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.

The effects of amphetamine 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 amphetamine on a glutamatergic synapse. A single electrical stimulus in the presence of the drug produced a train of action potentials in the axon innervating the neuromuscular junction, resulting in a staircase-like enhancement of the evoked excitatory junction potential; both effects were antagonized by relatively small doses of haloperidol. In contrast, amphetamine reduced the amplitude of the spontaneous miniature junctional potential, suggesting a postsynaptic site of action; this depressant response to the drug was not antagonized by haloperidol.

Characteristics of "reverse tolerance" to amphetamine-induced locomotor stimulation in mice.

The characteristics of chronically administered amphetamine on the locomotor and anticonvulsant effects were studied in adult CF-1 mice. The influence of dose of the drug and interdose interval on the development of "reverse tolerance" to the locomotor stimulation was investigated, in addition to the selectivity of the response and the persistence of the change in pharmacodynamics. Once-daily treatment with 6 mg/kg amphetamine for 4 weeks resulted in a 2-3 fold increase in locomotor activity.

Changes in neurotransmitter release at a neuromuscular junction of the lobster caused by cannabinoids.

In vitro intracellular recording techniques were used on an excitatory neuromuscular junction of a walking-limb stretcher muscle of the lobster in order to define the synaptic pharmacology of delta-9-tetrahydrocannabinol (THC), 11-hydroxy-THC and cannabidiol. Delta-9-tetrahydrocannabinol and 11-hydroxy-THC, in relatively small concentrations, increased the amplitude of the excitatory junctional potential and the mean quantum content of a muscle fiber, whereas larger concentrations produced depression. In contrast, cannabidiol reduced the excitatory junctional potential and the mean quantum content.

Effects of delta-9-tetrahydrocannabinol, 11-hydroxy-delta-9-tetrahydrocannabinol and cannabidiol on neuromuscular transmission in the frog.

Intracellular recording techniques were used on neuromuscular junctions of the sartorius muscle of the frog, in vitro, to define the synaptic pharmacology of delta-9-tetrahydrocannabinol (THC), 11-hydroxy-THC and cannabidiol (CBD). The frequency of miniature endplate potentials was increased by THC, decreased by CBD and was unaffected by 11-hydroxy-THC, whereas the amplitude of the miniature endplate potentials was depressed by all three cannabinoids. In addition, the mean quantum content of the endplate potential (m) was first increased and then decreased by THC and 11-hydroxy-THC, but CBD produced only depression.

Cannabidiol-caused depression of spinal motoneuron responses in cats.

Intracellular recording techniques were used on spinal motoneurons in the cat in order to define the synaptic pharmacology of cannabidiol (CBD). The cannabinoid produces only depression of electrophysiological responses of the motoneurons: For instance, the drug decreases the amplitude of excitatory postsynaptic potentials (EPSPs); this reduction does not appear to be the result of a change in the afferent input. In addition, CBD raises the firing threshold and decreases the amplitude of motoneuron action potentials; the effects on action potentials are related to changes in postsynaptic membrane conductances, probably involving at least sodium conductance.

Prolonged CNS hyperexcitability in mice after a single exposure to delta-9-tetrahydrocannabinol.

A single exposure to delta-9-tetrahydrocannabinol (THC) resulted in a "rebound" hyperexcitability in the CNS in mice, which was assessed in terms of the susceptibility of the CNS to electrically-induced convulsions. The magnitude of the hyperexcitability was dose-related (25-150 mg/kg, i.p.

Influence of 11-hydroxy-delta-9-tetrahydrocannabinol on spinal motoneurons in cat.

Intracellular recording techniques were used on spinal motoneurons in the cat in order to define the synaptic pharmacology of 11-hydroxy-delta-9-tetrahydrocannabinol (11-hydroxy-delta-9-THC), the principal metabolite of delta-9-tetrahydrocannabinol (delta-9-THC). The 11-hydroxy derivative increased the amplitude of excitatory postsynaptic potentials; such an excitatory response did not appear to be the result of changes in afferent input. The increase in excitatory postsynaptic potentials, however, may be accounted for by a rise in membrane resistance.

Interaction between delta-9-tetrahydrocannabinol and kindling by electrical and chemical stimuli in mice.

Mice were kindled to produce minimal convulsions by repeated application of either electrical or chemical stimuli. Electrical kindling involved the use of corneal electrodes; chemical kindling involved the use of pentylenetetrazol or picrotoxin. Delta-9-tetrahydrocannabinol (delta-9-THC) appeared to be capable of enhancing kindling to all three stimuli.

Effects of delta 9-tetrahydrocannabinol on cat spinal motoneurons.

The influence of delta 9-tetrahydrocannabinol (delta 9-THC) on cat spinal motoneurons was investigated with intracellular recording techniques in order to identify possible mechanisms of action of the drug's central excitatory and depressant properties. delta 9-THC increased the amplitude of the excitatory postsynaptic potentials (EPSPs) and decreased the amplitude of the inhibitory postsynaptic potentials (IPSPs); these excitatory effects do not appear to be the result of changes in the afferent input. However, an observed increase in membrane resistance may account for, or contribute to, the enhanced EPSPs.

Influence of different barbiturate anesthetics on delta-9-tetrahydrocannabinol effects on spinal monosynaptic reflexes.

Two barbiturates, pentobarbital and methohexital, were used as general anesthetics to evaluate their interactions with the effects of delta-9-tetrahydrocannabinol (delta-9-THC) on spinal monosynaptic reflexes in cats with transected spinal cords and ischemically destroyed brains. In animals initially anesthetized with pentobarbital, delta-9-THC over a wide dosage range produced only an enhancement of the reflex, whereas in methohexital-treated animals only depression was elicited. Because delta-9-THC is known to produce both excitatory and depressant effects in conscious animals, the results of the present study demonstrate that the choice of anesthetic may determine which effects manifest themselves.