of the reproducibility of results. (PsycINFO Database Record
    MeSH term(s) Animals ; Behavior, Animal/drug effects ; Cocaine/pharmacology ; Dopamine/metabolism ; Dopamine Agonists/administration & dosage ; Dopamine Agonists/pharmacology ; Dose-Response Relationship, Drug ; Male ; Quinpirole/pharmacology ; Rats ; Rats, Sprague-Dawley ; Receptors, Dopamine D1/agonists ; Receptors, Dopamine D2/agonists ; Reproducibility of Results ; Self Stimulation/drug effects ; Time Factors
    Chemical Substances Dopamine Agonists ; Receptors, Dopamine D1 ; Receptors, Dopamine D2 ; Quinpirole (20OP60125T) ; Cocaine (I5Y540LHVR) ; Dopamine (VTD58H1Z2X)
    Language English
    Publishing date 2016-06
    Publishing country United States
    Document type Journal Article
    ZDB-ID 1209960-0
    ISSN 1936-2293 ; 1064-1297
    ISSN (online) 1936-2293
    ISSN 1064-1297
    DOI 10.1037/pha0000067
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    Zs.A 4462: Show issues Location:
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  5. Article ; Online: Relief of Pain-Depressed Behavior in Rats by Activation of D1-Like Dopamine Receptors.

    Lazenka, Matthew F / Freitas, Kelen C / Henck, Sydney / Negus, S Stevens

    The Journal of pharmacology and experimental therapeutics

    2017  Volume 362, Issue 1, Page(s) 14–23

    Abstract: Clinically significant pain often includes a decrease in both behavior and mesolimbic dopamine signaling. Indirect and/or direct dopamine receptor agonists may alleviate pain-related behavioral depression. To test this hypothesis, the present study ... ...

    Abstract Clinically significant pain often includes a decrease in both behavior and mesolimbic dopamine signaling. Indirect and/or direct dopamine receptor agonists may alleviate pain-related behavioral depression. To test this hypothesis, the present study compared effects of indirect and direct dopamine agonists in a preclinical assay of pain-depressed operant responding. Male Sprague-Dawley rats with chronic indwelling microelectrodes in the medial forebrain bundle were trained in an intracranial self-stimulation (ICSS) procedure to press a lever for pulses of electrical brain stimulation. Intraperitoneal injection of dilute lactic acid served as an acute noxious stimulus to depress ICSS. Intraperitoneal lactic acid-induced depression of ICSS was dose-dependently blocked by the dopamine transporter inhibitor methylphenidate and the D1-selective agonist SKF82958, but not by the D2/3-selective agonists quinpirole, pramipexole, or sumanirole. The antinociceptive effects of methylphenidate and SKF82958 were blocked by the D1-selective antagonist SCH39166. Acid-induced stimulation of a stretching response was evaluated in separate groups of rats, but all agonists decreased acid-stimulated stretching, and antagonism experiments were inconclusive due to direct effects of the antagonists when administered alone. Taken together, these results suggest that D1-receptor stimulation is both sufficient to block acid-induced depression of ICSS and necessary for methylphenidate antinociception in this procedure. Conversely, D2/3-receptor stimulation is not sufficient to relieve pain-depressed behavior. These results support the hypothesis that pain-related depression of dopamine D1 receptor signaling contributes to pain-related depression of behavior in rats. Additionally, these results support further consideration of indirect dopamine agonists and direct D1 receptor agonists as candidate treatments for pain-related behavioral depression.
    MeSH term(s) Analgesics/pharmacology ; Animals ; Behavior, Animal/drug effects ; Benzazepines/pharmacology ; Conditioning, Operant/drug effects ; Depression/drug therapy ; Depression/etiology ; Depression/psychology ; Dopamine Agonists/therapeutic use ; Dopamine Uptake Inhibitors/pharmacology ; Dose-Response Relationship, Drug ; Electrodes, Implanted ; Lactic Acid ; Male ; Methylphenidate/pharmacology ; Pain/complications ; Pain/drug therapy ; Pain/psychology ; Pain Management ; Rats ; Rats, Sprague-Dawley ; Receptors, Dopamine D1/agonists ; Self Stimulation
    Chemical Substances Analgesics ; Benzazepines ; Dopamine Agonists ; Dopamine Uptake Inhibitors ; Receptors, Dopamine D1 ; Methylphenidate (207ZZ9QZ49) ; Lactic Acid (33X04XA5AT) ; SK&F 82958 (80751-65-1)
    Language English
    Publishing date 2017-04-14
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 3106-9
    ISSN 1521-0103 ; 0022-3565
    ISSN (online) 1521-0103
    ISSN 0022-3565
    DOI 10.1124/jpet.117.240796
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    Uf I Zs.40: Show issues Location:
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  6. Article ; Online: Effects of caffeine and its metabolite paraxanthine on intracranial self-stimulation in male rats.

    Lazenka, Matthew F / Moeller, F Gerard / Negus, S Stevens

    Experimental and clinical psychopharmacology

    2015  Volume 23, Issue 2, Page(s) 71–80

    Abstract: Caffeine is the most widely used psychostimulant in the world, though preclinical studies suggest weaker evidence for abuse-related effects than stimulants with high abuse liability, such as amphetamine or cocaine. Intracranial self-stimulation (ICSS) is ...

    Abstract Caffeine is the most widely used psychostimulant in the world, though preclinical studies suggest weaker evidence for abuse-related effects than stimulants with high abuse liability, such as amphetamine or cocaine. Intracranial self-stimulation (ICSS) is 1 procedure used to assess the abuse liability of drugs, and previous studies have produced mixed results regarding whether caffeine produces an abuse-related facilitation of ICSS. This study assessed both caffeine and its main metabolite in humans, paraxanthine, using a frequency-rate ICSS procedure and compared their effects to those of amphetamine and cocaine. Male Sprague-Dawley rats were implanted with intracranial electrodes targeting the medial forebrain bundle and trained to respond under a fixed-ratio 1 schedule for brain stimulation that varied across a range of frequencies (56-158 Hz in 0.05 log increments). Data analysis focused on 3 dependent measures: reinforced responding (defined as responses that produced brain stimulation), nonreinforced responding (defined as responses that occurred during each 0.5 s brain stimulation and that did not produce additional stimulation), and total responding (reinforced plus nonreinforced responding). Both amphetamine and cocaine produced robust increases in total, reinforced, and nonreinforced responses. Caffeine also increased total, reinforced, and nonreinforced responses, but the caffeine dose-effect curve had an inverted-U shape, and peak ICSS facilitation was less than that produced by amphetamine or cocaine. Paraxanthine increased only total responses and nonreinforced responses. These results suggest that paraxanthine has low abuse liability and does not mediate abuse-related effects of caffeine.
    MeSH term(s) Animals ; Caffeine/administration & dosage ; Conditioning, Operant/drug effects ; Conditioning, Operant/physiology ; Male ; Rats ; Rats, Sprague-Dawley ; Reinforcement (Psychology) ; Self Administration ; Self Stimulation/drug effects ; Self Stimulation/physiology ; Theophylline/administration & dosage ; Theophylline/metabolism
    Chemical Substances Caffeine (3G6A5W338E) ; Theophylline (C137DTR5RG) ; 1,7-dimethylxanthine (Q3565Y41V7)
    Language English
    Publishing date 2015-04
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 1209960-0
    ISSN 1936-2293 ; 1064-1297
    ISSN (online) 1936-2293
    ISSN 1064-1297
    DOI 10.1037/pha0000012
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  7. Article: Δ

    Lazenka, Matthew F / Kang, Minho / De, Dipanjana Datta / Selley, Dana E / Sim-Selley, Laura J

    Cannabis and cannabinoid research

    2017  Volume 2, Issue 1, Page(s) 224–234

    Abstract: Introduction: ...

    Abstract Introduction:
    Language English
    Publishing date 2017-08-01
    Publishing country United States
    Document type Journal Article
    ZDB-ID 2867624-5
    ISSN 2378-8763 ; 2378-8763 ; 2578-5125
    ISSN (online) 2378-8763
    ISSN 2378-8763 ; 2578-5125
    DOI 10.1089/can.2017.0022
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  8. Article ; Online: Attenuated dopamine receptor signaling in nucleus accumbens core in a rat model of chemically-induced neuropathy.

    Selley, Dana E / Lazenka, Matthew F / Sim-Selley, Laura J / Secor McVoy, Julie R / Potter, David N / Chartoff, Elena H / Carlezon, William A / Negus, S Stevens

    Neuropharmacology

    2020  Volume 166, Page(s) 107935

    Abstract: Neuropathy is major source of chronic pain that can be caused by mechanically or chemically induced nerve injury. Intraplantar formalin injection produces local necrosis over a two-week period and has been used to model neuropathy in rats. To determine ... ...

    Abstract Neuropathy is major source of chronic pain that can be caused by mechanically or chemically induced nerve injury. Intraplantar formalin injection produces local necrosis over a two-week period and has been used to model neuropathy in rats. To determine whether neuropathy alters dopamine (DA) receptor responsiveness in mesolimbic brain regions, we examined dopamine D
    MeSH term(s) Animals ; Conditioning, Operant/drug effects ; Conditioning, Operant/physiology ; Disease Models, Animal ; Dopamine Agonists/pharmacology ; Dopamine Antagonists/pharmacology ; Dose-Response Relationship, Drug ; Formaldehyde/toxicity ; Male ; Neuralgia/chemically induced ; Neuralgia/metabolism ; Nucleus Accumbens/drug effects ; Nucleus Accumbens/metabolism ; Rats ; Rats, Sprague-Dawley ; Receptors, Dopamine D1/agonists ; Receptors, Dopamine D1/antagonists & inhibitors ; Receptors, Dopamine D1/metabolism ; Receptors, Dopamine D2/agonists ; Receptors, Dopamine D2/metabolism ; Signal Transduction/drug effects ; Signal Transduction/physiology
    Chemical Substances DRD2 protein, rat ; Dopamine Agonists ; Dopamine Antagonists ; Drd1 protein, rat ; Receptors, Dopamine D1 ; Receptors, Dopamine D2 ; Formaldehyde (1HG84L3525)
    Language English
    Publishing date 2020-01-07
    Publishing country England
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 218272-5
    ISSN 1873-7064 ; 0028-3908
    ISSN (online) 1873-7064
    ISSN 0028-3908
    DOI 10.1016/j.neuropharm.2020.107935
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  9. Article ; Online: ΔFosB induction correlates inversely with CB₁ receptor desensitization in a brain region-dependent manner following repeated Δ⁹-THC administration.

    Lazenka, Matthew F / Selley, Dana E / Sim-Selley, Laura J

    Neuropharmacology

    2013  Volume 77, Page(s) 224–233

    Abstract: Repeated Δ(9)-tetrahydrocannabinol (THC) administration produces desensitization and downregulation of cannabinoid type 1 receptors (CB₁Rs) in the brain, but the magnitude of these adaptations varies among regions. CB₁Rs in the striatum and its output ... ...

    Abstract Repeated Δ(9)-tetrahydrocannabinol (THC) administration produces desensitization and downregulation of cannabinoid type 1 receptors (CB₁Rs) in the brain, but the magnitude of these adaptations varies among regions. CB₁Rs in the striatum and its output regions exhibit the least magnitude and slowest development of desensitization and downregulation. The molecular mechanisms that confer these region-dependent differences are not known. The stable transcription factor, ΔFosB, is induced in the striatum following repeated THC administration and could regulate CB₁Rs. To directly compare the regional profile of ΔFosB induction and CB₁R desensitization and downregulation, mice were treated with THC (10 mg/kg) or vehicle for 13.5 days. CP55,940-stimulated [(35)S]GTPγS autoradiography and immunohistochemistry were performed to measure CB₁R desensitization and downregulation, respectively, and ΔFosB expression was measured by immunoblot. Significant CB₁R desensitization and downregulation occurred in the prefrontal cortex, lateral amygdala and hippocampus; desensitization was found in the basomedial amygdala and no changes were seen in remaining regions. ΔFosB was induced in the prefrontal cortex, caudate-putamen, nucleus accumbens and lateral amygdala. An inverse regional relationship between ΔFosB expression and CB₁R desensitization was found, such that regions with the greatest ΔFosB induction did not exhibit CB₁R desensitization and areas without ΔFosB induction had the greatest desensitization, with remaining regions exhibiting intermediate levels of both. Dual immunohistochemistry in the striatum showed both CB₁R co-localization with ΔFosB in cells and CB₁R puncta surrounding ΔFosB-positive cells. THC-induced expression of ΔFosB was absent in the striatum of CB₁R knockout mice. These data suggest that transcriptional targets of ΔFosB might inhibit CB₁R desensitization and/or that ΔFosB induction could be limited by CB₁R desensitization.
    MeSH term(s) Animals ; Brain/drug effects ; Brain/metabolism ; Corpus Striatum/drug effects ; Corpus Striatum/metabolism ; Down-Regulation/drug effects ; Dronabinol/administration & dosage ; Guanosine 5'-O-(3-Thiotriphosphate)/genetics ; Guanosine 5'-O-(3-Thiotriphosphate)/metabolism ; Male ; Mice ; Mice, Inbred ICR ; Mice, Knockout ; Proto-Oncogene Proteins c-fos/metabolism ; Receptor, Cannabinoid, CB1/genetics ; Receptor, Cannabinoid, CB1/metabolism
    Chemical Substances Fosb protein, mouse ; Proto-Oncogene Proteins c-fos ; Receptor, Cannabinoid, CB1 ; Guanosine 5'-O-(3-Thiotriphosphate) (37589-80-3) ; Dronabinol (7J8897W37S)
    Language English
    Publishing date 2013-09-30
    Publishing country England
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 218272-5
    ISSN 1873-7064 ; 0028-3908
    ISSN (online) 1873-7064
    ISSN 0028-3908
    DOI 10.1016/j.neuropharm.2013.09.019
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  10. Article ; Online: Dissociable effects of the prodrug phendimetrazine and its metabolite phenmetrazine at dopamine transporters.

    Solis, Ernesto / Suyama, Julie A / Lazenka, Matthew F / DeFelice, Louis J / Negus, S Stevens / Blough, Bruce E / Banks, Matthew L

    Scientific reports

    2016  Volume 6, Page(s) 31385

    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 ... ...

    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.
    Language English
    Publishing date 2016-08-12
    Publishing country England
    Document type Journal Article
    ZDB-ID 2615211-3
    ISSN 2045-2322 ; 2045-2322
    ISSN (online) 2045-2322
    ISSN 2045-2322
    DOI 10.1038/srep31385
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