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G R King

Publications and source records attributed to G R King.

At least 19 recordsLinked to original sources
PubMed2000

The dopamine D2/D3 antagonist DS121 potentiates the effect of cocaine on locomotion and reduces tolerance in cocaine tolerant rats.

To explore the significance of dopamine (DA) autoreceptors in cocaine tolerance and cocaine induced locomotor activity rats were treated with saline and cocaine (40 mg/kg per day via osmotic minipump; normal and cocaine tolerant rats, respectively). Injections of DS121 (0-7 mg/kg, i.p.; S(-)-3-(3-(cyanophenyl)-N-n-propylpiperidine), a DA D2/3 and autoreceptor preferring antagonist, either alone (i.e. DS121 + saline injection) or in combination with cocaine (7.5 mg/kg, i.p.) were also given. DS121 (+ saline) increased locomotor activity in both saline and cocaine pump (CP) treated animals. DS121 also potentiated the effect of cocaine on locomotor activity; this effect was greatest in CP (tolerant) animals. It is concluded that DS121 can increase locomotor activity and that this effect is greatest when the DA tone is high, that is when cocaine is present, suggestive of a presynaptic mechanism. Furthermore, because DS121 potentiation of cocaine induced locomotor activity is greatest in tolerant animals it is concluded that supersensitive DA autoreceptors underlie this effect. These data further support our previous data, which show that DA autoreceptors are sensitized after continuous cocaine (minipump) treatment.

Animals↗
PubMed2000

Long-term blockade of the expression of cocaine sensitization by ondansetron, a 5-HT(3) receptor antagonist.

Intermittent cocaine administration induces sensitization (reverse tolerance) to its behavioral effects. The mechanism(s) mediating sensitization is not clear, however, previous research has implicated 5-HT(3) receptors in the expression of sensitization. The present experiment evaluated the ability of the 5-HT(3) receptor antagonist, ondansetron, administered during withdrawal from chronic intermittent cocaine administration, to block the expression of sensitization. Rats were pretreated for 14 days by daily subcutaneous injections of either 40 mg/kg cocaine or 0.9% saline. During the first 5 days of withdrawal from this pretreatment regimen, all rats received a daily subcutaneous injection of 0-1.0 mg/kg ondansetron. On days 7, 14 or 28 of withdrawal from the cocaine pretreatment, the rats received a 15.0-mg/kg cocaine challenge. Ambulatory behavior was automatically recorded for 60 min. Ondansetron had no significant effect on the subsequent behavioral response to cocaine in the saline control subjects. In contrast, daily injections of ondansetron blocked the expression of sensitization at all withdrawal times. We thus report that it is possible to permanently block the expression of sensitization once it has developed by administering a 5-HT(3) receptor antagonist.

Animals↗
PubMed1999

The effects of continuous cocaine dose on the induction of behavioral tolerance and dopamine autoreceptor function.

The current experiment evaluated the dose-dependent nature of the induction of behavioral tolerance, and changes in dopamine autoreceptor function, by continuously administering different doses of cocaine. For all experiments, rats were exposed to a 14-day pretreatment regimen involving the continuous administration of either 0, 5, 10, 20, or 40 mg/kg/day cocaine. All subjects were then withdrawn from the pretreatment regimen for 7 days. The subjects were placed in activity monitors, and ambulation measured. In experiment 1, the subjects were challenged with 0.0, 7.5, or 15.0 mg/kg i.p. cocaine on day 7 of withdrawal from the continuous cocaine administration regimen. The results indicated that all continuous cocaine doses induced significant tolerance to the 15.0 mg/kg cocaine challenge, relative to the control group. Furthermore, the 5.0 mg/kg/day group exhibited significantly less tolerance than the 40.0 mg/kg/day group. In experiment 2, the subjects were challenged with 0.0, 0.063, or 0.125 mg/kg quinpirole. The results indicated that the 0.063-mg/kg quinpirole challenge inhibited activity, while the 0.125 mg/kg quinpirole challenge enhanced behavior. The results further suggested that the inhibition of behavior was greater in the cocaine-pretreated subjects than in the saline control group. In experiment 3, the subjects were challenged with the same doses of quinpirole in combination with 15 mg/kg i.p. cocaine. The low quinpirole challenge dose inhibited cocaine-induced hyperactivity, while the higher challenge dose enhanced cocaine-induced hyperactivity. The results suggest that the induction of tolerance by continuous cocaine administration is dose-dependent. Continuous cocaine administration did induce dopamine autoreceptor supersensitivity. However, different continuous cocaine doses did not induce differential degrees of dopamine autoreceptor supersensitivity.

Animals↗
PubMed1999

Blockade of accumbens 5-HT3 receptor down-regulation by ondansetron administered during continuous cocaine administration.

The present experiment examined whether ondansetron, co-administered with continuous cocaine, would block the down regulation of accumbens 5-HT3 receptors. Rats were exposed to a 14-day pretreatment regimen that involved the continuous infusion of 40 mg kg(-1) day(-1) cocaine or 0.9% saline via a subcutaneously implanted osmotic minipump. In addition to the continuous cocaine or saline administration, all subjects received daily subcutaneous (s.c.) injections of either vehicle or 0.1 mg kg(-1) ondansetron for the entire 14-day pretreatment regimen. The rats were then withdrawn from this pretreatment regimen for seven days, and slices from the nucleus accumbens obtained. The slices were perfused with 25 mM K+ in the absence and presence of 0, 12.5, 25, or 50 microM m-Chlorophenyl-biguanide HCl (mCPBG). The efflux samples were assayed for dopamine content by high pressure liquid chromatography (HPLC) with electrochemical detection. Continuous cocaine administration significantly attenuated the ability of mCPBG to facilitate K+-induce dopamine overflow compared to saline control rats. In addition, the rats that received ondansetron and cocaine during the 14-day pretreatment period, the ability of mCPBG to enhance K+ stimulated dopamine release was not significantly different from the saline control subjects. For all groups except the cocaine alone group, the effects of mCPBG on K+ stimulated dopamine release were Ca2+ dependent, suggesting that these effects are receptor mediated. These results suggest that continuous cocaine administration functionally down-regulates 5-HT3 receptors in the nucleus accumbens, and that this down-regulation can be blocked by chronic ondansetron administration. Hence, a functional down regulation of accumbens 5-HT3 receptors represents a significant contribution to the tolerance induced by continuous cocaine administration.

Analysis of Variance↗
PubMed1999

Withdrawal from continuous cocaine administration: time dependent changes in accumbens 5-HT3 receptor function and behavioral tolerance.

We have previously reported that continuous cocaine administration functionally down regulates 5-HT3 receptors in the nucleus accumbens. The current experiments evaluated the duration of behavioral tolerance to cocaine and whether the duration of behavioral tolerance and 5-HT3 receptor down-regulation co-varied. Rats were withdrawn from a pretreatment regimen (40 mg/kg/per day cocaine or 0.9% saline for 14 days) for 1, 7 or 14 days. The rats were either sacrificed, and slices from the nucleus accumbens obtained, or were exposed to behavioral rating procedures. The results indicated that continuous cocaine administration significantly attenuated the ability of mCPBG to facilitate K+ -stimulated DA release on days 1 and 7, but not day 14, of withdrawal. Furthermore, continuous cocaine administration induced behavioral tolerance to a cocaine challenge on days 1 and 7, but not day 14, of withdrawal. These results suggest that continuous cocaine administration functionally down-regulates 5-HT3 receptors in the nucleus accumbens, and this functional down-regulation co-varies with the behavioral tolerance induced by continuous cocaine administration. Hence, a functional down-regulation of accumbens 5-HT3 receptors may represent a partial mechanism for the tolerance following continuous cocaine administration.

Animals↗
PubMed1999

Adding water to liquid scintillation cocktail for laboratory wipe tests.

As part of an ongoing laboratory survey process improvement program, we evaluated the addition of water to liquid scintillation cocktail to improve wipe test counting efficiency. Both polar and non-polar 3H and 14C-labeled compounds were used as model contaminants. Our results support the recommendations in the literature regarding the addition of water to scintillation cocktail We found an increase in the counting efficiency of the water-soluble material as a function of water content of the cocktail, but also observed a decrease in the efficiency of detection of the non-polar compound. The offsetting effects are believed to be the result of increased solubility of the polar compounds in water and increased quench of the already solubilized non-polar compound. The finding that adding water to the cocktail brought counting efficiencies of both polar and non-polar molecules to roughly the same value is novel and allows the use of a single quench curve for each radionuclide, regardless of chemical form.

Carbon Radioisotopes↗
PubMed1998

Blockade of the expression of sensitization and tolerance by ondansetron, a 5-HT3 receptor antagonist, administered during withdrawal from intermittent and continuous cocaine.

The present experiment evaluated the ability of the 5-HT3 antagonist, ondansetron, administered during withdrawal from chronic cocaine administration, to block the expression of sensitization and tolerance induced by the intermittent or continuous administration of cocaine, respectively. Rats were pretreated with 40 mg/kg/per day cocaine for 14 days by either s.c. injections or osmotic minipumps, or 0.9% saline, administered via osmotic minipump. During the first 5 days of withdrawal from this pretreatment regimen, all rats received a daily s.c. injection of 0-1.0 mg/kg ondansetron. On day seven of withdrawal from the cocaine pretreatment (2 days after the final ondansetron injection) all subjects received a 15.0 mg/kg i.p. cocaine challenge. Their behavior was then rated according to the Ellinwood and Balster (1974) scale for 60 min. The results indicated that daily injections of ondansetron, on days 1-5 of withdrawal from the pretreatment regimen, had no significant effect on the subsequent behavioral response to cocaine in the saline control subjects. In contrast, daily injections of ondansetron, on days 1-5 of withdrawal from intermittent cocaine administration, significantly blocked the expression of sensitization. In the continuous cocaine group, ondansetron injections, on days 1-5 of withdrawal from continuous cocaine administration, also blocked the expression of behavioral tolerance. The results therefore indicate that changes in 5-HT3 receptor function are associated with the expression of tolerance and sensitization, respectively.

Animals↗
PubMed1998

Alterations in baseline activity and quinpirole sensitivity in putative dopamine neurons in the substantia nigra and ventral tegmental area after withdrawal from cocaine pretreatment.

Using in vivo single-unit recording, we compared in rats the-effects of continuous infusion and once-a-day injections of cocaine on the activity of single putative dopamine neurons in the substantia nigra and ventral tegmental area. After a 7-day withdrawal, we determined: (1) the number of spontaneously active neurons and their bursting patterns and (2) sensitivity of these neurons to intravenous quinpirole. In the substantia nigra, continuous cocaine infusion reduced the number of neurons without affecting the bursting patterns; daily injections were without effects. In the ventral tegmental area, continuous infusion reduced the bursting activity without affecting the number of neurons, whereas injections increased number of neurons without changes in the bursting pattern. Acute sulpiride normalized all the changes in both cell body areas. The quinpirole sensitivity was selectively increased in the nigral neurons following withdrawal from continuous infusion. Possible role of D2/autoreceptor mechanisms in these changes is discussed.

Animals↗
PubMed1997

Blockade of cocaine sensitization and tolerance by the co-administration of ondansetron, a 5-HT3 receptor antagonist, and cocaine.

The present experiment evaluated the ability of the 5-HT3 antagonist, ondansetron, administered during chronic cocaine administration, to block the development of sensitization and tolerance induced by the intermittent or continuous administration of cocaine, respectively. Rats were pretreated with 40 mg/kg per day cocaine for 14 days by either SC injections or osmotic minipumps, or 0.9% saline, administered by SC injection. During this chronic (cocaine) treatment, all rats received a daily SC injection of 0-1.0 mg/kg ondansetron. The rats were then withdrawn from the pretreatment regimen for 7 days. On day 7 of withdrawal from the cocaine pretreatment all subjects received a 15.0 mg/kg IP cocaine challenge, and their behavior was then rated according to the modified Ellinwood and Balster scale for 60 min. The results indicated that daily injections of ondansetron had no consistent or significant effect on the subsequent behavioral response to cocaine in the saline control subjects. In contrast, daily injections of ondansetron with cocaine significantly blocked the development of sensitization with an inverted U-shape dose-response curve. In the continuous cocaine group ondansetron injections also attenuated the development of behavioral tolerance. The results therefore indicate that 5-HT3 receptor stimulation during continuous and intermittent cocaine administration is an important link in the development of behavioral tolerance and sensitization.

Animals↗
PubMed1997

5-HT3 receptor mediated dopamine release in the nucleus accumbens during withdrawal from continuous cocaine.

The present experiment examined changes in the ability of the selective 5-HT3 receptor agonist, 1-(m-chlorophenyl)-biguanide (mCPBG), to facilitate K(+)-induced dopamine (DA) release during withdrawal from continuous cocaine administration. Rats were withdrawn from continuous cocaine administration (40 mg/kg per day cocaine for 14 days) for 7 days, and then slices from the nucleus accumbens obtained. Following an equilibration period, the slices were perfused with 0, 12.5, 25, or 50 microM mCPBG in the absence and presence of 25 mM K+. The samples were assayed for DA content by HPLC with electrochemical detection. Continuous cocaine administration significantly attenuated the ability of mCPBG to facilitate K(+)-induced DA overflow compared to saline control rats. These results suggest that continuous cocaine administration functionally down-regulates 5-HT3 receptors in the nucleus accumbens. These results further suggest that 5-HT3 receptor subsensitivity may represent a partial mechanism for the tolerance induced by continuous cocaine administration.

Animals↗
PubMed1997

Cocaine and amphetamine elicit differential effects in rats with a unilateral injection of dopamine transporter antisense oligodeoxynucleotides.

We have developed an antisense oligodeoxynucleotide to the dopamine transporter and used it to discriminate the behavioral properties of amphetamine and cocaine. In SK-N-MC cells permanently transfected with the dopamine transporter complementary DNA, treatment with 5 mM antisense oligodeoxynucleotide reduced dopamine uptake by 25% when compared to sense control. Unilateral intranigral administration of dopamine transporter antisense (50 microM) twice daily in freely moving rats for 2.5 days was sufficient to reduce dopamine transporter messenger RNA by 70% as measured by in situ hybridization, but not protein levels as measured by [3H]mazindol binding. However, intranigral treatment via implanted osmotic minipump over a period of seven days produced reductions in both dopamine transporter messenger RNA and protein levels (32%) at a dose of 500 pmol/day. These results indicate a longer half-life for the dopamine transporter than expected. Potassium chloride depolarization of ipsilateral striatal slices showed a greater than 200% increase in dopamine overflow on the antisense-treated side compared to the control side. Since imbalance of dopamine tone is known to induce rotational activity, we tested this behavioral paradigm in rats treated with various oligodeoxynucleotides at different doses and time-points. We have found that antisense-treated animals did not rotate spontaneously under any experimental conditions. Using various psychostimulants that target the dopamine transporter and increase dopamine levels, we found that the antisense-treated animals consistently rotated contralaterally in response to amphetamine (2 mg/kg), but not to cocaine (10 mg/kg) or nomifensine (10 mg/kg). These results bring in vivo evidence for a different mode of action of amphetamine and cocaine on the dopamine transporter and lend direct support to the view that amphetamine acts as a dopamine releaser, whereas cocaine acts by blocking dopamine transport.

Amphetamine↗
PubMed1995

5-HT3 agonist-induced dopamine overflow during withdrawal from continuous or intermittent cocaine administration.

This experiment examined alterations in the ability of the highly selective 5-HT3 receptor agonist, 1-(m-chlorophenyl)-biguanide (mCPBG), to induce dopamine (DA) overflow in caudate brain slices obtained from rats withdrawn from continuous or intermittent cocaine administration. Rats were pretreated with 40 mg/kg per day cocaine for 14 days by either subcutaneous injections or osmotic minipumps, and then withdrawn from this regimen for 7 days. Caudate brain slices were obtained, and perfused with artificial cerebrospinal fluid. Following an equilibration period, the slices were then perfused with 25, 50, or 100 microM mCPBG. The samples were assayed for DA content by HPLC with electrochemical detection. The results indicated that the pretreatment with intermittent cocaine did not consistently alter the ability of mCPBG to induce DA overflow, although there was a reduction in the amount of DA released by the highest concentration of mCPBG. In contrast, pretreatment with continuous cocaine administration consistently and significantly attenuated the ability of mCPBG to induce DA overflow. The DA overflow induced by mCPBG was partially dependent on extracellular Ca2+ in the perfusion medium for the saline control and intermittent administration subjects: elimination of Ca2+ from the medium significantly reduced, but did not eliminate, DA overflow for these two groups. In contrast, elimination of Ca2+ from the perfusion medium had a significant enhancing effect on mCPBG-induced DA overflow in the continuous administration rats. These results suggest that distinct temporal patterns of cocaine administration differentially alter the ability of a 5-HT3 agonist to increase extracellular DA levels, and that this effect may be related to an impairment of Ca(2+)-dependent release.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

5-HT3 receptor modulation of behavior during withdrawal from continuous or intermittent cocaine.

The present experiments examined alterations in 5-HT3 receptors during withdrawal from continuous or intermittent cocaine. Rats were pretreated with 40 mg/kg/day cocaine for 14 days by either SC injections or osmotic minipumps. The rats were then withdrawn from the pretreatment regimen for 7 days. In Experiment 1, rats received 0-16 mg/kg IP injections of ondansetron, a selective 5-HT3 receptor antagonist. In Experiment 2, the rats received 0-16 mg/kg IP ondansetron in combination with a 15 mg/kg IP injection of cocaine. In Experiment 3, the subjects received 0-16 mg/kg IP injections of ondansetron in combination with a 7.5 mg/kg IP injection of cocaine. Following these injections, the subjects' behavior was rated using the Ellinwood and Balster (18) rating scale. The results of Experiment 1 indicated that ondansetron had no effect on the behavior of the subjects, nor was there a differential effect of pretreatment regimen the effects of ondansetron. The results of Experiment 2 indicated that ondansetron had no effect on cocaine-induced locomotion in the saline control rats, but did have a slight, statistically significant, suppressive effect in the injection rats. In contrast, ondansetron had a robust facilitative effect on cocaine-induced locomotion in the continuous infusion rats. The results of Experiment 3 indicated that ondansetron had no effect on cocaine-induced locomotion in the saline control rats or the cocaine injection pretreatment subjects. In the continuous infusion subjects, ondansetron did have a slight, statistically significant, facilitative effect on cocaine-induced locomotion.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

Continuous or intermittent cocaine administration: effects of amantadine treatment during withdrawal.

Research indicates that daily cocaine injections produce sensitization to, while the continuous infusion of cocaine produces tolerance to, its behavioral and neurochemical effects. The effects of the continuous infusion of cocaine are consistent with the withdrawal syndrome reported by human cocaine abusers. The present experiment examined whether amantadine administrations during withdrawal from continuous or intermittent cocaine attenuate and/or eliminate the behavioral effects produced by these administration regimens. The rats were pretreated for 14 days with either continuous or intermittent daily injections of cocaine, and were then withdrawn from the pretreatment regimen for 7 days. On days 1-5 of the withdrawal period, half the subjects received a 5.0 mg/kg IP injection of amantadine, and the other half received a 20.0 mg/kg IP injection of amantadine. On day 7 of withdrawal from the cocaine pretreatment, all rats were given a 15.0 mg/kg IP injection of cocaine. Their behavior was rated according to the modified Ellinwood and Balster (6) scale for 60 min. The results indicated that amantadine treatment during withdrawal eliminated the tolerance normally associated with the continuous infusion of cocaine. In contrast, in both the saline control and daily injection subjects amantadine treatment during withdrawal resulted in a slight, but statistically significant, reduction in the behavioral effects of cocaine. The present results therefore indicate that low doses of amantadine should be considered as a potential pharmacotherapy for the early stages of cocaine withdrawal. Furthermore, the present experimental procedures may represent an effective screening methodology for potential cocaine pharmacotherapies.

Amantadine↗
PubMed1994

Continuous or intermittent cocaine administration: effects of flupenthixol treatment during withdrawal.

Research indicates that chronic daily cocaine injections produce sensitization to, while the chronic continuous infusion of cocaine produces tolerance to, its behavioral and neurochemical effects. The present experiments examined whether flupenthixol administration during withdrawal would attenuate/eliminate the behavioral effects produced by these administration regimens. The rats were pretreated for 14 days with either continuous or intermittent daily injections of cocaine, and were then withdrawn from the pretreatment regimen for 7 days. On days 1-5 of the withdrawal period, subjects received a daily 0.125-2.0 mg/kg IP injection of flupenthixol. Then on day 7 of withdrawal from the cocaine pretreatment, all rats were given a 15.0 mg/kg IP injection of cocaine. Their behavior was rated according to a modified version of the Ellinwood and Balster (6) scale for 60 min. The results indicated that flupenthixol treatment during withdrawal eliminated the tolerance normally associated with the continuous infusion of cocaine. However, this effect of flupenthixol was not dose dependent: the lowest dose had the same effect as the highest dose of flupenthixol. In the cocaine-injection subjects, flupenthixol had a slight but statistically significant reduction in the behavioral effects of cocaine. The same was true in the saline-control rats, except for the highest dose of flupenthixol, which had a significant enhancing effect on the behavioral response to cocaine. The present results suggest that the current procedures may represent an effective screening methodology for potential cocaine pharmacotherapies.

Animals↗
PubMed1994

Intranigral administration of D2 dopamine receptor antisense oligodeoxynucleotides establishes a role for nigrostriatal D2 autoreceptors in the motor actions of cocaine.

Dopamine D2 autoreceptors found on nigrostriatal dopaminergic neurons are thought to inhibit dopamine release, tyrosine hydroxylase activation, and spontaneous firing rate. It is likely that these receptors play an important role in moderating the behavioral response to cocaine, but the lack of potent selective autoreceptor ligands has made it difficult to assess this contribution. We have developed an antisense phosphorothioate oligodeoxynucleotide (ODN) against D2 receptor mRNA, which was used to reduce levels of D2 receptors in vitro and in vivo. Unilateral administration of antisense ODN, via intracerebral cannula, into the substantia nigra of rats for several days caused dramatic contralateral rotational behavior in response to a subcutaneous injection of cocaine. This effect was maximal by 10 min after injection of cocaine and lasted for > 30 min; without cocaine, no spontaneous rotational behavior was noted. In striatal slices, the potency of sulpiride, a D2 antagonist, in enhancing electrically stimulated dopamine release was significantly reduced on the antisense-treated side; this is consistent with a decrease in the striatal D2 autoreceptor population. As measured by quantitative autoradiography, administration of antisense ODN caused a loss of approximately 40% of nigral D2 receptor [125I]iodosulpride binding, compared with the untreated side. In vitro, treatment of WERI-27 retinoblastoma cells with D2 antisense ODN at a concentration of 1 microM reduced D2 receptor levels by 57% after 3 days. The robustness of cocaine-induced rotation and the impaired ability of sulpiride to enhance dopamine release from slices suggest that nigrostriatal D2 autoreceptors play a direct role in reducing the motor response to cocaine administration. Furthermore, the absence of spontaneous rotation in antisense ODN-treated animals suggests that autoreceptor effects are masked by compensatory mechanisms during normal behavior.

Animals↗
PubMed1994

Withdrawal from continuous or intermittent cocaine administration: changes in D2 receptor function.

Intermittent cocaine administration produces sensitization, whereas the continuous administration of cocaine produces tolerance to the effects of subsequent cocaine administration during withdrawal. The present study examined whether the effects of these two dosing regimens are related to alterations in the functional status of dopamine (DA) D2 receptors. In all experiments, rats were withdrawn for 7 days from a 14-day pretreatment regimen involving either continuous or intermittent cocaine administration. Experiments examined changes in the behavioral response to an autoreceptor-selective dose of apomorphine, the effects of sulpiride on electrically stimulated DA release in striatal brain slices and striatal D2 receptor binding, and mRNA levels. The results indicate that the continuous administration of cocaine produces findings consistent with D2 autoreceptor supersensitivity; there was enhanced inhibition of behavior after the autoreceptor-selective dose of apomorphine, decreased electrically stimulated DA release in the absence of sulpiride, and enhanced electrically stimulated DA release in the presence of sulpiride. However, there were no changes in postsynaptic D2 receptor binding or mRNA levels. Intermittent cocaine administration did not produce evidence of D2 autoreceptor subsensitivity: there was no decrease in inhibition of behavior after the autoreceptor-selective dose of apomorphine, no changes in electrically stimulated DA release in the absence or presence of D2 receptor blockade, and no change in the levels of D2 receptor binding; however, D2 mRNA levels were decreased by 22%. Overall, the present results are consistent with the hypothesis that the expression of tolerance induced by continuous cocaine administration is associated with D2 autoreceptor supersensitivity.

Animals↗