Eggs of the bush-cricket Ephippiger cruciger may be subject to two periods of diapause during the... more Eggs of the bush-cricket Ephippiger cruciger may be subject to two periods of diapause during the course of embryogenesis. After oviposition not all eggs develop at temperatures favourable to morphogenesis, some cease activity at the unsegmented embryonic primordium stage. If these eggs are cooled for 10-30 days some develop on subsequent exposure to higher temperatures, but further prolongation of the cooling period does not render more eggs competent to develop. Although cooling for longer than the critical period does not affect the proportion of eggs which subsequently start to develop, it does affect the time within which reactivated eggs begin to develop. The delay in the initiation of development after cooling increases with the duration of the chilling period. Excessively long cooling periods, however, impair the eggs' ability to complete embryogenesis. It is evident that eggs laid in one season will develop and hatch over a number of years.
Background: Samidorphan is a novel μ-opioid antagonist with low intrinsic activity at κ- and δ-op... more Background: Samidorphan is a novel μ-opioid antagonist with low intrinsic activity at κ- and δ-opioid receptors. Aims: Because samidorphan is central nervous system-active, we investigated whether samidorphan (13.6, 40.8, 68 μg/kg/injection) served as a positive reinforcer in rats trained to self-administer heroin on a fixed ratio-5 schedule. Samidorphan’s relative reinforcing effect was evaluated by progressive ratio/break-point determination. Naltrexone (13.6, 40.8, 68 μg/kg/injection) and heroin (7.5, 15, 25 μg/kg/injection) were comparators. Results: All heroin doses maintained self-administration on fixed ratio-5 and progressive ratio/break-points at levels significantly greater than saline. Samidorphan and naltrexone had similar profiles on fixed ratio-5 with one samidorphan dose serving as a positive reinforcer and one naltrexone dose showing a strong trend ( p=0.053) for positive reinforcement. The numbers of injections of every samidorphan and naltrexone dose were significa...
Patients receiving the cytokine immunotherapy, interferon-alpha (IFN-α) frequently present with n... more Patients receiving the cytokine immunotherapy, interferon-alpha (IFN-α) frequently present with neuropsychiatric consequences and cognitive impairments. Patients (25-80%) report symptoms of depression, including, anhedonia, irritability, fatigue and impaired motivation. Our lab has previously demonstrated treatment (170,000IU/kg sc, 3 times per week for 4weeks) of the pro-inflammatory cytokine, IFN-α, induced a depressive phenotype in rats in the forced swim test (FST). Here, we examine the biological mechanisms underlying behavioral changes induced by IFN-α, which may be reflective of mechanisms underlying inflammation associated depression. We also investigate the potential of 3-carboxamido seco-nalmefene (3CS-nalmefene), a novel opioid modulator (antagonist at mu and partial agonist at kappa and delta opioid receptors in vitro), to reverse IFN-α induced changes. In vitro radioligand receptor binding assays and the [(35)S] GTPγS were performed to determine the affinity of 3CS-nalmefene for the mu, kappa and delta opioid receptors. IFN-α treatment increased circulating and central markers of inflammation and hypothalamic-pituitaryadrenal (HPA) axis activity (IL-6, IL-1β and corticosterone) while increasing immobility in the FST, impairing of object displacement learning in the object exploration task (OET), and decreasing neuronal proliferation and brain-derived neurotrophic factor (BDNF) in the hippocampus. Treatment with 3CS-nalmefene (0.3mg/kg/sc twice per day, 3 times per week for 4weeks) prevented IFN-α-induced immobility in the FST and impaired object displacement learning. In addition, 3CS-nalmefene prevented IFN-α-induced increases in inflammation and hyperactivity of the HPA-axis, the IFN-α-induced reduction in both neuronal proliferation and BDNF expression in the hippocampus. Overall, these preclinical data would support the hypothesis that opioid receptor modulation is a relevant target for treatment of depression.
Cognitive impairments in the aged present an increasingly important health problem. More than 11%... more Cognitive impairments in the aged present an increasingly important health problem. More than 11% of the U.S. population is 65 years of age or older, and many of these people suffer some degree of intellectual dysfunction. In 1.5–3 million people, this cognitive decline is greatly exacerbated by the presence of senile dementia of the Alzheimer’s type (SDAT). SDAT insidiously destroys the intellectual capacity of its victims (Reisberg et al. 1982), ultimately necessitating complete and perpetual institutional care. Annual costs for treatment and care are in excess of 20 billion dollars in the United States. At the same time, the devastating emotional burden and personal loss felt by family members, friends, and the patients themselves cannot be properly represented in financial terms. Improvement in other health care areas has been and is expected to continue to expand rapidly the aged sector of the population. The present magnitude of the health care problem posed by the elderly and clear projections for its increased incidence in the future demand a concerted efford to determine the nature, etiology, and treatment of cognitive impairments in the aged.
Among the many behavioral impairments that develop in the elderly (i.e., disturbances in cognitio... more Among the many behavioral impairments that develop in the elderly (i.e., disturbances in cognition, affect, psychomotor function, sleep, sexual function), loss of cognitive function is generally recognized as one of the most severe and consistent dysfunctions (Weinberg, 1980). Controlled laboratory studies indicate that the majority of healthy, elderly persons show reliable declines in cognition in the later phases of life (reviewed in Flicker et al., 1985). This problem is often exacerbated by the onset of senile dementia, estimated to affect over 2 million persons in the United States alone (U.S. Department of Health and Human Services, 1984), and is expected to increase to epidemic proportions during the current decade (Plum, 1979). This neurodegenerative disorder, initially involving cognitive and memory-related dysfunctions, causes tremendous emotional and financial burdens to families and society. Thus, a concerted effort to characterize the nature, etiology, and treatment possibilities for age-related cognitive impairments is necessary as the medical and financial burdens of a growing elderly population continue to increase.
N-Acyloxymethyl derivatives of pioglitazone (PIO) have been prepared and characterized as model c... more N-Acyloxymethyl derivatives of pioglitazone (PIO) have been prepared and characterized as model candidates for extended-release injectable formulations. All PIO derivatives prepared are crystalline solids as determined by powder X-ray diffraction, and the solubility in aqueous media is below 1 μM at 37 °C. The melting points steadily increase from 55 °C, for the hexanoyloxymethyl derivative, to 85 °C, for the palmitoyloxymethyl derivative; inversely, the solubilities in ethyl oleate decrease as a function of increasing acyl chain length. The butyroyloxymethyl ester has a higher melting point and a lower solubility in ethyl oleate than expected from the trend. The (13)C solid-state NMR spectra of the PIO homologues between the hexanoyloxymethyl derivative and stearoyloxymethyl derivative suggest a common structural motif with the acyl chains exchanging between two distinct conformations, and the rate of exchange is slower for longer chain derivatives. The butyroyloxymethyl derivative is efficiently converted to PIO in in vitro rat plasma with a half-life of <2 min at 37 (o) C, while the rate of enzymatic cleavage in rat plasma decreases as the ester chain length increases for the longer acyloxymethyl derivatives. The concentration of PIO in plasma increases rapidly, or "spikes," in the hours following intramuscular (IM) injection of either the HCl salt or the butyroyloxymethyl derivative. In contrast, the more lipophilic palmitoyloxymethyl derivative provides slow growth in the PIO concentration over the first day to reach levels that remain steady for 2 weeks. On the basis of its in vivo pharmacokinetic profile, as well as material and solubility properties, the PIO palmitoyloxymethyl derivative has potential as a once-monthly injectable medication to treat diabetes.
Over 30 years ago, we began to develop a nonhuman primate model to study cognitive deficits of ag... more Over 30 years ago, we began to develop a nonhuman primate model to study cognitive deficits of age-related neurodegenerative diseases and their neuroanatomical-neurochemical underpinnings for purposes of translating this work toward first pharmacotherapies. This effort produced several notable findings that eventually received consensus support, which we have been asked to review. A discussion of these findings, in the context of issues and obstacles confronted and principles applied, might facilitate the development of even more effective models and treatments, not only for Alzheimer's disease (AD) but for many other disorders involving cognitive deficits. Collectively, our research provided first evidence of the following: aged primates can be used as 'models' for human age-related neurodegenerative diseases; key cognitive deficits in early AD share important conceptual similarities to deficits in both aged monkeys as well as non-demented humans (e.g., age-associated memory impairment and mild cognitive impairment); pharmacological intervention can reduce age-related cognitive impairments in animals that are conceptually similar to those seen in human diseases, including AD; cholinergics would likely be the first approved therapeutics for AD; and that many other classes of drugs would not likely succeed. Despite the early promise shown by behavioral/functional approaches to develop treatment strategies, the dramatic shift in focus away from behavioral outcomes in animal neurodegenerative research that began 20 years ago has compromised further progress and continues to impede our ability to understand how these diseases impair human cognition and what pathways might lead to effective therapies. Principles applied successfully in the past should provide guidance for facilitating efforts in the future.
A monthly extended-release formulation of the opioid antagonist naltrexone (XR-NTX) is approved f... more A monthly extended-release formulation of the opioid antagonist naltrexone (XR-NTX) is approved for treatment of alcohol dependence. There is little research regarding overriding chronic (>21 days) competitive opioid receptor blockade with opioids for acute pain. Using the hot plate test after XR-NTX or placebo microsphere administration, rats were treated with an opioid analgesic to determine the dose required to produce the maximum response latency (MRL; 60 s). Rats were later treated with the same opioid to determine any potential effects on respiration rate or locomotor activity. In naïve rats, 15 mg/kg morphine, 0.1 mg/kg fentanyl and 8 mg/kg hydrocodone produced MRL. In XR-NTX treated rats, morphine produced 36% and 46% MRL at 90 mg/kg on days 4 and 19 and 96% MRL at 45 mg/kg on day 39. Fentanyl produced 100% MRL at 2.0 mg/kg on days 4 and 19 and at 0.5 mg/kg on day 39. Hydrocodone (80 mg/kg) produced 69%, 80% and 100% MRL on days 4, 19 and 39. Compared to placebo, these doses did not further depress respiration or alter locomotor activity. Thus, opioid receptor blockade with XR-NTX can be overcome in rats with higher doses of opioids without further affecting respiration or locomotor activity.
Eggs of the bush-cricket Ephippiger cruciger may be subject to two periods of diapause during the... more Eggs of the bush-cricket Ephippiger cruciger may be subject to two periods of diapause during the course of embryogenesis. After oviposition not all eggs develop at temperatures favourable to morphogenesis, some cease activity at the unsegmented embryonic primordium stage. If these eggs are cooled for 10-30 days some develop on subsequent exposure to higher temperatures, but further prolongation of the cooling period does not render more eggs competent to develop. Although cooling for longer than the critical period does not affect the proportion of eggs which subsequently start to develop, it does affect the time within which reactivated eggs begin to develop. The delay in the initiation of development after cooling increases with the duration of the chilling period. Excessively long cooling periods, however, impair the eggs' ability to complete embryogenesis. It is evident that eggs laid in one season will develop and hatch over a number of years.
Background: Samidorphan is a novel μ-opioid antagonist with low intrinsic activity at κ- and δ-op... more Background: Samidorphan is a novel μ-opioid antagonist with low intrinsic activity at κ- and δ-opioid receptors. Aims: Because samidorphan is central nervous system-active, we investigated whether samidorphan (13.6, 40.8, 68 μg/kg/injection) served as a positive reinforcer in rats trained to self-administer heroin on a fixed ratio-5 schedule. Samidorphan’s relative reinforcing effect was evaluated by progressive ratio/break-point determination. Naltrexone (13.6, 40.8, 68 μg/kg/injection) and heroin (7.5, 15, 25 μg/kg/injection) were comparators. Results: All heroin doses maintained self-administration on fixed ratio-5 and progressive ratio/break-points at levels significantly greater than saline. Samidorphan and naltrexone had similar profiles on fixed ratio-5 with one samidorphan dose serving as a positive reinforcer and one naltrexone dose showing a strong trend ( p=0.053) for positive reinforcement. The numbers of injections of every samidorphan and naltrexone dose were significa...
Patients receiving the cytokine immunotherapy, interferon-alpha (IFN-α) frequently present with n... more Patients receiving the cytokine immunotherapy, interferon-alpha (IFN-α) frequently present with neuropsychiatric consequences and cognitive impairments. Patients (25-80%) report symptoms of depression, including, anhedonia, irritability, fatigue and impaired motivation. Our lab has previously demonstrated treatment (170,000IU/kg sc, 3 times per week for 4weeks) of the pro-inflammatory cytokine, IFN-α, induced a depressive phenotype in rats in the forced swim test (FST). Here, we examine the biological mechanisms underlying behavioral changes induced by IFN-α, which may be reflective of mechanisms underlying inflammation associated depression. We also investigate the potential of 3-carboxamido seco-nalmefene (3CS-nalmefene), a novel opioid modulator (antagonist at mu and partial agonist at kappa and delta opioid receptors in vitro), to reverse IFN-α induced changes. In vitro radioligand receptor binding assays and the [(35)S] GTPγS were performed to determine the affinity of 3CS-nalmefene for the mu, kappa and delta opioid receptors. IFN-α treatment increased circulating and central markers of inflammation and hypothalamic-pituitaryadrenal (HPA) axis activity (IL-6, IL-1β and corticosterone) while increasing immobility in the FST, impairing of object displacement learning in the object exploration task (OET), and decreasing neuronal proliferation and brain-derived neurotrophic factor (BDNF) in the hippocampus. Treatment with 3CS-nalmefene (0.3mg/kg/sc twice per day, 3 times per week for 4weeks) prevented IFN-α-induced immobility in the FST and impaired object displacement learning. In addition, 3CS-nalmefene prevented IFN-α-induced increases in inflammation and hyperactivity of the HPA-axis, the IFN-α-induced reduction in both neuronal proliferation and BDNF expression in the hippocampus. Overall, these preclinical data would support the hypothesis that opioid receptor modulation is a relevant target for treatment of depression.
Cognitive impairments in the aged present an increasingly important health problem. More than 11%... more Cognitive impairments in the aged present an increasingly important health problem. More than 11% of the U.S. population is 65 years of age or older, and many of these people suffer some degree of intellectual dysfunction. In 1.5–3 million people, this cognitive decline is greatly exacerbated by the presence of senile dementia of the Alzheimer’s type (SDAT). SDAT insidiously destroys the intellectual capacity of its victims (Reisberg et al. 1982), ultimately necessitating complete and perpetual institutional care. Annual costs for treatment and care are in excess of 20 billion dollars in the United States. At the same time, the devastating emotional burden and personal loss felt by family members, friends, and the patients themselves cannot be properly represented in financial terms. Improvement in other health care areas has been and is expected to continue to expand rapidly the aged sector of the population. The present magnitude of the health care problem posed by the elderly and clear projections for its increased incidence in the future demand a concerted efford to determine the nature, etiology, and treatment of cognitive impairments in the aged.
Among the many behavioral impairments that develop in the elderly (i.e., disturbances in cognitio... more Among the many behavioral impairments that develop in the elderly (i.e., disturbances in cognition, affect, psychomotor function, sleep, sexual function), loss of cognitive function is generally recognized as one of the most severe and consistent dysfunctions (Weinberg, 1980). Controlled laboratory studies indicate that the majority of healthy, elderly persons show reliable declines in cognition in the later phases of life (reviewed in Flicker et al., 1985). This problem is often exacerbated by the onset of senile dementia, estimated to affect over 2 million persons in the United States alone (U.S. Department of Health and Human Services, 1984), and is expected to increase to epidemic proportions during the current decade (Plum, 1979). This neurodegenerative disorder, initially involving cognitive and memory-related dysfunctions, causes tremendous emotional and financial burdens to families and society. Thus, a concerted effort to characterize the nature, etiology, and treatment possibilities for age-related cognitive impairments is necessary as the medical and financial burdens of a growing elderly population continue to increase.
N-Acyloxymethyl derivatives of pioglitazone (PIO) have been prepared and characterized as model c... more N-Acyloxymethyl derivatives of pioglitazone (PIO) have been prepared and characterized as model candidates for extended-release injectable formulations. All PIO derivatives prepared are crystalline solids as determined by powder X-ray diffraction, and the solubility in aqueous media is below 1 μM at 37 °C. The melting points steadily increase from 55 °C, for the hexanoyloxymethyl derivative, to 85 °C, for the palmitoyloxymethyl derivative; inversely, the solubilities in ethyl oleate decrease as a function of increasing acyl chain length. The butyroyloxymethyl ester has a higher melting point and a lower solubility in ethyl oleate than expected from the trend. The (13)C solid-state NMR spectra of the PIO homologues between the hexanoyloxymethyl derivative and stearoyloxymethyl derivative suggest a common structural motif with the acyl chains exchanging between two distinct conformations, and the rate of exchange is slower for longer chain derivatives. The butyroyloxymethyl derivative is efficiently converted to PIO in in vitro rat plasma with a half-life of <2 min at 37 (o) C, while the rate of enzymatic cleavage in rat plasma decreases as the ester chain length increases for the longer acyloxymethyl derivatives. The concentration of PIO in plasma increases rapidly, or "spikes," in the hours following intramuscular (IM) injection of either the HCl salt or the butyroyloxymethyl derivative. In contrast, the more lipophilic palmitoyloxymethyl derivative provides slow growth in the PIO concentration over the first day to reach levels that remain steady for 2 weeks. On the basis of its in vivo pharmacokinetic profile, as well as material and solubility properties, the PIO palmitoyloxymethyl derivative has potential as a once-monthly injectable medication to treat diabetes.
Over 30 years ago, we began to develop a nonhuman primate model to study cognitive deficits of ag... more Over 30 years ago, we began to develop a nonhuman primate model to study cognitive deficits of age-related neurodegenerative diseases and their neuroanatomical-neurochemical underpinnings for purposes of translating this work toward first pharmacotherapies. This effort produced several notable findings that eventually received consensus support, which we have been asked to review. A discussion of these findings, in the context of issues and obstacles confronted and principles applied, might facilitate the development of even more effective models and treatments, not only for Alzheimer's disease (AD) but for many other disorders involving cognitive deficits. Collectively, our research provided first evidence of the following: aged primates can be used as 'models' for human age-related neurodegenerative diseases; key cognitive deficits in early AD share important conceptual similarities to deficits in both aged monkeys as well as non-demented humans (e.g., age-associated memory impairment and mild cognitive impairment); pharmacological intervention can reduce age-related cognitive impairments in animals that are conceptually similar to those seen in human diseases, including AD; cholinergics would likely be the first approved therapeutics for AD; and that many other classes of drugs would not likely succeed. Despite the early promise shown by behavioral/functional approaches to develop treatment strategies, the dramatic shift in focus away from behavioral outcomes in animal neurodegenerative research that began 20 years ago has compromised further progress and continues to impede our ability to understand how these diseases impair human cognition and what pathways might lead to effective therapies. Principles applied successfully in the past should provide guidance for facilitating efforts in the future.
A monthly extended-release formulation of the opioid antagonist naltrexone (XR-NTX) is approved f... more A monthly extended-release formulation of the opioid antagonist naltrexone (XR-NTX) is approved for treatment of alcohol dependence. There is little research regarding overriding chronic (>21 days) competitive opioid receptor blockade with opioids for acute pain. Using the hot plate test after XR-NTX or placebo microsphere administration, rats were treated with an opioid analgesic to determine the dose required to produce the maximum response latency (MRL; 60 s). Rats were later treated with the same opioid to determine any potential effects on respiration rate or locomotor activity. In naïve rats, 15 mg/kg morphine, 0.1 mg/kg fentanyl and 8 mg/kg hydrocodone produced MRL. In XR-NTX treated rats, morphine produced 36% and 46% MRL at 90 mg/kg on days 4 and 19 and 96% MRL at 45 mg/kg on day 39. Fentanyl produced 100% MRL at 2.0 mg/kg on days 4 and 19 and at 0.5 mg/kg on day 39. Hydrocodone (80 mg/kg) produced 69%, 80% and 100% MRL on days 4, 19 and 39. Compared to placebo, these doses did not further depress respiration or alter locomotor activity. Thus, opioid receptor blockade with XR-NTX can be overcome in rats with higher doses of opioids without further affecting respiration or locomotor activity.
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Papers by Reginald Dean