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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

Whole-cell voltage-clamp study of sodium current in neuroblastoma cells: effects of inhibition of neurite outgrowth by colchicine.

A method is described for the production of large numbers of neurite-free neuroblastoma cells that are especially suitable for studies involving whole-cell voltage clamp. Differentiation in the presence of colchicine yielded cells having abundant sodium channels, highly reproducible peak currents and no space-clamp problems. Treatment with this drug did not alter the electrophysiological properties of the cells.

Reverse tolerance to amphetamine evokes reverse tolerance to 5-hydroxytryptophan.

Repeated intermittent administration of amphetamine in mice caused reverse tolerance to 5-hydroxy-L-tryptophan (5-HTP)-induced head twitch, as well as to amphetamine-induced stereotypy. The repeated administration of 5-HTP alone also resulted in reverse tolerance in the head-twitch test. Daily pretreatment with haloperidol prior to amphetamine administration blocked the development of both reverse tolerance to amphetamine and to 5-HTP, whereas daily pretreatment with cyproheptadine prior to amphetamine blocked only the reverse tolerance to 5-HTP.

Effects of cocaine on neuromuscular transmission in the lobster.

In vitro electrophysiological techniques were used on an excitatory neuromuscular junction of a walking-limb stretcher muscle of the lobster in order to define the pharmacology of cocaine on a glutamatergic synapse. Cocaine reduced the amplitudes of the excitatory and the miniature junction potentials, as well as the mean quantum content of the muscle fiber. The effect on mean quantum content points to a presynaptic site of action of the drug, and the effect on miniature junctional potential suggests a postsynaptic site of action of the drug.

Pentylenetetrazol kindling in mice.

Kindling with pentylenetetrazol to produce minimal and maximal convulsions was investigated in CF-1 mice. Like electrical kindling, the kindling effect was directly proportional to the dose or the intensity of the kindling stimulus. Similarly, the kindling effect was persistent, as was emphasized by the ability to kindle with an interdose interval of 3 days and by the convulsions produced by a challenge with pentylenetetrazol 30 days after withdrawal from the kindling treatment.

Proconvulsant and anticonvulsant effects in mice of acute and chronic treatment with cocaine.

The proconvulsant and anticonvulsant effects of acute and chronic exposure to cocaine were investigated in adult, male, CF-1 mice. The proconvulsant effects of cocaine in mice only manifested themselves after daily exposure to motor-stimulant doses. Although daily treatment decreased electroshock convulsion threshold, no motor convulsions were observed.

Blockade of "reverse tolerance" to cocaine and amphetamine by MK-801.

"Reverse tolerance" was produced in rats and mice by repeated exposure to either cocaine or amphetamine. The locomotorstimulant effect was studied in mice; stereotypy and convulsions in rats. MK-801, the NMDA antagonist, blocked the development of "reverse tolerance" to all three effects.