John Elsworth

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University of Waterloo

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Kansas State University

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École Normale Supérieure de Lyon

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Sorbonne Université, Université Pierre et Marie Curie & CNRS

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Emory University

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Universidade Federal do Rio Grande do Norte

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Universidad Nacional Autónoma de México

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Rajiv Gandhi University of Health Sciences

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Selective monoamine-oxidase inhibition in man : a biochemical and pharmacological study

ABSTRACT

Clonidine suppression of noradrenergic hyperactivity during morphine withdrawal by clonidine: Biochemical studies in rodents and primates

The Journal of Clinical Psychiatry

In rodents, naloxone-precipitated withdrawal of morphine-dependent animals causes an increase in ... more In rodents, naloxone-precipitated withdrawal of morphine-dependent animals causes an increase in NE turnover and MHPG accumulation in certain regions of the brain. This increase in NE turnover and MHPG accumulation is suppressed by clonidine to a dose-dependent degree via a naloxone-insensitive mechanism. In general, drugs which have been shown by electrophysiological studies to cause changes in the activity of NE neurons in the locus coeruleus also alter the brain levels of MHPG. These studies suggest that the brain levels of MHPG may be used as a biochemical measure of alterations of impulse flow in NE neurons of the locus coeruleus. In morphine-dependent vervet monkeys, administration of naloxone or naltrexone causes an increase in the brain levels of MHPG. The increase in MHPG observed during withdrawal is suppressed by clonidine. Brain levels of MHPG measured in both drug-treated and control monkeys correlate significantly with plasma and CSF measures of MHPG. These observations suggest that under controlled conditions plasma MHPG can provide a reasonable measure of brain NE metabolism in primates. Pilot data from clinical studies taken together with the more direct observations made in non-human primates are consistent with the hypothesis that in humans brain NE systems become hyperactive during opiate withdrawal and that this hyperactivity of NE systems is suppressed by clonidine.

Ethanol and endogenous ligands in humans

Psychopharmacology bulletin

Tribulin: an endogenous monoamine oxidase inhibitor/benzodiazepine receptor ligand

Progress in clinical and biological research

Tribulin is a low molecular weight inhibitor both of monoamine oxidase and of benzodiazepine rece... more Tribulin is a low molecular weight inhibitor both of monoamine oxidase and of benzodiazepine receptor binding. It has been highly purified from human urine and has also been isolated from human plasma and animal brain. Its structure is still unknown but its properties do not appear to correspond with any known monoamine or benzodiazepine receptor binding inhibitor. Tribulin output has been found to be increased in a variety of states associated with stress and anxiety, including lactate-induced panic attacks, alcohol or benzodiazepine withdrawal and generalized anxiety disorder.

Monoamine oxidase and its inhibition: Some clinical implications

Cocaethylene inhibits uptake of dopamine and can reach high plasma concentrations following combined cocaine and ethanol use

NIDA research monograph

Biochemical Changes Induced by Embryonic Substantia Nigra Transplanted to the Striatum of Parkinsonian Monkeys

Neural Plasticity

Parkinsonian behavioral deficits are improved following transplantation of fetal dopamine (DA) ne... more Parkinsonian behavioral deficits are improved following transplantation of fetal dopamine (DA) neurons to the striatum of MPTP-treated monkeys, although the mechanism of the recovery has not been resolved. While there is good evidence for the survival of grafted tyrosine hydroxylase (TH)-positive cells following their placement in caudate nucleus, it is not known whether they provide sufficient DA to the caudate nucleus to account for the behavioral effects of transplantation.

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Quantitative Behavioral Assessment Methods for the Analysis of Graft-Induced Motor and Cognitive Function in the MPTP-Treated Parkinsonian Monkey

Neural Plasticity

Although the MPTP-treated monkey is the best available model of Parkinson's disease in terms of n... more Although the MPTP-treated monkey is the best available model of Parkinson's disease in terms of neuropathophysiology, the usefulness of the model for the functional analysis of neural grafts requires methods that can determine the severity and persistence of the symptoms. Wide variation in response to MPTP and reports of "spontaneous" recovery may warrant a variety of assessment methods to determine the severity of parkinsonism and this requires large numbers of subjects and groups. It is critical that the severity of the MPTP deficit be known in order to compare MPTP-treated subjects with fetal substantia nigra (SN) implanted into the caudate nucleus (CN) with similarly affected subjects given sham surgery, "inappropriate" surgery (cerebellar tissue into the CN or SN tissue into the cortex), or no surgery. If subjects in these groups are not compared by severity it will not be possible to differentiate between graftinduced and spontaneously-induced improvements. We have aimed to establish a variety of behavioral assessment methods that can identify the severity of the MPTP-induced behavioral deficit. With these methods we can more accurately study the restorative effects of grafts in MPTP-treated monkeys with which the biochemical and morphological effects can be compared. We have used the following methodologies in our studies: 1) spontaneous behavioral ratings; 2) cognitive and subtle motor skill task performance, and 3) eye-blink rate measurements.

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D1 and D2 dopamine receptors independently regulate spontaneous blink rate in the vervet monkey

Journal of Pharmacology and Experimental Therapeutics

Previous studies have revealed the involvement of a dopaminergic link in the regulation of sponta... more Previous studies have revealed the involvement of a dopaminergic link in the regulation of spontaneous eye blink rate in primates. Based on the effect of dopamine D2 receptor-selective drugs and the anecdotal failure of the partial D1 agonist, SKF 38393, to alter blink rate in monkeys, it was assumed that D1 dopamine receptors did not control blink rate. The recent availability of dihydrexidine, a full D1 agonist, prompted us to reevaluate the role of D1 and D2 receptors in the regulation of blink rate. African green monkeys (n = 5) were used in all studies. Dihydrexidine produced a rapid and dose-dependent (up to 1 mg/kg, i.m.) increase in blink rate. The elevation in blink rate elicited by 0.3 mg/kg dihydrexidine was completely reversed by prior administration of a specific D1 antagonist, SCH 23390 (0.01 mg/kg, i.m.), but was unaffected by prior administration of a specific D2 antagonist, remoxipride (1 mg/kg, i.m.). Treatment with the specific D2 agonist, (+)-4-propyl-9-hydroxynaphthoxazine, led to a rapid and dose-dependent (up to 0.01 mg/kg, i.m.) increase in blink rate. The raised blink rate produced by (+)-4-propyl-9-hydroxynaphthoxazine (0.001 mg/kg) was abolished by pretreatment with remoxipride, but was not influenced by pretreatment with SCH 23390. These data indicate that spontaneous blink rate in the primate can be regulated by both D1 and D2 dopamine receptors. Furthermore, the receptor subtypes appear to affect blink rate in the same direction, yet function independently. Measurement of blink rate may provide a noninvasive method to assess the potency and selectivity of dopamine agonists and antagonists in primates.

Sensitization to the locomotor activating effects of cocaine following cocaethylene-preexposure

Brain Research

The present study assessed the ability of cocaethylene to induce sensitization to the behavioral ... more The present study assessed the ability of cocaethylene to induce sensitization to the behavioral activating effects of cocaine in the male Sprague-Dawley rat. Preexposure to cocaethylene (15 or 25 mg/kg) significantly enhanced the locomotor activating effects of a subsequent cocaine (15 mg/kg) challenge injection. In addition, acute intraperitoneal administration at several doses (10, 15, or 25 mg/kg) confirmed previous reports of increased bioavailability of cocaine in brain and plasma relative to cocaethylene. These data are discussed in terms of previous work in which a significant augmentation of cocaine-induced locomotor activity was not observed following cocaethylene preexposure.

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Phencyclidine increases forebrain monoamine metabolism in rats and monkeys: Modulation by the isomers of HA966

The Journal of Neuroscience : The Official Journal of the Society for Neuroscience

The noncompetitive NMDA receptor antagonist phencyclidine (PCP) has psychotomimetic properties in... more The noncompetitive NMDA receptor antagonist phencyclidine (PCP) has psychotomimetic properties in humans and activates the frontal cortical dopamine innervation in rats, findings that have contributed to a hyperdopaminergic hypothesis of schizophrenia. In the present studies, the effects of the enantiomers of 3-amino-1-hydroxypyrrolid-2-one (HA966) on PCP-induced changes in monoamine metabolism in the forebrain of rats and monkeys were examined, because HA966 has been shown previously to attenuate stress-or drug-induced activation of dopamine systems. In rats, PCP (10 mg/kg, i.p.) potently activated dopamine (DA) turnover in the medial prefrontal cortex (PFC) and nucleus accumbens. Serotonin utilization was also increased in PFC. Pretreatment with either R-(ϩ)HA966 (15 mg/kg, i.p.) or S-(Ϫ)HA966 (3 mg/kg, i.p.) partially blocked PCP-induced increases in PFC DA turnover, whereas neither enantiomer altered the effect of PCP on DA turnover in the nucleus accumbens or the PCP-induced increases in serotonin turnover in PFC. PCP (0.3 mg/kg, i.m.) exerted regionally selective effects on the dopaminergic and serotonergic innervation of the monkey frontal cortex, effects blocked by pretreatment with S-(Ϫ)HA966 (3 mg/kg, i.m.). Importantly, these data demonstrate that in the primate, PCP has potent effects on dopamine transmission in the frontal cortex, a brain region thought to be dysfunctional in schizophrenia. In addition, a role for S-(Ϫ)HA966 as a modulator of cortical monoamine transmission in primates is posited.

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(S)-(-)-HA-966, a γ-hydroxybutyrate-like agent, prevents enhanced mesocorticolimbic dopamine metabolism and behavioral correlates of restraint stress, conditioned fear and cocaine sensitization

Journal of Pharmacology and Experimental Therapeutics

This report investigates the effect of the negative enantiomer of 1-hydroxy-3-aminopyrrolidone-2 ... more This report investigates the effect of the negative enantiomer of 1-hydroxy-3-aminopyrrolidone-2 (HA-966) on behavioral and biochemical changes elicited by pharmacological or experimental paradigms which activate mesocorticolimbic dopaminergic neurotransmission. Several paradigms were used, including cocaine sensitization and two stressors: restraint for 30 min and an aversive conditioning model.

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Lidow MS, Elsworth JD, Goldman-Rakic PS. Down-regulation of the D1 and D5 dopamine receptors in the primate prefrontal cortex by chronic treatment with antipsychotic drugs. J Pharmacol Exp Ther 281: 597-603

Journal of Pharmacology and Experimental Therapeutics

ABSTRACT

Chapter 12. Fetal Grafts in Parkinson's Disease

ABSTRACT

Leranth C, Roth RH, Elswoth JD, Naftolin F, Horvath TL, Redmond Jr DE. Estrogen is essential for maintaining nigrostriatal dopamine neurons in primates: implications for Parkinson's disease and memory. J Neurosci 20: 8604-8609

The Journal of Neuroscience : The Official Journal of the Society for Neuroscience

There are sexual differences in several parameters of the nigrostriatal dopamine neurons, as well... more There are sexual differences in several parameters of the nigrostriatal dopamine neurons, as well as in the progression of diseases associated with this system, e.g., Parkinson's disease and dementia. These differences, as well as direct experimental data in rodents, suggest that gonadal hormones play a role in modulating this system. To determine whether circulating estrogen might have long-term effects by altering the number of dopamine neurons, the density of dopamine neurons was calculated in the compact zone of the substantia nigra of male and intact female short-(10 d) and longer-term (30 d) ovariectomized and short-and longer-term ovariectomized but estrogenreplaced nonhuman primates (African green monkeys). Furthermore, the number of tyrosine hydroxylase-expressing neurons, the total number of all types of neurons, and the volume of the compact zone of the substantia nigra were calculated in 30 d ovariectomized and in 30 d ovariectomized and estrogen-replaced monkeys. Unbiased stereological analyses demonstrated that a 30 d estrogen deprivation results in an apparently permanent loss of Ͼ30% of the total number of substantia nigra dopamine cells. Furthermore, the density calculations showed that brief estrogen replacement restores the density of tyrosine hydroxylase-immunoreactive cells after a 10 d, but not after a 30 d, ovariectomy. Moreover, the density of dopamine cells is higher in females than in males. These observations show the essential role of estrogen in maintaining the integrity of the nigral dopamine system, suggest a new treatment strategy for patients with Parkinson's disease and with certain forms of memoryimpairing disorders, and provide another rationale for estrogen replacement therapy for postmenopausal women.

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Fetal dopamine neural grafts: Extended reversal of methylphenyltetrahydropyridine-induced parkinsonism in monkeys

Progress in brain research

Axo-Axonic Structures in the Medial Prefrontal Cortex of the Rat: Reduction by Prenatal Exposure to Cocaine

The Journal of Neuroscience : The Official Journal of the Society for Neuroscience

The cognitive deficits associated with prenatal exposure to cocaine have been hypothesized to be ... more The cognitive deficits associated with prenatal exposure to cocaine have been hypothesized to be the results of changes in the anatomy and function of the frontal cortex. In this study, pregnant dams were treated with cocaine (3 mg/kg i.v. twice a day) and the resulting adolescent (postnatal day, ϳ45) male offspring were killed for immunocytochemical determination of the total linear measure, number, location, and lengths of inhibitory GABA transporter-1 immunoreactive axo-axonic structures commonly called "candles" or "cartridges" in the medial prefrontal cortex. These inhibitory structures are the axon terminals of GABAergic cells that impinge on the initial axon segments of excitatory pyramidal neurons. We report that prenatal cocaine exposure decreased the number of these inhibitory candles. The greatest reduction of candles was observed in the ventral prelimbic cortex. Additionally, there was a subtle difference in the pattern of distribution of candles, namely the depth of the initial candle in the ventral portions of the prefrontal cortex was greater in rats exposed to prenatal cocaine. However, there was no overt change in the number of cells that were immunoreactive for the calcium-binding protein parvalbumin, an indicator of a subset of GABAergic interneurons that includes axo-axonic chandelier cells. We conclude that exposure to cocaine in utero disrupts the development of the axo-axonic cells in the prefrontal cortex and this disruption could contribute to the cognitive deficits reported with prenatal cocaine exposure.

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Morrow BA, Elsworth JD, Rasmusson AM, Roth RH. The role of mesofrontal dopamine neurons in the acquisition and expression of conditioned fear in the rat. Neuroscience 92: 553-564

Neuroscience

The mesoprefrontal dopamine neurons are sensitive to physical, pharmacological and psychological ... more The mesoprefrontal dopamine neurons are sensitive to physical, pharmacological and psychological stressors. In this report, the role of these neurons in the response to classical fear conditioning was investigated. 6-Hydroxydopamine lesions to the medial prefrontal cortex reduced dopamine levels to about 13% of controls but did not alter behavior during the acquisition of fear conditioning. As expected, conditioned fear increased dopamine metabolism (3,4-dihydroxyphenylacetic acid/dopamine ratio) in the nucleus accumbens in sham-lesion rats. The medial prefrontal 6-hydroxydopamine lesions did not alter this effect. During the expression, however, lesioned rats demonstrated a delayed extinction of the conditioned response without an overall increase in the initial conditioned response. This effect was consistent in rats receiving 6-hydroxydopamine lesions before or after the acquisition period. The calculated rates of extinction showed that the 6-hydroxydopamine lesioned rats had a r...

Neuropsychopharmacology 2001--Vol. 24, No. 5

this paper, we have examined the effects of nAChR inactivation on DA turnover and fos-related ant... more this paper, we have examined the effects of nAChR inactivation on DA turnover and fos-related antigen expression in the basal ganglia, two parameters related to cocaine action on DA pathways. Low dose cocaine (5 mg/kg) is able to elicit a reduction in DOPAC/ DA ratio in #2#/# mice on the C57Bl/6 background, as has previously been shown in the ICR line of mice (Hadfield 1995; Hadfield and Milio 1992). In contrast, stimulation by 5 mg/kg cocaine is not sufficient to alter DA turnover in #2#/# mice. #2#/# mice also show a trend toward decreased basal DA turnover in the striatal /telencephalon regions of the brain, perhaps suggesting that DA utilization under basal conditions is altered in mice lacking the high affinity neuronal nAChR. Although this is still a hypothesis, these data may imply that altered DA utilization in mice lacking high affinity nAChRs could be the primary mechanism involved in the decreased cocaine place preference seen in these animals. An alternate hypothesis is ...

Chapter 25 Transplantation of fetal dopamine neurons in primate brain reverses MPTP induced parkinsonism

Progress in Brain Research, 1987

Selective monoamine-oxidase inhibition in man : a biochemical and pharmacological study

ABSTRACT

Clonidine suppression of noradrenergic hyperactivity during morphine withdrawal by clonidine: Biochemical studies in rodents and primates

The Journal of Clinical Psychiatry

Ethanol and endogenous ligands in humans

Psychopharmacology bulletin

Tribulin: an endogenous monoamine oxidase inhibitor/benzodiazepine receptor ligand

Progress in clinical and biological research

Monoamine oxidase and its inhibition: Some clinical implications

Cocaethylene inhibits uptake of dopamine and can reach high plasma concentrations following combined cocaine and ethanol use

NIDA research monograph

Biochemical Changes Induced by Embryonic Substantia Nigra Transplanted to the Striatum of Parkinsonian Monkeys

Neural Plasticity

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Quantitative Behavioral Assessment Methods for the Analysis of Graft-Induced Motor and Cognitive Function in the MPTP-Treated Parkinsonian Monkey

Neural Plasticity

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D1 and D2 dopamine receptors independently regulate spontaneous blink rate in the vervet monkey

Journal of Pharmacology and Experimental Therapeutics

Sensitization to the locomotor activating effects of cocaine following cocaethylene-preexposure

Brain Research

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Phencyclidine increases forebrain monoamine metabolism in rats and monkeys: Modulation by the isomers of HA966

The Journal of Neuroscience : The Official Journal of the Society for Neuroscience

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(S)-(-)-HA-966, a γ-hydroxybutyrate-like agent, prevents enhanced mesocorticolimbic dopamine metabolism and behavioral correlates of restraint stress, conditioned fear and cocaine sensitization

Journal of Pharmacology and Experimental Therapeutics

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Journal of Pharmacology and Experimental Therapeutics

ABSTRACT

Chapter 12. Fetal Grafts in Parkinson's Disease

ABSTRACT

The Journal of Neuroscience : The Official Journal of the Society for Neuroscience

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Fetal dopamine neural grafts: Extended reversal of methylphenyltetrahydropyridine-induced parkinsonism in monkeys

Progress in brain research

Axo-Axonic Structures in the Medial Prefrontal Cortex of the Rat: Reduction by Prenatal Exposure to Cocaine

The Journal of Neuroscience : The Official Journal of the Society for Neuroscience

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Morrow BA, Elsworth JD, Rasmusson AM, Roth RH. The role of mesofrontal dopamine neurons in the acquisition and expression of conditioned fear in the rat. Neuroscience 92: 553-564

Neuroscience

Neuropsychopharmacology 2001--Vol. 24, No. 5

Chapter 25 Transplantation of fetal dopamine neurons in primate brain reverses MPTP induced parkinsonism

Progress in Brain Research, 1987

John Elsworth

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