scholarly journals Lorcaserin maintenance fails to attenuate heroin vs. food choice in rhesus monkeys

2019 ◽  
Author(s):  
E. Andrew Townsend ◽  
S. Stevens Negus ◽  
Justin L. Poklis ◽  
Matthew L. Banks
Keyword(s):  
Food Choice ◽  
Rhesus Monkeys ◽  
Therapeutic Potential ◽  
Day Treatment ◽  
Fixed Ratio ◽  
Dose Effect ◽  
Continuous Treatment ◽  
Opioid Antagonist ◽  
Opioid Use ◽  
Preclinical Research

AbstractBackgroundThe current opioid crisis has reinvigorated preclinical research in the evaluation of non-opioid candidate treatments for opioid use disorder (OUD). Emerging evidence suggests 5-HT2C receptor agonists may attenuate the abuse-related effects of opioids. This study evaluated effectiveness of 7-day treatment with the clinically available 5-HT2C agonist lorcaserin on heroin-vs.-food choice in rhesus monkeys. Lorcaserin effects were compared to effects produced by saline substitution and by 7-day treatment with the opioid antagonist naltrexone.MethodsAdult male (1) and female (6) rhesus monkeys were trained to respond under a concurrent schedule of food delivery (1g pellets, fixed-ratio 100 schedule) and intravenous heroin injections (0-0.032 mg/kg/injection, fixed-ratio 10 schedule) during daily 2h sessions. Heroin choice dose-effect functions were determined daily before and following 7-day saline substitution or 7-day continuous treatment with naltrexone (0.0032-0.032 mg/kg/h, IV) or lorcaserin (0.032-0.32 mg/kg/h, IV).ResultsUnder baseline conditions, increasing heroin doses maintained a dose-dependent increase in heroin choice. Both saline substitution and 7-day naltrexone treatment significantly attenuated heroin choice and produced a reciprocal increase in food choice. Continuous lorcaserin treatment significantly increased heroin choice.ConclusionsIn contrast to saline substitution and naltrexone, lorcaserin treatment was ineffective to reduce heroin-vs.-food choice. These preclinical results do not support the therapeutic potential of lorcaserin as a candidate OUD treatment.

scholarly journals Extinguishing cocaine-associated discriminative stimuli attenuates cocaine vs food choice in male rhesus monkeys

2019 ◽  
Author(s):  
Matthew L Banks ◽  
Blake A. Hutsell ◽  
S Stevens Negus
Keyword(s):  
Food Choice ◽  
Rhesus Monkeys ◽  
Fixed Ratio ◽  
Concurrent Schedule ◽  
Food Delivery ◽  
Self Administration ◽  
Discriminative Stimuli ◽  
Choice Procedure ◽  
Choice Procedures ◽  
Male Rhesus

ABSTRACTBackgroundIn drug addiction, relapse can be triggered by cues that function as discriminative stimuli to signal contingencies of drug availability and promote drug-taking behavior. Extinction procedures can weaken the association between drug-associated cues and drug use and may reduce the probability of relapse. This study evaluated effects of a regimen of extinction training on cocaine self-administration maintained in rhesus monkeys under a cocaine-vs.-food choice procedure that has been used previously to evaluate effectiveness of other candidate treatments for cocaine abuse.MethodsBehavior was initially maintained under a concurrent schedule of food delivery (1-g food pellets; fixed-ratio 100 schedule) and cocaine injections (0-0.1 mg/kg/injection; fixed-ratio 10 schedule) during daily 2-h choice sessions in male rhesus monkeys (n=4). Subsequently, choice sessions were supplemented by daily 20-h extinction sessions for 14 consecutive days. During extinction sessions, cocaine-associated discriminative stimuli were presented, but responding did not produce cocaine injections. Cocaine continued to be available during choice sessions.ResultsPrior to extinction, cocaine maintained a dose-dependent increase in cocaine vs. food choice. Responding during extinction sessions declined to low levels by the fifth day. Exposure to extinction sessions produced a more gradual but significant decline in cocaine choice and a complementary increase in food choice during choice sessions.ConclusionsThese preclinical results support the effectiveness of extinguishing cocaine-associated discriminative stimuli as a non-pharmacological treatment strategy for reducing cocaine choice. Moreover, these results also support the construct validity of preclinical drug vs. food choice procedures as a tool for candidate treatment evaluation for cocaine addiction.

scholarly journals Cannabidiol as a Potential Treatment for Anxiety and Mood Disorders: Molecular Targets and Epigenetic Insights from Preclinical Research

2021 ◽  
Vol 22 (4) ◽  
pp. 1863
Author(s):  
Philippe A. Melas ◽  
Maria Scherma ◽  
Walter Fratta ◽  
Carlo Cifani ◽  
Paola Fadda
Keyword(s):  
Mood Disorders ◽  
Cannabinoid Receptors ◽  
Transient Receptor Potential ◽  
Therapeutic Potential ◽  
Molecular Targets ◽  
Receptor Potential ◽  
Transient Receptor Potential Vanilloid ◽  
Preclinical Research ◽  
Neuropsychiatric Diseases ◽  
Transient Receptor

Cannabidiol (CBD) is the most abundant non-psychoactive component of cannabis; it displays a very low affinity for cannabinoid receptors, facilitates endocannabinoid signaling by inhibiting the hydrolysis of anandamide, and stimulates both transient receptor potential vanilloid 1 and 2 and serotonin type 1A receptors. Since CBD interacts with a wide variety of molecular targets in the brain, its therapeutic potential has been investigated in a number of neuropsychiatric diseases, including anxiety and mood disorders. Specifically, CBD has received growing attention due to its anxiolytic and antidepressant properties. As a consequence, and given its safety profile, CBD is considered a promising new agent in the treatment of anxiety and mood disorders. However, the exact molecular mechanism of action of CBD still remains unknown. In the present preclinical review, we provide a summary of animal-based studies that support the use of CBD as an anxiolytic- and antidepressant-like compound. Next, we describe neuropharmacological evidence that links the molecular pharmacology of CBD to its behavioral effects. Finally, by taking into consideration the effects of CBD on DNA methylation, histone modifications, and microRNAs, we elaborate on the putative role of epigenetic mechanisms in mediating CBD’s therapeutic outcomes.

scholarly journals Effects of Phendimetrazine Treatment on Cocaine vs Food Choice and Extended-Access Cocaine Consumption in Rhesus Monkeys

2013 ◽  
Vol 38 (13) ◽  
pp. 2698-2707 ◽  
Author(s):  
Matthew L Banks ◽  
Bruce E Blough ◽  
Timothy R Fennell ◽  
Rodney W Snyder ◽  
S Stevens Negus
Keyword(s):  
Food Choice ◽  
Rhesus Monkeys ◽  
Extended Access

scholarly journals Mice with High FGF21 Serum Levels Had a Reduced Preference for Morphine and an Attenuated Development of Acute Antinociceptive Tolerance and Physical Dependence

2021 ◽  
Author(s):  
Louben Dorval ◽  
Brian I. Knapp ◽  
Olufolake A. Majekodunmi ◽  
Sophia Eliseeva ◽  
Jean M Bidlack
Keyword(s):  
Pain Treatment ◽  
Therapeutic Potential ◽  
Physical Dependence ◽  
Serum Levels ◽  
Opioid Use Disorder ◽  
Fibroblast Growth Factor 21 ◽  
Opioid Use ◽  
Chronic Morphine ◽  
Hot Plate ◽  
Antinociceptive Tolerance

As a result of the opioid epidemic, there is a desire to identify new targets for treating opioid use disorder. Previous studies showed that fibroblast growth factor 21 (FGF21) decreased alcohol and sweet preference in mice. In this study, FGF21-transgenic (FGF21-Tg) mice, expressing high FGF21 serum levels, and wildtype (WT) C57BL/6J littermates were treated with morphine and saline to determine if differences exist in their physiological and behavioral responses to opioids. FGF21-Tg mice displayed reduced preference for morphine in the conditioned place preference assay compared to WT littermates. Similarly, FGF21-Tg mice had an attenuation of the magnitude and rate of acute morphine antinociceptive tolerance development, and acute and chronic morphine physical dependence, but exhibited no change in chronic morphine antinociceptive tolerance. The ED50 values for morphine-induced antinociception in the 55-degree C hot plate and the 55-degree C warm-water tail withdrawal assays were similar in both strains of mice. Likewise, FGF21-Tg and WT littermates had comparable responses to morphine-induced respiratory depression. Overall, FGF21-Tg mice had an attenuated preference for morphine, a reduced development of morphine-induced dependence, and a reduction in the development of acute morphine antinociceptive tolerance. FGF21 and its receptor have therapeutic potential for reducing opioid withdrawal symptoms and craving, and augmenting opioid therapeutics for acute pain treatment.

An Introduction to Cannabis

2017 ◽  
Author(s):  
Linda A. Parker
Keyword(s):  
Therapeutic Potential ◽  
Scientific Investigation ◽  
Human History ◽  
Preclinical Research ◽  
Cannabinoid Compounds ◽  
Psychoactive Effects ◽  
The Brain

Although cannabis has been used throughout human history, the scientific investigation of its effects only began with the isolation of THC in the 1960’s. Once discovered it was another 20 years before the mechanism by which THC produces its psychoactive effects in the brain, the CB1 receptor, was discovered. Cannabis contains over 80 cannabinoid compounds, but THC is the only intoxicating compound. Recent preclinical research is being directed towards evaluating the therapeutic potential of other cannabinoid compounds found in cannabis, including CBD. The pharmacokinetics of THC, methods of administration, and dosing issues are explored in Chapter 1.

scholarly journals Biased Opioid Antagonists as Modulators of Opioid Dependence: Opportunities to Improve Pain Therapy and Opioid Use Management

Molecules ◽  
2020 ◽  
Vol 25 (18) ◽  
pp. 4163 ◽  
Author(s):  
Wolfgang Sadee ◽  
John Oberdick ◽  
Zaijie Wang
Keyword(s):  
Opioid Dependence ◽  
Pain Therapy ◽  
Active Form ◽  
Opioid Analgesics ◽  
Opioid Antagonist ◽  
Opioid Antagonists ◽  
Opioid Use ◽  
Opioid Agonist ◽  
Opposing Effects

Opioid analgesics are effective pain therapeutics but they cause various adverse effects and addiction. For safer pain therapy, biased opioid agonists selectively target distinct μ opioid receptor (MOR) conformations, while the potential of biased opioid antagonists has been neglected. Agonists convert a dormant receptor form (MOR-μ) to a ligand-free active form (MOR-μ*), which mediates MOR signaling. Moreover, MOR-μ converts spontaneously to MOR-μ* (basal signaling). Persistent upregulation of MOR-μ* has been invoked as a hallmark of opioid dependence. Contrasting interactions with both MOR-μ and MOR-μ* can account for distinct pharmacological characteristics of inverse agonists (naltrexone), neutral antagonists (6β-naltrexol), and mixed opioid agonist-antagonists (buprenorphine). Upon binding to MOR-μ*, naltrexone but not 6β-naltrexol suppresses MOR-μ*signaling. Naltrexone blocks opioid analgesia non-competitively at MOR-μ*with high potency, whereas 6β-naltrexol must compete with agonists at MOR-μ, accounting for ~100-fold lower in vivo potency. Buprenorphine’s bell-shaped dose–response curve may also result from opposing effects on MOR-μ and MOR-μ*. In contrast, we find that 6β-naltrexol potently prevents dependence, below doses affecting analgesia or causing withdrawal, possibly binding to MOR conformations relevant to opioid dependence. We propose that 6β-naltrexol is a biased opioid antagonist modulating opioid dependence at low doses, opening novel avenues for opioid pain therapy and use management.

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