An array of evidence indicates that long-term exposure to cocaine alters several components of th... more An array of evidence indicates that long-term exposure to cocaine alters several components of the brain dopamine system. Because the release of dopamine in the nucleus accumbens (NAc) has been implicated in mediating the reinforcing effects of cocaine, changes in dopamine function can have profound effects on drug-seeking and drug-taking behavior. The present study examined the effects of the chronic self-administration of cocaine on the D1 family of dopamine receptors in the rhesus monkey. The brains of three rhesus monkeys that had intravenously self-administered an average of 1.35 mg/kg cocaine per day for 18-22 months were compared to the brains of three cocaine-naive controls. The in vitro quantitative autoradiographic technique was used to quantify binding densities of the D1 ligand [3H]SCH-23390 on cryostat-cut sections of fresh frozen tissue. In animals that self-administered cocaine, the density of D1 binding was significantly lower in the regions of the striatum at the level where the nucleus accumbens is most fully developed. The shell of the NAc showed the largest difference with significantly lower D1 binding also detected in adjacent regions of the caudate nucleus and the putamen. No differences were found in the rostral pole of the NAc or the dorsal striatum at that level. These findings suggest that chronic self-administration of cocaine can modulate the density of dopamine D1 receptors in specific portions of the primate striatum. Such changes might underlie some of the behavioral consequences, like drug dependence and craving, of long-term cocaine use.
Microtubules (MTs) are structural units in the cytoskeleton. In brain cells they are responsible ... more Microtubules (MTs) are structural units in the cytoskeleton. In brain cells they are responsible for axonal transport, information processing, and signaling mechanisms. Proper function of these processes is critical for healthy brain functions. Alcohol and substance use disorders (AUD/SUDs) affects the function and organization of MTs in the brain, making them a potential neuroimaging marker to study the resulting impairment of overall neurobehavioral and cognitive processes. Our lab reported the first brain-penetrant MT-tracking Positron Emission Tomography (PET) ligand [11C]MPC-6827 and demonstrated its in vivo utility in rodents and non-human primates. To further explore the in vivo imaging potential of [11C]MPC-6827, we need to investigate its mechanism of action. Here, we report preliminary in vitro binding results in SH-SY5Y neuroblastoma cells exposed to ethanol (EtOH) or cocaine in combination with multiple agents that alter MT stability. EtOH and cocaine treatments increase...
White Carneau pigeons were trained to discriminate 1.0 mg/kg buspirone from saline when key pecki... more White Carneau pigeons were trained to discriminate 1.0 mg/kg buspirone from saline when key pecking was maintained under a fixed-ratio 30 schedule of food presentation. Buspirone (0.3–10.0 mg/kg), the serotonin 1A (5-HT1A) agonist 8-OH-DPAT (0.1–1.0mg/kg), the buspirone analog BMY 7378 (3.0–5.6mg/kg), the mixed 5-HT1A/1B agonist RU 24969 (3.0–10.0mg/kg) and the 5-HT1A agonist spiroxatrine (0.1–1.0mg/kg) occasioned at least 80% buspirone-appropriate responding in all subjects tested. Administration of the 5-HT1B agonist (TFMPP 0.1–10.0mg/kg) or the 5-HT3 antagonist (MDL 72222 (3.0–17.0mg/kg) resulted in primarily saline-key responding. The dopamine receptor antagonist chlorpromazine (1.0–17.0mg/kg), the specific D-2 receptor antagonist eticlopride (0.03–0.56mg/kg), the noradrenergic alpha-2 antagonist yohimbine (0.1–1.0mg/kg), the alpha-2 agonist clonidine (0.003–0.10mg/kg) and (±) and (-) propranolol (3.0–30.0mg/kg) all produced primarily saline-appropriate responding. Coadministration of the β-adrenergic agonist isoproterenol (1.0–5.6mg/kg) or the 5-HT1A partial agonist BMY 7378 (0.01–10.0mg/kg) with 1.0mg/kg buspirone did not block the discriminative stimulus effects of buspirone. However, 3.0–10.0mg/kg BMY 7378, in combination with a lower dose of buspirone (0.3mg/kg) decreased drug-key responding to approximately 50%. Results from the present study suggest that (1) the discriminative stimulus effects of buspirone, 8-OH-DPAT, BMY 7378, RU 24969 and spiroxatrine are mediated through the 5-HT1A receptor; (2) buspirone's discriminative stimulus effects do not interact with the noradrenergic or dopaminergic system; and 3) under this procedure BMY 7378 was a partial agonist at 5-HT1A receptors.
Research involving nonhuman primates (NHPs) has played a vital role in many of the medical and sc... more Research involving nonhuman primates (NHPs) has played a vital role in many of the medical and scientific advances of the past century. NHPs are used because of their similarity to humans in physiology, neuroanatomy, reproduction, development, cognition, and social complexity—yet it is these very similarities that make the use of NHPs in biomedical research a considered decision. As primate researchers, we feel an obligation and responsibility to present the facts concerning why primates are used in various areas of biomedical research. Recent decisions in the United States, including the phasing out of chimpanzees in research by the National Institutes of Health and the pending closure of the New England Primate Research Center, illustrate to us the critical importance of conveying why continued research with primates is needed. Here, we review key areas in biomedicine where primate models have been, and continue to be, essential for advancing fundamental knowledge in biomedical an...
An array of evidence indicates that long-term exposure to cocaine alters several components of th... more An array of evidence indicates that long-term exposure to cocaine alters several components of the brain dopamine system. Because the release of dopamine in the nucleus accumbens (NAc) has been implicated in mediating the reinforcing effects of cocaine, changes in dopamine function can have profound effects on drug-seeking and drug-taking behavior. The present study examined the effects of the chronic self-administration of cocaine on the D1 family of dopamine receptors in the rhesus monkey. The brains of three rhesus monkeys that had intravenously self-administered an average of 1.35 mg/kg cocaine per day for 18-22 months were compared to the brains of three cocaine-naive controls. The in vitro quantitative autoradiographic technique was used to quantify binding densities of the D1 ligand [3H]SCH-23390 on cryostat-cut sections of fresh frozen tissue. In animals that self-administered cocaine, the density of D1 binding was significantly lower in the regions of the striatum at the level where the nucleus accumbens is most fully developed. The shell of the NAc showed the largest difference with significantly lower D1 binding also detected in adjacent regions of the caudate nucleus and the putamen. No differences were found in the rostral pole of the NAc or the dorsal striatum at that level. These findings suggest that chronic self-administration of cocaine can modulate the density of dopamine D1 receptors in specific portions of the primate striatum. Such changes might underlie some of the behavioral consequences, like drug dependence and craving, of long-term cocaine use.
Microtubules (MTs) are structural units in the cytoskeleton. In brain cells they are responsible ... more Microtubules (MTs) are structural units in the cytoskeleton. In brain cells they are responsible for axonal transport, information processing, and signaling mechanisms. Proper function of these processes is critical for healthy brain functions. Alcohol and substance use disorders (AUD/SUDs) affects the function and organization of MTs in the brain, making them a potential neuroimaging marker to study the resulting impairment of overall neurobehavioral and cognitive processes. Our lab reported the first brain-penetrant MT-tracking Positron Emission Tomography (PET) ligand [11C]MPC-6827 and demonstrated its in vivo utility in rodents and non-human primates. To further explore the in vivo imaging potential of [11C]MPC-6827, we need to investigate its mechanism of action. Here, we report preliminary in vitro binding results in SH-SY5Y neuroblastoma cells exposed to ethanol (EtOH) or cocaine in combination with multiple agents that alter MT stability. EtOH and cocaine treatments increase...
White Carneau pigeons were trained to discriminate 1.0 mg/kg buspirone from saline when key pecki... more White Carneau pigeons were trained to discriminate 1.0 mg/kg buspirone from saline when key pecking was maintained under a fixed-ratio 30 schedule of food presentation. Buspirone (0.3–10.0 mg/kg), the serotonin 1A (5-HT1A) agonist 8-OH-DPAT (0.1–1.0mg/kg), the buspirone analog BMY 7378 (3.0–5.6mg/kg), the mixed 5-HT1A/1B agonist RU 24969 (3.0–10.0mg/kg) and the 5-HT1A agonist spiroxatrine (0.1–1.0mg/kg) occasioned at least 80% buspirone-appropriate responding in all subjects tested. Administration of the 5-HT1B agonist (TFMPP 0.1–10.0mg/kg) or the 5-HT3 antagonist (MDL 72222 (3.0–17.0mg/kg) resulted in primarily saline-key responding. The dopamine receptor antagonist chlorpromazine (1.0–17.0mg/kg), the specific D-2 receptor antagonist eticlopride (0.03–0.56mg/kg), the noradrenergic alpha-2 antagonist yohimbine (0.1–1.0mg/kg), the alpha-2 agonist clonidine (0.003–0.10mg/kg) and (±) and (-) propranolol (3.0–30.0mg/kg) all produced primarily saline-appropriate responding. Coadministration of the β-adrenergic agonist isoproterenol (1.0–5.6mg/kg) or the 5-HT1A partial agonist BMY 7378 (0.01–10.0mg/kg) with 1.0mg/kg buspirone did not block the discriminative stimulus effects of buspirone. However, 3.0–10.0mg/kg BMY 7378, in combination with a lower dose of buspirone (0.3mg/kg) decreased drug-key responding to approximately 50%. Results from the present study suggest that (1) the discriminative stimulus effects of buspirone, 8-OH-DPAT, BMY 7378, RU 24969 and spiroxatrine are mediated through the 5-HT1A receptor; (2) buspirone's discriminative stimulus effects do not interact with the noradrenergic or dopaminergic system; and 3) under this procedure BMY 7378 was a partial agonist at 5-HT1A receptors.
Research involving nonhuman primates (NHPs) has played a vital role in many of the medical and sc... more Research involving nonhuman primates (NHPs) has played a vital role in many of the medical and scientific advances of the past century. NHPs are used because of their similarity to humans in physiology, neuroanatomy, reproduction, development, cognition, and social complexity—yet it is these very similarities that make the use of NHPs in biomedical research a considered decision. As primate researchers, we feel an obligation and responsibility to present the facts concerning why primates are used in various areas of biomedical research. Recent decisions in the United States, including the phasing out of chimpanzees in research by the National Institutes of Health and the pending closure of the New England Primate Research Center, illustrate to us the critical importance of conveying why continued research with primates is needed. Here, we review key areas in biomedicine where primate models have been, and continue to be, essential for advancing fundamental knowledge in biomedical an...
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Papers by Michael Nader