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1.
Neuropharmacology ; 52(3): 985-94, 2007 Mar.
Article in English | MEDLINE | ID: mdl-17157884

ABSTRACT

The preclinical pharmacology of the alpha4beta2 nicotinic acetylcholine receptor (nAChR) partial agonist varenicline, a novel smoking cessation agent is described. Varenicline binds with subnanomolar affinity only to alpha4beta2 nAChRs and in vitro functional patch clamp studies in HEK cells expressing nAChRs show that varenicline is a partial agonist with 45% of nicotine's maximal efficacy at alpha4beta2 nAChRs. In neurochemical models varenicline has significantly lower (40-60%) efficacy than nicotine in stimulating [(3)H]-dopamine release from rat brain slices in vitro and in increasing dopamine release from rat nucleus accumbens in vivo, while it is more potent than nicotine. In addition, when combined with nicotine, varenicline effectively attenuates the nicotine-induced dopamine release to the level of the effect of varenicline alone, consistent with partial agonism. Finally, varenicline reduces nicotine self-administration in rats and supports lower self-administration break points than nicotine. These data suggest that varenicline can reproduce to some extent the subjective effects of smoking by partially activating alpha4beta2 nAChRs, while preventing full activation of these receptors by nicotine. Based on these findings, varenicline was advanced into clinical development and recently shown to be an effective and safe aid for smoking cessation treatment.


Subject(s)
Behavior, Animal/drug effects , Benzazepines/pharmacology , Nicotinic Agonists/pharmacology , Quinoxalines/pharmacology , Smoking Cessation/methods , Animals , Brain/cytology , Brain/drug effects , Brain/physiology , Cell Line, Transformed , Dopamine/metabolism , Dose-Response Relationship, Drug , Drug Administration Schedule , Humans , In Vitro Techniques , Male , Membrane Potentials/drug effects , Membrane Potentials/physiology , Nicotine/administration & dosage , Patch-Clamp Techniques/methods , Protein Binding/drug effects , Rats , Rats, Long-Evans , Rats, Sprague-Dawley , Self Administration , Transfection , Varenicline
2.
J Pharmacol Exp Ther ; 294(2): 588-97, 2000 Aug.
Article in English | MEDLINE | ID: mdl-10900236

ABSTRACT

Corticotropin-releasing factor 1 (CRF(1)) receptor antagonists may represent a novel group of drugs for the pharmacotherapy of depression and/or anxiety disorders. We have investigated the behavioral, endocrine, and neurochemical effects of chronic administration of a selective CRF(1) receptor antagonist, CP-154,526. After 9 to 10 days of treatment with CP-154,526 (3.2 mg/kg/day), defensive withdrawal behavior was significantly decreased suggesting anxiolytic activity. In animals treated for 14 days with the low dose of CP-154,526, serum corticosterone concentrations returned to baseline levels faster after application of an airpuff startle. Using in situ hybridization, no changes in CRF(1) receptor mRNA expression were detected in parietal cortex, basolateral amygdala, or cerebellum after chronic treatment with CP-154,526. A dose-dependent decrease in CRF mRNA expression was observed in the hypothalamic paraventricular nucleus (PVN) and the Barrington's nucleus, an effect that was significant at the high but not the low dose of CP-154,526. CP-154,526 did not alter central CRF(2A) receptor binding or mRNA expression, or urocortin mRNA expression. The present findings suggest that chronic administration of CP-154, 526 produces anxiolytic-like effects but no evidence of adrenal insufficiency. Previous postmortem studies revealed increased CRF peptide and mRNA levels in the PVN of depressed patients, which may mediate the hyperactivity of the hypothalamic-pituitary-adrenal axis observed in such patients. In view of a possible use for CRF(1) receptor antagonists in the treatment of depression, the present finding that CP-154,526 decreases CRF synthesis in the PVN is of considerable interest.


Subject(s)
Behavior, Animal/drug effects , Brain/drug effects , Endocrine System/drug effects , Pyrimidines/pharmacology , Pyrroles/pharmacology , Receptors, Corticotropin-Releasing Hormone/antagonists & inhibitors , Adrenal Glands/anatomy & histology , Adrenal Glands/drug effects , Adrenocorticotropic Hormone/blood , Animals , Anti-Anxiety Agents/pharmacology , Brain/metabolism , Corticosterone/blood , Corticotropin-Releasing Hormone/biosynthesis , Drug Administration Schedule , Endocrine System/metabolism , Male , Organ Size/drug effects , RNA, Messenger/biosynthesis , RNA, Messenger/metabolism , Rats , Receptors, Corticotropin-Releasing Hormone/biosynthesis , Receptors, Corticotropin-Releasing Hormone/metabolism , Reflex, Startle/drug effects , Stress, Physiological/drug therapy , Urocortins
3.
J Med Chem ; 40(11): 1749-54, 1997 May 23.
Article in English | MEDLINE | ID: mdl-9171885

ABSTRACT

The syntheses of a centrally active nonpeptide CRF1 receptor antagonist 2, butylethyl[2,5-dimethyl-7-(2,4,6-trimethylphenyl)-7H-pyrrolo [2,3-d]pyrimidin-4-yl]amine (CP-154,526), and its analogs 11-14 and [3H]-2 are reported. The in vitro CRF1 receptor binding affinity in the series 2, the pharmacokinetic properties of 2 in rats, and the anxiolytic-like effects of orally administered 2 are presented.


Subject(s)
Pyrimidines/chemical synthesis , Pyrroles/chemical synthesis , Receptors, Corticotropin-Releasing Hormone/antagonists & inhibitors , Animals , Anti-Anxiety Agents/pharmacology , Fear , Male , Molecular Structure , Pyrimidines/pharmacokinetics , Pyrimidines/pharmacology , Pyrroles/pharmacokinetics , Pyrroles/pharmacology , Rats , Rats, Sprague-Dawley , Receptors, Corticotropin-Releasing Hormone/metabolism , Reflex, Startle/drug effects , Structure-Activity Relationship
4.
J Neurochem ; 67(5): 2204-7, 1996 Nov.
Article in English | MEDLINE | ID: mdl-8863532

ABSTRACT

In vivo microdialysis in guinea pig hypothalamus was used to study the effect of serotonin [5-hydroxytryptamine (5-HT)] subtype 1D autoreceptor blockade on the increase in extracellular 5-HT levels produced by a selective 5-HT reuptake inhibitor (SSRI). Administration of the selective 5-HT1D antagonist GR127935 at 0.3 mg/kg had no effect, but 5 mg/kg significantly increased extracellular levels of 5-HT and 5-hydroxyindoleacetic acid to 135% of basal values. Moreover, at these doses GR127935 significantly attenuated the decrease in extracellular 5-HT levels following local perfusion with the selective 5-HT1D agonist CP-135,807. The SSRI sertraline at 2 mg/kg increased 5-HT levels to 130% of basal levels. The combination of this low dose of sertraline with either dose of GR127935 resulted in a pronounced, long-lasting increases in 5-HT levels to 230% of basal values. These results indicate that the effects of an SSRI on terminal 5-HT are significantly enhanced by coadministration of a 5-HT1D antagonist and confirm that in addition to somatodendritic 5-HT1A autoreceptors, terminal 5-HT1D autoreceptors mitigate the effect of SSRIs on terminal 5-HT. As such, antagonists of the 5-HT1D autoreceptor could be useful as rapidly acting antidepressants and may shorten the onset of antidepressant action when combined with SSRIs.


Subject(s)
1-Naphthylamine/analogs & derivatives , Hypothalamus/metabolism , Indoles/pharmacology , Oxadiazoles/pharmacology , Piperazines/pharmacology , Pyridines/pharmacology , Receptors, Serotonin/metabolism , Selective Serotonin Reuptake Inhibitors/pharmacology , Serotonin/metabolism , 1-Naphthylamine/pharmacology , 8-Hydroxy-2-(di-n-propylamino)tetralin/pharmacology , Animals , Drug Synergism , Guinea Pigs , Hydroxyindoleacetic Acid/metabolism , Hypothalamus/drug effects , Kinetics , Neurons/metabolism , Receptor, Serotonin, 5-HT1D , Serotonin Antagonists/pharmacology , Sertraline
5.
Proc Natl Acad Sci U S A ; 93(19): 10477-82, 1996 Sep 17.
Article in English | MEDLINE | ID: mdl-8816826

ABSTRACT

Here we describe the properties of CP-154,526, a potent and selective nonpeptide antagonist of corticotropin (ACTH) releasing factor (CRF) receptors. CP-154,526 binds with high affinity to CRF receptors (Ki < 10 nM) and blocks CRF-stimulated adenylate cyclase activity in membranes prepared from rat cortex and pituitary. Systemically administered CP-154,526 antagonizes the stimulatory effects of exogenous CRF on plasma ACTH, locus coeruleus neuronal firing and startle response amplitude. Potential anxiolytic activity of CP-154,526 was revealed in a fearpotentiated startle paradigm. These data are presented in the context of clinical findings, which suggest that CRF is hypersecreted in certain pathological states. We propose that a CRF antagonist such as CP-154,526 could affirm the role of CRF in certain psychiatric diseases and may be of significant value in the treatment of these disorders.


Subject(s)
Adrenocorticotropic Hormone/metabolism , Cerebral Ventricles/physiology , Corticotropin-Releasing Hormone/pharmacology , Locus Coeruleus/physiology , Neurons/physiology , Pyrimidines/pharmacology , Pyrroles/pharmacology , Receptors, Corticotropin-Releasing Hormone/metabolism , Reflex, Startle/drug effects , Acoustic Stimulation , Adenylyl Cyclases/metabolism , Adrenocorticotropic Hormone/blood , Animals , Binding, Competitive , Callithrix , Cell Line , Cell Membrane/enzymology , Cerebral Cortex/enzymology , Cerebral Ventricles/drug effects , Corticotropin-Releasing Hormone/administration & dosage , Dogs , Guinea Pigs , Humans , Injections, Intraventricular , Kinetics , Male , Neurons/drug effects , Pituitary Gland/enzymology , Pyrimidines/administration & dosage , Pyrimidines/metabolism , Pyrroles/administration & dosage , Pyrroles/metabolism , Rats , Rats, Sprague-Dawley , Receptors, Corticotropin-Releasing Hormone/antagonists & inhibitors
6.
J Pharmacol Exp Ther ; 275(1): 101-13, 1995 Oct.
Article in English | MEDLINE | ID: mdl-7562537

ABSTRACT

Ziprasidone (CP-88,059) is a combined 5-HT (serotonin) and dopamine receptor antagonist which exhibits potent effects in preclinical assays predictive of antipsychotic activity. Whereas the compound is a dopamine antagonist in vitro and in vivo, its most potent action is antagonism of 5-HT2A receptors, where its affinity is an order of magnitude greater than that observed for dopamine D2 sites. Laboratory and clinical findings have led to a hypothesis that antagonism of 5-HT2A receptors in the brain limits the undesirable motor side effects associated with dopamine receptor blockade and improves efficacy against the negative symptoms of schizophrenia. Ziprasidone possesses an in vitro 5-HT2A/dopamine D2 receptor affinity ratio higher than any clinically available antipsychotic agent. In vivo, ziprasidone antagonizes 5-HT2A receptor-induced head twitch with 6-fold higher potency than for blockade of d-amphetamine-induced hyperactivity, a measure of central dopamine D2 receptor antagonism. Ziprasidone also has high affinity for the 5-HT1A, 5-HT1D and 5-HT2C receptor subtypes, which may further enhance its therapeutic potential. The prediction of antipsychotic efficacy without severe motor side effects is supported by the relatively weak potency of ziprasidone to produce catalepsy in animals, contrasted with its potent antagonism of conditioned avoidance responding and dopamine agonist-induced locomotor activation and stereotypy. The compound is well tolerated in animals at doses producing effective dopamine antagonism in the brain. Ziprasidone should be a valuable addition to the treatment of psychotic disorders.


Subject(s)
Antipsychotic Agents/pharmacology , Dopamine Antagonists/pharmacology , Piperazines/pharmacology , Serotonin Antagonists/pharmacology , Thiazoles/pharmacology , Adenylyl Cyclases/metabolism , Amphetamine/antagonists & inhibitors , Animals , Antipsychotic Agents/metabolism , Apomorphine/antagonists & inhibitors , Behavior, Animal/drug effects , Biogenic Monoamines/metabolism , Brain/drug effects , Brain/metabolism , CHO Cells , Catalepsy/chemically induced , Cattle , Choroid Plexus/drug effects , Choroid Plexus/metabolism , Cricetinae , Cyclic AMP/metabolism , Guinea Pigs , Humans , Male , Mice , Mice, Inbred Strains , Motor Activity/drug effects , Neurotransmitter Uptake Inhibitors/pharmacology , Piperazines/metabolism , Quipazine/antagonists & inhibitors , Rats , Receptors, Adrenergic/metabolism , Receptors, Dopamine/metabolism , Receptors, Dopamine/physiology , Receptors, Serotonin/metabolism , Receptors, Serotonin/physiology , Serotonin Antagonists/metabolism , Swine , Thiazoles/metabolism
7.
Diabetes ; 44(2): 190-5, 1995 Feb.
Article in English | MEDLINE | ID: mdl-7859940

ABSTRACT

To address the problem of the pathogenesis of diabetic neuropathy, rats were made diabetic by alloxan administration, and sciatic nerves were sampled for electrolyte and water content and levels of selected carbohydrates and intermediates in energy metabolism at 3, 6, and 26 weeks. Significant increases were seen in the nerve content of glucose, sorbitol, and fructose. Decreases of myo-inositol were not statistically significant. Glucose-6-phosphate was increased at all times; fructose-1,6-bisphosphate was elevated at 6 and 26 weeks. Nerve ATP and phosphocreatine levels were both increased concomitantly, as was the energy charge. Nerve lactate levels increased only at 26 weeks when plasma lactate levels were also high. Plasma ketone bodies were elevated throughout the 26-week experimental interval. It is postulated that ketone bodies were being used as alternative metabolic fuels in diabetic nerve, thereby causing inhibition of pyruvate oxidation and increased aerobic production of lactate. Increased plasma ketone body levels could also inhibit hepatic lactate uptake. There was no other evidence for hypoxia/ischemia. Lactate:pyruvate ratios did not differ from control values at any time in these ketotic hypoinsulinemic animals. Five major hypotheses have been proposed to explain the pathogenesis of diabetic neuropathy: 1) hypoxia/ischemia, 2) hyperglycemic pseudohypoxia, 3) myo-inositol deficiency, 4) fructose and polyol accumulation and osmotic disequilibrium, and 5) nonenzymatic glycation of macromolecules by fructose and glucose. The data obtained in this study seem to fit best with hypotheses 4 and perhaps 5.


Subject(s)
Carbohydrate Metabolism , Diabetes Mellitus, Experimental/metabolism , Diabetic Neuropathies/etiology , Energy Metabolism , Peripheral Nervous System Diseases/etiology , Sciatic Nerve/metabolism , Acute Disease , Adenosine Triphosphate/metabolism , Animals , Chronic Disease , Electrolytes/metabolism , Fructose/metabolism , Glucose/metabolism , Male , Phosphocreatine/metabolism , Polymers/metabolism , Rats , Rats, Sprague-Dawley , Sorbitol/metabolism
9.
J Neurochem ; 61(6): 2225-32, 1993 Dec.
Article in English | MEDLINE | ID: mdl-8245973

ABSTRACT

Specific and reproducible changes involving the cholinergic and dopaminergic systems have been described in both the aging rodent and the human nervous system. Nevertheless, relatively little information is available on changes in nicotinic cholinergic receptors occurring in normal aging, and there have been few attempts to correlate alterations in receptor densities with changes in nicotinic actions. We have utilized the nicotine-mediated stimulation of endogenous dopamine efflux in a striatal slice preparation as a functional index of responsiveness to nicotine in aging. Following incubation with nicotine, this efflux was significantly lower in 25-month-old (aged) as opposed to 4-month-old (young) rats. In contrast, the release of striatal dopamine following a high-potassium stimulus was similar at both ages. Binding studies in young and aged animals did not reveal any significant change with age in the total number of striatal nicotinic receptors recognized by either [3H]nicotine or the neuronal nicotinic antagonist 125I-neuronal bungarotoxin. However, there was a nearly 80% decline in the subpopulation of striatal nicotinic receptors jointly recognized by both nicotine and neuronal bungarotoxin, but not by alpha-bungarotoxin. Quantitative autoradiography demonstrated declines with age in this receptor subtype in several brain regions examined. Decrements in this specific subpopulation of nicotinic receptors or in the nerve cells expressing these receptors may contribute to the functional declines that take place in the aging motor and visual systems.


Subject(s)
Aging/physiology , Corpus Striatum/metabolism , Dopamine/metabolism , Nicotine/pharmacology , Receptors, Nicotinic/metabolism , Animals , Autoradiography , Cell Membrane/metabolism , Corpus Striatum/drug effects , Corpus Striatum/growth & development , In Vitro Techniques , Iodine Radioisotopes , Kinetics , Organ Specificity , Potassium/pharmacology , Rats , Tritium
11.
J Neurosci ; 11(1): 287-97, 1991 Jan.
Article in English | MEDLINE | ID: mdl-1986068

ABSTRACT

Neuronal bungarotoxin (NBT), a snake venom neurotoxin, selectively blocks nicotinic receptors in many peripheral and central neuronal preparations. alpha-Bungarotoxin (alpha BT), on the other hand, a second toxin isolated from the venom of the same snake, is an ineffective nicotinic antagonist in most vertebrate neuronal preparations studied thus far. To examine central nicotinic receptors recognized by NBT, we have characterized the binding of 125I-labeled NBT (125I-NBT) to rat brain membranes and have mapped the distribution of 125I-NBT binding in brain sections using quantitative light microscopic autoradiography. The binding of 125I-NBT was found to be saturable, of high affinity, and heterogeneously distributed in the brain. Pharmacological studies suggested that more than one population of sites is labeled by 125I-NBT. For example, one component of 125I-NBT binding was also recognized by alpha BT, while a second component, not recognized by alpha BT, was recognized by the nicotinic agonist nicotine. The highest densities of these alpha BT-insensitive, nicotine-sensitive sites were found in the fasciculus retroflexus, the lateral geniculate nucleus, the medial terminal nucleus of the accessory optic tract, and the olivary pretectal nucleus. alpha BT-sensitive NBT binding sites were found in highest density in the lateral geniculate nucleus, the subthalamic nucleus, the dorsal tegmental nucleus, and the medial mammillary nucleus (lateral part). The number of brain regions with a high density of 125I-NBT binding sites, blocked either by alpha BT or by nicotine, is low when compared with results obtained using other approaches to studying the central distribution of nicotinic receptors, such as labeling with 3H-nicotine or labeling with cDNA probes to mRNAs coding for putative receptor subunits. It is proposed that 125I-NBT labels a subpopulation of nicotinic receptors in the rat brain, and that, given its ability to block nicotinic receptors in a variety of neuronal preparations, NBT will be a useful probe for studying the functional properties of these sites.


Subject(s)
Brain/metabolism , Bungarotoxins/metabolism , Neurotoxins/metabolism , Receptors, Nicotinic/metabolism , Animals , Autoradiography , Binding, Competitive , Cell Membrane/metabolism , Corpus Striatum/metabolism , Iodine Radioisotopes , Kinetics , Male , Organ Specificity , Rats , Rats, Inbred Strains , Receptors, Nicotinic/analysis
12.
J Med Chem ; 33(8): 2087-93, 1990 Aug.
Article in English | MEDLINE | ID: mdl-2374139

ABSTRACT

The synthesis and in vitro and in vivo characteristics of 3-(1,2,5,6-tetrahydropyrid-4-yl)pyrrolo[3,2-b]pyrid-5-one (1, CP-93,129) are described. This rotationally restricted phenolic analogue of RU-24,969 is a potent (15 nM) and selective (200x vs the 5-HT1A receptor, 150x vs the 5HT1D receptor) functional agonist for the 5-HT1B receptor. Direct infusion of 1 into the paraventricular nucleus of the hypothalamus of rats significantly inhibits food intake, implicating the role of 5-HT1B receptors in regulating feeding behavior in rodents. 3-(1,2,5,6-Tetrahydropyrid-4-yl)pyrrolo[3,2-b]pyrid-5-one (1) has also been shown to be biochemically discriminatory in its ability to selectively inhibit forskolin-stimulated adenylate cyclase activity only at the 5-HT1B receptor. The source of the selectivity of 1 appears to lie in the ability of a pyrrolo[3,2-b]pyrid-5-one to act as a rotationally restricted bioisosteric replacement for 5-hydroxyindole.


Subject(s)
Indoles/pharmacology , Pyridines/pharmacology , Pyrroles/pharmacology , Serotonin/physiology , Adenylyl Cyclase Inhibitors , Animals , Chemical Phenomena , Chemistry , Colforsin/pharmacology , Cyclization , Eating/drug effects , Guinea Pigs , Hippocampus/enzymology , Molecular Structure , Paraventricular Hypothalamic Nucleus/drug effects , Paraventricular Hypothalamic Nucleus/physiology , Pyridines/chemical synthesis , Pyridines/metabolism , Pyrroles/chemical synthesis , Pyrroles/metabolism , Rats , Receptors, Serotonin/drug effects , Receptors, Serotonin/physiology , Serotonin/pharmacology , Substantia Nigra/metabolism
13.
Neurosci Lett ; 98(3): 310-6, 1989 Apr 10.
Article in English | MEDLINE | ID: mdl-2566962

ABSTRACT

Nicotinic receptors in the brain are receiving increased attention due in part to the recent cloning of receptor subunits and to postmortem studies revealing alterations in receptor density associated with Alzheimer's disease. The peptide neurotoxin neuronal bungarotoxin (NBT) has been shown to block nicotinic cholinergic responses in autonomic ganglia and in retinal ganglion cells. These findings suggest that NBT may be a useful probe for studying nicotinic receptors in the brain. Therefore, we have investigated the effects of NBT on the nicotine-mediated enhancement of endogenous dopamine release from rat striatal slices. It was found that the transient increase in dopamine release caused by 100 microM nicotine was completely blocked by 100 nM NBT, indicating that NBT is a functional nicotinic antagonist in this system.


Subject(s)
Bungarotoxins , Corpus Striatum/metabolism , Dopamine/metabolism , Receptors, Nicotinic/physiology , Animals , Calcium/physiology , Corpus Striatum/drug effects , Hexamethonium , Hexamethonium Compounds/pharmacology , In Vitro Techniques , Male , Nicotine/pharmacology , Rats , Rats, Inbred Strains , Receptors, Nicotinic/drug effects
15.
Neurotoxicol Teratol ; 10(4): 279-85, 1988.
Article in English | MEDLINE | ID: mdl-2465482

ABSTRACT

Rats treated with triethyllead (TEL) exhibit a behavioral supersensitivity to challenge with dopamine agonists at 7 days following administration of TEL. In the present series of experiments, some neurochemical mechanisms which may affect this behavioral supersensitivity were detected. Administration of a single dose of TEL chloride (7.88 mg/kg, SC) to male Fischer-344 rats decreased the concentrations of dopamine in hippocampus, and of serotonin in olfactory tubercle, at Day 7 posttreatment. The ratio of 5-hydroxyindoleacetic acid/5-hydroxytryptamine (one estimate of serotonin turnover) was increased in nucleus accumbens (p less than 0.05), with a similar trend in olfactory tubercle and striatum (p less than 0.10). No changes were detected in binding of [3H]spiperone to D2 dopamine receptors in striatum or olfactory tubercle. However, although basal adenylate cyclase activity was unaltered in TEL-treated rats, the Vmax for dopamine-stimulated adenylate cyclase activity was significantly elevated in olfactory tubercle. Conversely, TEL at micromolar concentrations markedly attenuated both basal and dopamine-stimulated adenylate cyclase activity in vitro in striatal homogenates. These data suggest the hypothesis that administration of TEL to rats results in an up-regulation of D1 dopamine receptors in olfactory tubercle, and that the behavioral supersensitivity of TEL-treated animals to dopamine agonists may, in part, be a result of this receptor supersensitivity.


Subject(s)
Brain/metabolism , Dopamine/metabolism , Neurotoxins/pharmacology , Organometallic Compounds/toxicity , Serotonin/metabolism , Animals , Brain/drug effects , Cyclic AMP/metabolism , Hydroxyindoleacetic Acid/metabolism , Male , Rats , Receptors, Serotonin/drug effects , Receptors, Serotonin/metabolism , Spiperone/metabolism , Time Factors
16.
Brain Res ; 398(1): 23-36, 1986 Nov 19.
Article in English | MEDLINE | ID: mdl-3801898

ABSTRACT

Bilateral injection of 3.5 micrograms of colchicine into two levels of the dentate gyrus produced a selective loss of dentate granule cells and persistent behavioral effects in male Fischer rats. Histological analysis confirmed that this dosage of colchicine resulted in the selective loss of most granule cells in both superior and inferior blades of the dentate gyrus near the injection sites, while sparing pyramidal cells in CA1, CA2, CA3, and CA4, and GABAergic interneurons throughout the hippocampus. Rats injected with colchicine were significantly more active than cerebrospinal fluid-injected controls 2, 7, 14, 21 and 28 days after treatment. Behavioral reactivity, assessed by the magnitude of the acoustic startle response and the latency to respond in a hot-plate test, was not affected at any of these time points. Retention of a step-through passive avoidance task was impaired in the colchicine group one month after surgery. Their step-through latencies were significantly shorter than control latencies, and they exhibited more partial entries during the retention test. Acquisition and performance in a radial-arm maze, measured up to 3 months after surgery, were also impaired by colchicine. Animals injected with colchicine required more trials to acquire the task and were less accurate in the task even after their performance had stabilized. These data suggest that the hippocampus modulates motor behavior and cognitive function. The results of these experiments also support the use of colchicine as a means of defining the functional and anatomical consequences following selective destruction of the granule cell population of the dentate gyrus.


Subject(s)
Behavior, Animal/drug effects , Colchicine/pharmacology , Hippocampus/drug effects , Animals , Avoidance Learning/drug effects , Colchicine/administration & dosage , Glutamate Decarboxylase/metabolism , Hippocampus/enzymology , Hippocampus/pathology , Histocytochemistry , Hot Temperature , Male , Memory, Short-Term/drug effects , Motor Activity/drug effects , Phosphopyruvate Hydratase/metabolism , Rats , Rats, Inbred F344 , Reaction Time , Reflex, Startle/drug effects
17.
Metab Brain Dis ; 1(2): 129-46, 1986 Jun.
Article in English | MEDLINE | ID: mdl-3508238

ABSTRACT

This study compares early and late effects of the injection of hyperosmolar NaCl and urea of equal osmolarity on selected aspects of brain water, electrolyte, carbohydrate, amino acid, urea, and energy metabolism in normal suckling-weanling mice. One hour after treatment, salt-treated mice were critically ill, while the behavior of urea-treated animals could not be distinguished from that of controls. This clinical difference could not be explained on the basis of differences in plasma osmolality, the brain water content, or the degree of hemorrhagic encephalopathy. The injection of NaCl induced a 14-fold increase in plasma insulin and a progressive fall in the plasma glucose concentration (a reduction of 66% at 1 hr). In contrast, plasma glucose levels in urea-injected mice were unchanged. Prior to the fall in plasma glucose levels, metabolite changes in the brains of NaCl-injected mice were compatible with facilitation of transfer of glucose from the blood to the brain, increased metabolic flux in the Embden-Meyerhof and Krebs citric acid cycle pathways, and increased energy production. With the exception of the glucose content (unchanged), similar metabolite changes were seen in brain soon after urea injection. In the brains of the hypoglycemic NaCl-treated mice, glucose levels were reduced 80%, and glycogen 41%. Other metabolite changes were compatible with decreased glycolysis and metabolic flux through the Krebs citric acid cycle. In contrast, with few exceptions, at a similar time after injection, metabolite levels had returned to normal in the urea-treated mice. Permeability of the brain to urea was also examined. Brain urea reached high levels at 2 hr but returned to near baseline at 6 hr. Both hyperosmolar solutions increased the brain content of aspartic and glutamic acids 1 hr after injection. The failure of hypoglycemic mice with hypernatremia and elevated plasma osmolality (range, 416-434 mOsm/kg H2O) to respond to 1 M glucose (30 ml/kg) may have been due to the ill effects of the additional hyperosmolar load. The possibility remains that the encephalopathy induced by hyperosmolar NaCl, but not by hyperosmolar urea, is in some way related to the sudden elevation of brain Na+ and/or Cl- ions.


Subject(s)
Amino Acids/metabolism , Brain/metabolism , Carbohydrate Metabolism , Hypoglycemia/chemically induced , Saline Solution, Hypertonic/pharmacology , Sodium Chloride/pharmacology , Urea/pharmacology , Water-Electrolyte Balance/drug effects , Animals , Blood Glucose/metabolism , Hypoglycemia/metabolism , Mice
18.
J Pharmacol Exp Ther ; 236(3): 838-45, 1986 Mar.
Article in English | MEDLINE | ID: mdl-3512819

ABSTRACT

SCH23390 is a dopamine antagonist which has a high affinity for D1-like dopaminergic receptors. Receptor binding studies demonstrated significant levels of specific SCH23390 binding within nigral tissue. Therefore, electrophysiological experiments were conducted to determine if this antagonist influenced apomorphine-induced suppressions of unit firing recorded from dopaminergic cells of the substantia nigra zona compacta. Results presented in this report indicate that the autoreceptors located on dendrites and cell bodies of dopamine-containing neurons are not directly acted upon by SCH23390. This conclusion is drawn because: doses of SCH23390 known to block behaviors caused by dopamine agonists were ineffective in blocking rate reductions produced by apomorphine and pretreatment with 0.1 mg/kg of SCH23390 did not change the apomorphine dose-response curve for inhibition of dopaminergic neurons. Consistent with this finding, microinjections of SCH23390 into the zona compacta did not alter apomorphine-induced behaviors which are known to be blocked by haloperidol (a D2-like antagonist) intranigral injections. However, when only the larger apomorphine doses (64 and 128 micrograms/kg i.v.) are considered, SCH23390 pretreatment did attenuate the maximum response to apomorphine in some nigral cells. Because larger apomorphine concentrations alter striatal activity, such results may be reflective of alterations in a subpopulation of nigral neurons which are postsynaptic to neurons containing D1-like receptors and located elsewhere in the brain (e.g., in striatum). Collectively, these results agree with previous studies which suggest that dopamine receptors located on dopamine-containing neurons of the substantia nigra zona compacta are likely not of the D1-type.


Subject(s)
Apomorphine/pharmacology , Benzazepines/pharmacology , Dopamine Antagonists , Receptors, Dopamine/drug effects , Substantia Nigra/drug effects , Analysis of Variance , Animals , Behavior, Animal/drug effects , Benzazepines/metabolism , Corpus Striatum/drug effects , Dose-Response Relationship, Drug , In Vitro Techniques , Male , Rats , Rats, Inbred Strains , Spiperone/metabolism , Substantia Nigra/physiology , Tritium
20.
Brain Res ; 363(2): 222-9, 1986 Jan 22.
Article in English | MEDLINE | ID: mdl-3942894

ABSTRACT

Acute exposure to triethyl lead chloride (7.88 mg/kg) enhanced the behavioral effects of both direct- and indirect-acting dopaminergic agonists. Rats treated with lead 1 week before testing exhibited an increased response to the motor stimulant effects of D-amphetamine and apomorphine. The dose-response curves for D-amphetamine (1.25, 2.0, 3.15 and 5.0 mg/kg)- and apomorphine (0.2, 0.5, 1.25 and 2.0 mg/kg)-induced hyperactivity were shifted to the left in the triethyl lead group. Finally, apomorphine (1 mg/kg) produced more stereotypy in rats pretreated with triethyl lead. This enhanced sensitivity to dopaminergic agonists was not due to altered pharmacokinetics of the challenge drugs, since the onset and duration of their behavioral effects were not affected by triethyl lead. Furthermore, the regional distribution and accumulation of D-[3H]amphetamine was not altered by triethyl lead. These data suggest that acute exposure to triethyl lead enhances the responsiveness of dopaminergic processes which contribute to locomotor activity. The involvement of brain dopamine in other aspects of organolead neurotoxicity is discussed.


Subject(s)
Brain Diseases/chemically induced , Dopamine/metabolism , Lead/toxicity , Motor Activity/drug effects , Organometallic Compounds/toxicity , Animals , Apomorphine/toxicity , Dextroamphetamine/toxicity , Drug Interactions , Male , Rats , Rats, Inbred F344 , Stereotyped Behavior/chemically induced
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