Almtraet--The formation of respiratory 14COz from injected tryptophan-14C is reduced in vivo afte... more Almtraet--The formation of respiratory 14COz from injected tryptophan-14C is reduced in vivo after the simultaneous administration of certain analogs of tryptophan, a-Hydrazinotryptophan lowered the rate of metabolism of tryptophan-2-x4C (label in the pyrrole ring) and, to an even greater extent, that of tryptophan-y-14C (label in the side chain). The oxidation of tryptophan-benzene-laC was unaffected by this analog, a-Hydrazino-5-hydroxytryptophan had the same relative action on the metabolism of tryptophan-2and -Y-IaC, but the effect was smaller. Several compounds that diminished the rate of oxidation of tryptophan in vivo inhibited tryptophan pyrrolase in vitro. A notable exception is tryptophol, which inhibited tryptophan pyrrolase by 92 per cent when present at a concentration of 10 -3 M in vitro, but which gave inconclusive results in vivo. The pattern of inhibition of the breakdown of differentially labeled metabolites provides a useful tool in detecting rate-limiting steps in a metabolic sequence in vivo.
Http Dx Doi Org 10 1080 0964704x 2012 678199, Jan 16, 2013
The 1975 publication of Seeman et al. (Proc Nat Acad Sci, USA), reporting the discovery of the an... more The 1975 publication of Seeman et al. (Proc Nat Acad Sci, USA), reporting the discovery of the antipsychotic receptor in the brain, is a classic example of translational medicine research. In searching for a pathophysiological mechanism of psychosis, the team sought to identify sites that bound the antipsychotic drug haloperidol. Their criterion was that haloperidol bound to the site at one to two nanomoles per liter, corresponding to haloperidol concentrations found in spinal fluid or plasma water in treated patients. They requested de novo synthesis of tritiated haloperidol, and it readily detected specific haloperidol binding sites in brain striatum. With dopamine binding the haloperidol-labeled sites with higher potency than other neurotransmitters, the sites were named antipsychotic/dopamine receptors (now designated dopamine D2 receptors). Most significantly, they found that all antipsychotics bound these sites at concentrations and with a rank order of potencies that were directly related to the mean daily antipsychotic dose taken by patients with schizophrenia. Their findings enabled screening for new antipsychotics, initiated D2 receptor measurements in brain of living patients, and determination of minimum occupancy (65%) of D2 receptors for antipsychotic benefit. The collective work is generally viewed as providing a fundamental basis for the dopamine hypothesis of schizophrenia.
Fluorescent probes have been designed and developed for dopamine D-1 and D-2 receptors. Fluoresce... more Fluorescent probes have been designed and developed for dopamine D-1 and D-2 receptors. Fluorescein and/or NBD (7-nitrobenz-2-oxa-1,3-diazol-4-yl) derivatives of PPHT (D-2 agonist), spiperone (D-2 antagonist), SKF 38393 (D-1 agonist), and SKF 83566 (D-1 antagonist) were synthesized via their amino-functionalized analogues and all ligands were pharmacologically evaluated by measuring their ability to displace [3H]SCH 23390 and [3H]spiperone from D-1 and D-2 receptor sites in caudate putamen of monkeys (Macaca fascicularis). The fluorescein derivatives of PPHT and SKF 83566 and the NBD derivatives of spiperone and SKF 83566 retained the high affinity and selectivity of the parent ligands. The NBD derivatives of PPHT showed higher D-2 receptor affinity and selectivity than their parent ligands. The enantiomers of the fluorescent derivatives of PPHT were also synthesized and were found to exhibit stereoselectivity in binding to the D-2 receptor, with the S enantiomers having a considerably higher affinity than their R analogues. In contrast to these results, the fluorescein derivative of SKF 38393 showed only a low affinity for the D-1 receptor. These fluorescein- and NBD-coupled D-1 and D-2 receptor ligands have considerable significance as potential probes in the study of distribution of the receptors at the cellular/subcellular level and of their mobility in membranes in normal/diseased states by use of fluorescence microscopic and fluorescence photobleaching recovery techniques, respectively. The development of these novel fluorescent probes should also provide new leads for the design and synthesis of additional fluorescent ligands with better fluorescent properties and/or higher affinity/selectivity for the DA receptors.
Although cannabinoid effects on motor function have been extensively studied in rodents, the role... more Although cannabinoid effects on motor function have been extensively studied in rodents, the role of cannabinoids in regulating behavior in primates is relatively unknown. We compared the effects of cannabinoid agonists and dopamine antagonists on unconditioned behaviors in cynomolgus monkeys (Macaca fascicularis). We further investigated the therapeutic potential of cannabinoid antagonists in a primate model of Parkinson's disease. Drugs were administered i.m., and sessions were videotaped and rated by a "blind" observer using a rating scale. The dopamine antagonist haloperidol decreased locomotor activity and increased bradykinesia in three subjects. Haloperidol also produced a dose-dependent increase in freezing and catalepsy in two out of the three subjects. The cannabinoid agonist levonantradol dose-dependently decreased general and locomotor activity and increased bradykinesia. In contrast to haloperidol, levonantradol failed to produce freezing or catalepsy. At the dose range studied, tetrahydrocannabinol did not affect general or locomotor activity, but increased bradykinesia. In view of the psychomotor slowing induced by cannabinoid agonists, we investigated the therapeutic potential of the cannabinoid receptor antagonist SR141716A in an early and advanced stage of 1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine-induced parkinsonism. In both models of Parkinson's disease, SR141716A failed to alleviate the motor deficits of parkinsonism. Cannabinoid agonists do not induce catalepsy in primates, a finding that differs from their effects in rodents. The primate may be more suitable than rodents for predicting the effects of cannabinoids and their therapeutic potential on select primate behaviors.
How do 'stimulants' reduce hyperactivity in children and adults? How can drugs wh... more How do 'stimulants' reduce hyperactivity in children and adults? How can drugs which raise extracellular dopamine result in psychomotor slowing of hyperactive children when dopamine is known to enhance motor activity, such as in Parkinson's disease? These apparent paradoxes are the focus of this brief review on the mechanism of action of stimulant medications used in the treatment of children, and of an increasing number of adults who meet diagnostic criteria for attention deficit hyperactivity disorder.
How do 'stimulants' reduce hyperactivity in children and adults? How can drugs which rais... more How do 'stimulants' reduce hyperactivity in children and adults? How can drugs which raise extracellular dopamine result in psychomotor slowing of hyperactive children when dopamine is known to enhance motor activity, such as in Parkinson's disease? These apparent paradoxes are the focus of this brief review on the mechanism of action of stimulant medications used in the treatment of children, and of an increasing number of adults who meet diagnostic criteria for attention deficit hyperactivity disorder.
The spontaneous behavior of humans can be altered dramatically by repeated exposure to psychomoto... more The spontaneous behavior of humans can be altered dramatically by repeated exposure to psychomotor stimulants. We have developed a primate model for analyzing the neurobiology underlying such drug-induced behavioral changes. We performed ethogram-based behavioral assays on squirrel monkeys given single or multiple cocaine treatments, and in the same monkeys made anatomical plots of striatal neurons that were activated to express early-gene proteins. A final cocaine challenge after chronic intermittent exposure to cocaine induced highly patterned behavioral changes in the monkeys, affecting individual behavioral motifs in distinct ways. In the striatum, the challenge dose induced striosome-predominant expression combined with intense dorsal early-gene expression, especially in the putamen. These patterns of gene expression were highly predictive of the levels of stereotypy exhibited by the monkeys in response to cocaine challenge. The total levels of expression, on the other hand, appeared to reflect increased spontaneous behavioral activation during the drug-free period after the cocaine exposure. We suggest that in the primate, compartmentally and regionally specific striatal activation patterns contribute to the striatal modulation of psychostimulant-induced behaviors. These observations in nonhuman primates raise the possibility that monitoring such basal ganglia activity patterns could help to delineate the neural mechanisms underlying drug-induced repetitive behaviors and related syndromes in which stereotypies are manifest.
Various transplanted leukemias and normal tissues of the mouse were tested for asparagine synthet... more Various transplanted leukemias and normal tissues of the mouse were tested for asparagine synthetase activity. Leukemias susceptible to suppression by asparaginase have little or no synthetase activity. In contrast, leukemias insensitive to asparaginase exhibit substantial and often very high asparagine synthetase activity. Asparaginase-resistant variants of sensitive leukemias also have considerable synthetase activity. Thus the requirement by certain malignant cells of exogenous asparagine, which entails sensitivity to asparaginase, may be ascribed to lack of asparagine synthetase. Development of asparaginase-resistant variants from asparaginase-sensitive lines is consistently associated with acquisition of asparagine synthetase activity.
Although cannabinoid effects on motor function have been extensively studied in rodents, the role... more Although cannabinoid effects on motor function have been extensively studied in rodents, the role of cannabinoids in regulating behavior in primates is relatively unknown. We compared the effects of cannabinoid agonists and dopamine antagonists on unconditioned behaviors in cynomolgus monkeys (Macaca fascicularis). We further investigated the therapeutic potential of cannabinoid antagonists in a primate model of Parkinson's disease. Drugs were administered i.m., and sessions were videotaped and rated by a "blind" observer using a rating scale. The dopamine antagonist haloperidol decreased locomotor activity and increased bradykinesia in three subjects. Haloperidol also produced a dose-dependent increase in freezing and catalepsy in two out of the three subjects. The cannabinoid agonist levonantradol dose-dependently decreased general and locomotor activity and increased bradykinesia. In contrast to haloperidol, levonantradol failed to produce freezing or catalepsy. At the dose range studied, tetrahydrocannabinol did not affect general or locomotor activity, but increased bradykinesia. In view of the psychomotor slowing induced by cannabinoid agonists, we investigated the therapeutic potential of the cannabinoid receptor antagonist SR141716A in an early and advanced stage of 1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine-induced parkinsonism. In both models of Parkinson's disease, SR141716A failed to alleviate the motor deficits of parkinsonism. Cannabinoid agonists do not induce catalepsy in primates, a finding that differs from their effects in rodents. The primate may be more suitable than rodents for predicting the effects of cannabinoids and their therapeutic potential on select primate behaviors.
DI and D2 dopamine receptors were characterized in the caudate-putamen region of nonhuman primate... more DI and D2 dopamine receptors were characterized in the caudate-putamen region of nonhuman primate brains (Macaca fascicularis). D1 dopamine receptors were identified with [3H]SCH 23390 and D2 receptors with [3H]spiperone. Scatchard analysis of [3H]SCH 23390 saturation data using washed membranes revealed a single high-affinity binding site (KD, 0.352 f 0.027 nM) with a density (Bmm) of 35.7 f 2.68 pmol/g original wet tissue weight (n = 10). The affinity of [3H]spiperone for the D2 site was 0.039 f 0.007 nMand the density was 25.7 f 1.97 pmol/g original wet tissue weight (n = 10). D1 and D2 receptors in nonhuman primates may be differentiated on the basis of drug affinities and stereoselectivity. In competition experiments, RS-SKF 38393 was the most selective D1 agonist, whereas (+)-4-propyl-9-hydroxynaphthoxazine [( +)-PHNO] was the most selective D2 agonist. Apomorphine was essentially nonselective for D1 or D2 binding sites. Of Abbreviations used: (+)-PHNO, (+)-4-propyl-9-hydroxynaphthoxazine; N-0434, 2-(N-propyl-N-phenylethylamino)-5-hydroxytetralin; N-0437, 2-(N-propyl-N-2-thienylethylamino)-5-hydroxy-tetralin; SCH 23390, (R)-(+)- ,5-tetrahydro-3methyl-5-phenyl-1 H-3-benzazepine-7-01; SCH 23388, S-SCH 23390; R-SKF 83566, (R)-7-bromo-8-hydroxyl-3-methyl-1-pheny1-2,3,4,5-tetrahydro-lH-3-benzazepine; SKF 38393, 1phenyl-2,3,4,5-tetrahydro-lH-3-benzazepine-7,8-diol; RS-SKF 83692, 2,3,4,5-tetrahydro-3-methyl-5-phenyl-lH-3-benzazepine-7-01; YM-09 15 1-2, cis-N-( 1 -benzyl-2-methylpyrrolidine-3-yl)-5chloro-2-methoxy-4-methylaminobenzamide.
The metabolism of a-methyltryptophan was studied in the rat. The amethylamino acid was measured b... more The metabolism of a-methyltryptophan was studied in the rat. The amethylamino acid was measured by calorimetric and radioactive methods (the latter used for tritium-labeled material) at various time intervals after its intraperitoneal injection. The specific uptake (pg/g organ) was highest in the kidneys, pancreas, and intestinal tract. The amino acid was detectable in these organs, as well as in the liver and plasma, for at least four days. There were low concentrations in the brain, spleen, heart, and lungs. a-Methyltryptophan caused an increased excretion of kynurenic and xanthurenic acids for two days after its administration, thus displaying an effect on the metabolism of endogenous tryptophan.
How do 'stimulants' reduce hyperactivity in children and adults? How can drugs which raise extrac... more How do 'stimulants' reduce hyperactivity in children and adults? How can drugs which raise extracellular dopamine result in psychomotor slowing of hyperactive children when dopamine is known to enhance motor activity, such as in Parkinson's disease? In summary, the hypothesis for the anti-hyperactivity effects of the stimulants is as follows: during normal nerve activity, extracellular dopamine levels transiently rise 60-fold. At low therapeutic doses (0.2-0.5 mg/kg) to treat attention-deficit hyperactivity disorder, stimulant drugs such as methylphenidate and dextroamphetamine reduce locomotion in both humans and animals. The drugs raise resting extracellular levels of dopamine several-fold, but reduce the extent to which dopamine is released with nerve impulses, compared to the impulse-associated release in the absence of the drug. This relatively reduced amplitude of impulse-associated dopamine would result in less activation of post-synaptic dopamine receptors which drive psychomotor activity. At higher doses, stimulants produce generalized stimulation of the nervous system, as a result of the very high concentrations of extracellular dopamine at rest, and the markedly increased release of dopamine with nerve impulses. These high levels of resting and pulsatile dopamine cause widespread stimulation of post-synaptic dopamine receptors, overcoming any concomitant presynaptic inhibition of dopamine release.
The potent cocaine analog 2 beta-carbomethoxy-3 beta-(4-fluorophenyl)-tropane (CFT, also designat... more The potent cocaine analog 2 beta-carbomethoxy-3 beta-(4-fluorophenyl)-tropane (CFT, also designated WIN 35,428) was tritiated and evaluated as a molecular probe for cocaine receptors in caudate putamen membranes of cynomolgus monkeys. Kinetic, saturation, and competition experiments indicated that [3H]CFT, like [3H]cocaine, bound to at least two components. Association and dissociation of the radioligand at 0-4 degrees occurred in two phases; the t 1/2 for dissociation of the fast and slow components was 2.5 and 23 min, respectively. Saturation analysis revealed high and low affinity binding components with affinities (Kd) of 4.7 +/- 1.2 and 60 +/- 12 nM (means +/- SE) and densities (Bmax) of 50 +/- 18 and 290 +/- 20 pmol/g of tissue, respectively. [3H]CFT was displaced stereoselectively by the enantiomers of cocaine and by the diastereoisomers of the phenyltropane analog of cocaine. Most congeners displaced [3H]CFT fully, with shallow competition curves (nH, 0.69-0.81). In contrast...
Pharmacology Biochemistry and Behavior, Sep 1, 1991
administration of the high-affinity cocaine analog 2f3-carbomethoxy-3f3-(4-fluorophenyl)tropane. ... more administration of the high-affinity cocaine analog 2f3-carbomethoxy-3f3-(4-fluorophenyl)tropane. PHARMACOL BIOCHEM BEHAV 39(4) [1011][1012][1013] 1991.--Self-administration of the high-affinity cocaine analog 2[3-carbomethoxy-313-(4-fluorophenyl)tropane (CFT) and cocaine were compared in squirrel monkeys responding under a second-order schedule of IV drug injection. Both CFF and cocaine maintained self-administration in all subjects. As the dose of either drug was increased, the rate of responding first increased and then decreased. Although the two drugs had qualitatively similar effects, CFT was approximately six times more potent than cocaine. This potency relation corresponds closely with the potency relations reported for CFT and cocaine in studies of dopamine uptake inhibition and binding at cocaine recognition sites. The results are consistent with the view that the reinforcing effects of cocaine-like drugs are mediated at cocaine recognition sites associated with the dopamine uptake system, and suggest that radioligand probes based on CFT may be suitable markers for these sites.
Journal of Pharmacology and Experimental Therapeutics, Mar 1, 2000
In primates, CB 1 cannabinoid receptor agonists produce sedation and psychomotor slowing, in cont... more In primates, CB 1 cannabinoid receptor agonists produce sedation and psychomotor slowing, in contrast to behavioral stimulation produced by high doses of dopamine receptor agonists. To investigate whether dopamine agonists attenuate the sedative effects of a cannabinoid agonist in monkeys, we compared the effects of D 1 or D 2 dopamine receptor agonists on spontaneous behavior in three to six cynomolgus monkeys (Macaca fasicularis) alone and after administration of a low dose of the CB 1 agonist levonantradol. Alone, the CB 1 cannabinoid receptor agonist levonantradol (0.01-0.3 mg/kg) induced sedation, ptosis, and decreased locomotor and general activity. Alone, D 2 -type dopamine agonists quinelorane (0.001-1.0 mg/kg; n ϭ 4) or pergolide (0.01-1.0 mg/kg) or a D 1 dopamine agonist 6-chloro-7,8-dihydroxy-1-phenyl-2,3,4,5-tetrahydro-3-allyl-[1H]-3-benzazepine (0.3-3.0 mg/kg) produced either no effect or promoted hyperactivity. Thirty minutes after
Almtraet--The formation of respiratory 14COz from injected tryptophan-14C is reduced in vivo afte... more Almtraet--The formation of respiratory 14COz from injected tryptophan-14C is reduced in vivo after the simultaneous administration of certain analogs of tryptophan, a-Hydrazinotryptophan lowered the rate of metabolism of tryptophan-2-x4C (label in the pyrrole ring) and, to an even greater extent, that of tryptophan-y-14C (label in the side chain). The oxidation of tryptophan-benzene-laC was unaffected by this analog, a-Hydrazino-5-hydroxytryptophan had the same relative action on the metabolism of tryptophan-2and -Y-IaC, but the effect was smaller. Several compounds that diminished the rate of oxidation of tryptophan in vivo inhibited tryptophan pyrrolase in vitro. A notable exception is tryptophol, which inhibited tryptophan pyrrolase by 92 per cent when present at a concentration of 10 -3 M in vitro, but which gave inconclusive results in vivo. The pattern of inhibition of the breakdown of differentially labeled metabolites provides a useful tool in detecting rate-limiting steps in a metabolic sequence in vivo.
Http Dx Doi Org 10 1080 0964704x 2012 678199, Jan 16, 2013
The 1975 publication of Seeman et al. (Proc Nat Acad Sci, USA), reporting the discovery of the an... more The 1975 publication of Seeman et al. (Proc Nat Acad Sci, USA), reporting the discovery of the antipsychotic receptor in the brain, is a classic example of translational medicine research. In searching for a pathophysiological mechanism of psychosis, the team sought to identify sites that bound the antipsychotic drug haloperidol. Their criterion was that haloperidol bound to the site at one to two nanomoles per liter, corresponding to haloperidol concentrations found in spinal fluid or plasma water in treated patients. They requested de novo synthesis of tritiated haloperidol, and it readily detected specific haloperidol binding sites in brain striatum. With dopamine binding the haloperidol-labeled sites with higher potency than other neurotransmitters, the sites were named antipsychotic/dopamine receptors (now designated dopamine D2 receptors). Most significantly, they found that all antipsychotics bound these sites at concentrations and with a rank order of potencies that were directly related to the mean daily antipsychotic dose taken by patients with schizophrenia. Their findings enabled screening for new antipsychotics, initiated D2 receptor measurements in brain of living patients, and determination of minimum occupancy (65%) of D2 receptors for antipsychotic benefit. The collective work is generally viewed as providing a fundamental basis for the dopamine hypothesis of schizophrenia.
Fluorescent probes have been designed and developed for dopamine D-1 and D-2 receptors. Fluoresce... more Fluorescent probes have been designed and developed for dopamine D-1 and D-2 receptors. Fluorescein and/or NBD (7-nitrobenz-2-oxa-1,3-diazol-4-yl) derivatives of PPHT (D-2 agonist), spiperone (D-2 antagonist), SKF 38393 (D-1 agonist), and SKF 83566 (D-1 antagonist) were synthesized via their amino-functionalized analogues and all ligands were pharmacologically evaluated by measuring their ability to displace [3H]SCH 23390 and [3H]spiperone from D-1 and D-2 receptor sites in caudate putamen of monkeys (Macaca fascicularis). The fluorescein derivatives of PPHT and SKF 83566 and the NBD derivatives of spiperone and SKF 83566 retained the high affinity and selectivity of the parent ligands. The NBD derivatives of PPHT showed higher D-2 receptor affinity and selectivity than their parent ligands. The enantiomers of the fluorescent derivatives of PPHT were also synthesized and were found to exhibit stereoselectivity in binding to the D-2 receptor, with the S enantiomers having a considerably higher affinity than their R analogues. In contrast to these results, the fluorescein derivative of SKF 38393 showed only a low affinity for the D-1 receptor. These fluorescein- and NBD-coupled D-1 and D-2 receptor ligands have considerable significance as potential probes in the study of distribution of the receptors at the cellular/subcellular level and of their mobility in membranes in normal/diseased states by use of fluorescence microscopic and fluorescence photobleaching recovery techniques, respectively. The development of these novel fluorescent probes should also provide new leads for the design and synthesis of additional fluorescent ligands with better fluorescent properties and/or higher affinity/selectivity for the DA receptors.
Although cannabinoid effects on motor function have been extensively studied in rodents, the role... more Although cannabinoid effects on motor function have been extensively studied in rodents, the role of cannabinoids in regulating behavior in primates is relatively unknown. We compared the effects of cannabinoid agonists and dopamine antagonists on unconditioned behaviors in cynomolgus monkeys (Macaca fascicularis). We further investigated the therapeutic potential of cannabinoid antagonists in a primate model of Parkinson's disease. Drugs were administered i.m., and sessions were videotaped and rated by a "blind" observer using a rating scale. The dopamine antagonist haloperidol decreased locomotor activity and increased bradykinesia in three subjects. Haloperidol also produced a dose-dependent increase in freezing and catalepsy in two out of the three subjects. The cannabinoid agonist levonantradol dose-dependently decreased general and locomotor activity and increased bradykinesia. In contrast to haloperidol, levonantradol failed to produce freezing or catalepsy. At the dose range studied, tetrahydrocannabinol did not affect general or locomotor activity, but increased bradykinesia. In view of the psychomotor slowing induced by cannabinoid agonists, we investigated the therapeutic potential of the cannabinoid receptor antagonist SR141716A in an early and advanced stage of 1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine-induced parkinsonism. In both models of Parkinson's disease, SR141716A failed to alleviate the motor deficits of parkinsonism. Cannabinoid agonists do not induce catalepsy in primates, a finding that differs from their effects in rodents. The primate may be more suitable than rodents for predicting the effects of cannabinoids and their therapeutic potential on select primate behaviors.
How do 'stimulants' reduce hyperactivity in children and adults? How can drugs wh... more How do 'stimulants' reduce hyperactivity in children and adults? How can drugs which raise extracellular dopamine result in psychomotor slowing of hyperactive children when dopamine is known to enhance motor activity, such as in Parkinson's disease? These apparent paradoxes are the focus of this brief review on the mechanism of action of stimulant medications used in the treatment of children, and of an increasing number of adults who meet diagnostic criteria for attention deficit hyperactivity disorder.
How do 'stimulants' reduce hyperactivity in children and adults? How can drugs which rais... more How do 'stimulants' reduce hyperactivity in children and adults? How can drugs which raise extracellular dopamine result in psychomotor slowing of hyperactive children when dopamine is known to enhance motor activity, such as in Parkinson's disease? These apparent paradoxes are the focus of this brief review on the mechanism of action of stimulant medications used in the treatment of children, and of an increasing number of adults who meet diagnostic criteria for attention deficit hyperactivity disorder.
The spontaneous behavior of humans can be altered dramatically by repeated exposure to psychomoto... more The spontaneous behavior of humans can be altered dramatically by repeated exposure to psychomotor stimulants. We have developed a primate model for analyzing the neurobiology underlying such drug-induced behavioral changes. We performed ethogram-based behavioral assays on squirrel monkeys given single or multiple cocaine treatments, and in the same monkeys made anatomical plots of striatal neurons that were activated to express early-gene proteins. A final cocaine challenge after chronic intermittent exposure to cocaine induced highly patterned behavioral changes in the monkeys, affecting individual behavioral motifs in distinct ways. In the striatum, the challenge dose induced striosome-predominant expression combined with intense dorsal early-gene expression, especially in the putamen. These patterns of gene expression were highly predictive of the levels of stereotypy exhibited by the monkeys in response to cocaine challenge. The total levels of expression, on the other hand, appeared to reflect increased spontaneous behavioral activation during the drug-free period after the cocaine exposure. We suggest that in the primate, compartmentally and regionally specific striatal activation patterns contribute to the striatal modulation of psychostimulant-induced behaviors. These observations in nonhuman primates raise the possibility that monitoring such basal ganglia activity patterns could help to delineate the neural mechanisms underlying drug-induced repetitive behaviors and related syndromes in which stereotypies are manifest.
Various transplanted leukemias and normal tissues of the mouse were tested for asparagine synthet... more Various transplanted leukemias and normal tissues of the mouse were tested for asparagine synthetase activity. Leukemias susceptible to suppression by asparaginase have little or no synthetase activity. In contrast, leukemias insensitive to asparaginase exhibit substantial and often very high asparagine synthetase activity. Asparaginase-resistant variants of sensitive leukemias also have considerable synthetase activity. Thus the requirement by certain malignant cells of exogenous asparagine, which entails sensitivity to asparaginase, may be ascribed to lack of asparagine synthetase. Development of asparaginase-resistant variants from asparaginase-sensitive lines is consistently associated with acquisition of asparagine synthetase activity.
Although cannabinoid effects on motor function have been extensively studied in rodents, the role... more Although cannabinoid effects on motor function have been extensively studied in rodents, the role of cannabinoids in regulating behavior in primates is relatively unknown. We compared the effects of cannabinoid agonists and dopamine antagonists on unconditioned behaviors in cynomolgus monkeys (Macaca fascicularis). We further investigated the therapeutic potential of cannabinoid antagonists in a primate model of Parkinson's disease. Drugs were administered i.m., and sessions were videotaped and rated by a "blind" observer using a rating scale. The dopamine antagonist haloperidol decreased locomotor activity and increased bradykinesia in three subjects. Haloperidol also produced a dose-dependent increase in freezing and catalepsy in two out of the three subjects. The cannabinoid agonist levonantradol dose-dependently decreased general and locomotor activity and increased bradykinesia. In contrast to haloperidol, levonantradol failed to produce freezing or catalepsy. At the dose range studied, tetrahydrocannabinol did not affect general or locomotor activity, but increased bradykinesia. In view of the psychomotor slowing induced by cannabinoid agonists, we investigated the therapeutic potential of the cannabinoid receptor antagonist SR141716A in an early and advanced stage of 1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine-induced parkinsonism. In both models of Parkinson's disease, SR141716A failed to alleviate the motor deficits of parkinsonism. Cannabinoid agonists do not induce catalepsy in primates, a finding that differs from their effects in rodents. The primate may be more suitable than rodents for predicting the effects of cannabinoids and their therapeutic potential on select primate behaviors.
DI and D2 dopamine receptors were characterized in the caudate-putamen region of nonhuman primate... more DI and D2 dopamine receptors were characterized in the caudate-putamen region of nonhuman primate brains (Macaca fascicularis). D1 dopamine receptors were identified with [3H]SCH 23390 and D2 receptors with [3H]spiperone. Scatchard analysis of [3H]SCH 23390 saturation data using washed membranes revealed a single high-affinity binding site (KD, 0.352 f 0.027 nM) with a density (Bmm) of 35.7 f 2.68 pmol/g original wet tissue weight (n = 10). The affinity of [3H]spiperone for the D2 site was 0.039 f 0.007 nMand the density was 25.7 f 1.97 pmol/g original wet tissue weight (n = 10). D1 and D2 receptors in nonhuman primates may be differentiated on the basis of drug affinities and stereoselectivity. In competition experiments, RS-SKF 38393 was the most selective D1 agonist, whereas (+)-4-propyl-9-hydroxynaphthoxazine [( +)-PHNO] was the most selective D2 agonist. Apomorphine was essentially nonselective for D1 or D2 binding sites. Of Abbreviations used: (+)-PHNO, (+)-4-propyl-9-hydroxynaphthoxazine; N-0434, 2-(N-propyl-N-phenylethylamino)-5-hydroxytetralin; N-0437, 2-(N-propyl-N-2-thienylethylamino)-5-hydroxy-tetralin; SCH 23390, (R)-(+)- ,5-tetrahydro-3methyl-5-phenyl-1 H-3-benzazepine-7-01; SCH 23388, S-SCH 23390; R-SKF 83566, (R)-7-bromo-8-hydroxyl-3-methyl-1-pheny1-2,3,4,5-tetrahydro-lH-3-benzazepine; SKF 38393, 1phenyl-2,3,4,5-tetrahydro-lH-3-benzazepine-7,8-diol; RS-SKF 83692, 2,3,4,5-tetrahydro-3-methyl-5-phenyl-lH-3-benzazepine-7-01; YM-09 15 1-2, cis-N-( 1 -benzyl-2-methylpyrrolidine-3-yl)-5chloro-2-methoxy-4-methylaminobenzamide.
The metabolism of a-methyltryptophan was studied in the rat. The amethylamino acid was measured b... more The metabolism of a-methyltryptophan was studied in the rat. The amethylamino acid was measured by calorimetric and radioactive methods (the latter used for tritium-labeled material) at various time intervals after its intraperitoneal injection. The specific uptake (pg/g organ) was highest in the kidneys, pancreas, and intestinal tract. The amino acid was detectable in these organs, as well as in the liver and plasma, for at least four days. There were low concentrations in the brain, spleen, heart, and lungs. a-Methyltryptophan caused an increased excretion of kynurenic and xanthurenic acids for two days after its administration, thus displaying an effect on the metabolism of endogenous tryptophan.
How do 'stimulants' reduce hyperactivity in children and adults? How can drugs which raise extrac... more How do 'stimulants' reduce hyperactivity in children and adults? How can drugs which raise extracellular dopamine result in psychomotor slowing of hyperactive children when dopamine is known to enhance motor activity, such as in Parkinson's disease? In summary, the hypothesis for the anti-hyperactivity effects of the stimulants is as follows: during normal nerve activity, extracellular dopamine levels transiently rise 60-fold. At low therapeutic doses (0.2-0.5 mg/kg) to treat attention-deficit hyperactivity disorder, stimulant drugs such as methylphenidate and dextroamphetamine reduce locomotion in both humans and animals. The drugs raise resting extracellular levels of dopamine several-fold, but reduce the extent to which dopamine is released with nerve impulses, compared to the impulse-associated release in the absence of the drug. This relatively reduced amplitude of impulse-associated dopamine would result in less activation of post-synaptic dopamine receptors which drive psychomotor activity. At higher doses, stimulants produce generalized stimulation of the nervous system, as a result of the very high concentrations of extracellular dopamine at rest, and the markedly increased release of dopamine with nerve impulses. These high levels of resting and pulsatile dopamine cause widespread stimulation of post-synaptic dopamine receptors, overcoming any concomitant presynaptic inhibition of dopamine release.
The potent cocaine analog 2 beta-carbomethoxy-3 beta-(4-fluorophenyl)-tropane (CFT, also designat... more The potent cocaine analog 2 beta-carbomethoxy-3 beta-(4-fluorophenyl)-tropane (CFT, also designated WIN 35,428) was tritiated and evaluated as a molecular probe for cocaine receptors in caudate putamen membranes of cynomolgus monkeys. Kinetic, saturation, and competition experiments indicated that [3H]CFT, like [3H]cocaine, bound to at least two components. Association and dissociation of the radioligand at 0-4 degrees occurred in two phases; the t 1/2 for dissociation of the fast and slow components was 2.5 and 23 min, respectively. Saturation analysis revealed high and low affinity binding components with affinities (Kd) of 4.7 +/- 1.2 and 60 +/- 12 nM (means +/- SE) and densities (Bmax) of 50 +/- 18 and 290 +/- 20 pmol/g of tissue, respectively. [3H]CFT was displaced stereoselectively by the enantiomers of cocaine and by the diastereoisomers of the phenyltropane analog of cocaine. Most congeners displaced [3H]CFT fully, with shallow competition curves (nH, 0.69-0.81). In contrast...
Pharmacology Biochemistry and Behavior, Sep 1, 1991
administration of the high-affinity cocaine analog 2f3-carbomethoxy-3f3-(4-fluorophenyl)tropane. ... more administration of the high-affinity cocaine analog 2f3-carbomethoxy-3f3-(4-fluorophenyl)tropane. PHARMACOL BIOCHEM BEHAV 39(4) [1011][1012][1013] 1991.--Self-administration of the high-affinity cocaine analog 2[3-carbomethoxy-313-(4-fluorophenyl)tropane (CFT) and cocaine were compared in squirrel monkeys responding under a second-order schedule of IV drug injection. Both CFF and cocaine maintained self-administration in all subjects. As the dose of either drug was increased, the rate of responding first increased and then decreased. Although the two drugs had qualitatively similar effects, CFT was approximately six times more potent than cocaine. This potency relation corresponds closely with the potency relations reported for CFT and cocaine in studies of dopamine uptake inhibition and binding at cocaine recognition sites. The results are consistent with the view that the reinforcing effects of cocaine-like drugs are mediated at cocaine recognition sites associated with the dopamine uptake system, and suggest that radioligand probes based on CFT may be suitable markers for these sites.
Journal of Pharmacology and Experimental Therapeutics, Mar 1, 2000
In primates, CB 1 cannabinoid receptor agonists produce sedation and psychomotor slowing, in cont... more In primates, CB 1 cannabinoid receptor agonists produce sedation and psychomotor slowing, in contrast to behavioral stimulation produced by high doses of dopamine receptor agonists. To investigate whether dopamine agonists attenuate the sedative effects of a cannabinoid agonist in monkeys, we compared the effects of D 1 or D 2 dopamine receptor agonists on spontaneous behavior in three to six cynomolgus monkeys (Macaca fasicularis) alone and after administration of a low dose of the CB 1 agonist levonantradol. Alone, the CB 1 cannabinoid receptor agonist levonantradol (0.01-0.3 mg/kg) induced sedation, ptosis, and decreased locomotor and general activity. Alone, D 2 -type dopamine agonists quinelorane (0.001-1.0 mg/kg; n ϭ 4) or pergolide (0.01-1.0 mg/kg) or a D 1 dopamine agonist 6-chloro-7,8-dihydroxy-1-phenyl-2,3,4,5-tetrahydro-3-allyl-[1H]-3-benzazepine (0.3-3.0 mg/kg) produced either no effect or promoted hyperactivity. Thirty minutes after
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Papers by Bertha Madras