Ralph Karler

AMPHETAMINE BEHAVIORAL SENSITIZATION AND THE EXCITATORY AMINO ACIDS

The effects of 8 selective neuroeffector agonists and antagonists were measured in mice in order to identify specific functional changes associated with behavioral sensitization to amphetamine-induced stereotypy. The changes observed included a decreased convulsive threshold to N-methyl-DL-aspartic acid, an increased convulsive threshold to bicuculline, and an increased head-twitch response to 5-hydroxytryptophan. Of these effects, only the persistence of the two convulsive threshold changes correlated with the persistence of the behavioral sensitization. The induction of behavioral sensitization was blocked by haloperidol, dizocilpine or ketamine, but not affected by cyproheptadine or diazepam: therefore, the mechanism of the enhanced responsiveness involves not only a functional dopamine system, but also a functional N-methyl-D-aspartic acid component of the excitatory amino acid system. The block of behavioral sensitization also prevented the amphetamine-induced changes in the convulsive thresholds. Finally, neither ketamine nor dizocilpine affected the expression of the enhanced response in the behaviorally sensitized animals. The data indicate that the characteristics of amphetamine behavioral sensitization to stereotypy are similar to those of long-term potentiation.

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).

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.

The Cannabinoids as Potential Antiepileptics

Abstract: Comparative studies of the anticonvulsant properties of the cannabinoids and prototype antiepileptic drugs in numerous animal seizure models demonstrate that (1) as an anticonvulsant, cannabidiol (CBD), in contrast to Δ9‐tetrahydrocannabinol (THC), is relatively selective in terms of both central nervous system (CNS) depressant and excitatory properties; (2) the potency of cannabidiol, unlike that of phenytoin and phenobarbital, varies greatly with the species; (3) the large potency difference between the cannabinoids and the antiepileptics in the mouse appears to be due to dispositional differences, because brain concentrations of all the drugs are very similar; (4) tolerance to the anticonvulsant properties of cannabidiol is not a prominent feature; in three seizure models, tolerance developed in one, but “reverse tolerance” developed in the other two; and (5) the results of a study of the electrophysiologic mechanisms of action indicate that cannabidiol produces some unique effects and that its spectrum of antiepileptic activity may be different from that of the prototype drugs. The anticonvulsant nature of cannabidiol suggests that it has a therapeutic potential in at least three of the four major types of epilepsy: grand mal, cortical focal, and complex partial seizures.

The anticonvulsant activity of cannabidiol and cannabinol

Abstract The anticonvulsant activity of delta-9-tetrahydrocannabinol was compared with that of two other naturally occurring cannabinoids, cannabidiol and cannabinol, in a maximal electroshock test in mice. The drugs were administered as an emulsion of sesame seed oil, Tween 80 and saline to mice i.p. The results indicate that all three cannabinoids are effective anticonvulsants. The time for peak effect is about 2 hr. In terms of relative potencies, cannabidiol and delta-9-THC are similar but both of them are more active than cannabinol.

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.

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.

Anticonvulsant properties of Δ9-tetrahydrocannabinol and other cannabinoids

Abstract Anticonvulsant doses of Δ9-tetrahydrocannabinol (Δ9-THC) markedly lower body temperature in mice at an ambient temperature of 22°C, but there is little such effect at 30°C. The anticonvulsant properties of Δ9-THC are as follows: The drug abolishes hind-limb extension in a maximal electroshock (MES) test, elevates both the MES (extensor) and 6-Hz-electroshock thresholds, exerts no effect on the 60-Hz-electroshock threshold, and enhances minimal seizures caused by pentylenetetrazol. All anticonvulsant properties studied, with the exception of the 60-Hz-electroshock threshold, were unaffected by the hypothermia resulting at 22°C. Additional experiments with Δ9-THC indicated that chronic treatment results in the development of tolerance, as determined by the MES test with rats. The four principal naturally occurring cannabinoids, Δ9-THC, Δ8-THC, cannabinol and cannabidiol, display anticonvulsant activity, as does the major, primary metabolite of Δ9-THC, 11-hydroxy-Δ9-THC. Of all agents investigated in mice, the synthetic cannabinoids, dimethylheptylpyran and its isomers, are the most potent anticonvulsants. The results of a study of the relative motor toxicity and anticonvulsant activity of the cannabinoids demonstrate that these properties are at least partially separable among the various agents.

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.

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.