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Biomedical subjects

N Uretsky

Publications and source records attributed to N Uretsky.

At least 19 recordsLinked to original sources
PubMed1997

Effect of pertussis toxin injected into the ventral tegmental area on amphetamine-induced Fos protein in the nucleus accumbens.

Amphetamine produces an enhanced locomotor stimulatory response in animals injected with pertussis toxin into the ventral tegmental area. This response is dependent on the activation of D1 receptors in the nucleus accumbens. The immediate early gene, c-Fos, has been used as a cellular marker for increases in dopamine neurotransmission in the nucleus accumbens. The purpose of the present study was to determine whether the administration of pertussis toxin into the ventral tegmental area results in an increased ability of amphetamine to induce Fos-positive immunoreactivity in the nucleus accumbens. Amphetamine (1 mg/kg and 2 mg/kg IP) produced a greater number of Fos-positive cells in the nucleus accumbens of pertussis toxin-treated animals as compared to vehicle-treated controls. However, the increase in Fos immunoreactivity at the higher amphetamine dose was not associated with a corresponding increase in locomotor activity. These data suggest that amphetamine produces an enhanced increase in dopamine neurotransmission in the nucleus accumbens of pertussis toxin-treated animals, resulting in an increased induction of Fos-related antigens.

Amphetamine↗
PubMed1996

Role of dopaminergic mechanisms in the stimulatory effects of MK-801 injected into the ventral tegmental area and the nucleus accumbens.

The bilateral administration of 10 micrograms of (+)MK-801, but not (-)MK-801, into either the VTA or the N.Ac. stimulated locomotor activity. The stimulation induced by (+)MK-801 at both sites was inhibited by reserpine (5 mg/kg, SC) and the D1 antagonist, SCH 23390 (0.1 mg/kg, SC). Eticlopride (0.03 mg/kg, SC), a D2 antagonist, inhibited the stimulation produced by MK-801 in the VTA but not in the N.Ac. Baclofen (32 ng), a GABAB receptor agonist, injected into the VTA inhibited the stimulatory response to MK-801 injected systemically, into the VTA, or into the N.Ac., but did not significantly inhibit spontaneous locomotion or the stimulatory response to apomorphine (5 mg/kg, SC). These observations suggest that the stimulatory effects of MK-801 in the VTA and the N.Ac. are dependent on endogenous dopamine. In addition, the effects produced by MK-801 injected into the VTA closely resemble those produced by the systemic administration of low doses of MK-801, suggesting that this is the primary site of action of MK-801.

Adrenergic Uptake Inhibitors↗
PubMed1996

Spontaneous and drug-stimulated locomotor activity after the administration of pertussis toxin into the ventral tegmental area.

Pertussis toxin (PTX) injected into the ventral tegmental area (VTA) produces an enhanced locomotor response to amphetamine. In the present study, we have evaluated the role of dopamine receptors on spontaneous locomotor activity and the enhanced locomotor response to dopaminergic agonists after the administration of PTX into the VTA. PTX injected into the VTA of rats produced a delayed increase in spontaneous locomotor activity with a latency of 4 d. This activity was markedly increased by day 6 and remained elevated for at least 28 d after PTX treatment. This increased spontaneous locomotor activity of PTX-treated animals was antagonized by the administration of the D1 receptor antagonist SCH23390 (0.03 and 0.1 mg/kg sc), but not by the D2 receptor antagonist eticlopride (0.1 and 0.3 mg/kg sc). After adaptation to the locomotor cages, the animals showed a markedly enhanced motor response to amphetamine (0.5 mg/kg ip) and apomorphine (5 mg/kg sc). The heightened locomotor responses to these dopaminergic agonists could be elicited for at least 2 mo after PTX administration. The enhanced response to amphetamine was antagonized by the administration of SCH23390 (0.03 and 0.1 mg/kg sc), but not by eticlopride (0.1 mg/kg). The increased response to apomorphine in PTX-treated animals was inhibited by SCH23390 (0.1 mg/kg sc) and partially inhibited by eticlopride (0.1 mg/kg sc). Both of these antagonists inhibited the spontaneous and the drug-induced locomotor responses in vehicle-treated control animals. These results suggest that the administration of PTX into the VTA leads to an increase in spontaneous and drug-induced locomotor activity in which D1 receptors seem to play an important role.

Animals↗
PubMed1994

Effects of cocaine on sensory inhibition in rats: preliminary data.

The purpose of this study was to determine the effect of cocaine on inhibitory sensory processing mechanisms in the brain. To accomplish this aim, recording electrodes were surgically placed into the vertex region of 12 rats. After recovery from surgery, rats were injected once daily for 5 days with either cocaine (20 mg/kg, IP) or saline. Immediately and 23 hr after each injection, the rats were tested for sensory gating mechanisms. They were presented with a series of two clicking sounds, a conditioning and testing click, delivered 0.5 sec apart, and the amplitude of the N40 responses to each of these clicks was recorded. The ratios of the amplitude of the N40 response to the testing click over that of the conditioning click (T/C ratio) were calculated for each animal for each testing period. The T/C ratios of the control (Saline-injected) animals were less than one, indicating that the conditioning stimulus was able to activate inhibitory neural pathways, producing a decrease in the response to the testing stimulus. The T/C ratios of the cocaine-treated animals were significantly greater than those of controls when the tests were conducted either immediately after injection or 23 hr later. These observations suggest that cocaine can impair mechanisms involved in the gating of responses to auditory stimuli. The higher T/C ratio found at 23 hr after cocaine injection suggests that an impairment in the gating mechanism may be produced by an arousal response that is associated with the environment in which the animals had been injected with cocaine.

Acoustic Stimulation↗
PubMed1993

The interaction of ammonium, sulfonium, and sulfide analogues of metoclopramide with the dopamine D2 receptor.

A series of permanently charged ammonium and sulfonium analogues of metoclopramide as well as a permanently uncharged sulfide analogue were synthesized and evaluated for their ability to inhibit apomorphine-induced responses on mouse striatal slices. Three of the four permanently charged analogues were found to inhibit apomorphine's effects, although at higher concentrations than either metoclopramide or its dimethyl analogue. In contrast, the sulfide analogue was inactive at concentrations up to 100 microM. These findings are consistent with earlier studies of chlorpromazine and sulpiride analogues and provide further evidence that dopamine antagonists bind in their charged molecular forms to anionic sites on the D2 receptor. Further, the results of this study in conjunction with those of our earlier sulpiride study would seem to indicate that differences in the biological profiles of metoclopramide, a type 1 benzamide useful as a gastric prokinetic agent, and sulpiride, a type 2 benzamide useful for its antipsychotic effects, are not due to any appreciable differences in the binding of the basic nitrogen atom of these molecules.

Animals↗
PubMed1993

Interaction of AZA analogs of chlorpromazine with the dopamine D2 receptor.

1. Permanently charged AZA analogs of chlorpromazine inhibited the binding of [3H]spiperone and antagonized the apomorphine-induced inhibition of the potassium evoked release of [3H]acetylcholine. 2. The AZA analogs were more potent in binding affinity and antagonist activity than the trimethylammonium analog of chlorpromazine but less potent than chlorpromazine. 3. These results suggest that it is possible to enhance the binding of the permanently charged trimethylammonium analog of chlorpromazine by the addition of a functional group near the quaternary nitrogen which is capable of forming a hydrogen bond with the D2 dopamine receptor. 4. However, it appears that for optimal binding, as achieved with chlorpromazine, the hydrogen-bonding proton should be on the charged nitrogen.

Acetylcholine↗
PubMed1989

Synthesis and D2 dopaminergic activity of pyrrolidinium, tetrahydrothiophenium, and tetrahydrothiophene analogues of sulpiride.

All of the existing dopamine receptor models recognize the amine nitrogen of agonist and antagonist drugs as playing a crucial role in receptor interactions. However, there has been some controversy as to which molecular form of the amine, charged or uncharged, is most important in these interactions. We have synthesized and examined the biological activity of permanently charged and permanently uncharged analogues of the dopaminergic antagonist, sulpiride. Sulpiride and the permanently charged pyrrolidinium (6,7) and tetrahydrothiophenium (9) analogues were able to antagonize the inhibitory effect of apomorphine on the K+-induced release of [3H]acetylcholine from striatal slices. In contrast, the permanently uncharged tetrahydrothiophene analogue 8 was inactive at concentrations up to 100 microM. Additionally, both sulpiride and the tetrahydrothiophenium analogue were able to displace [3H]spiperone from D2 binding sites, while the tetrahydrothiophene analogue was unable to produce any significant displacement. These results are consistent with our previous observations on permanently charged chlorpromazine analogues and provide further evidence that dopaminergic antagonists bind in their charged molecular forms to anionic sites on the D2 receptor.

Acetylcholine↗
PubMed1988

Interaction of permanently uncharged dopamine analogs with the D-2 dopaminergic receptor.

The purpose of this study was to determine if structural analogs of dopamine in which the side chain nitrogen has been replaced by a permanently uncharged monomethylsulfide, monomethylselenide or sulfoxide group are capable of binding to the striatal D-2 dopamine receptor and acting as agonists at this receptor. All the permanently uncharged dopamine analogs were found to bind to the D-2 dopamine receptor as evidenced by their abilities to inhibit significantly [3H]spiperone binding to striatal homogenates. However, the inhibition of [3H]spiperone binding by the uncharged dopamine analogs was incomplete and was almost abolished by the addition of NaCl (125 mM) to the incubation medium or by the addition of dopamine or quinpirole at a concentration that that saturates the high-affinity state of the D-2 dopamine receptor. These effects of NaCl, dopamine and quinpirole suggest that the uncharged dopamine analogs bind primarily to the high-affinity state of the D-2 dopamine receptor. Whether the uncharged monomethylsulfide and sulfoxide analogs could function as dopamine agonists at the striatal D-2 dopamine receptor was assessed by determining the abilities of these compounds to inhibit the K+-evoked release of [3H]acetylcholine from striatal slices. Both the monomethylsulfide and sulfoxide analogs inhibited the K+-evoked release of [3H]acetylcholine, but this inhibitory effect does not appear to be due to the activation of the D-2 dopamine receptor since it was not reversed by the selective D-2 dopamine antagonist, sulpiride. Additionally, the uncharged monomethylsulfide and sulfoxide dopamine analogs were found to antagonize the ability of apomorphine to inhibit the K+-evoked release of [3H]acetylcholine, but this antagonistic effect does not appear to be due to the reversible blockade of the D-2 dopamine receptor since it was not reduced by increasing the concentration of apomorphine. Therefore, while the permanently uncharged analogs of dopamine appear to bind to the high-affinity state of the D-2 dopamine receptor, they are not dopamine agonists or antagonists at the striatal D-2 dopamine receptor involved in regulating the release of acetylcholine. These results suggest that a positive charge may be a requirement for the activation of the striatal D-2 dopamine receptor.

Acetylcholine↗
PubMed1987

Interaction of permanently charged analogs of dopamine with the D-2 dopaminergic receptor.

Dopamine can exist in both charged and uncharged forms at physiological pH. At present it is unclear which of these forms is responsible for dopaminergic agonist activity. The purpose of this study was to determine whether permanently charged structural analogs of dopamine containing either a nitrogen, sulfur, or selenium atom in the side chain can bind to and activate the D-2 dopamine receptor. Binding to and activation of the D-2 dopamine receptor were measured by determining the abilities of the permanently charged dopamine analogs to inhibit [3H]spiperone binding to striatal homogenates and to inhibit K+-stimulated [3H]acetylcholine release from striatal slices respectively. The quaternary ammonium, dimethylsulfonium and dimethylselenonium analogs of dopamine were all found to inhibit [3H]spiperone binding to the same extent and in a manner qualitatively similar to the parent amines, dopamine and dimethyldopamine. Thus, [3H]spiperone inhibition curves for dopamine, dimethyldopamine and the permanently charged dopamine analogs were generally shallow and fit best to a two-site binding model as indicated by computer-assisted analyses. The addition of 125 mM NaCl to the incubation medium resulted in a significant decrease in the proportion of high affinity binding sites for both the permanently charged analogs and the parent amines. Similarly, the permanently charged dopamine analogs were found to maximally inhibit the K+-stimulated release of [3H]acetylcholine to the same extent as dopamine and dimethyldopamine. However, the permanently charged analogs were less potent in inhibiting both [3H]spiperone binding and K+-stimulated [3H]acetylcholine release than dopamine and dimethyldopamine. These results show that dopamine analogs possessing a permanent positive charge in the side chain can bind to and activate the D-2 dopamine receptor. The lower potencies of the permanently charged analogs in binding to and activation of the D-2 dopamine receptor suggest that, while the ability of a compound to exist in an uncharged form is not a requirement, both charged and uncharged forms of the agonist molecule appear to play a role in D-2 dopamine agonist activity.

Acetylcholine↗
PubMed1987

Effect of permanently charged and uncharged dopaminergic agonists on the potassium-induced release of [3H]acetylcholine from striatal slices.

The effects of chemical analogs of dopamine, which are permanently charged or which lack a net positive charge, on the potassium-evoked release of [3H]acetylcholine from mouse striatal slices were studied in order to determine whether a positive charge on the dopamine agonist molecule is required to activate dopaminergic receptors. The striatal slices were first preincubated with [3H]choline, transferred to a superfusion chamber, and then superfused in physiological medium. [3H]Acetylcholine release was evoked by exposure of the slices to a high potassium medium and potential dopamine agonist drugs were added to the medium 10 min before superfusing with high potassium. A permanently charged quaternary ammonium analog and dimethylselenonium analog of dopamine inhibited the potassium-evoked release of [3H]acetylcholine, and this inhibition was antagonized by sulpiride, a dopamine receptor antagonist. However, this inhibition was not antagonized by reserpine and alpha-methyl-p-tyrosine, which was shown to completely antagonize the inhibitory effect of amphetamine, an indirectly acting amine. This suggests that the charged dopamine analogs are acting directly on dopaminergic receptors. In contrast to the permanently charged dopamine analogs, analogs of dopamine with no net positive charge produced no inhibition of the potassium-evoked [3H]acetylcholine release. These in vitro observations are in agreement with a behavioral model in which a permanently uncharged monomethylsulfide analog of dopamine was ineffective in eliciting circling behavior after its unilateral injection into the striatum of rats in which dopamine neurons were previously lesioned by the injection of 6-hydroxydopamine into the medial forebrain bundle. In contrast, under these same conditions, the intrastriatal injection of the charged quaternary ammonium or dimethylsulfonium analog of dopamine elicited intense contralateral circling. These results suggest that the charged form of a dopamine agonist molecule is required to bind to and activate the dopamine receptor regulating [3H]acetylcholine release and circling behavior.

Acetylcholine↗
PubMed1987

Dopamine agonists: effects of charged and uncharged analogues of dopamine.

Dopamine, at physiological pH, may exist as either an uncharged amine or a charged ammonium species. In order to gain insight as to which species is better suited for interaction with the dopamine receptor, we have synthesized dopamine analogues in which the nitrogen atom is replaced with a neutral methyl sulfide, a neutral methyl selenide, a charged dimethylsulfonium iodide, and a charged dimethylselenonium iodide. These analogues were tested for their ability to inhibit the K+-stimulated release of [3H]acetylcholine from striatal slices. At 30 microM concentration, the charged sulfonium and selenonium salts possessed significant agonist activity while the corresponding neutral species were inactive, suggesting that a charged species is optimal for dopamine agonist activity. In addition, the methyl sulfide was converted into the corresponding sulfoxide and sulfone; however, neither of these oxidation products possessed significant activity as dopaminergic agonists.

Acetylcholine↗
PubMed1987

Charged analogues of chlorpromazine as dopamine antagonists.

Chlorpromazine (1, CPZ) is a potent dopamine antagonist that has been used widely as an antipsychotic agent. Since dopaminergic antagonists, like dopaminergic agonists, exist in solution as the charged and uncharged molecular species, it is not clear which form of the amine is most important for interaction with the dopamine receptor. Previous work from our laboratory has indicated that a variety of permanently charged species could replace the amine/ammonium moiety of dopamine and retain dopamine agonist activity. This paper describes the synthesis and dopamine antagonist activity of both the trimethylammonium iodide and the dimethylsulfonium iodide analogues of chlorpromazine. The permanently uncharged methyl sulfide analogue was also synthesized; however, due to its lack of aqueous solubility, its pharmacological activity could not be evaluated. Binding of both the dimethylsulfonium iodide and the trimethylammonium iodide analogues to D-2 dopamine receptors of rat striatal tissue was observed. The observed relative order of binding was CPZ greater than CPZ sulfonium analogue greater than CPZ ammonium analogue. These compounds had a similar order of activity in antagonizing the apomorphine-induced inhibition of potassium-induced release of [3H]acetylcholine from mouse striatal slices.

Acetylcholine↗
PubMed1984

Effect of a sulfonium analog of dopamine on the depolarization-induced release of [3H]acetylcholine from mouse striatal slices.

P3 have synthesized a chemical analog or dopamine in which the amino group has been replaced by a charged dimethylsulfonium group. The dopaminergic activity of this drug was evaluated by determining its ability to inhibit the depolarization-evoked release of [3H]acetylcholine from mouse striatal slices. The slices were preincubated with [3H]choline (0.1 microM) and then superfused in physiological medium. [3H]Acetylcholine release was induced by exposure of the slices to a high potassium medium (12.5 mM) for 5 min. The sulfonium analog of dopamine, dopamine, and apomorphine inhibited the evoked [3H]acetylcholine release with IC50 values of approximately 10, 2.0, and 0.3 microM respectively. The inhibition by the sulfonium analog was reversed by fluphenazine (1 microM), suggesting that the inhibition of [3H]acetylcholine release was due to the activation of dopaminergic receptors. The sulfonium analog also inhibited the uptake of [3H]dopamine into striatal slices and caused the release of exogenously taken up [3H]dopamine from these slices. The release of [3H]dopamine by the sulfonium analog was inhibited by cocaine (3 microM), suggesting that the drug-induced release of [3H]dopamine was dependent on the carrier-mediated uptake of the sulfonium analog into dopaminergic neurons. The inhibition of the evoked [3H]acetylcholine release by high concentrations (30 and 60 microM) of the sulfonium analog did not appear to be mediated by endogenous dopamine release, since the analog still inhibited [3H]acetylcholine release from slices after reserpine-alpha-methyl-p-tyrosine treatment. However, the inhibitory effect of the sulfonium analog at 10 microM was reduced by reserpine-alpha-methyl-p-tyrosine treatment, suggesting that the inhibition at lower concentrations was mediated through endogenous DA release. These results suggest that a charged compound can act as a substrate for the dopamine carrier and can activate the dopamine receptor regulating acetylcholine release. They also indicate that the nitrogen on the dopamine molecule is not essential for dopamine agonist activity.

Acetylcholine↗
PubMed1984

Effect of 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine (MPTP) on monoamine neurotransmitters in mouse brain & heart.

The effect of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) was studied on dopamine (DA), norepinephrine (NE), serotonin (5HT) and gamma-aminobutyric acid (GABA) neurons in mouse brain and on NE neurons of mouse heart. MPTP (45 mg/kg) was administered s.c. to mice twice daily for 2 consecutive days. This dosage regimen produced a decrease in the forebrain concentrations of DA and NE at 7 and 20 days after injection. In contrast, the forebrain concentrations of 5HT and GABA were not significantly decreased at either time. MPTP administration also produced a marked decrease in the uptake of 3H-DA into striatal slices and 3H-NE into cerebral cortical slices. In contrast, the uptake of 3H-NE into hypothalamic slices and the uptake of 3H-5HT into slices from several brain regions were not altered. MPTP initially reduced the concentration of NE in the heart, but unlike the persistent decreases in the forebrain concentrations of NE and DA, the NE concentration in the heart returned to control levels at approximately 20 days after MPTP administration. These results, showing that MPTP can produce a long lasting and selective decrease in the forebrain concentrations of NE and DA and in the uptake of radioactive DA and NE into brain slices, suggest that MPTP can cause the destruction of catecholamine neurons in mouse brain. In contrast, MPTP administration does not appear to produce long term changes in either 5HT or GABA neurons.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1984

Dopaminergic agonists: comparative actions of amine and sulfonium analogues of dopamine.

We have investigated the possibility that structural modifications of the sulfonium analogue of dopamine (4) would produce the same pattern of biological activity as structural modifications of dopamine. A series of methyl- tetralinyl -, and naphthalenylsulfonium analogues 5-7 were prepared and tested for their ability to inhibit the potassium-evoked release of [3H]acetylcholine from striatal slices. All compounds were tested under normal conditions and after depletion of dopamine stores with reserpine and alpha-methyl-p-tyrosine. The amine and sulfonium analogues 2-6 all showed direct agonist activity. The sulfonium analogue 7 produced, predominantly, indirect activity. In contrast to the amine analogues, chemical modifications of the sulfonium compounds produced little change in their dopamine agonist activity.

Acetylcholine↗
PubMed1981

Synthesis and pharmacological evaluation of sulfonium analogues of dopamine: nonclassical dopamine agonists.

In order to test whether the nitrogen/ammonium moiety in the dopamine molecule is required for dopaminergic activity, we have synthesized two sulfonium analogues of dopamine and tested them for biological activity in an in vivo and in an in vitro system. These analogues have provided a means of investigating (1) the ability of the sulfonium function to serve as a bioisostere for the dopamine amino group and (2) whether charged molecules have the ability to bind to dopamine receptors. Both sulfonium analogues, 1 and 2, as well as dopamine, when injected directly into the striatum of rats, previously lesioned unilaterally with 6-hydroxydopamine (6-OHDA), produced circling behavior. The potency of the sulfonium analogues was approximately one-tenth that of dopamine. The effects of all three compounds on circling were inhibited by the dopamine antagonist haloperidol. In addition, both sulfonium analogues inhibited the high affinity binding of radiolabeled dopamine to a crude membrane fraction prepared from the striatum. This study suggests that the nitrogen atom found in th dopamine molecule is not essential for dopaminergic activity, since the nitrogen can be replaced by a sulfonium functional group for this activity.

Animals↗
PubMed1978

Does intervention by a nurse improve medication compliance?

A random sample of patients taking two or more drugs, at least one of which was digoxin or methyldopa, was drawn from a medical clinic population. After giving informed consent, the patients were randomized into control and experimental groups. The experimental group was seen by a specially prepared nurse interventionist who attempted to improve medication compliance. The levels of the drugs in the blood were taken as indicators of medication compliance. Our results document that patients exposed to nurse intervention were more compliant than the general clinic population, but were not more compliant than a nonintervention control group. Problems encountered in the collection and interpretation of compliance study data were identified and discussed.

Aged↗