Adv. Pharmacol. [JOURNAL]
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200 papers
Pharmacological developments in antihypertensive treatment through nitric oxide-cGMP modulation.
Jüttner AA, Danser AHJ, Roks AJM
Adv Pharmacol · 2022 · PMID 35659377 · Publisher ↗
Treatment of hypertension until now has been directed at inhibition of vasoconstriction, of cardiac contractility and of blood volume regulation. Despite the arsenal of drugs available for this purpose, the control of ta...
Treatment of hypertension until now has been directed at inhibition of vasoconstriction, of cardiac contractility and of blood volume regulation. Despite the arsenal of drugs available for this purpose, the control of target blood pressure is still a difficult goal to reach in outpatients. The nitric oxide-cyclic guanosine monophosphate signaling is one of the most important mediators of vasodilation. It might therefore be a potential and most welcome drug target for optimization of the treatment of hypertension. In this chapter we review the problems that can occur in this signaling system, the attempts that have been made to correct these problems, and those that are still under investigation. Recently developed, clinically safe medicines that are currently approved for other applications, such as myocardial infarction, await to be tested for essential systemic hypertension. We conclude that despite many years of research without translation, stimulation of nitric oxide-cyclic guanosine monophosphate is still a viable strategy in the prevention of the health risk posed by chronic hypertension.
Beyond hypertension: Diastolic dysfunction associated with cancer treatment in the era of cardio-oncology.
Minotti G, Menna P, Camilli M … +2 more , Salvatorelli E, Levi R
Adv Pharmacol · 2022 · PMID 35659376 · Publisher ↗
Cancer patients are at an increased risk of cardiovascular events. Both old-generation cytostatics/cytotoxics and new-generation "targeted" drugs can in fact damage cardiomyocytes, endothelial cells of veins and arteries...
Cancer patients are at an increased risk of cardiovascular events. Both old-generation cytostatics/cytotoxics and new-generation "targeted" drugs can in fact damage cardiomyocytes, endothelial cells of veins and arteries, specialized cells of the conduction system, pericardium, and valves. A new discipline, cardio-oncology, has therefore developed with the aim of protecting cancer patients from cardiovascular events, while also providing them with the best possible oncologic treatment. Anthracyclines have long been known to elicit cardiotoxicity that, depending on treatment- or patient-related factors, may progress with a variable velocity toward cardiomyopathy and systolic heart failure. However, early compromise of diastolic function may precede systolic dysfunction, and a progression of early diastolic dysfunction to diastolic rather than systolic heart failure has been documented in long-term cancer survivors. This chapter first describes general notions about hypertension in the cancer patient and then moves on reviewing the pathophysiology and clinical trajectories of diastolic dysfunction, and the molecular mechanisms of anthracycline-induced diastolic dysfunction. Diastolic dysfunction can in fact be caused and/or aggravated by hypertension. Pharmacologic foundations and therapeutic opportunities to prevent or treat diastolic dysfunction before it progresses toward heart failure are also reviewed, with a special emphasis on the mechanisms of action of drugs that raised hopes to treat diastolic dysfunction in the general population (sacubitril/valsartan, guanylyl cyclase activators, phosphodiesterase inhibitors, ranolazine, inhibitors of type-2 sodium-glucose-inked transporter). Cardio-oncologists will be confronted with the risk:benefit ratio of using these drugs in the cancer patient.
Orally active epoxyeicosatrienoic acid analogs in hypertension and renal injury.
Imig JD
Adv Pharmacol · 2022 · PMID 35659375 · Full text
Epoxyeicosatrienoic acids (EETs) are arachidonic acid metabolites synthesized by cytochrome P450 epoxygenases. Biological activities for EETs include vasodilation, decreasing inflammation, opposing apoptosis, and inhibit...
Epoxyeicosatrienoic acids (EETs) are arachidonic acid metabolites synthesized by cytochrome P450 epoxygenases. Biological activities for EETs include vasodilation, decreasing inflammation, opposing apoptosis, and inhibiting renal sodium reabsorption. These actions are beneficial in lowering blood pressure and slowing kidney disease progression. Furthermore, evidence in human and experimental animal studies have found that decreased EET levels contribute to hypertension and kidney diseases. Consequently, EET mimics/analogs have been developed as a potential therapeutic for hypertension and acute and chronic kidney diseases. Their development has resulted in EET analogs that are orally active with favorable pharmacological profiles. Analogs for 8,9-EET, 11,12-EET, and 14,15-EET have been tested in several hypertension and kidney disease animal models. More recently, kidney targeted EET analogs have been synthesized and tested against drug-induced nephrotoxicity. Experimental evidence has demonstrated compelling therapeutic potential for EET analogs to oppose cardiovascular and kidney diseases. These EET analogs lower blood pressure, decrease kidney inflammation, improve vascular endothelial function, and decrease kidney fibrosis and apoptosis. Overall, these preclinical studies support the likelihood that EET analogs will advance to clinical trials for hypertension and associated comorbidities or acute and chronic kidney diseases.
ADAM and ADAMTS disintegrin and metalloproteinases as major factors and molecular targets in vascular malfunction and disease.
Yang H, Khalil RA
Adv Pharmacol · 2022 · PMID 35659374 · Full text
A Disintegrin and Metalloproteinase (ADAM) and A Disintegrin and Metalloproteinase with Thrombospondin Motifs (ADAMTS) are two closely related families of proteolytic enzymes. ADAMs are largely membrane-bound enzymes tha...
A Disintegrin and Metalloproteinase (ADAM) and A Disintegrin and Metalloproteinase with Thrombospondin Motifs (ADAMTS) are two closely related families of proteolytic enzymes. ADAMs are largely membrane-bound enzymes that act as molecular scissors or sheddases of membrane-bound proteins, growth factors, cytokines, receptors and ligands, whereas ADAMTS are mainly secreted enzymes. ADAMs have a pro-domain, and a metalloproteinase, disintegrin, cysteine-rich and transmembrane domain. Similarly, ADAMTS family members have a pro-domain, and a metalloproteinase, disintegrin, and cysteine-rich domain, but instead of a transmembrane domain they have thrombospondin motifs. Most ADAMs and ADAMTS are activated by pro-protein convertases, and can be regulated by G-protein coupled receptor agonists, Ca ionophores and protein kinase C. Activated ADAMs and ADAMTS participate in numerous vascular processes including angiogenesis, vascular smooth muscle cell proliferation and migration, vascular cell apoptosis, cell survival, tissue repair, and wound healing. ADAMs and ADAMTS also play a role in vascular malfunction and cardiovascular diseases such as hypertension, atherosclerosis, coronary artery disease, myocardial infarction, heart failure, peripheral artery disease, and vascular aneurysm. Decreased ADAMTS13 is involved in thrombotic thrombocytopenic purpura and microangiopathies. The activity of ADAMs and ADAMTS can be regulated by endogenous tissue inhibitors of metalloproteinases and other synthetic small molecule inhibitors. ADAMs and ADAMTS can be used as diagnostic biomarkers and molecular targets in cardiovascular disease, and modulators of ADAMs and ADAMTS activity may provide potential new approaches for the management of cardiovascular disorders.
Cardiovascular effects of GLP-1 receptor agonism.
Winquist RJ, Gribkoff VK
Adv Pharmacol · 2022 · PMID 35659373 · Publisher ↗
Glucagon-like peptide-1 (GLP-1) receptor agonists are extensively used in type 2 diabetic patients for the effective control of hyperglycemia. It is now clear from outcomes trials that this class of drugs offers importan...
Glucagon-like peptide-1 (GLP-1) receptor agonists are extensively used in type 2 diabetic patients for the effective control of hyperglycemia. It is now clear from outcomes trials that this class of drugs offers important additional benefits to these patients due to reducing the risk of developing major adverse cardiac events (MACE). This risk reduction is, in part, due to effective glycemic control in patients; however, the various outcomes trials, further validated by subsequent meta-analysis of the outcomes trials, suggest that the risk reduction in MACE is also dependent on glycemic-independent mechanisms operant in cardiovascular tissues. These glycemic-independent mechanisms are likely mediated by GLP-1 receptors found throughout the cardiovascular system and by the complex signaling cascades triggered by the binding of agonists to the G-protein coupled receptors. This heterogeneity of signaling pathways underlying different downstream effects of GLP-1 agonists, and the discovery of biased agonists favoring specific signaling pathways, may have import in the future treatment of MACE in these patients. We review the evidence supporting the glycemic-independent evidence for risk reduction of MACE by the GLP-1 receptor agonists and highlight the putative mechanisms underlying these benefits. We also comment on the different signaling pathways which appear important for mediating these effects.
Relaxin/serelaxin for cardiac dysfunction and heart failure in hypertension.
Chunduri P, Patel SA, Levick SP
Adv Pharmacol · 2022 · PMID 35659372 · Publisher ↗
The pregnancy related hormone relaxin is produced throughout the reproductive system. However, relaxin also has important cardiovascular effects as part of the adaptation that the cardiovascular system undergoes in respo...
The pregnancy related hormone relaxin is produced throughout the reproductive system. However, relaxin also has important cardiovascular effects as part of the adaptation that the cardiovascular system undergoes in response to the extra demands of pregnancy. These effects are primarily mediated by the relaxin family peptide receptor 1, which is one of four known relaxin receptors. The effects of relaxin on the cardiovascular system during pregnancy, as well as its anti-fibrotic and anti-inflammatory properties, have led to extensive studies into the potential of relaxin therapy as an approach to treat heart failure. Cardiomyocytes, cardiac fibroblasts, and endothelial cells all possess relaxin family peptide receptor 1, allowing for direct effects of therapeutic relaxin on the heart. Many pre-clinical animal studies have demonstrated a beneficial effect of exogenous relaxin on adverse cardiac remodeling including inflammation, fibrosis, cardiomyocyte hypertrophy and apoptosis, as well as effects on cardiac contractile function. Despite this, clinical studies have yielded disappointing results for the synthetic seralaxin, even though seralaxin was well tolerated. This article will provide background on relaxin in the context of normal physiology, as well as the role of relaxin in pregnancy-related adaptations of the cardiovascular system. We will also present evidence from pre-clinical animal studies that demonstrate the potential benefits of relaxin therapy, as well as discussing the results from clinical trials. Finally, we will discuss possible reasons for the failure of these clinical trials as well as steps being taken to potentially improve relaxin therapy for heart failure.
Polymorphisms in common antihypertensive targets: Pharmacogenomic implications for the treatment of cardiovascular disease.
Brown D, Alcala H, Oelschlaeger P … +1 more , Andresen BT
Adv Pharmacol · 2022 · PMID 35659371 · Publisher ↗
The idea of personalized medicine came to fruition with sequencing the human genome; however, aside from a few cases, the genetic revolution has yet to materialize. Cardiovascular diseases are the leading cause of death...
The idea of personalized medicine came to fruition with sequencing the human genome; however, aside from a few cases, the genetic revolution has yet to materialize. Cardiovascular diseases are the leading cause of death globally, and hypertension is a common prelude to nearly all cardiovascular diseases. Thus, hypertension is an ideal candidate disease to apply tenants of personalized medicine to lessen cardiovascular disease. Herein is a survey that visually depicts the polymorphisms in the top eight antihypertensive targets. Although there are numerous genome-wide association studies regarding cardiovascular disease, few studies look at the effects of receptor polymorphisms on drug treatment. With 17,000+ polymorphisms in the combined target proteins examined, it is expected that some of the clinical variability in the treatment of hypertension is due to polymorphisms in the drug targets. Recent advances in techniques and technology, such as high throughput examination of single mutations, structure prediction, computational power for modeling, and CRISPR models of point mutations, allow for a relatively rapid and comprehensive examination of the effects of known and future polymorphisms on drug affinity and effects. As hypertension is easy to measure and has a plethora of clinically viable ligands, hypertension makes an excellent disease to study pharmacogenomics in the lab and the clinic. If the promises of personalized medicine are to materialize, a concerted effort to examine the effects polymorphisms have on drugs is required. A clinician with the knowledge of a patient's genotype can then prescribe drugs that are optimal for treating that specific patient.
The CYP/20-HETE/GPR75 axis in hypertension.
Froogh G, Garcia V, Laniado Schwartzman M
Adv Pharmacol · 2022 · PMID 35659370 · Full text
20-Hydroxyeicosatetraenoic acid (20-HETE) is a bioactive lipid generated from the ω-hydroxylation of arachidonic acid (AA) by enzymes of the cytochrome P450 (CYP) family, primarily the CYP4A and CYP4F subfamilies. 20-HET...
20-Hydroxyeicosatetraenoic acid (20-HETE) is a bioactive lipid generated from the ω-hydroxylation of arachidonic acid (AA) by enzymes of the cytochrome P450 (CYP) family, primarily the CYP4A and CYP4F subfamilies. 20-HETE is most notably identified as a modulator of vascular tone, regulator of renal function, and a contributor to the onset and development of hypertension and cardiovascular disease. 20-HETE-mediated signaling promotes hypertension by sensitizing the vasculature to constrictor stimuli, inducing endothelial dysfunction, and potentiating vascular inflammation. These bioactions are driven by the activation of the G-protein coupled receptor 75 (GPR75), a 20-HETE receptor (20HR). Given the capacity of 20-HETE signaling to drive pro-hypertensive mechanisms, the CYP/20-HETE/GPR75 axis has the potential to be a significant therapeutic target for the treatment of hypertension and cardiovascular diseases associated with increases in blood pressure. In this chapter, we review 20-HETE-mediated cellular mechanisms that promote hypertension, highlight important data in humans such as genetic variants in the CYP genes that potentiate 20-HETE production and describe recent findings in humans with 20HR/GPR75 mutations. Special emphasis is given to the 20HR and respective receptor blockers that have the potential to pave a path to translational and clinical studies for the treatment of 20-HETE-driven hypertension, and obesity/metabolic syndrome.
Preface.
Li JX
Adv Pharmacol · 2022 · PMID 35341575 · Publisher ↗
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Human behavioral pharmacology of stimulant drugs: An update and narrative review.
Strzelecki A, Weafer J, Stoops WW
Adv Pharmacol · 2022 · PMID 35341574 · Publisher ↗
Stimulant use disorders present an enduring public health concern. Chronic stimulant use is associated with a range of health problems, with notable increases in stimulant overdose that disproportionately affect marginal...
Stimulant use disorders present an enduring public health concern. Chronic stimulant use is associated with a range of health problems, with notable increases in stimulant overdose that disproportionately affect marginalized populations. With these persistent problems, it is important to understand the behavioral and pharmacological factors that contribute to stimulant use in humans. The purpose of this chapter is to provide an update and narrative review on recent human laboratory research that has evaluated the behavioral pharmacology of stimulant drugs. We focus on two prototypic stimulants: cocaine as a prototype monoamine reuptake inhibitor and d-amphetamine as a prototype monoamine releaser. As such, placebo controlled human laboratory studies that involved administration of doses of cocaine or d-amphetamine and were published in peer reviewed journals within the last 10 years (i.e., since 2011) are reviewed. Primary outcomes from these studies are subjective effects, reinforcing effects, cognitive/behavioral effects, and discriminative stimulus effects. Both cocaine and d-amphetamine produce classical stimulant-like behavioral effects (e.g., increase positive subjective effects, function as reinforcers), but there are notable gaps in the literature including understanding sex differences in response to stimulant drugs, cognitive-behavioral effects of stimulants, and influence of use history (e.g., relatively drug naïve vs drug experienced) on stimulant effects.
Substance abuse and neurotransmission.
Davis S, Zhu J
Adv Pharmacol · 2022 · PMID 35341573 · Full text
The number of people who suffer from a substance abuse disorder has continued to rise over the last decade; particularly, the number of drug-related overdose deaths has sharply increased during the COVID-19 pandemic. Con...
The number of people who suffer from a substance abuse disorder has continued to rise over the last decade; particularly, the number of drug-related overdose deaths has sharply increased during the COVID-19 pandemic. Converging lines of clinical observations, supported by imaging and neuropsychological performance testing, have demonstrated that substance abuse-induced dysregulation of neurotransmissions in the brain is critical for development and expression of the addictive properties of abused substances. Recent scientific advances have allowed for better understanding of the neurobiological processes that mediates drugs of abuse and addiction. This chapter presents the past classic concepts and the recent advances in our knowledge about how cocaine, amphetamines, opioids, alcohol, and nicotine alter multiple neurotransmitter systems, which contribute to the behaviors associated with each drug. Additionally, we discuss the interactive effects of HIV-1 or COVID-19 and substance abuse on neurotransmission and neurobiological pathways. Finally, we introduce therapeutic strategies for development of pharmacotherapies for substance abuse disorders.
Trace amine-associated receptor 1 and drug abuse.
Wu R, Liu J, Li JX
Adv Pharmacol · 2022 · PMID 35341572 · Full text
Trace amine-associated receptor 1 (TAAR1) is the best characterized receptor selectively activated by trace amines. It is broadly expressed in the monoaminergic system in the brain including ventral tegmental area (VTA),...
Trace amine-associated receptor 1 (TAAR1) is the best characterized receptor selectively activated by trace amines. It is broadly expressed in the monoaminergic system in the brain including ventral tegmental area (VTA), nucleus accumbens (NAc), dorsal raphe (DR) and substantial nigra (SN). Extensive studies have suggested that TAAR1 plays an important role in the modulation of monoaminergic system, especially dopamine (DA) transmission which may underlie the mechanisms by which TAAR1 interventions affect drug abuse-like behaviors. TAAR1 activation inhibits the rewarding and reinforcing effects of drugs from different classes including psychostimulants, opioid and alcohol as well as drug-induced increase in DA accumulation. The mechanisms of TAAR1's function in mediating drug abuse-like behaviors are not clear. However, it is hypothesized that TAAR1 interaction with DA transporter (DAT) and dopamine D2 receptor (D2) and the subsequent modulation of cellular cascades may contribute to the effects of TAAR1 in regulating drug abuse. Further studies are needed to investigate the role of TAAR1 in other drugs of abuse-related behaviors and its safety and efficacy for prolonged medications. Together, TAAR1 inhibits drug-induced DA transmission and drug abuse-related behaviors. Therefore, TAAR1 may be a promising therapeutic target for the treatment of drug addiction.
In vitro and in vivo pharmacology of kratom.
Hiranita T, Obeng S, Sharma A … +3 more , Wilkerson JL, McCurdy CR, McMahon LR
Adv Pharmacol · 2022 · PMID 35341571 · Publisher ↗
Kratom products have been historically and anecdotally used in south Asian countries for centuries to manage pain and opioid withdrawal. The use of kratom products has dramatically increased in the United States. More th...
Kratom products have been historically and anecdotally used in south Asian countries for centuries to manage pain and opioid withdrawal. The use of kratom products has dramatically increased in the United States. More than 45 kratom alkaloids have been isolated, yet the overall pharmacology of the individual alkaloids is still not well characterized. The purpose of this chapter is to summarize in vitro and in vivo opioid activities of the primary kratom alkaloid mitragynine and its more potent metabolite 7-hydroxymitragynine. Following are experimental procedures described to characterize opioid receptor activity; receptor binding and functional assays, antinociceptive assays, operant conditioning assays, and respiratory plethysmography. The capacity of kratom alkaloids to confer tolerance and physical dependence as well as their pharmacokinetic properties are also summarized. The data reviewed here suggest that kratom products and mitragynine possess low efficacy agonist activity at the mu-opioid receptor in vivo. In addition, kratom products and mitragynine have been demonstrated to antagonize the effects of high efficacy mu-opioid agonists. The data further suggest that 7-hydroxymitragynine formed in vivo by metabolism of mitragynine may be minimally involved in the overall behavioral profile of mitragynine and kratom, whereas 7-hydroxymitragynine itself, at sufficiently high doses administered exogenously, shares many of the same abuse- and dependence-related behavioral effects associated with traditional opioid agonists. The apparent low efficacy of kratom products and mitragynine at mu-opioid receptors supports the development of these ligands as effective and potentially safe medications for opioid use disorder.
Potential therapeutic targets for the treatment of opioid abuse and pain.
Kiguchi N, Ko MC
Adv Pharmacol · 2022 · PMID 35341570 · Full text
Although μ-opioid peptide (MOP) receptor agonists are effective analgesics available in clinical settings, their serious adverse effects put limits on their use. The marked increase in abuse and misuse of prescription op...
Although μ-opioid peptide (MOP) receptor agonists are effective analgesics available in clinical settings, their serious adverse effects put limits on their use. The marked increase in abuse and misuse of prescription opioids for pain relief and opioid overdose mortality in the past decade has seriously impacted society. Therefore, safe analgesics that produce potent analgesic effects without causing MOP receptor-related adverse effects are needed. This review highlights the potential therapeutic targets for the treatment of opioid abuse and pain based on available evidence generated through preclinical studies and clinical trials. To ameliorate the abuse-related effects of opioids, orexin-1 receptor antagonists and mixed nociceptin/MOP partial agonists have shown promising results in translational aspects of animal models. There are several promising non-opioid targets for selectively inhibiting pain-related responses, including nerve growth factor inhibitors, voltage-gated sodium channel inhibitors, and cannabinoid- and nociceptin-related ligands. We have also discussed several emerging and novel targets. The current medications for opioid abuse are opioid receptor-based ligands. Although neurobiological studies in rodents have discovered several non-opioid targets, there is a translational gap between rodents and primates. Given that the neuroanatomical aspects underlying opioid abuse and pain are different between rodents and primates, it is pivotal to investigate the functional profiles of these non-opioid compounds compared to those of clinically used drugs in non-human primate models before initiating clinical trials. More pharmacological studies of the functional efficacy, selectivity, and tolerability of these newly discovered compounds in non-human primates will accelerate the development of effective medications for opioid abuse and pain.
Receptor mechanisms underlying the CNS effects of cannabinoids: CB receptor and beyond.
Hempel B, Xi ZX
Adv Pharmacol · 2022 · PMID 35341569 · Full text
Cannabis legalization continues to progress in many US states and other countries. Δ-tetrahydrocannabinol (Δ-THC) is the major psychoactive constituent in cannabis underlying both its abuse potential and the majority of...
Cannabis legalization continues to progress in many US states and other countries. Δ-tetrahydrocannabinol (Δ-THC) is the major psychoactive constituent in cannabis underlying both its abuse potential and the majority of therapeutic applications. However, the neural mechanisms underlying cannabis action are not fully understood. In this chapter, we first review recent progress in cannabinoid receptor research, and then examine the acute CNS effects of Δ-THC or other cannabinoids (WIN55212-2) with a focus on their receptor mechanisms. In experimental animals, Δ-THC or WIN55212-2 produces classical pharmacological effects (analgesia, catalepsy, hypothermia, hypolocomotion), biphasic changes in affect (reward vs. aversion, anxiety vs. anxiety relief), and cognitive deficits (spatial learning and memory, short-term memory). Accumulating evidence indicates that activation of CBRs underlies the majority of Δ-THC or WIN55121-2's pharmacological and behavioral effects. Unexpectedly, glutamatergic CBRs preferentially underlie cannabis action relative to GABAergic CBRs. Functional roles for CBRs expressed on astrocytes and mitochondria have also been uncovered. In addition, Δ-THC or WIN55212-2 is an agonist at CBR, GPR55 and PPARγ receptors and recent studies implicate these receptors in a number of their CNS effects. Other receptors (such as serotonin, opioid, and adenosine receptors) also modulate Δ-THC's actions and their contributions are detailed. This chapter describes the neural mechanisms underlying cannabis action, which may lead to new discoveries in cannabis-based medication development for the treatment of cannabis use disorder and other human diseases.
Examining the effects of psychoactive drugs on complex behavioral processes in laboratory animals.
Kangas BD
Adv Pharmacol · 2022 · PMID 35341568 · Publisher ↗
Behavioral pharmacology has been aided significantly by the development of innovative cognitive tasks designed to examine complex behavioral processes in laboratory animals. Performance outcomes under these conditions ha...
Behavioral pharmacology has been aided significantly by the development of innovative cognitive tasks designed to examine complex behavioral processes in laboratory animals. Performance outcomes under these conditions have provided key metrics of drug action which serve to supplement traditional in vivo assays of physiologic and behavioral effects of psychoactive drugs. This chapter provides a primer of cognitive tasks designed to assay different aspects of complex behavior, including learning, cognitive flexibility, memory, attention, motivation, and impulsivity. Both capstone studies and recent publications are highlighted throughout to illustrate task value for two distinct but often interconnected translational strategies. First, task performance in laboratory animals can be utilized to elucidate how drugs of abuse affect complex behavioral processes. Here, the expectation is that adverse effects on such processes will have predictive relevance to consequences that will be experienced by humans. Second, these same task outcomes can be used to evaluate candidate therapeutics. In this case, the extent to which drug doses with medicinal value perturb task performance can contribute critical information for a more complete safety profile appraisal and advance the process of medications development. Methodological and theoretical considerations are discussed and include an emphasis on determining selectivity in drug action on complex behavioral processes.
Environmental influence on the preclinical evaluation of substance use disorder therapeutics.
Banks ML
Adv Pharmacol · 2022 · PMID 35341567 · Publisher ↗
Substance use disorders (SUD) develop as a result of complex interactions between the environment, the subject, and the drug of abuse. Preclinical basic research investigating each of these tripartite components of SUD i...
Substance use disorders (SUD) develop as a result of complex interactions between the environment, the subject, and the drug of abuse. Preclinical basic research investigating each of these tripartite components of SUD individually has resulted in advancements in our fundamental knowledge regarding the progression from drug abuse to SUD and severe drug addiction and the underlying behavioral and neurobiological mechanisms. How these complex interactions between the environment, the subject, and the drug of abuse impact the effectiveness of candidate or clinically used medications for SUD has not been as extensively investigated. The focus of this chapter will address the current state of our knowledge how these environmental, subject, and pharmacological variables have been shown to impact candidate or clinical SUD medication evaluation in preclinical research using drug self-administration procedures as the primary dependent measure. The results discussed in this chapter highlight the importance of considering environmental variables such as the schedule of reinforcement, concurrent availability of alternative nondrug reinforcers, and experimental housing conditions in the context of SUD therapeutic evaluation. The thesis of this chapter is that improved understanding of environmental variables in the context of SUD research will facilitate the utility of preclinical drug self-administration studies in the evaluation and development of candidate SUD therapeutics.
The incentive amplifying effects of nicotine: Roles in alcohol seeking and consumption.
King CP, Meyer PJ
Adv Pharmacol · 2022 · PMID 35341566 · Full text
Nicotine has a unique profile among drugs of abuse. To the noninitiated user, nicotine has powerful aversive effects and its relatively weak euphorigenic effects undergo rapid tolerance. Despite this, nicotine is commonl...
Nicotine has a unique profile among drugs of abuse. To the noninitiated user, nicotine has powerful aversive effects and its relatively weak euphorigenic effects undergo rapid tolerance. Despite this, nicotine is commonly abused despite negative heath consequences, and nicotine users have enormous difficulty quitting. Further, nicotine is one of the most commonly co-abused substances, in that it is often taken in combination with other drugs. One explanation of this polydrug use is that nicotine has multiple appetitive and consummatory conditioning effects. For example, nicotine is a reinforcement enhancer in that it can potently increase the incentive value of other stimuli, including those surrounding drugs of abuse such as alcohol. In addition, nicotine also has a unique profile of neurobiological effects that alter regulation of alcohol intake and interoception. This review discusses the psychological and biological mechanisms surrounding nicotine's appetitive conditioning and consummatory effects, particularly its interactions with alcohol.
Stimulus functions of nicotine.
LeSage MG
Adv Pharmacol · 2022 · PMID 35341565 · Full text
Behavioral pharmacology has made vital contributions to the concepts and methods used in tobacco and other drug use research, and is largely responsible for the now generally accepted notion that nicotine is the primary...
Behavioral pharmacology has made vital contributions to the concepts and methods used in tobacco and other drug use research, and is largely responsible for the now generally accepted notion that nicotine is the primary component in tobacco that engenders and maintains tobacco use. One of the most important contributions of behavioral pharmacology to the science of drug use is the notion that drugs can act as environmental stimuli that control behavior in many of the same ways as other stimuli (e.g., visual, gustatory, olfactory). The purpose of this chapter is to provide an overview of research that illustrates the respondent and operant stimulus functions of nicotine, using a contemporary taxonomy of stimulus functions as a general framework. Each function is formally defined and examples from research on the behavioral pharmacology of nicotine are presented. Some of the factors that modulate each function are also discussed. The role of nicotine's stimulus functions in operant and respondent theories of tobacco use is examined and some suggestions for future research are presented. The chapter illustrates how a taxonomy of stimulus functions can guide conceptions of tobacco use and direct research and theory accordingly.
Human behavioral pharmacology of psychedelics.
Strickland JC, Johnson MW
Adv Pharmacol · 2022 · PMID 35341564 · Publisher ↗
The past decade has witnessed a rapid growth of research on the basic science and clinical understanding of psychedelics. This chapter provides an overview of the human behavioral pharmacology of psychedelics focusing on...
The past decade has witnessed a rapid growth of research on the basic science and clinical understanding of psychedelics. This chapter provides an overview of the human behavioral pharmacology of psychedelics focusing on three prototypic classic psychedelics-psilocybin, lysergic acid diethylamide (LSD), and dimethyltryptamine (DMT). A brief historical overview of the classic psychedelics and naming and drug classification is first specified. Next, special considerations in the conduct of human behavioral pharmacology work with psychedelics is described including the role of set and setting, mystical experience measurement, the use of effective blinding and placebos, and the abuse liability of psychedelics. Following, a description of the subjective, physiological, and clinical effects of psilocybin, LSD, and DMT is provided. This body of work clearly documents a unique and complex collection of subjective effects following psychedelic use, both during acute drug administration and as related to long-term behavior change following use. Clinical research demonstrates potential therapeutic utility with early phase clinical trials showing positive and enduring effects in many difficult-to-treat conditions including treatment-resistant depression, alcohol use disorder, and cigarette smoking. Future work in this newly reemerged field is needed to reveal mechanisms of behavior change in psychedelic drug action. Behavioral pharmacology is ultimately well served to provide this direction answering questions at the intersection of environment and pharmacology.
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