Biomedical subjects

I A Paul

Publications and source records attributed to I A Paul.

At least 19 recordsLinked to original sources

PubMed2002

Reinforcing strength of a novel dopamine transporter ligand: pharmacodynamic and pharmacokinetic mechanisms.

Drugs that block dopamine uptake often function as positive reinforcers but can differ along the dimension of strength or effectiveness as a positive reinforcer. The present study was designed to examine pharmacological mechanisms that might contribute to differences in reinforcing strength between the piperidine-based cocaine analog (+)-methyl 4beta-(4-chlorophenyl)-1-methylpiperidine-3-alpha-carboxylate [(+)-CPCA] and cocaine. Drugs were made available to rhesus monkeys (n = 5) for i.v. self-administration under a progressive ratio schedule. Both compounds maintained responding with sigmoidal or biphasic dose-response functions (0.1-1.0 mg/kg/injection). (+)-CPCA was one-fourth as potent as cocaine and maintained fewer injections per session, at maximum. For in vitro binding in monkey brain tissue, (+)-CPCA was about one-half as potent as cocaine at the dopamine transporter (DAT), and the two compounds had similar affinities at the norepinephrine transporter. (+)-CPCA was less than 1/10 as potent as cocaine at the serotonin transporter. In ex vivo binding in rat striatum, occupancy of the DAT increased directly with dose to a maximum of approximately 80% for both compounds, and (+)-CPCA was about one-fourth as potent as cocaine. Ex vivo DAT occupancy was significantly higher for cocaine than (+)-CPCA at 2 min after injection but similar at other times. Thus, the primary differences between these compounds were in serotonin transporter affinity and the kinetics of DAT binding. These results suggest that (+)-CPCA is a weaker positive reinforcer than cocaine because it has a slower onset of action over the first few minutes after i.v. injection.

Animals↗

PubMed2001

Role of the dopamine transporter and the sodium channel in the cocaine-like discriminative stimulus effects of local anesthetics in rats.

RATIONALE: Local anesthetics bind to the dopamine transporter (DAT), inhibit dopamine (DA) uptake and have been reported to have cocaine-like discriminative stimulus effects. The hypothesis of the present study was that affinity at the DAT and potency as a DA uptake blocker determines potency as a cocaine-like discriminative stimulus among local anesthetics, and maximum DA uptake inhibition determines maximum cocaine-like discriminative stimulus effects. OBJECTIVES: Cocaine-like discriminative potency was compared to DAT affinity and DA uptake inhibition potency, and maximum cocaine-like discriminative stimulus effects were compared to maximum DA uptake inhibition for procaine, chloroprocaine, dimethocaine, tetracaine and lidocaine. METHODS: Discriminative stimulus effects were determined in two groups of rats using 10 mg/kg and 3.0 mg/kg cocaine training doses. DAT affinity and DA uptake inhibition effects were determined in vitro in rat caudate nucleus tissue. Additionally, sodium channel affinity was determined in rat frontal cortex tissue. RESULTS: In the 10 mg/kg group, none of the local anesthetics fully substituted for cocaine and all decreased response rate. Rate decreasing potencies were positively correlated with sodium channel affinities. In the low training dose group, all the local anesthetics except tetracaine substituted fully for cocaine. Discriminative potencies were positively correlated with sodium channel affinities. Maximum DA uptake inhibition did not adequately predict maximum discriminative stimulus effects. CONCLUSIONS: Cocaine-like discriminative stimulus effects of local anesthetics were more prominent at a low than at a high training dose of cocaine. Sodium channels seem to have a direct influence on discriminative effects at low cocaine doses, whereas they have an indirect influence on discriminative effects at high cocaine doses by decreasing response rates.

Anesthetics, Local↗

PubMed2001

Group housing of mice increases immobility and antidepressant sensitivity in the forced swim and tail suspension tests.

The forced swim test and tail suspension test are often used in laboratory practice to identify compounds that possess antidepressant-like activity. This experiment was conducted to determine whether housing conditions per se influence the response of mice in these antidepressant screening procedures. Male NIH Swiss mice were housed individually or in groups (five per cage) for 8 weeks prior to testing. After 8 weeks, the animals were exposed to the forced swim and tail-suspension tests. Group housed mice displayed high levels of immobility in the forced swim and tail suspension tests. Desipramine injection 60 min prior testing, in doses 7.5 and 15 mg/kg, produced significant reductions in the immobility time in forced swimming and tail suspension tests. Individually housed mice, when exposed to these tests, displayed lower levels of immobility with a magnitude comparable to the effect of desipramine in group housed mice. Desipramine given to individually housed mice did not reduce the duration of immobility either in the forced swim test or in the tail suspension test. These results indicate that both tests are sensitive to housing conditions. This observation suggests that long lasting group housing may be critical to the behavioral response in these preclinical screening procedures in mice.

Animals↗

PubMed2000

LP-BM5 infection impairs spatial working memory in C57BL/6 mice in the Morris water maze.

Previous studies show that the LP-BM5 murine leukemia virus causes an acquired immunodeficiency syndrome in C57BL/6 mice (MAIDS) and impairs learning and memory without gross motor impairment. To assess spatial working memory impairment after LP-BM5 infection and the time course of this impairment, we tested mice in a modified working-memory version of the Morris water maze. Twenty mice were inoculated with LP-BM5; controls received medium (Minimum Essential Medium). In the test procedure, animals had two 1-min training sessions to learn the position of a randomly placed hidden platform. Thirty seconds after the second training session, animals were placed in the maze without the platform, and time and pathlength spent in each quadrant of the maze were measured. For 9 weeks after LP-BM5 infection, both groups showed preference for the target quadrant compared to the opposite quadrant. At 10 and 11 weeks after infection, the LP-BM5 virus infected mice lost this target quadrant preference. We conclude that LP-BM5 infection impaired spatial working memory in a modified working-memory version of the Morris water maze test in C57BL/6 mice at 10 and 11 weeks after virus infection.

Animals↗

PubMed2000

Noradrenergic lesion antagonizes desipramine-induced adaptation of NMDA receptors.

Repeated administration of the tricyclic antidepressant, desipramine, for 28 days to mice effected a decrease in the potency of glycine to displace [3H]5,7-dichlorokynurenic acid (5,7-DCKA) in mouse cortical homogenates. Pre-treatment with the noradrenergic neurotoxin DSP-4, while having no effect alone, attenuated the desipramine-induced effect. The present findings support a norepinephrine-dependent adaptation of the NMDA receptor complex in vivo following chronic desipramine treatment. The inter-relationship of norepinephrine and glutamate transmission may provide insight into the mechanism underlying the action of antidepressant drugs.

Adaptation, Physiological↗

PubMed2000

On the relationship between the dopamine transporter and the reinforcing effects of local anesthetics in rhesus monkeys: practical and theoretical concerns.

RATIONALE: Drugs that are self-administered appear to vary in their potency and effectiveness as positive reinforcers. Understanding mechanisms that determine relative effectiveness of drugs as reinforcers will enhance our understanding of drug abuse. OBJECTIVES: The hypothesis of the present study was that differences among dopamine transporter (DAT) ligands in potency and effectiveness as a positive reinforcers were related to potency and effectiveness as DA uptake inhibitors. Accordingly, self-administration of a group of local anesthetics that are DAT ligands was compared to their effects as DA uptake blockers in vitro in brain tissue. METHODS: Rhesus monkeys were allowed to self-administer cocaine and other local anesthetics i.v. under a progressive-ratio schedule. The same compounds were compared in standard in vitro DA uptake assays using monkey caudate tissue. RESULTS: The rank order of both potency and effectiveness as reinforcers was cocaine > dimethocaine > procaine > chloroprocaine. Tetracaine did not maintain self-administration. For inhibiting DA uptake, the potency order was cocaine > dimethocaine > tetracaine > procaine > chloro-procaine. At maximum, these compounds were equally effective in blocking DA uptake. Lidocaine did not inhibit DA uptake. CONCLUSIONS: The potency of local anesthetics as positive reinforcers is likely related to their potency as DA uptake inhibitors. Variation in their effectiveness as positive reinforcers was not a function of differences in effectiveness as DA uptake blockers, but may be related to relative potency over the concentrations that are achieved in vivo. Effects at sodium channels may limit the reinforcing effects of local anesthetics.

Anesthetics, Local↗

PubMed2000

3'- and 4'-chloro-substituted analogs of benztropine: intravenous self-administration and in vitro radioligand binding studies in rhesus monkeys.

RATIONALE: The reinforcing effects of many psychomotor stimulants have been related to increased dopaminergic neurotransmission. Drugs that block dopamine (DA) uptake have generally been found to function as positive reinforcers. Benztropine (BZT) and several of its halogenated analogs have previously been characterized as potent DA-uptake inhibitors with behavioral profiles that indicate diminished psychomotor stimulant effects relative to cocaine. OBJECTIVES: The present experiments were designed to examine, in rhesus monkeys, the reinforcing effects of the DA-uptake inhibitor BZT and two chloro-analogs 3'-Cl-BZT and 4'-Cl-BZT, and to compare self-administration and binding profiles. METHODS: Four rhesus monkeys self-administered cocaine i.v. under a fixed-ratio 10 (FR10) schedule until stable responding was established. Saline, and various doses of cocaine, BZT, and the BZT analogs were then made available for self-administration. Binding of these compounds to monoaminergic and cholinergic sites in monkey brain were determined using standard radioligand binding techniques. RESULTS: Self-administration was maintained by both 3'-Cl-BZT and 4'-Cl-BZT, but not by BZT. Results suggested that 3'-Cl-BZT and 4'-Cl-BZT were weak positive reinforcers. BZT and analogs bound DA transporters (DAT) with affinities higher than that of cocaine and had affinity for muscarinic binding sites. CONCLUSIONS: Surprisingly, high affinity at DATs was associated with weak or no reinforcing effects. The mechanism(s) that may underlie this dissociation between DAT actions and reinforcing effects remains to be established. These data support the proposal that a lead for the discovery of a pharmacotherapeutic agent for cocaine abuse may come from this group of compounds.

Animals↗

PubMed2000

Chronic glycine treatment desensitizes the behavioral response to 1-aminocyclopropanecarboxylic acid (ACPC), a partial agonist at the strychnine-insensitive glycine site of the NMDA receptor complex.

Chronic treatment with 1-aminocyclopropanecarboxylic acid (ACPC) but not with dizocilpine or imipramine produces desensitization to the behavioral response in ACPC challenge in the forced swim test (forced swim test). The mechanism by which ACPC produces this effect is unclear and may depend upon either its functional antagonist or its agonist properties at the NMDA receptor. We now report that chronic treatment with glycine or ACPC desensitizes the behavioral effect of challenge with ACPC in the forced swim test. The desensitization of the acute effects of ACPC cannot be explained by the presence of residual glycine because 24 h after the last of 14 daily glycine injections (i.e. the time of forced swim test) cortical and hippocampal glycine concentrations were unchanged. Likewise, the affinity of glycine to displace specific [3H]5,7-DCKA binding to glycine sites of the NMDA receptor complex was unchanged by chronic glycine administration. These results support the hypothesis that antidepressants produce adaptation of the NMDA receptor complex by mechanisms other than simply increasing synaptic glycine concentrations. Moreover, these results indicate that the behavioral adaptation in the forced swim test induced by chronic treatment with ACPC results from its agonist properties.

Amino Acids↗

PubMed2000

Sucrose and quinine intake by maternally-deprived and control rhesus monkeys.

Clinical depression is often characterized by a loss of interest or pleasure in formerly enjoyable activities. Analogs of anhedonia are established in rats, but the generality of this phenomenon to other species is unknown. Maternally-deprived rhesus macaques show a wide range of behavioral abnormalities that are reversed by chronic antidepressant treatment. We tested consumption by maternally deprived versus control macaques of sweetened (seven sucrose concentrations) or bitter water (four quinine concentrations) versus plain water to evaluate a non-human primate model of depression for signs of anhedonia. All monkeys consumed more sweetened than tap water, but maternally-deprived monkeys had a diminished preference for sweetened water than did controls. However, maternally deprived animals consumed more bitter water than did controls. Baseline fluid consumption did not differ. The data suggest that 'anhedonia' in animal models may be secondary to a generally attenuated responsiveness to stimuli, rather than a unitary reduction in responsiveness to the appetitive properties of stimuli. We conclude that maternally-deprived rhesus monkeys do not display gustatory signs of anhedonia, but rather of insensitivity to gustatory stimuli.

Animals↗

PubMed1999

Prenatal hypoxia-ischemia alters expression and activity of nitric oxide synthase in the young rat brain and causes learning deficits.

Inhibition of nitric oxide synthase (NOS) is known to possibly impair learning and memory. Our previous studies have demonstrated that prenatal hypoxia-ischemia (HI) decreases NOS expression and NOS activity in the neonatal rat brain. To investigate whether effects of prenatal HI on NOS expression continue and whether prenatal HI affects learning and memory in young rats, NOS expression and NOS activity were determined in the hippocampus of rat brains at 28 days of age following a prenatal HI insult on G17. Performances in the passive avoidance test and the Morris water maze test were also studied in these young rats prior to sampling. Rat fetuses were subjected to either a 30-min prenatal HI insult or a sham operation (SH) on gestation day 17 and rat pups were delivered naturally. Increased locomotor activity was observed in the prenatal HI rats as compared to the SH rats on postnatal days 13 and 15, but not on postnatal days 20 and 30. Prenatal HI affected learning ability in these young rats at 28 days of age, as indicated by a delayed acquisition of passive avoidance and by longer escape latency in the Morris water maze test as compared to the SH group. Prenatal HI did not affect retention of passive avoidance and spatial memory. Concomitant with these learning deficits, expression of neuronal NOS and endothelial NOS mRNAs as well as Ca2(+)-dependent NOS activity in the hippocampus of the prenatal HI rat brain were significantly decreased as compared to the SH group. These results suggest that a 30-min prenatal HI insult on gestation day 17 in rats has long-lasting effects on NOS expression and NOS activity in the offspring brain and on learning ability of these young rats. The learning deficit in offspring is possibly associated with the reduction in expression of NOS mRNA and NOS activity in the hippocampus of these animals.

Animals↗

PubMed1999

Nitric oxide synthase inhibitors have antidepressant-like properties in mice. 1. Acute treatments are active in the forced swim test.

Previous studies have demonstrated that antagonists at the NMDA receptor are as efficacious as tricyclic antidepressants in pre-clinical antidepressant screening procedures and in blocking or reversing the behavioral deficits associated with animal analogs of major depressive symptomatology. The NMDA receptor complex gates Ca2+, which interacts with calmodulin to subsequently activate nitric oxide (NO) synthase. We hypothesized that NO synthase antagonists might display antidepressant-like properties, similar to NMDA receptor antagonists. We examined the effects of N(G)-nitro-L-arginine (L-NNA), its dextrorotatory enantiomer, D-NNA, N(G)-nitro-L-arginine methyl ester (L-NAME) and N(G)-monomethyl-L-arginine (L-NMMA) at doses from 1 to 30 mg/kg in the forced swim test in mice. We now report that NO synthase antagonists are as efficacious as imipramine (15 mg/kg) in reducing the duration of immobility in the mouse forced swim test. The effects of NO synthase antagonists, as well as those of imipramine were blocked by pre-treatment with L-arginine (L-Arg) (500 mg/kg). In contrast to imipramine, the NO synthase antagonists were without effect on locomotor activity over the dose range active in the forced swim test (3-10 mg/kg). Likewise, L-Arg was without effect on locomotor activity. These data support the hypothesis that NO synthase antagonists possess antidepressant properties and may represent a novel class of therapeutics for major depressive disorders.

Animals↗

PubMed1999

Nitric oxide synthase inhibitors have antidepressant-like properties in mice. 2. Chronic treatment results in downregulation of cortical beta-adrenoceptors.

Down-regulation of cortical beta-adrenoceptors is observed in rodents following chronic treatment with many clinically effective antidepressant therapies. [3H]dihydroalprenolol binding to cortical beta-adrenoceptors was examined in mice treated with the nitric oxide (NO) synthase antagonist N(G)-nitro-L-arginine (L-NNA). Administration of L-NNA (0.1, 0.3 mg/kg) for 21 days produced a significant reduction (28%, 31%, respectively, P<0.05) in [3H]dihydroalprenolol binding to cortical membranes without affecting Kd. Dose 1 mg/kg of L-NNA given chronically also produced a 20% decrease in beta-adrenoceptor density, but this effect was not statistically significant. While chronic treatment with imipramine (15 and 30 mg/kg) produced respectively a 30% and 25% (P<0.05) reduction in the density of [3H]dihydroalpenolol, single injection of either imipramine (15 and 30 mg/kg) or L-NNA (0.1, 0.3, and 1 mg/kg) had no effect on [3H]dihydroalprenolol binding. These findings are consistent with the hypothesis that drugs which can affect the Ca2+ -calmodulin/nitric oxide synthase/guanylyl cyclase signaling pathway may represent a novel approach to the treatment of depression and are congruent with our previous observation, which has demonstrated the antidepressant-like properties of NO synthase inhibitors in the forced swim test.

Adrenergic Uptake Inhibitors↗

PubMed1999

Comparison between dopamine transporter affinity and self-administration potency of local anesthetics in rhesus monkeys.

Local anesthetics bind to dopamine transporters and inhibit dopamine uptake in rodent brain. Additionally, local anesthetics are self-administered in rhesus monkeys. The present study determined binding affinities of cocaine and five local anesthetics at dopamine transporters in rhesus monkey brain, and compared binding affinities to published self-administration potencies in rhesus monkeys. The affinity order at dopamine transporters was cocaine > dimethocaine > tetracaine > procaine > or = chloroprocaine > lidocaine. The correlation between dopamine transporter affinities and self-administration potencies was significant. Binding affinities were also determined at sodium (Na2+) channels in rhesus monkey brain. There was not a significant correlation between Na2+ channel affinities and self-administration potencies Local anesthetics with high dopamine transporter and low Na2+ channel affinities were self-administered, whereas those with either high or low affinity at both sites were not consistently self-administered. These data suggest that affinity at dopamine transporters is related to the reinforcing effects of local anesthetics in rhesus monkeys, and Na2+ channel effects may interfere with the reinforcing effect of these drugs.

Anesthetics, Local↗

PubMed1999

Increased discriminative stimulus potency of phencyclidine in C57B1/6 mice infected with the LP-BM5 retrovirus.

Drug discrimination procedures in mice are used to study the neuropharmacology of a wide variety of drugs. In C57 B1/6 mice, infection with the LP-BM5 murine leukemia virus leads to a syndrome (murine acquired immunodeficiency syndrome-MAIDS) characterized by immunocompromise, neurochemical alterations, and learning and memory deficits. Because the neurochemical and behavioral changes suggest that altered glutamatergic neurotransmission follows LP-BM5 infection, we studied the effects of infection on discriminative stimulus properties of phencyclidine (PCP), a Ca2+ channel blocker at NMDA receptors. We also tested D-amphetamine and dizocilpine to assess the specificity of the discrimination. As expected, dizocilpine produced PCP-like responding. After animals were trained to discriminate PCP from saline, they were inoculated with LP-BM5 and the PCP dose-response functions repeatedly determined. The potency of PCP in this procedure was unchanged 3 weeks after infection, but was increased approximately fivefold 6 and 9 weeks after infection. Amphetamine 9 weeks after inoculation did not produce PCP-like responding, showing that the results were not caused by a loss of specificity of the discrimination. The time course for changes in PCP potency is similar to those of other behavioral and neurochemical changes reported after LP-BM5 infection. The results are consistent with an action of LP-BM5 infection at glutamatergic synapses.

Adrenergic Agents↗

PubMed1998

Dopamine D1 and D2 receptor selectivities of phenyl-benzazepines in rhesus monkey striata.

Several phenyl-benzazepine compounds, putatively selective dopamine D1 receptor agonists, have been used to study the effects of dopamine D1 receptor stimulation in rodents and nonhuman primates. However, the dopamine receptor selectivities of these compounds have not been established in nonhuman primates. Accordingly, the relative selectivities of six phenyl-benzazepines for dopamine D1-like and D2-like receptors were assessed in rhesus monkey and, for comparison, rat striata. The compounds tested had higher affinity for D1 than D2 receptors in both species; however, their selectivity varied by up to three orders of magnitude. GTP (100 microM) reduced agonist binding at the high-affinity state of the dopamine D1 receptor, but the magnitude of the effect of GTP did not reliably predict a compound's efficacy. Furthermore, a history of cocaine self-administration did not appear to influence dopamine receptor binding characteristics in the rhesus monkeys in this study. The present results will aid the comparison of dopamine receptor binding characteristics and behavioral effects of D1 dopamine receptor agonists.

Animals↗

PubMed1998

LP-BM5 infection impairs acquisition, but not performance, of active avoidance responding in C57B1/6 mice.

LP-BM5 murine leukemia virus infection causes an AIDS-like syndrome--murine acquired immunodeficiency syndrome--in C57B1/6 mice and impairs spatial learning in the Morris water maze without gross motor impairment. We used a shuttle shock-avoidance procedure to examine the effects of LP-BM5 infection on learning and retention of avoidance behavior. Thirty mice were inoculated with LP-BM5; 30 received vehicle (DMEM) injections. Fifteen LP-BM5 and 15 DMEM mice were trained in avoidance 7 wk after inoculation; retention of the avoidance response was tested 4 wk later. The remaining mice were trained 11 wk after inoculation. In animals trained 7 wk after inoculation, the groups performed similarly, with a marginally significant tendency for LP-BM5-infected animals to make more avoidance responses. This group difference was significant when animals were retested at 11 wk. However, LP-BM5 animals trained 11 wk after inoculation made significantly fewer avoidance responses than controls trained at the same time. We conclude that in later stages of disease, LP-BM5 impairs response acquisition, but not performance, in the active avoidance procedure. Results extend the use of the LP-BM5-infected mouse as a model of AIDS dementia complex.

Animals↗

PubMed1997

Chronic imipramine treatment upregulates IR2-imidazoline receptive sites in rat brain.

A low density of brain IR2-imidazoline receptive sites has previously been linked to depression. In this study we evaluated brain IR2-binding sites in a rat model of depression, olfactory bulbectomy, and determined the effects of chronic imipramine treatment in vivo on these sites. Compared with sham-operated controls, adaptation to olfactory bulbectomy had no effect on either the density (Bmax) or affinity (KD) of [3H]-idazoxan binding to brain IR2 sites. However, 25 days of imipramine treatment (i.p., 20 mg/kg/day) enhanced significantly the density of IR2 binding sites, with no change in affinity in both the model and the control group. These results indicate that the brain IR2-imidazoline receptive sites might be a target for antidepressants.

Animals↗

PubMed1997

Developmental lead exposure and two-way active avoidance training alter the distribution of protein kinase C activity in the rat hippocampus.

Long-term exposure to a low level of lead is associated with learning deficits. Several types of learning have been correlated to hippocampal protein kinase C (PKC) activation. This study was designed to determine if there is a correlation between the effects of lead on hippocampal PKC activation and those on learning performance. Rats were exposed to 0.2% (w/v) lead acetate at different developmental stages including a maternally exposed group, a postweaning exposed group, and a continuously exposed group. The continuously lead exposed rats tended to avoid less frequently and not respond more frequently in two-way active avoidance training than did controls. This training process was associated with translocation of hippocampal PKC activity from cytosol to membrane. Two-way analysis of variance of data indicates that there is a significant training and lead treatment interaction in the ratio of membrane to cytosolic PKC activity (F3,32 = 3.013; p = 0.044). The interaction is attributable to the absence of the training-induced PKC translocation in the continuously lead exposed rats. In addition, no significant changes were observed in learning performance and training-induced hippocampal PKC activation after maternal and postweaning lead exposure. Continuous and longer duration of lead exposure appears to affect the learning performance and hippocampal PKC activation. These data suggest that a change in the activation of hippocampal PKC may be involved in the lead-induced deficit in learning.

Analysis of Variance↗