Biomedical subjects

R Karler

Publications and source records attributed to R Karler.

At least 19 recordsLinked to original sources

PubMed1998

The role of dopamine and GABA in the frontal cortex of mice in modulating a motor-stimulant effect of amphetamine and cocaine.

The results of previous studies have indicated that the activation of dopaminergic and GABAergic systems in the prefrontal cortex can decrease dopaminergic and glutamatergic activity in the striatum, ostensibly by the inhibition of corticofugal glutamatergic pathways. The present studies were designed to investigate the cortical influence of dopamine and GABA agonists and antagonists on the motor response to systemically administered amphetamine and cocaine in the mouse. The results show that both dopamine and THIP, the GABA(A) agonist, injected intracortically (i.c.) depress amphetamine- or cocaine-induced stereotypy. That these responses are functionally significant is illustrated by the i.c. effects of sulpiride and bicuculline; they enhance the motor activity of the stimulants, suggesting that both dopaminergic and GABAergic systems in the cortex are activated by systemically administered amphetamine or cocaine. Additional experiments demonstrated that bicuculline i.c. can antagonize the depressant effect of dopamine i.c.; therefore, the dopaminergic inhibition in the cortex appears to be mediated by the activation of a cortical GABA system. These results show that systemically administered amphetamine or cocaine causes dopaminergic effects not only in the striatum but also in the cortex, and that the dopaminergic effect in the cortex may activate a cortical GABAergic system, which in turn, may account for the noted cortical inhibition of the dopaminergic motor-stimulatory action in the striatum.

Amphetamine↗

PubMed1998

The role of dopamine in the mouse frontal cortex: a new hypothesis of behavioral sensitization to amphetamine and cocaine.

In previous studies we demonstrated that dopamine, specifically a D2-receptor system, in the frontal cortex of the mouse functions to inhibit the motor response elicited by systemically administered amphetamine or cocaine; the inhibition appears to be the result of the dopaminergic activation of a GABAergic system. In the present study the inhibitory role of dopamine and GABA in the cortex was investigated in animals that were behaviorally sensitized to stimulant-induced stereotypy. For these studies various dopaminergic and GABAergic drugs were injected intracortically (i.c.) and their effects on stimulant-induced stereotypy were compared in nonsensitized and sensitized mice. The results indicate that the dopaminergic system in the cortex of sensitized animals, in contrast to nonsensitized controls, no longer functions to inhibit the motor response to the stimulants. The change in dopaminergic function in sensitized animals appears to be the result of a qualitative change in the D2 dopamine receptor system and not the result of a change in the associated GABA system. The loss of the inhibitory activity of dopamine in the cortex correlated with the persistence of sensitization. These results suggest a new mechanism to account for behavioral sensitization; that is, the phenomenon is the result of a loss of stimulant-induced dopaminergic inhibition of motor activity normally mediated by the frontal cortex.

Amphetamine↗

PubMed1997

The role of the frontal cortex in the mouse in behavioral sensitization to amphetamine.

Pharmacological studies have shown that a variety of neuroeffectors are involved in behavioral sensitization to amphetamine-induced stereotypy. In the present work, the effect of some of these drugs on sensitization was studied after intracortical administration in order to determine the role of the cortex in mediating their systemic effects. The dopamine antagonists sulpiride and spiperone were both ineffective against the acute response to amphetamine; nevertheless, both blocked the induction of sensitization, suggesting that the mesocortical dopamine pathway is not involved in the acute response but is necessary for the induction of sensitization. Both CPP, an NMDA receptor antagonist, and THIP, a GABA(A) agonist, blocked the acute response and the induction of sensitization to amphetamine. On the other hand, mecamylamine, the nicotinic cholinergic antagonist, failed to affect either the acute response or the induction of sensitization, which suggests that the cortex is not a locus of its activity. Anisomycin, an inhibitor of protein synthesis, and diltiazem, a calcium-channel blocker, were both ineffective against the acute response, but both blocked induction. All of the drugs, except CPP and THIP, were ineffective against the expression of sensitization; therefore, the ability of the other drugs to block expression must reside within another locus. Bicuculline injected intracortically in non-convulsant doses produced a stereotypy indistinguishable from that induced by amphetamine; and the effect was readily antagonized by CPP administered either systemically or intracortically. In contrast, sulpiride by either route of administration failed to block the bicuculline-induced stereotypy; we conclude, therefore, that the stereotypic effect of bicuculline is not mediated by dopamine. These results imply that amphetamine-induced stereotypy is mediated in the cortex by the removal of the inhibitory control of the excitatory system. The data also suggest that cortical dopamine, as well as the NMDA and GABA(A) systems, is important in sensitization to amphetamine. In general the data demonstrate that different neuroeffectors involved in sensitization exert their effects at different brain loci.

Amphetamine↗

PubMed1997

The role of the striatum in the mouse in behavioral sensitization to amphetamine.

Previous results of pharmacological studies of the mechanisms of amphetamine- and cocaine-induced stereotypy in the mouse suggest the involvement of dopaminergic, glutamatergic and GABAergic systems in the striatum. The present experiments were designed to evaluate pharmacologically the role of these neuroeffector systems in behavioral sensitization. Whether administered systemically or in the striatum, pretreatment with the neurotransmitter antagonists, sulpiride, bicuculline and CPP, blocked both the induction and the expression of behavioral sensitization. Efforts to induce sensitization or evoke expression with intrastriatal microinjections of amphetamine, NMDLA or THIP were not successful. The data indicate that these three neuroeffector systems interact at the level of the striatum to mediate the induction and expression of behavioral sensitization to amphetamine. The results are discussed in light of our previous reports and lead to the conclusion that two groups of drugs that affect sensitization can be defined: (1) antagonists of the dopaminergic, GABAergic and glutamatergic systems which block the acute effects of amphetamine as well as the induction and expression of sensitization and (2) another group of drugs which antagonize only sensitization-associated phenomena. The mouse data suggest that both the induction and the expression of sensitization involve not only multiple loci but also novel neuroeffector systems.

Amphetamine↗

PubMed1996

A novel nicotinic-cholinergic role in behavioral sensitization to amphetamine-induced stereotypy in mice.

Cholinergic antagonists were used to investigate the role of the cholinergic system in amphetamine- and cocaine-induced behavioral sensitization to stereotypy in mice. Systemically, mecamylamine (1 mg/kg) and dihydro-beta-erythroidine (2 mg/kg) - nicotinic antagonists - and atropine (2 mg/kg) - a muscarinic antagonist - were ineffective against psychostimulant-induced stereotypy in naive animals. The nicotinic antagonists, however, blocked both the induction and expression of sensitization to amphetamine; in contrast, atropine was ineffective. All three drugs were ineffective against either the induction or expression of cocaine sensitization. Intrastriatally, the nicotinic antagonists blocked induction but not expression of amphetamine-induced sensitization. The results suggest that the nicotinic system participates in sensitization induced by amphetamine but not cocaine; that the nicotinic component of the amphetamine response in sensitized animals is novel as compared to the response in naive animals; and that the striatum is a locus for the nicotinic involvement in induction but not expression. The data add support to the inference that behavioral sensitization represents not only a quantitative but a qualitative change in response to amphetamine.

Acetylcholine↗

PubMed1996

Comparative behavioral sensitization to stereotypy by direct and indirect dopamine agonists in CF-1 mice.

The present experiments were designed to compare the properties of behavioral sensitization induced by the indirect agonists, amphetamine and cocaine, to that induced by the direct dopamine agonists, apomorphine and PPHT. Both classes of agonist produced sensitization when administered either in relatively low daily doses or in a single high dose. Mice sensitized to the indirect agonists were cross-sensitized to the direct agonists and vice versa. A pharmacological evaluation of the sensitization induced by the two types of agonist demonstrated both similarities and dissimilarities. Induction to the indirect agonists is blocked by CPP, DNQX and diltiazem, whereas only CPP and diltiazem blocked induction to the direct agonists. Furthermore, although none of these antagonists block the expression of sensitization by the direct agonists, all three were previously shown to block the amphetamine expression of sensitization. Striking differences were also observed in the persistence of the sensitization induced by the two types of agonists. While the indirect agonist-induced sensitization is long lasting, the direct agonist-induced sensitization is relatively short-lived. Furthermore, cross-sensitization of PPHT in amphetamine-sensitized animals was also short-lived, as was amphetamine cross-sensitization in PPHT-sensitized animals. The data suggest that the induction of sensitization consists of two separable mechanisms, one for induction per se, the other for persistence.

Amphetamine↗

PubMed1995

The dopaminergic, glutamatergic, GABAergic bases for the action of amphetamine and cocaine.

The present experiments were designed to evaluate pharmacologically the role of three neuroanatomically related systems--dopamine, glutamate and GABA--in the motor-stimulant response to amphetamine and cocaine. The data indicate that stimulant-induced stereotypy is blocked by antagonists of all three systems and that agonists of all three systems administered into the striatum induce stereotypy. Furthermore, the interaction among them occurs in the striatum; and the reaction sequence, as determined by the effect of the relatively selective antagonists on agonist-induced stereotypy, appears to be a dopaminergic activation of a glutamatergic system which in turn activates a GABAergic system. Because the GABAergic system represents the major efferents from the striatum, the evidence suggests that the motor-stimulatory effects of amphetamine and cocaine result from a disinhibition of inhibitory systems in the thalamus, resulting in facilitation of excitation in the cortex.

Amphetamine↗

PubMed1994

A dopaminergic-glutamatergic basis for the action of amphetamine and cocaine.

The behavioral effects of amphetamine and cocaine are generally considered to be the result of their indirect dopaminergic activity. Recent reports, however, suggest that the activity of the psychomotor stimulants involves not only the dopaminergic but also the glutamatergic system. In the present study the role of the glutamate system in the action of the stimulants was investigated in mice with the use of glutamatergic agonists and antagonists administered either intraperitoneally or intracranially into the striatum. CPP, an NMDA-type glutamate antagonist, given systemically or intrastriatally, blocked stereotypy induced by either amphetamine or cocaine. These results represent pharmacological evidence that the glutamate system is an essential component in the expression of the stereotypic effect of the psychomotor stimulants, and that a locus of this action of glutamate is in the striatum. These conclusions were supported further by the observation that NMDLA administered focally into the striatum caused stereotypy which was indistinguishable from that produced by either amphetamine or dopamine. Stereotypy induced by amphetamine injected into the striatum was blocked by CPP or sulpiride administered either systemically or directly into the striatum; in contrast, stereotypy induced by NMDLA given into the striatum was blocked by CPP but not by sulpiride, regardless of whether the antagonists were presented systemically or into the striatum. The data suggest that stereotypy induced by amphetamine or cocaine is mediated by a dopaminergic activation of a glutamatergic system within the striatum.

Amphetamine↗

PubMed1994

Cocaine behavioral sensitization and the excitatory amino acids.

Studies were conducted to identify neuroeffector systems involved in behavioral sensitization to cocaine-induced stereotypy in mice, and to compare the results with those from our previous amphetamine studies. The effects of eight relatively selective neuroeffector agonists and antagonists were measured in mice in order to identify specific functional changes associated with the sensitization. In contrast to amphetamine, the only neuroeffector response altered by cocaine sensitization was a decrease in convulsive threshold to kainate. The persistence of the change in convulsive threshold correlated with the persistence of behavioral sensitization. The induction of sensitization was blocked by pretreatment with four different classes of drugs, represented by haloperidol, dizocilpine, diltiazem and DNQX. These results suggest that the mechanism of induction to cocaine is similar to that of amphetamine; both the glutamate and dopaminergic systems appear to be involved in induction. The expression of the sensitized cocaine response was blocked by haloperidol, CPP and diltiazem. These results differed from those obtained previously insofar as CPP did not affect the expression of sensitization to amphetamine. Furthermore, DNQX, in contrast to its antagonism of the expression of amphetamine sensitization, did not affect the expression of cocaine sensitization. The pharmacological data suggest that the mechanism of induction differs from that of expression, and that the mechanism of expression for cocaine sensitization differs from that for amphetamine.

Amphetamine↗

PubMed1993

Blockade of behavioral sensitization to cocaine and amphetamine by inhibitors of protein synthesis.

Anisomycin and cycloheximide were used to investigate the role of protein synthesis in the mechanism of behavioral sensitization to the stereotypic effects of cocaine and amphetamine in mice. The drugs completely antagonize induction and partially block expression of the sensitization. Because these drugs were found to be neither antidopaminergic nor antiglutamatergic, it seems that they disrupt sensitization at a novel locus. The antagonism of expression is limited to that quantitative fraction of the response derived from the sensitization reaction; the acute response is unaffected by the inhibitors of protein synthesis. The results differ from those obtained with haloperidol which can completely block either the acute or sensitized response to the stimulants. These results suggest that the sensitized response is functionally different from that of the acute response. The blockage of sensitization induction by the protein synthesis inhibitors may be related to other reports that the stimulants induce the transcription of immediate early genes; however, the relationship between the activation of immediate early genes and behavioral sensitization remains to be determined.

Amphetamine↗

PubMed1993

Effects of L-type calcium channel antagonists on the serotonin-depleting actions of MDMA in rats.

The calcium channel antagonists verapamil nifedipine and flunarizine all increased the threshold for convulsions induced by N-methyl-D-aspartate in rats. By contrast, only flunarizine blocked the long-term serotonin-depleting effects of 3,4-methylenedioxymethamphetamine. Flunarizine was also the only drug that antagonized methamphetamine-induced stereotypy. These findings suggest that calcium influx through L-type channels does not participate in the neurotoxic mechanism of MDMA, and that the neuroprotective actions of flunarizine are probably related to its anti-dopaminergic activity.

3,4-Methylenedioxyamphetamine↗

PubMed1992

Role for protein synthesis in the neurotoxic effects of methamphetamine in mice and rats.

The mechanism by which the amphetamines damage selectively nigrostriatal dopaminergic neurons in experimental animals remains uncertain. The observation that neuronal cell death during embryogenesis involves an activation of gene expression and new protein synthesis, coupled with recent reports indicating that the amphetamines are capable of inducing neuropeptide biosynthesis, offers a possible clue as to their neurotoxic mechanism of action. Based on these considerations, we evaluated the effects of two different inhibitors of protein synthesis, cycloheximide and anisomycin, on the long-term, amine-depleting effects of methamphetamine (METH) in mice and rats. Both inhibitors were found to block the amine-depleting effects of METH in these species. In other experiments, cycloheximide did not affect the functional integrity of dopaminergic or glutamatergic neurons, transmitter systems previously implicated in the neurotoxic mechanism of action of METH. These findings raise the possibility that the neuronal-damaging effects of METH are mediated via a synthesis of 'neurotoxic' proteins.

Animals↗

PubMed1992

Excitatory amino acids and the actions of cocaine.

Antagonists of the N-methyl-D-aspartate (NMDA) type of excitatory amino acid (EAA) receptors blocked cocaine-induced stereotypy, locomotor stimulation and convulsions. These effects in general appear to involve selectively NMDA type of receptors. The results suggest that NMDA-activated systems are an integral component in the reaction sequences involved in the expression of several behavioral effects of cocaine.

Animals↗

PubMed1991

Differential effects of delta-9-tetrahydrocannabinol and its 11-hydroxy metabolite on sodium current in neuroblastoma cells.

Whole-cell voltage-clamp techniques were used to study the comparative effects of delta-9-tetrahydrocannabinol (THC) and its principal metabolite, 11-hydroxy-delta-9-tetrahydrocannabinol (11-OH-THC), on the voltage-gated sodium current in neuroblastoma cells. The parent compound markedly depressed the inward sodium current with minimal reduction of the outward current, demonstrating that the effects of the drug were related to the membrane potential. In addition, THC reduced the reversal potential, indicating that the drug modified the ion selectivity of the channel. 11-OH-THC similarly depressed inward sodium current; however, in marked contrast to the effects of the parent compound, the drug equally depressed the outward voltage-gated sodium current, indicating that its effects were not related to the membrane potential. Furthermore, 11-OH-THC differed from THC in that it did not alter the reversal potential. The results demonstrate that THC and its 11-OH metabolite both reduce inward sodium current, but their effects on the outward current and ion selectivity are distinctly different. The sum of the actions of these two cannabinoids on the voltage-gated sodium channel provides a plausible cellular basis for THC's depression of action potentials in vivo and for some of its central depressant effects.

Dronabinol↗

PubMed1991

DNQX blockade of amphetamine behavioral sensitization.

The role of the N-methyl-D-aspartate (NMDA) and non-NMDA excitatory amino acid (EAA) receptors in the mechanism of behavioral sensitization to amphetamine-induced sterotypy was investigated in mice. The results confirm previous observations that NMDA antagonists can block the induction of the phenomenon but not the expression; in contrast, DNQX, a non-NMDA receptor antagonist, can block both the induction and the expression of the sensitization. The differential effects of the two classes of antagonists suggest that the induction and the expression are the result of different mechanisms, both of which involve the EAA system. The DNQX results differ from those of haloperidol, which can also block both the induction and expression, because haloperidol can completely block the amphetamine-induced responses in naive and in sensitized animals; whereas DNQX is without effect on the amphetamine activity in naive animals and, in the sensitized animal, can block only that portion of the response that is derived from the sensitization phenomenon. The effects of the EAA antagonists support the hypothesis that the enhanced responsiveness in the sensitized animals is derived from the activation of EAA receptors, which, in turn, increases the release of dopamine in the striatum. Finally, the involvement of the non-NMDA receptors in the expression of the behavioral sensitization further substantiates the postulate that the amphetamine-induced sensitization is a behavioral manifestation of long-term potentiation (LTP).

Amphetamine↗

PubMed1991

Calcium channel blockers and excitatory amino acids.

The calcium channel blockers (CCB), diltiazem, verapamil and nifedipine, antagonize in mice both N-methyl-DL-aspartate- (NMDLA) and kainate-induced convulsions, which were not affected by carbamazepine and ethosuximide. The CCB, on the other hand, were ineffective against convulsions induced by bicuculline, pentylenetetrazol and electroshock. The results suggest that the CCB may be efficacious in the treatment of those neurodegenerative diseases putatively caused by the excitatory amino acids.

Amino Acids↗

PubMed1991

Calcium channel blockers and behavioral sensitization.

Behavioral sensitization to amphetamine-induced stereotypy was previously shown to consist of two separable phenomena, induction and expression, both of which involve the excitatory amino acids (EAA). In the present experiments, the calcium channel blockers (CCB), nifedipine, diltiazem and verapamil, were shown to block both phenomena; these results are similar to those reported earlier for DNQX, an antagonist of the non-N-methyl-D-aspartate receptors for the EAA. The CCB, like DNQX, affect only that percentage of the stereotypic response which results from the sensitization reaction, without affecting the quantitative portion of the response attributable to the acute effect of amphetamine. The results support previous conclusions that the sensitization response consists of two quantitative components, only one of which involves the EAA. The antagonism exhibited by the CCB suggests that behavioral sensitization involves Ca++ and L-type calcium channels.

Amphetamine↗

PubMed1991

Delta-9-tetrahydrocannabinol depresses inward sodium current in mouse neuroblastoma cells.

Whole-cell voltage-clamp techniques were used in order to define the effects of delta-9-tetrahydrocannabinol (THC) on the voltage-gated sodium current in neuroblastoma cells. With regard to the inward sodium current, THC decreased the peak amplitude and increased both the time to peak and tau for recovery. The reversal potential was unchanged, suggesting that channel selectivity for sodium was not altered by the drug. With regard to the outward sodium current, THC had no effect on the peak amplitude, time to peak or tau for recovery. This functional alteration of the voltage-gated sodium channel may contribute to the depressant effects of the cannabinoid.

Animals↗