Gerald Gianutsos - Academia.edu (original) (raw)

Papers by Gerald Gianutsos

Pharmacology Biochemistry and Behavior, 1994

Repeated scopolamine injections sensitize rats to pilocarpine-induced vacuous jaw movements and e... more Repeated scopolamine injections sensitize rats to pilocarpine-induced vacuous jaw movements and enhance striatal muscarinic receptor binding. PHARMACOL BIOCHEM BEHAV 49(2) [437][438][439][440][441][442] 1994. --This experiment was conducted to determine if repeated administration of the muscarinic antagonist scopolamine could increase pilocarpine-induced vacuous jaw movements and also enhance muscarinic receptor binding. Rats received dally injections of either scopolamine (0.5 mg/kg IP) or saline for 14 days. On day 15 rats received no injections of scopolamine, but did receive injections of pilocarpine (1.0, 2.0 or 4.0 mg/kg IP) or saline. After administration of pilocarpine or saline, all rats were observed for vacuous jaw movements and rearing behavior. The day after pilocarpine injections, rats were sacrificed and samples of tissue from the lateral neostriatum were removed to assess muscarinic receptor binding using 3H-QNB as the ligand. Analyses of the vacuous jaw movement data indicated that there was a significant dose-related increase in vacuous jaw movements induced by pilocarpine, and also that there was a significant enhancement of pilocarpine-induced vacuous jaw movements in rats pretreated with repeated scopolamine injections. There was not a significant scopolamine x pilocarpine interaction, suggesting that pretreatment with scopolamine produced an apparent parallel shift in the pilocarpine dose-response curve. Pilocarpine significantly suppressed rearing behavior, and scopolamine pretreatment significantly enhanced the suppression of rearing produced by pilocarpine. Analysis of the receptor binding data indicated that there was a significant increase in the number of muscarinic receptor sites (Bmu) in rats that received repeated scopolamine injections as compared to saline-treated rats. These results demonstrate that repeated administration of scopolamine sensitizes rats to the induction of vacuous jaw movements produced by pilocarpine, and also indicate that vacuous jaw movements may be a useful behavioral procedure for assessing striatal muscarinic supersensitivity.

Neuropharmacology, 1985

ABSTRACT Chronic treatment with the antidepressants imipramine or nomifensine, or the gamma-amino... more ABSTRACT Chronic treatment with the antidepressants imipramine or nomifensine, or the gamma-aminobutyric acid (GABAergic) agents, baclofen or THIP, produced a decrease in the Bmax for binding sites of GABAergic and noradrenergic receptors. Chronic treatment with imipramine or nomifensine produced a decrease in the Bmax of both binding of [3H]dihydroalprenolol and [3H]GABA receptors in the cerebral cortex and hippocampus. Chronic treatment with baclofen or THIP also produced a decrease in the Bmax of binding of [3H]dihydroalprenolol receptor in the cerebral cortex and hippocampus. These results suggest a possible link between the GABAergic and noradrenergic systems, which may be important in understanding the mechanism of action of antidepressant drugs, and suggests a possible role for GABA in affective disorders.

Psychopharmacology communications

Clonidine, a proposed alpha-noradrenergic receptor stimulant, intensifies the aggression occuring... more Clonidine, a proposed alpha-noradrenergic receptor stimulant, intensifies the aggression occuring during morphine-withdrawal or following the administration of apomorphine. The possibility of a noradrenergic/dopaminergic interaction in drug-induced aggression is discussed.

Psychopharmacology

gamma-Butyrolactone (GBL) increased the dopamine concentration in the forebrain of the mouse. Apo... more gamma-Butyrolactone (GBL) increased the dopamine concentration in the forebrain of the mouse. Apomorphine dose-dependently antagonized the GBL effect, while piribedil was less effective. Haloperidol prevented the antagonism of GBL by apomorphine but pimozide was ineffective in blocking apomorphine. After chronic treatment with haloperidol or pimozide, there was no alteration of the maximum GBL-induced increase in dopamine nor was there any significant change in the antagonism by apomorphine, although a trend toward increased sensitivity to apomorphine was noted in the group withdrawn from haloperidol. These results suggest that in the mouse, haloperidol is a more effective antagonist of presynaptic dopamine autoreceptors than pimozide, while apomorphine is a better presynaptic agonist than piribedil.

Research communications in chemical pathology and pharmacology

Two or 3 days after a single high-dose (20 mg/Kg) of p-chloroamphetamine (PCA) aggression was rel... more Two or 3 days after a single high-dose (20 mg/Kg) of p-chloroamphetamine (PCA) aggression was reliably observed in male mice. This agression was not produced when the same dose of d-amphetamine was injected or when PCA was injected one hour before testing. However, PCA produced an increase in locomotor activity one hour, but not 24 hours, after injection.

Life Sciences

ABSTRACT Rats were trained to bar press on either one of two levers depending on whether they rec... more ABSTRACT Rats were trained to bar press on either one of two levers depending on whether they received an injection of morphine (10 mg/kg) or saline. The rats responded on the morphine-correct lever when injected with another narcotic, fentanyl, but responded on the saline-correct lever when injected with a narcotic antagonist or another CNS active, but non-narcotic, drug (e.g., amphetamine, apomorphine). The narcotic antagonist, naloxone, prevented the occurrence of the narcotic discriminable stimulus, but the rats responded on the morphine-correct lever when injected with morphine plus any of a number of potent CNS active, but non-narcotic compounds. These results are discussed with reference to the specificity of this procedure for detecting drugs with narcotic agonist or antagonist properties.

Journal of Pharmacology and Experimental Therapeutics

Acute injections of baclofen or gamma-butyrolactone (GBL) into mice caused dose-dependent depress... more Acute injections of baclofen or gamma-butyrolactone (GBL) into mice caused dose-dependent depression of locomotor activity and an elevation of the dopamine content and a reduction of dopamine turnover in the brain. An acute injection of baclofen, but not of GBL, was less effective in producing these effects in mice maintained on a diet containing baclofen for 10 to 12 days. This suggests that baclofen and GBL may influence dopamine neurons by different mechanisms. Acute injections of both baclofen and GBL were less effective in producing behavioral and neurochemical effects in mice pre-treated for 13 days with injections of GBL. Tolerance to the behavioral and neurochemical actions of baclofen and GBL do not appear to be the result of metabolic tolerance but possibly result from changes in the properties of the dopamine neurons.

Modern problems of pharmacopsychiatry, 1978

Comparative biochemistry and physiology. C: Comparative pharmacology, 1977

Comp. Biochem. Physiol.. 1977. VoL 58C. pp. 157 to 159. Perlamon Press, Printed in Great Britain ... more Comp. Biochem. Physiol.. 1977. VoL 58C. pp. 157 to 159. Perlamon Press, Printed in Great Britain THE REGIONAL DISTRIBUTION OF DOPAMINE AND NOREPINEPHRINE IN SCHISTOSOMA MANSONI AND FASCIOLA HEPATICA GERALD GIANUTSOS AND JAMES LEROY ...

Journal of applied physiology (Bethesda, Md. : 1985), 1999

To investigate the role of sensory C-fiber stimulation and tachykinin release in the immediate na... more To investigate the role of sensory C-fiber stimulation and tachykinin release in the immediate nasal responses to the sensory irritant acrolein, the upper respiratory tract of the urethan-anesthetized male Fischer 344 rat was isolated via insertion of an endotracheal tube, and acrolein-laden air [2, 5, 10, or 20 parts/million (ppm)] was drawn continuously through that site at a flow rate of 100 ml/min for 50 min. Uptake of the inert vapor acetone was measured throughout the exposure to assess nasal vascular function. Plasma protein extravasation into nasal tissue and nasal lavage fluid was also assessed via injection of Evans blue dye. At 20 ppm, acrolein induced 1) a twofold increase in acetone uptake, indicative of vasodilation, followed by a progressive decline toward basal levels and 2) increased plasma protein extravasation, as indicated by dye leakage into nasal tissue and nasal lavage. These responses were inhibited by capsaicin pretreatment and the neurokinin type 1 antagoni...

The Journal of pharmacology and experimental therapeutics, 1983

ABSTRACT The effect of long-term treatment with the antipsychotic drugs fluphenazine and clozapin... more ABSTRACT The effect of long-term treatment with the antipsychotic drugs fluphenazine and clozapine on brain dopaminergic and muscarinic receptor binding sites was examined. Mice were treated with fluphenazine in their drinking water (0.005 and 0.001% w/v) or with clozapine-containing diet (0.075% w/w) for up to 12 weeks. Both drug treatments elicited increases in striatal [ 3H] spiroperidol binding. Muscarinic binding of [ 3H]quinuclidinyl benzilate was decreased only in striatum of animals treated with fluphenazine for 12 but not for 3 weeks. This reduction in binding density was not accompanied by alteration in K(d) nor was the relative distribution of high- to low-affinity agonist sites affected. Tolerance to fluphenazine-induced catalepsy was obtained after 14 days, whereas catalepsy to a challenge dose of pilocarpine was observed after 42 days of fluphenazine treatment. Twelve weeks of clozapine administration elicited increases in [ 3H]quinuclidinyl benzilate binding densities in the striatum, cortex and hippocampus. No alteration in striatal muscarinic agonist sites was obtained in clozapine-treated mice. Furthermore, no alteration in fluphenazine- or pilocarpine-elicited catalepsy was detected in clozapine-treated animals. Choline acetyl transferase activity was not affected by long-term fluphenazine treatment; however, clozapine administration induced an increase in striatal enzyme activity. These data indicate that whereas fluphenazine and clozapine elicit increases in striatal dopamine receptor sensitivities, they differ with regard to their effects on brain muscarinic cholinergic receptors. This differential response may be attributed to the high antidopaminergic/low anticholinergic potency of fluphenazine and the potent direct antimuscarinic efficacy of clozapine. These data suggest that the incidence of tardive dyskinesia during long-term treatment with antipsychotic drugs may be related to the ratio of dopamine supersensitivity/muscarinic subsensitivity induced by the drug.

Toxicology and applied pharmacology, 1985

The lethality of organophosphate (OP) cholinesterase (CHE) inhibitors is thought to result from d... more The lethality of organophosphate (OP) cholinesterase (CHE) inhibitors is thought to result from depression of the respiratory center in the brain stem, constriction of and increased secretion by the airways, and paralysis of the respiratory musculature. While tolerance to the cholinergic toxicity of OPs has been well documented, such studies have not included investigations of the brain stem and extrapulmonary airways. In this report tolerance to the insecticide malathion is demonstrated. At 24 hr after 14 daily doses of malathion (400 mg/kg, ip), CHE activities were 27, 26, and 28% of control in striatum (ST), hippocampus (HI), and cortex (CX), respectively, while brain stem CHE activity was 41% of control. In addition, the numbers of muscarinic receptors (Bmax) decreased 30, 20, and 22% in ST, HI, and CX, respectively. In contrast, there was no change in brain stem Bmax. The lack of parallelism between CHE inhibition and Bmax effects in brain stem as compared to all other tissues ...

Neurotoxicology, 1985

Treatment of mice with IDPN (4 injections of 1 gm/kg on alternate days) produced a characteristic... more Treatment of mice with IDPN (4 injections of 1 gm/kg on alternate days) produced a characteristic syndrome of abnormal movements which was associated with neurotransmitter changes in the extrapyramidal and other regions of the brain. A decrease in the concentration of GABA was observed in the striatum and hippocampus both 1 and 10 days after the last injection, along with a transient decrease in the cerebral cortex. In addition, the specific binding of GABA was increased by this treatment in the striatum and cerebral cortex but reduced in the cerebellum. Other striatal changes included a transient increase in dopamine content and a decrease in choline acetyltransferase activity. No biochemical or behavioral changes were observed after acute injection of IDPN or following 4 injections of the non-neurotoxic analog BAPN. These neurochemical alterations may play a role in the abnormal movements produced by IDPN.

The Journal of pharmacology and experimental therapeutics, 1988

Recent behavioral evidence suggests that enhancement of noradrenergic neurotransmission may alter... more Recent behavioral evidence suggests that enhancement of noradrenergic neurotransmission may alter the functional sensitivity of serotonin2 (5-HT2) receptors in the central nervous system. The present studies have examined the effects of two types of noradrenergic denervation [neurotoxic: via N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP4) treatment; and pharmacologic: via chronic beta adrenergic receptor blockade] on the 5-HT2-mediated head shake response and cortical beta adrenergic and 5-HT2 receptor number in the rat. No changes in quipazine-induced head shakes were observed 3 days after DSP4 lesion. However, the frequency of head shakes was significantly enhanced 10 days after DSP4 treatment in the presence of a 39% up-regulation of beta adrenergic receptors. Pretreatment with propranolol 10 days after DSP4 lesion selectively antagonized the enhancement of the behavioral response to quipazine without altering base-line response rate, whereas pretreatment with the 5-HT2 antag...

Toxicology and applied pharmacology, Jan 30, 1988

gamma-Hexachlorocyclohexane (gamma-HCH), the active ingredient of the insecticide lindane, has be... more gamma-Hexachlorocyclohexane (gamma-HCH), the active ingredient of the insecticide lindane, has been shown to be a seizure-inducing agent in mammals. gamma-HCH and two non-convulsant isomers of HCH (alpha and delta) were compared as to their CNS-related pharmacological and biochemical effects. gamma-HCH was a potent seizure-inducing agent in mice while the alpha or the delta isomer significantly decreased mouse motor activity. Acute administration of gamma-HCH increased the severity of seizure activity of either pentylenetetrazol (PTZ) or picrotoxin (PIC). However, acute exposure to alpha- or delta-HCH inhibited the seizure activity due to PTZ but increased that of PIC. gamma-, alpha-, and delta-HCH inhibited the binding of 3H-TBOB (a ligand for the GABA-A receptor linked chloride channel) to mouse whole brain membranes with IC50 values of 4.6, 20.0, and 31.8 microM, respectively. All three isomers were weak inhibitors of GABA-stimulated uptake of 36Cl into mouse brain neurosynaptoso...

Research communications in chemical pathology and pharmacology, 1977

Clozapine elevates the concentration of dopamine in the brains of mice injected with doses of 5-2... more Clozapine elevates the concentration of dopamine in the brains of mice injected with doses of 5-20 mg/kg while a 40 mg/kg dose has no effect. This biphasic change in dopamine content is seen in both the striatum and olfactory tubercle. The elevated dopamine concentration is dose-dependently antagonized by apomorphine, while a corresponding clozapine-induced reduction in norepinephrine concentrations is unaffected by apomorphine. These results suggest that part of the action of clozapine may be to reduce the release of dopamine.

Life sciences, 1975

ABSTRACT Because of many practical difficulties which are encountered in obtaining direct evidenc... more ABSTRACT Because of many practical difficulties which are encountered in obtaining direct evidence for the involvement of brain neurotransmitters in the action of narcotic drugs, several indirect procedures are often employed. One such method is to compare on the same measures of drug action the narcotic drugs with a non-narcotic drug having a known mechanism of action. Haloperidol is a prototype non-narcotic drug which blocks dopamine receptors and many of its actions are believed to be associated with this receptor blockade. In this paper we compare various actions of haloperidol or other neuroleptics with morphine or other narcotic analgesics using the same testing parameters. We hope that such a comparison would evaluate the role of dopamine receptors in narcotic action and narcotic dependence. This discussion is limited only to the behavioral measures as a comparison of neurochemical measures was recently reviewed in another paper (1).

European Journal of Pharmacology - EUR J PHARMACOL, 1999

Four muscarinic receptor antagonists with varying selectivities for the four pharmacologically-de... more Four muscarinic receptor antagonists with varying selectivities for the four pharmacologically-defined muscarinic receptor subtypes (M1–M4) were administered into the lateral ventricle to determine their relative potency in reducing tremulous jaw movements induced by i.p. injection of the muscarinic receptor agonist pilocarpine (4.0 mg/kg). All four muscarinic receptor antagonists reduced tremulous jaw movements in a dose-dependent manner, with the following rank order of potency: scopolamine>methoctramine≥telenzepine>pirenzepine. This pattern is inconsistent with the rank order of affinity of these agents at the muscarinic M1 receptor, and is consistent with their rank order of affinity at muscarinic M2 or M4 receptors. Because tremulous jaw movements are related to striatal function, and the muscarinic M4 receptor is more predominant than the muscarinic M2 receptor as a post-synaptic receptor in striatum, the present results suggest that pilocarpine induces jaw movements due...

Toxicology Letters, 1985

4-Aminobutyric acid (GABA) turnover was measured in mice 8 h after an acute injection of 1 g/kg o... more 4-Aminobutyric acid (GABA) turnover was measured in mice 8 h after an acute injection of 1 g/kg of technical grade chlordane in corn oil. Significant decreases in GABA turnover were observed in the cortex, striatum, hippocampus and hypothalamus after chlordane treatment. A smaller, though significant, decrease was also observed in the cerebellum. These results may help to explain the hyperexcitability and convulsions observed after acute high-dose exposure to this compound.

Toxicology Letters, 1987

The disposition and toxicity of methylcyclopentadienyl manganese tricarbonyl (MMT) was studied in... more The disposition and toxicity of methylcyclopentadienyl manganese tricarbonyl (MMT) was studied in Sprague-Dawley rats after subcutaneous administration at a dose of 4 mg/kg. Blood, lung, liver and kidney Mn levels were increased between 1.5 and 96 h after MMT injection, with peak organ levels occurring at 3-6 h. At this time the MMT-derived Mn concentration in lung, liver and kidney averaged 13-, 4- and 4-fold higher, respectively, than in the blood, indicating the accumulation and retention of MMT (or metabolite) in these tissues. Maximal pulmonary toxicity, as assessed by pulmonary lavage protein levels, occurred 24-48 h after injection. Plasma urea and sorbitol dehydrogenase levels were not increased at any time after MMT, suggesting minimal or no hepatic or renal injury. That maximal pulmonary toxicity occurred after peak Mn accumulation, and that the organ-specific toxicity of MMT correlated with its accumulation and retention, suggests a causal relationship between tissue Mn accumulation and MMT-induced toxicity.