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. On the other hand, 5-HTP-induced reverse tolerance was blocked by daily pretreatment with cyproheptadine, but not with haloperidol. There appears to be no difference in the persistence of the reverse tolerance to 5-HTP, whether induced by amphetamine or by 5-HTP; in both instances, the persistence does not correlate with the persistence of reverse tolerance to amphetamine. The data suggest that the reverse tolerance to amphetamine and the associated reverse tolerance to 5-HTP are independent events, both of which are mediated by dopaminergic mechanisms.     

Anticonvulsant and behavioral actions of triterpene isolated from Rubia cordifolia Linn

Effect of a triterpene isolated from the acetone soluble part of petroleum ether extract of R. cordifolia was studied on convulsions induced by maximum electro shock (MES), electrical kindling and various chemoconvulsants in rats and mice. The effect of triterpene was also investigated on behavior and gamma-aminobutyric acid (GABA) and serotonin (5-HT) content in mouse brain. Triterpene inhibited seizures induced by MES, electrical kindling, pentylenetetrazol (PTZ), and lithium-pilocarpine. However, seizures induced by strychnine were not inhibited. Triterpene reduced locomotion as well as rearing. Pentobarbitone induced sleep was potentiated and amphetamine induced stereotypy was inhibited. The triterpene was found to possess anxiogenic activity. Brain GABA and 5-HT contents were raised by the compound. The study suggests that the triterpene isolated from R. cordifolia bear a potential for further study.     

Delay in formation of phenamine tolerance after epiphysectomy in rats

Amphetamine-induced stereotyped behavior is a nonsteady oscillatory process with minute fluctuations rate of head turnings. After acute amphetamine stereotypy have lower amplitude and limited rhythmicity in pinealectomized rats as compared with intact animals. Pinealectomy also delayed tolerance after chronic administration of amphetamine (5 mg/kg/day, 14 days) without usual decrease number of short period (2-3 min) fluctuations in time course of stereotypy.     

Alterations in amphetamine stereotypy following acute lesions of substantia nigra

Stereotypy induced by high doses of amphetamine has been related to the ability of this drug to increase the release of dopamine in the caudate nucleus and to block its reuptake. Since amphetamine-stimulated dopamine release in the caudate is blocked by acute lesions of the nigrostriatal pathway, the mechanism by which amphetamine acts to produce stereotypy may be dependent upon intact nigrostriatal impulse flow. The present study examined the involvement of nigrostriatal impulse flow in amphetamine stereotypy by determining the effect of acute, bilateral lesions of substantia nigra pars compacta on measures of stimulant-induced stereotypy and motility. Acute nigral lesions did not significantly alter the stereotypy or motility induced by 3.0 or 6.0 mg/kg amphetamine. These results suggest that the observed behavioral effects of amphetamine do not require an intact nigrostriatal pathway, and thus may involve changes in spontaneous release or reuptake of dopamine rather than in changes in impulse-coupled dopamine release.     

Evidence of serotonin-dopamine involvement in the inhibition of d-amphetamine stereotypy and appearance of stereotyped movements found respectively after acute and long-term treatment with morphine and methadone in rats

P-chlorophenylalanine, an inhibitor of serotonin synthesis, was found to completely prevent the inhibitory effect of morphine and methadone on the stereotypy caused by d-amphetamine and methyl-phenidate in rats. d-Fenfluramine and m-chlorophenylpiperazine, two drugs supposed to increase serotonin transmission, and halo-peridol, an antagonist of dopamine at central receptors, blocked the stereotyped movements induced by repeated treatment with morphine and methadone. The results suggest that a) brain serotonin mediates the effect of morphine and methadone on amphetamine and methylphenidate stereotypy b) serotonin and dopamine are involved in the stereotyped movements caused by long-term treatment with these narcotics in the rat.     

Chronic Inhibition of Dopamine β-Hydroxylase Facilitates Behavioral Responses to Cocaine in Mice

The anti-alcoholism medication, disulfiram (Antabuse), decreases cocaine use in humans regardless of concurrent alcohol consumption and facilitates cocaine sensitization in rats, but the functional targets are unknown. Disulfiram inhibits dopamine β-hydroxylase (DBH), the enzyme that converts dopamine (DA) to norepinephrine (NE) in noradrenergic neurons. The goal of this study was to test the effects of chronic genetic or pharmacological DBH inhibition on behavioral responses to cocaine using DBH knockout (Dbh −/−) mice, disulfiram, and the selective DBH inhibitor, nepicastat. Locomotor activity was measured in control (Dbh +/−) and Dbh −/− mice during a 5 day regimen of saline+saline, disulfiram+saline, nepicastat+saline, saline+cocaine, disulfiram+cocaine, or nepicastat+cocaine. After a 10 day withdrawal period, all groups were administered cocaine, and locomotor activity and stereotypy were measured. Drug-naïve Dbh −/− mice were hypersensitive to cocaine-induced locomotion and resembled cocaine-sensitized Dbh +/− mice. Chronic disulfiram administration facilitated cocaine-induced locomotion in some mice and induced stereotypy in others during the development of sensitization, while cocaine-induced stereotypy was evident in all nepicastat-treated mice. Cocaine-induced stereotypy was profoundly increased in the disulfiram+cocaine, nepicastat+cocaine, and nepicastat+saline groups upon cocaine challenge after withdrawal in Dbh +/− mice. Disulfiram or nepicastat treatment had no effect on behavioral responses to cocaine in Dbh −/− mice. These results demonstrate that chronic DBH inhibition facilitates behavioral responses to cocaine, although different methods of inhibition (genetic vs. non-selective inhibitor vs. selective inhibitor) enhance qualitatively different cocaine-induced behaviors.     

Reverse tolerance to amphetamine of mice bearing unilateral striatal lesions: effect upon the circling response to apomorphine

When mice bearing unilateral lesions of the striatum receive weekly doses of amphetamine, their circling responses increase with successive doses, i.e., they become reverse tolerant (1). The present work was undertaken to ascertain whether presynaptic dopaminergic changes might underlie this phenomenon. This was approached by observing whether the response to a direct dopaminergic agent would be affected by the development of reverse tolerance to amphetamine. The circling responses of unilaterally electrothermally lesioned mice to apomorphine, 0.4 mg/kg s.c., increased significantly after four weekly 4 mg/kg s.c. doses of d-amphetamine. The responses to apomorphine of mice not exposed to amphetamine declined over the same interval. The conclusion drawn is that presynaptic effects are not likely to underlie the phenomenon of reverse tolerance.     

Comparative behavioral pharmacology and toxicology of cocaine and its ethanol-derived metabolite, cocaine ethyl-ester (cocaethylene).

The present study compared the behavioral and toxic effects of cocaine and its ethanol derived metabolite, cocaine ethyl-ester (cocaethylene). Both drugs produced qualitatively similar psychomotor stimulant effects. Cocaine and cocaethylene increased locomotor activity in mice, with cocaine approximately four times more potent than cocaethylene. The durations of action of ED75 doses of each of the drugs were comparable. Each of the drugs also produced stimulation of operant responding in rats. In rats and squirrel monkeys trained to discriminate cocaine injections from saline, cocaine was approximately three to five times more potent than cocaethylene in producing these cocaine-like interoceptive effects. In contrast to the behavioral effects, cocaine and cocaethylene were equipotent in producing convulsions, and cocaethylene was more potent than cocaine in producing lethality. These results suggest that the conversion of cocaine to cocaethylene with simultaneous cocaine and alcohol use may produce an increased risk of toxicity due to a decrease in the potency of cocaethylene in producing psychomotor stimulant effects, and its increased potency in producing toxicity.     

Drug-environment interaction: Context dependency of cocaine-induced behavioral sensitization

The effect of the environmental context in which rats received cocaine upon subsequent cocaine-induced hyperactivity and stereotypy was explored. “Cocaine test cage” animals were injected with cocaine in the test cage and then received saline upon leaving it 40 minutes later, while in the “saline test cage” group the injections, were in the reverse order. Thus, all animals had identical injections, handling, and environmental exposure, differing only in whether they received cocaine during or after their test cage experience. The cocaine test cage animals displayed increasing response (p < .001) to the 10 daily cocaine injections, i.e., behavioral sensitization. However, in contrast, the “saline-test cage” animals had significantly less cocaine-induced activation upon 2 of 3 challenges with cocaine and showed no significant evidence of behavioral sensitization even though they had received the same dose and number of previous cocaine injections in a different environment. Thus, this study reveals environment- specific drug effects and suggests that environmental context plays a role in the development and manifestation of behavioral sensitization to cocaine.     

Effect of glucose on amphetamine-induced motor behavior

The effect of 1 g/kg D-glucose on amphetamine-induced increases in activity; stereotypy; and rotation in rats with unilateral 6-OHDA lesions of nigro-striatal neurons was examined. The amphetamine dose-response curve for stereotypy was shifted to the right by glucose but retained the same slope as the control curve, suggesting that glucose competes for amphetamine or dopamine receptors that mediate this behavior. The slope of the dose-response curve for activity was significantly decreased by glucose, suggesting that glucose reduces activity levels in a manner that is non-competitive with the action of amphetamine or dopamine. Amphetamine-induced turning was unaffected by glucose at all doses tested. These data suggest that the effect of amphetamine on each of the three motor behaviors may be mediated by different dopamine-containing neurons, or by different post-synaptic dopamine receptors. The findings are also consistent with other data suggesting that glucose antagonizes dopamine function, but they suggest that this antagonism may not be uniform over all dopaminergic neurons or receptor types.     

Differential effects of the pharmacological manipulation of serotonin systems on cocaine and amphetamine self-administration in rats

The effects of the administration of serotonergic drugs on infusion rates of rats self-administering cocaine and amphetamine on an FR-10 schedule of reinforcement in daily 4 hour sessions were compared. Pretreatment with fluoxetine (2.5, 5, and 10 mg/kg), an inhibitor of serotonin reuptake, significantly decreased rates of responding maintained by amphetamine, but had no effect on responding maintained by cocaine at any of the doses tested. Pretreatment with cinanserin (3, 10, and 17.5 mg/kg), a serotonergic receptor antagonist, decreased rates of amphetamine self-administration at the highest dose tested, and also had no effect on cocaine self-administration. These data suggest a differential sensitivity of cocaine and amphetamine self-administration to pharmacological manipulation of central serotonin systems. They are consistent with biochemical data which demonstrates a negative correlation between the reinforcing potency of amphetamine-like drugs, but not cocaine-like drugs and their potency at serotonin binding sites.     

Effect of antiepileptic drugs on metrazol convulsions during ontogenesis in the rat

The effect of ethosuximide, dipropylacetate and clonazepam on metrazol convulsions induced by a dose of 80 mg/kg was studied in 314 male albino rats aged from 5 days to adult. In a standard dose of 125 mg/kg, ethosuximide reliably protected only adult and 25-day-old rats, i.e. the age groups in which a mature minimal seizure was the only type of convulsion induced; in younger animals, not even a much higher dose (tested in 12-day-old rats) afforded reliable protection. Dipropylacetate and clonazepam had a manifest protective effect in all age groups, irrespective of the type of seizure. Isolated myoclonic jerks were less sensitive to antiepileptics and only dipropylacetate blocked them in the youngest age groups. In 21-day-old and older animals dipropylacetate induced stereotype head movement reminiscent of the serotonergic stereotypy described in the literature.     

Differences in dopamine responsiveness to drugs of abuse in the nucleus accumbens shell and core of Lewis and Fischer 344 rats

The use of inbred rat strains provides a tool to investigate the role of genetic factors in drug abuse. Two such strains are Lewis and Fischer 344 rats. Although several biochemical and hormonal differences have been observed between Lewis and Fischer 344 strains, a systematic comparison of the effect of different drugs of abuse on dopamine (DA) transmission in the shell and core of the nucleus accumbens of these strains is lacking. We therefore investigated, by means of dual probe microdialysis, the effect of different doses of morphine (1.0, 2.5, and 5.0 mg/kg), amphetamine (0.25, 0.5, and 1.0 mg/kg) and cocaine (5, 10, and 20 mg/kg) on DA transmission in the shell and in the core of nucleus accumbens. Behavior was monitored during microdialysis. In general, Lewis rats showed greater DA responsiveness in the NAc core compared to F344 rats except after 2.5 mg/kg of morphine and 20 mg/kg of cocaine. In the NAc shell, different effects were obtained depending on drug and dose: after 1.0 mg/kg of morphine no strain differences were observed, at 2.5 and 5.0 mg/kg Lewis rats showed greater increase in DA in the NAc shell. Following amphetamine and cocaine challenge, Lewis rats showed greater DA increase in the shell after 0.25 mg/kg of amphetamine and 20 mg/kg of cocaine. Behavioral activation was greater in Lewis rats in response to the lowest dose of morphine (1.0 mg/kg), to the highest dose of amphetamine (1.0 mg/kg) and to all doses of cocaine. These differences might be the basis for the different behavioral responses of these strains to drugs of abuse.     

Effects of caerulein + haloperidol on amphetamine-induced locomotor stereotypy in rats

The combination of haloperidol + caerulein has been reported to produce a long-lasting reduction of amphetamine-induced hyperlocomotions in rats. This study was designed to replicate those findings and to determine whether haloperidol + caerulein produce any unique effect on amphetamine-induced locomotor stereotypy. In two experiments, haloperidol + caerulein failed to produce a long-lasting reduction in amphetamine-induced hyperlocomotions. Although haloperidol reduced the locomotor stereotypy produced by higher doses of amphetamine, caerulein had no effect, either alone or combined with haloperidol.     

Extended access of cocaine self‐administration results in tolerance to the dopamine‐elevating and locomotor‐stimulating effects of cocaine

Tolerance to the neurochemical and psychoactive effects of cocaine after repeated use is a hallmark of cocaine addiction in humans. However, comprehensive studies on tolerance to the behavioral, psychoactive, and neurochemical effects of cocaine following contingent administration in rodents are lacking. We outlined the consequences of extended access cocaine self‐administration as it related to tolerance to the psychomotor activating, dopamine (DA) elevating, and DA transporter (DAT) inhibiting effects of cocaine. Cocaine self‐administration (1.5 mg/kg/inj; 40 inj; 5 days), which resulted in escalation of first hour intake, caused reductions in evoked DA release and reduced maximal rates of uptake through the DAT as measured by slice voltammetry in the nucleus accumbens core. Furthermore, we report reductions in cocaine‐induced uptake inhibition and a corresponding increase in the dose of cocaine required for 50% inhibition of DA uptake (K_i) at the DAT. Cocaine tolerance at the DAT translated to reductions in cocaine‐induced DA overflow as measured by microdialysis. In addition, cocaine‐induced elevations in locomotor activity and stereotypy were reduced, while rearing behavior was enhanced in animals with a history of cocaine self‐administration. Here, we demonstrate both neurochemical and behavioral cocaine tolerance in an extended‐access rodent model of cocaine abuse, which allows for a better understanding of the neurochemical and psychomotor tolerance that develops to cocaine in human addicts.

     

Distinct temperature-dependent dopamine-releasing effect of drugs of abuse in the olfactory bulb

It was recently shown in the olfactory bulb (OB) that the response to olfactory stimulation might be related to local reinforcement mechanisms involved in discrimination of different odors. Therefore, it seemed interesting to study the effects of several drugs of abuse on the release of dopamine (DA) in the OB. Nicotine, amphetamine, 3,4-methylenedioxymethamphetamine (MDMA, "ecstasy"), and cocaine at 37 degrees C increased the release of [3H] DA from olfactory bulb slice preparations of the rats. While nicotine, amphetamine, and MDMA directly evoked DA release, cocaine, by inhibiting the reuptake processes, enhanced the electrical stimulation-evoked release. At low temperature (17 degrees C), a condition in which the transmitter uptake carriers of the plasma membrane in both the normal and reverse mode of operation are inhibited, the nicotine-evoked [3H] DA release was potentiated, whereas those evoked by amphetamine and MDMA were inhibited. At low temperature the field stimulation-evoked [3H] DA release was potentiated, but under this condition cocaine failed to increase the release. Our results show that low temperature (a) increases the concentration of extracellular DA released by Ca(2+)-dependent vesicular exocytosis elicited by nicotine, (b) inhibits the extracellular Ca(2+)-independent amphetamine- and MDMA-induced release of DA that occurs by the reverse operation of membrane carriers transporting DA from the cytoplasm of presynaptic terminals to the extraneuronal space, and (c) does not alter the inhibitory effect of cocaine on DA uptake that increases the concentration of extracellular DA released by field stimulation. The findings that the drugs of abuse tested all enhanced the release of DA in the olfactory bulb suggest that local reinforcing mechanisms may also exist in this brain area. In addition, we also show that lowering the temperature in in vitro experiments is an easy and straightforward method for separating vesicular and cytoplasmic release of transmitters, and is suitable for studying the mechanism of catecholamine release evoked by drugs of abuse. This technique may be applicable in other neurochemical studies that need inhibition of the uptake carriers without the blockade of the ligand-gated ion channels caused by reuptake inhibitor drugs.     

RGS mRNA expression in rat striatum: modulation by dopamine receptors and effects of repeated amphetamine administration

Single injections of cocaine, amphetamine, or methamphetamine increased RGS2 mRNA levels in rat striatum by two- to fourfold. The D1 dopamine receptor-selective antagonist SCH-23390 had no effect by itself but strongly attenuated RGS2 mRNA induction by amphetamine. In contrast, the D2 receptor-selective antagonist raclopride induced RGS2 mRNA when administered alone and greatly enhanced stimulation by amphetamine. To examine the effects of repeated amphetamine on RGS2 expression, rats were treated with escalating doses of amphetamine (1.0-7.5 mg/kg) for 4 days, followed by 8 days of multiple daily injections (7.5 mg/kg/2 h x four injections). Twenty hours after the last injection the animals were challenged with amphetamine (7.5 mg/kg) or vehicle and killed 1 h later. In drug-naive animals, acute amphetamine induced the expression of RGS2, 3, and 5 and the immediate early genes c-fos and zif/268. RGS4 mRNA levels were not affected. Prior repeated treatment with amphetamine strongly suppressed induction of immediate early genes and RGS5 to a challenge dose of amphetamine. In sharp contrast, prior exposure to amphetamine did not reduce the induction of RGS2 and RGS3 mRNAs to a challenge dose of amphetamine, indicating that control of these genes is resistant to amphetamine-induced tolerance. These data establish a role for dopamine receptors in the regulation of RGS2 expression and suggest that RGS2 and 3 might mediate some aspects of amphetamine-induced tolerance.     

Estrogen potentiates the stereotypy induced by dopamine agonists in the rat

Repeated weekly treatment with 100 μg/kg of estradiol benzoate (EB) to ovariectomized female rats intensified the stereotypy induced by the dopamine agonists amphetamine and apomorphine. A similar effect on amphetamine-stereotypy was produced 48 hours after a single injection of 10 μg/kg of EB. The fact that EB failed to increase blood or brain levels of either ³H-amphetamine or ³H-apomorphine suggests that these behavioral effects were not due to altered peripheral drug metabolism or uptake into the brain. The enhancement of stereotypy produced by EB is viewed as one manifestation of a more complex modulatory influence of estrogen on DA function.     

Pharmacology of Acorus calamus L

Water soluble dried powder of alcoholic extract of roots and rhizomes of A. calamus L. was used. The in vivo experiments involved strychnine convulsant activity in frogs, spontaneous motor activity and amphetamine hyperactivity in mice, pentobarbitone sleeping-time in rats and local anaesthetic activity in guinea pigs and rabbits. Frog skeletal muscle and heart preparations and rat phrenic nerve diaphragm constituted the in vitro experiments. Plant extracts at 10, 20 mg/kg ip did not afford protection to strychnine (1,5,2.5 mg/kg) induced convulsions and same effect was found on acetylcholine induced contractions of rectus muscle except that it inhibited caffeine citrate contractions in frog. At 1, 10 and 100 micrograms/ml doses, it caused negative iono- and chronotropic effects in frogs. Dosages of 10, 25, 50 mg/kg ip of herbal extract antagonize spontaneous motor activity and also amphetamine induced hyperactivity in mice. It was less potent than chloropromazine, though exerts sedative and tranquilizing action. Local anaesthetic activity was found to be absent at 0.5 and 1% dose levels.     

Central nervous system actions of 2, 5-bis (3,4-dimethoxybenzyl) cyclopentyl amine,a peripheral dopamine blocking agent

The behavioral and brain catecholamine effects of 2,5-bis (3,4-dimethoxybenzyl) cyclopentyl amine were investigated in mice. It rapidly depleted norepinephrine. Chronic dosing also depleted dopamine, but to a lesser degree. As indicated by a lack of effect on amphetamine induced stereotypy and apomorphine induced emesis and failure to induce catalepsy, the compound does not block brain dopamine receptors. It has no effect on brain catecholamine synthesis or dopamine-β-hydroxylase activity.