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K M Kantak

Publications and source records attributed to K M Kantak.

At least 19 recordsLinked to original sources
PubMed2001

Time course of changes in cocaine self-administration behavior in rats during immunization with the cocaine vaccine IPC-1010.

RATIONALE: Following a 6-week immunization period consisting of three biweekly injections of the cocaine vaccine IPC-1010, the reacquisition of cocaine self-administration behavior in rats was previously shown to be reduced in a manner that was dependant on serum antibody level. The present studies were conducted to examine additional issues relevant to the clinical use of the vaccine. OBJECTIVES: One experiment was conducted to address the issue of whether exposure to cocaine during the immunization period would influence the ability of the vaccine to block cocaine self-administration. A second experiment was conducted to determine if the reductions in drug-seeking behavior and drug intake by the vaccine were behaviorally specific, or if behavior maintained by a non-drug reinforcer would be similarly affected. METHODS: Identical second-order schedules of cocaine (1 mg/kg) or food pellet (45 mg) delivery were used in rats. In both studies, the time course of changes in behavior during the 6-week immunization period was examined in vaccine and alum-treated control rats following baseline and extinction conditions. RESULTS: The cocaine vaccine IPC-1010 induced average serum antibody levels of 0.07 mg/ml and significantly reduced self-administration behavior during the 2-week period following the third vaccine boost in a subgroup of rats with serum antibody levels greater than the average value. Cocaine self-administration behavior at this time point significantly correlated with serum antibody level. IPC-1010 did not alter responding maintained by food throughout the immunization period although serum antibody levels reached a similar average of 0.06 mg/ml in this group of rats. CONCLUSIONS: These findings suggest that the reductions in drug-seeking behavior and drug intake after immunization with IPC-1010 did not result from a reduced ability of the rats to respond on the lever. Furthermore, daily exposure to cocaine during the immunization period did not influence the ability of the vaccine to reduce cocaine self-administration behavior that emerged gradually over time. These findings also confirm the need for a sufficiently high antibody level to blunt the reinforcing effects of cocaine.

Animals↗
PubMed2001

Effects of nitric oxide synthase inhibitors on the discriminative stimulus effects of cocaine in rats.

RATIONALE: Nitric oxide synthase (NOS) inhibitors may modulate the discriminative stimulus effects of cocaine because they alter dopamine (DA) release. OBJECTIVES: The effects of the NOS inhibitors NG-nitro-L-arginine methyl ester (L-NAME) and 7-nitro-indazole (7-NI) were examined in experiments designed to better understand the mechanisms that may underlie the interactions between NOS inhibitors and cocaine. METHODS: Rats were trained to discriminate 10 mg/kg cocaine from saline, and then substitution and pretreatment tests with L-NAME and 7-NI were conducted. To determine if the combined effects of NOS inhibitors and cocaine might be related to DA mechanisms and/or to N-methyl-D-aspartate (NMDA) receptor mechanisms, substitution tests with other indirect DA agonists and NMDA antagonists were carried out in the presence and absence of L-NAME. In addition, the roles of the D1 and D2 families of DA receptors in mediating the cocaine-altering effects of L-NAME and 7-NI were examined in antagonism tests using SCH 23390 and haloperidol, respectively. RESULTS: The results demonstrated that neither NOS inhibitor alone substituted for the 10 mg/kg cocaine training dose, but when given as a pretreatment, 100 mg/kg L-NAME as well as 10 mg/kg 7-NI enhanced the discriminative stimulus and rate-decreasing effects of cocaine. L-NAME pretreatment also enhanced the potency of (+)-amphetamine and GBR 12909, but not MK-801, phencyclidine, or NPC 17742, for producing discriminative stimulus and rate-decreasing effects in substitution tests. Further testing showed that the cocaine-enhancing effects of L-NAME and 7-NI were attenuated by doses of haloperidol and SCH 23390 that minimally altered the effects of cocaine alone. CONCLUSIONS: These findings suggest that L-NAME and 7-NI may increase the potency of cocaine and other indirect DA agonists through a central mechanism whereby DA neurotransmission is directly enhanced by NOS inhibition.

Animals↗
PubMed2001

Temporal factors affecting cocaine-opioid interactions: a cocaine drug discrimination study in rats.

RATIONALE: Increasing concomitant abuse of cocaine and morphine-like opioids has prompted a number of studies aimed at understanding how these drugs interact. OBJECTIVE: The present study was designed to determine if variations in opioid pretreatment time would affect how mu opioid agonists interact with cocaine. METHODS: Rats were trained to discriminate 10 mg/kg cocaine from saline. One group of subjects (n=6) received morphine (5.6 mg/kg) 0.5 h, 1 h or 4 h prior to cumulative doses of cocaine (0.1-17.8 mg/kg). These pretreatment times were selected to overlap with states of acute opioid tolerance (approximately 1 h) or acute opioid dependence (approximately 4 h) as demonstrated by previous studies. A second group (n=6) was administered naloxone (0.3 mg/kg) 5 min prior to cumulative cocaine doses, with or without a 4-h morphine (5.6 mg/kg) or methadone (3.0 mg/kg) pretreatment. In a third procedure, the same subjects used in the second experiment were also tested for time-dependent changes in the analgesic effect of morphine using a hot-plate assay. RESULTS: Morphine pretreatment 1 h prior to assessment of the cocaine dose-response function significantly enhanced the discriminative stimulus effects of cocaine. However, neither 0.5-h or 4-h morphine pretreatment had any effect. In contrast, when naloxone was administered 4 h following either morphine or methadone and 5 min prior to assessment of the cocaine dose-response curve, the discriminative stimulus effects of cocaine were significantly attenuated. In assessing morphine-induced analgesia, paw-lick latency was significantly longer at 1 h and shorter at 4 h following morphine administration. CONCLUSIONS: The results illustrate the importance of temporal parameters for interactions between cocaine and mu opioid agonists.

Analgesics, Opioid↗
PubMed2001

Cognitive task performance after lidocaine-induced inactivation of different sites within the basolateral amygdala and dorsal striatum.

To determine whether discrete components of amygdaloid and striatal memory systems could interact to guide behavior in a radial arm maze, conditioned cue preference (CCP) and win-stay accuracy were examined after lidocaine inactivation of either the rostral (rBLA) or caudal (cBLA) basolateral amygdala, the lateral (lDST) or medial (mDST) dorsal striatum, or a control site in rats. CCP expression was blocked only after rBLA or cBLA inactivation. lDST inactivation prevented attainment of criteria win-stay performance, whereas rBLA and mDST inactivation delayed it. Control site inactivation did not influence performance in either task. These findings suggest that the amygdala works independently of other memory systems to regulate learned responses in the CCP task, the rBLA may work cooperatively with the lDST to guide behavior in the win-stay task, and the mDST is less critical than the lDST for attaining criteria performance in the win-stay task.

Amygdala↗
PubMed2000

Evaluation of anti-cocaine antibodies and a cocaine vaccine in a rat self-administration model.

RATIONALE: Previous pre-clinical studies with an anti-cocaine monoclonal antibody left open several issues critical to assessing the effectiveness of a vaccine for altering cocaine self-administration behavior. OBJECTIVES: The objectives of this study were to determine, first, whether changes in self-administration behavior would be systematically related to antibody level and, second, how the antibody affected the self-administration of different doses of cocaine. METHODS: Two experiments were conducted using a second-order schedule of drug delivery in rats. The first was a passive-administration study using the anti-cocaine monoclonal antibody MO240 to examine the relationship between antibody level and cocaine self-administration behavior, and the second was an active-immunization study to examine the efficacy of the cocaine vaccine IPC-1010 for blocking various doses of self-administered cocaine. RESULTS: The passive-administration experiment with control and 4-mg or 12-mg MO240 treatments showed that antagonism of the 1 mg/kg cocaine training dose was dependent on antibody level. In animals whose serum antibody levels were sustained above 0.05 mg/ml, there was a sufficient amount of antibody to reduce drug-seeking behavior and drug intake. In the active-immunization experiment, the cocaine vaccine IPC-1010 induced average serum antibody levels of 0.08 mg/ml and reduced the reacquisition of behavior by 1 mg/kg cocaine. Antagonism of cocaine self-administration after immunization was evident across a range of doses of cocaine and was only apparent in animals whose serum antibody levels exceeded 0.05 mg/ml. Furthermore, there was no evidence that the antagonism was surmountable within the dose range examined (up to 5.6 mg/kg). CONCLUSIONS: Antagonism of cocaine self-administration across a range of doses is feasible after immunization with a cocaine vaccine as long as antibody levels are of a sufficient concentration.

Animals↗
PubMed1999

Cocaine-opioid interactions in groups of rats trained to discriminate different doses of cocaine.

RATIONALE: The growing abuse of cocaine combined with morphine-like opiates ("speedballs") in human addicts has prompted efforts to characterize the roles of different opioid receptor subtypes in mediating their combined effects. Previous drug discrimination studies in rats have been inconsistent in showing significant interactions between cocaine and opioid agonists in subjects trained to discriminate a relatively high dose of cocaine from vehicle. It is known, however, that the training dose of cocaine can play a key role in drug-substitution and drug-interaction profiles and, therefore, training rats to discriminate a relatively low dose of cocaine may influence its interactions with opioid agonists. OBJECTIVES: The objectives of this study were to examine the degree to which a relatively high (10 mg/kg) versus a relatively low (3.0 mg/kg) cocaine training dose influenced the interactions between cocaine and either the mu opioid agonist morphine or the kappa opioid agonist U50,488. METHODS: Substitution tests with cumulative doses of cocaine, morphine and U50,488 were conducted, as were studies in which selected doses of morphine or U50,488 were administered prior to cumulative doses of cocaine. RESULTS: In substitution tests, cocaine was 2.9 times more potent under the low- than the high-dose training condition. Morphine substituted fully for cocaine in the majority of subjects trained to discriminate the low, but not the high, dose of cocaine. U50,488 engendered mainly saline-lever responses under both training conditions. In pretreatment studies, morphine enhanced and U50,488 attenuated the discriminative stimulus effects of cocaine in low-dose, but not high-dose, trained rats. In low-dose trained rats, cocaine was five- to eightfold more potent after morphine and three- to fourfold less potent after U50,488 pretreatments. CONCLUSIONS: The results demonstrate that cocaine-opioid interactions are dependent on the training dose of cocaine in rats and suggest an opposing influence of mu and kappa opioid receptors in modifying the discriminative stimulus effects of cocaine.

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗
PubMed1998

Modulation of the discriminative stimulus and rate-altering effects of cocaine by competitive and noncompetitive N-methyl-D-aspartate antagonists.

The purpose of this study was to determine the extent to which N-methyl-D-aspartic acid (NMDA) antagonists modified the discriminative stimulus effects of cocaine in rats trained to discriminate 5 mg/kg cocaine from vehicle on a fixed-ratio schedule of food presentation as well as the rate-altering effects of cocaine in rats maintained on a fixed-interval schedule of food presentation. NMDA-associated ion channel blockers (dizocilpine, phencyclidine, and magnesium chloride) and competitive NMDA antagonists (NPC 17742 and CGP 37849) displayed similar behavioral effects when administered alone: each drug engendered intermediate levels of cocaine-appropriate responses and rate-dependent effects on food-reinforced operant responding. Selected doses of dizocilpine, magnesium chloride, and phencyclidine given in combination with 1 mg/kg cocaine produced more cocaine-appropriate responses than this dose of cocaine alone. In addition, dizocilpine and magnesium chloride each attenuated the discriminative stimulus effects of higher doses of cocaine. The competitive NMDA antagonists did not appreciably modify the discriminative stimulus effects of any dose of cocaine. Under the fixed-interval schedule, each NMDA antagonist attenuated the effects of 3 mg/kg cocaine, which normally produced maximal increases in response rate. Attenuation of the rate-decreasing effects of the highest dose of cocaine (30 mg/kg) also were observed after pretreatment with dizocilpine and magnesium chloride. These findings demonstrated differences in the way that NMDA-associated ion channel blockers and competitive NMDA antagonists interact with cocaine, and suggest that some NMDA-associated ion channel blockers may either enhance or antagonize the effects of cocaine, depending on the dose and type of behavioral procedure.

2-Amino-5-phosphonovalerate↗
PubMed1997

Discriminative stimulus effects of magnesium chloride: substitution studies with monoamine uptake inhibitors and N-methyl-D-aspartate antagonists.

Previous studies suggest that magnesium chloride may have discriminative stimulus effects that partially overlap with those of noncompetitive N-methyl-D-aspartate antagonists as well as certain monoamine uptake inhibitors. In our study, rats were trained to discriminate 100 mg/kg magnesium chloride from saline and its discriminative stimulus effects were characterized with respect to N-methyl-D-aspartate receptor and monoamine transporter functions in substitution tests. The discriminative stimulus effects of magnesium chloride were acquired within a moderate number of training sessions and showed dose-related substitution after either subcutaneous (3-300 mg/kg) or intracerebroventricular (0.3-300 microg) administration. The intracerebroventricular administration of magnesium chloride was over 4000 times more potent than its s.c. administration. The monoamine uptake inhibitors cocaine, GBR 12909, talsupram and citalopram fully substituted (> or =90% magnesium-appropriate responses) for magnesium chloride in the majority of subjects tested and the group averages reached a maximum of 72 to 82% responses on the magnesium-appropriate lever. Based on relative potency analysis, the rank order of potency of these four drugs for producing magnesium-appropriate responses was talsupram = cocaine > citalopram = GBR 12909. The N-methyl-D-aspartate receptor antagonists dizocilpine, phencyclidine and NPC 17742 engendered maximum group averages of 49 to 65% responses on the magnesium-appropriate lever. The results suggest that the centrally mediated discriminative stimulus effects of magnesium chloride may be more directly related to interactions with monoamine neurotransmitter functions than to N-methyl-D-aspartate receptor blockade.

Amino Acids↗
PubMed1996

Efficacy of a therapeutic cocaine vaccine in rodent models.

Cocaine abuse is a major medical and public health concern in the United States, with approximately 2.1 million people dependent on cocaine. Pharmacological approaches to the treatment of cocaine addiction have thus far been disappointing, and new therapies are urgently needed. This paper describes an immunological approach to cocaine addiction. Antibody therapy for neutralization of abused drugs has been described previously, including a recent paper demonstrating the induction of anti-cocaine antibodies. However, both the rapidity of entry of cocaine into the brain and the high doses of cocaine frequently encountered have created challenges for an antibody-based therapy. Here we demonstrate that antibodies are efficacious in an animal model of addiction. Intravenous cocaine self-administration in rats was inhibited by passive transfer of an anti-cocaine monoclonal antibody. To actively induce anti-cocaine antibodies, a cocaine vaccine was developed that generated a high-titer, long-lasting antibody response in mice. Immunized mice displayed a significant change in cocaine pharmacokinetics, with decreased levels of cocaine measured in the brain of immunized mice only 30 seconds after intravenous (i.v.) administration of cocaine. These data establish the feasibility of a therapeutic cocaine vaccine for the treatment of cocaine addiction.

Animals↗
PubMed1995

Effects of N-methyl-D-aspartate antagonists in rats discriminating different doses of cocaine: comparison with direct and indirect dopamine agonists.

Dose-response functions for selected N-methyl-D-aspartate (NMDA) antagonists and direct and indirect dopamine agonists were compared in rats trained to discriminate either a low (2 mg/kg) or a high (10 mg/kg) dose of cocaine from vehicle. The NMDA-associated ion channel blockers, dizocilpine, phencyclidine and MgCl2, substituted fully for cocaine (> or = 90% cocaine-appropriate responses) in the majority of subjects under the low-dose training condition, but showed little or no substitution for cocaine under the high-dose training condition. The competitive NMDA antagonist [2R,4R,5S-(2-amino-4,5-(1,2-cyclohexyl)-7-phosphonoheptanoic acid)] did not substitute for cocaine under either training condition. Cocaine, 1-(2-[bis(4-fluorophenyl)methoxyl)-4-(3-phenylpropyl)piperazine, (+)-amphetamine and the D1 receptor agonist SKF 77434 engendered full substitution for cocaine under both training conditions. Dose-response functions for all four drugs were displaced to the left and average ED50 values were reduced by 3-fold or more under the low-dose compared to the high-dose training condition. The nonselective DA receptor agonist (-)-apomorphine substituted substantially for cocaine only under the low-dose training condition, whereas the D2 receptor agonist (+)-4-propyl-9-hydroxynapthoxazine substituted similarly for cocaine under both training conditions. The results show that change in the training dose of cocaine can affect both the shape and position of the dose-response functions for representative NMDA-associated ion channel blockers and direct and indirect dopamine agonists. The findings further show that under low-dose training conditions, NMDA-associated ion channel blockers can engender cocaine-like stimulus effects comparable to those of direct and indirect dopamine agonists.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed1992

Acute and multiple injection effects of magnesium on responding maintained by cocaine, extinction from cocaine, glucose + saccharin, and food.

In a variety of behavioral experiments, magnesium has effects that are similar to cocaine and other psychomotor stimulants. Of particular relevance to the present experiments is the recent finding that magnesium maintains responding in cocaine-trained rats. It would be expected, therefore, that injections of magnesium would alter the rate of responding maintained by self-administered cocaine in rats. Five experiments examined the specificity and selectivity of this interaction. Acute and multiple injections of MgCl2 (15-250 mg/kg) produced dose-dependent reductions in responding maintained by cocaine (0.1-2 mg/kg/infusion). Testing for acute injection effects occurred following injections, while testing for multiple injection effects occurred prior to daily injections. Doses of 30 and 125 mg/kg MgCl2 reduced responding maintained by doses of cocaine that were below the training dose of 0.75 mg/kg/infusion. MgCl2 in a dose of 250 mg/kg markedly suppressed responding maintained by each dose of cocaine. A magnesium-deficient diet produced a dose-dependent increase in responding maintained by 0.1 mg/kg/infusion cocaine. In order to determine the specificity and selectively of these effects, acute and multiple injections of MgCl2 were examined on glucose + saccharin- and food-maintained responding. The acute effects of MgCl2 injections were specific because food-maintained responding was not affected, except by the highest dose of 250 mg/kg. This demonstrates that lever pressing was not nonspecifically reduced by 30 and 125 mg/kg MgCl2 during cocaine availability. However, the effects on cocaine-maintained responding were not selective for cocaine because glucose + saccharin-maintained responding and responding during extinction from cocaine were affected by MgCl2 in a manner similar to cocaine-maintained responding.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1991

Magnesium-maintained self-administration responding in cocaine-trained rats.

Magnesium chloride (MgCl2) produces behavioral effects similar to those of psychomotor stimulants in a variety of behavioral situations. Because MgCl2 appears to have stimulant properties, the ability of MgCl2 to maintain responding in a rat self-administration paradigm was examined in seven experiments under different access and schedule conditions in cocaine-trained rats. These varied from the availability of MgCl2 for a single day's test session subsequent to 1 h availability of cocaine, to the availability of MgCl2 for 10 or 20 days after cocaine availability was totally discontinued. Fixed ratio 1, fixed ratio 5, and progressive ratio 1, 2 and 3 schedules of drug delivery were used. The results demonstrate that MgCl2 may substitute for self-administered cocaine because it maintained responding; it did so dose dependently to maintain a constant level of MgCl2 intake; and it did so over a 10-day period of time both with and without access to cocaine on test days. Responding maintained by MgCl2 when cocaine was no longer available was similar under fixed ratio 1 and 5 schedule conditions. The progressive ratio breakpoints for MgCl2 were significantly higher than those for saline, but significantly lower than those for cocaine. These data indicate that MgCl2 has some reinforcing efficacy in cocaine-trained rats, particularly under fixed ratio 1 and 5 schedules, but has a low abuse potential compared to cocaine.

Animals↗
PubMed1990

Failure of magnesium to maintain self-administration in cocaine-naive rats.

Previous research has shown that magnesium interacts with cocaine in such a way that it potentiates its action in a variety of behavioral situations. More recently, it has been demonstrated that magnesium will dose dependently substitute for cocaine self-administration and reduce the intake of cocaine. It is of considerable interest to determine if magnesium would be self-administered in cocaine-naive animals. The results of two experiments demonstrate that magnesium is not self-administered by cocaine-naive rats since although responding for magnesium chloride is above hypertonic saline control levels on day 1 of access, this responding is not maintained on subsequent days, does not occur in a regularly spaced pattern over time, and is not inversely related to dose. Taken together these data indicate that magnesium is a substitute for cocaine that has low abuse potential.

Animals↗
PubMed1990

Enhancement of apomorphine and l-amphetamine-induced behaviors by magnesium.

The behavioral effects of magnesium suggest that this divalent cation has psychomotor stimulant-like properties. Because deficiencies of this cation lead to reductions in drug-induced behaviors dependent on the levels of norepinephrine and dopamine, and numerous in vitro studies have demonstrated a relationship between magnesium and catecholamine activity, the present experiments investigate whether administration of magnesium will lead to increases in stereotyped and locomotor behaviors induced by apomorphine and l-amphetamine. Such changes would suggest that magnesium is increasing the activity of catecholamines in vivo. The results demonstrate that magnesium dose dependently increases the potency of these drugs by producing greater behavioral effects at certain drug doses, by producing shifts to the left in dose-response functions, and by producing decreases in the ED50 as dose of magnesium increases.

Amphetamine↗
PubMed1990

Postconditioning effects of magnesium on cocaine conditioned place preference in mice.

Magnesium chloride (MgCl2) has recently been shown to have stimulant-like properties. Because stimulants are known to induce conditioned place preference (CPP), the CPP procedure was used to test the hypothesis that cocaine and MgCl2 share similar stimulus properties. This would be shown if cocaine-induced CPP could be enhanced in a postconditioning preference test by MgCl2 and other stimulants. Mice were conditioned with 5.0 mg/kg cocaine to the nonpreferred end of a three-compartment straight shuttle box. All groups showed significant shifts in preference from the preconditioning test to the postconditioning test. There were no changes in place preference over test days in mice that were injected only with saline and therefore not conditioned. When animals were given acute injections of either saline, 5.0 mg/kg cocaine, 1.0 mg/kg amphetamine, 30 mg/kg MgCl2, 10 mg/kg pentobarbital, or 0.25 mg/kg haloperidol following conditioning with cocaine, amphetamine and MgCl2 elevated the conditioned cocaine effect, and pentobarbital and haloperidol decreased the conditioned cocaine effect compared to saline. In addition, there was a dose-dependent influence of MgCl2, with 30 mg/kg producing the maximum effect on the conditioned cocaine effect.

Animals↗
PubMed1990

Magnesium-induced conditioned place preference in mice.

A conditioned place preference procedure was used in mice to test the hypothesis that magnesium possesses reinforcing properties. Mice were conditioned to the nonpreferred end of a three-compartment straight shuttle box with MgCl2 injections alternating with saline injections on the preferred end. Dose of MgCl2 was varied (0, 15, 30, 125 mg/kg) as well as number of conditioning trials (8 or 16). On the day after the first postconditioning test, animals were given acute injections of 5 mg/kg cocaine, or other test drug, to determine if the conditioned effect on behavior would be potentiated, maintained or blocked by these test drugs. Results demonstrated that 15 mg/kg MgCl2 induced the greatest amount of conditioning and that increasing the number of MgCl2/place pairings did not enhance the amount of conditioning, but rather, it decreased it. Amphetamine potentiated MgCl2-induced place preference; cocaine and pentobarbital maintained it; and haloperidol blocked it. These data indicate that MgCl2 has some primary reinforcing properties in mice and that MgCl2 shares stimulus properties with other stimulants and reinforcing substances.

Animals↗