Cocaine-like Effects Research Articles

Bidirectional microdialysis in vivo shows differential dopaminergic potency of cocaine, procaine and lidocaine in the nucleus accumbens using capillary electrophoresis for calibration of drug outward diffusion

Cocaine and two other local anesthetics were applied directly into the nucleus accumbens for 20 min by diffusion from a 4 mm microdialysis probe in freely moving rats. Cocaine (7.3 mM) increased the extracellular concentration of dopamine (DA). Equimolar procaine did also, but was not as potent as cocaine. Equimolar lidocaine had no effect. The concentration of these drugs outside the probe as measured by capillary electrophoresis in vitro was about 28% of that inside the probe, i.e. 72% remained inside. However, an in vivo test showed that about 53% cocaine and procaine, and 37% lidocaine remained in the perfusion fluid after passing through a probe inserted in the brain. This suggests that in vivo about 68 nmol cocaine diffused into the nucleus accumbens (NAC) during the 20 min. Five conclusions are drawn: (1) this confirms our earlier finding that local injection of cocaine increases extracellular DA, but in this case the cocaine was infused via the probe without disturbing the animal; (2) the action of cocaine on dopamine terminals in the accumbens is independent of local anesthesia; (3) procaine may enhance mood by a cocaine-like effect; (4) capillary electrophoresis has potential for measuring cocaine levels in small samples and (5) in vitro calibrations are of limited value to evaluate in vivo performance of microdialysis probes.

Análise química e perfil farmacológico do Erythroxylum argentinum

Foram efetuados estudos químicos e farmacológicos dos extratos brutos hidroalcóolicos obtidos das folhas ou das raízes de E. argentinum ou de frações semi-purificadas desta planta. Os testes químicos revelaram a existência de alcalóides, fitoesteróides, leucoantocianidinas, glicosídeos flavonóides, cumarinas e taninos. A análise farmacológica in vivo demonstrou que o extrato das folhas é menos tóxico que o da raiz. Tanto o extrato bruto como as frações semi-purificadas obtidas das folhas reduziram a locomoção e pressão arterial de rato e potenciaram o sono barbiturico em camundongos. O extrato bruto, principalmente o da raiz, reduziu o edema induzido por carragenina na pata de rato. Testes in vitro demonstraram que o extrato bruto ou as frações semi-purificadas das folhas produziram uma ação semelhante à cocaína avaliada no canal deferente de rato. Além disso, o extrato bruto produziu relaxamento inespecífico no útero de rata e contração do íleo de cobaia. Os resultados obtidos sugerem que esta planta possui constituintes ativos dotados de distintas propriedades farmacológicas, destacando-se o efeito anti-inflamatório, além de uma ação tipo cocaína, merecendo, portanto, estudos químicos e farmacológicos complementares.

Effects of a monoamine oxidase A inhibitor, FLA 668 (+) on the adrenergic mechanisms of the dog saphenous vein

FLA 668 (+) [(S)-(+)-4-amino-2, alpha-dimethylethylphenethylamine (+)-hydrogen bitartrate] selectively inhibited MAO type A in homogenates of dog saphenous vein, with a IC50 of 1 mumol/l for MAO A and greater than 1 mmol/l for MAO B. At concentrations of 1 mumol/l and higher, FLA 668(+) progressively decreased the formation of deaminated metabolites by saphenous vein strips incubated with 3H-noradrenaline, with a preferential action on DOPEG formation. Normetanephrine formation increased but this increase did not wholly compensate for the reduction in the formation of deaminated metabolites. FLA 668(+) caused increased reactivity of saphenous vein strips to noradrenaline and markedly reduced the accumulation of 3H-noradrenaline in the incubated tissue; both effects were still evident in the presence of clorgyline. After cocaine, FLA 668(+) caused no further increase in sensitivity. It is concluded that FLA 668(+) is, in the saphenous vein of the dog, a selective inhibitor of MAO type A and that it exerts a cocaine-like effect.

On the mechanism of action of amezinium methylsulphate on the dog saphenous vein

Strips of dog saphenous vein were used to study the multiple effects of amezenium methylsulphate (AM) on adrenergic mechanisms. The ED50 of the contractile effect was 0.55 μM. After the maximal response to AM had been obtained, increasing the concentration of AM resulted in relaxation; a larger contraction occured after washout. AM was not able to cause contruction of strips obtained from dogs pretreated with reserpine; phentolamine shifted the dose-response curve of AM to the right. AM 0.1 and 10 μM enhanced the sensitivity of the strips to noradrenaline (NA) about 3.5 and 11 times respectively. When the cocaine-like effect was excluded (by using cocaine itself, either alone or after pretreatment with reserpine) an α blocking effect of AM was demonstrated at a concentration of 100 to 150 μM. In homogenates from venous tissue, AM inhibited monoamine oxidase (MAO) activity. AM inhibited preferentially MAO type A, since the IC50 was 5 μM for MAO A and > 1mM for MAO B. In the intact tissue, AM 0.01 μM reduced the formation of [3H]dihydroxyphenylglycol ([3H]DDPEG) without significantly altering the accumulation of [3H]NA or the formation of the other metabolites. AM 0.1 reduced the accumulation of NA, and AM 10 μM abolished the accumulation of [3H]NA, reduced the formation of deaminated metabolites and enhanced the formation of [3H]normatanephrine ([3H]NMN). In washout experiments of strips preloaded with [3H]NA, AM enhanced the efflux of [3H]NA and the effect began with 1 μM; washout of AM sustained the efflux of [3H]NA for at least 30 min. The deaminated metabolite [3H]DOPEG was significantly decreased.

Cocaine cue in pigeons: time course studies and generalization to structurally related compounds (norcocaine, WIN 35,428 and 35,065-2) and (+)-amphetamine.

1 Pigeons trained to discriminate between the presence or absence of effects induced by cocaine hydrochloride (5.6 mg/kg) were tested for generalization with norcocaine and two phenyltropane analogues (WIN 35,428 and WIN 35,065-2). Separate dose-effect curves were obtained at different intervals after the injections so that possible changes both in potency and duration of action could be evaluated.2 Results showed that all of these drugs fully generalized to cocaine. The order of potency was WIN 35,428 > norcocaine > WIN 35,065-2 > cocaine when tested either at 15 or 60 min after injection. The cocaine-like effects were strongest for all drugs when tested 15 min after injection as compared to the tests at the 60 min interval. The decay of the cocaine-like stimulus effects occurred at about the same rate.3 Apomorphine (0.3, 0.56 and 1 mg/kg), morphine (3 and 5.6 mg/kg), Delta(9)-tetrahydrocannabinôl (0.3 and 0.56 mg/kg), and lysergic acid diethylamide (LSD-25, 0.056 and 0.1 mg/kg) did not induce more than 30% cocaine appropriate responses. (+)-Amphetamine produced 73% and 85% cocaine appropriate responses depending on the injection-test interval used, 15 and 30 min respectively.4 The amphetamine homologue, para-hydroxyamphetamine (3.8 mg/kg) did not generalize to cocaine. Tests with 30 mg/kg of procaine produced 40% cocaine appropriate responses. Cocaine is effective also when administered by gavage into the opening of the proventriculus.5 The use of the drug discrimination technique for studying structure activity relationships of drugs is discussed.

Stereoselectivity in the metabolism of 3H-noradrenaline during uptake into and efflux from the isolated rat vas deferens.

1. The metabolism of 3H-(-)- and 3H-(±)-noradrenaline (NA) was studied in the isolated rat vas deferens either under conditions of uptake or of efflux of the amine. Any differences obtained between 3H-(-)-and 3H-(±)NA as substrate were interpreted as being a reflection of differences between the two isomers of the amine. 2. Uptake experiments (0.13 μM; 7.5 min) showed that neuronal mechanisms of amine disposition prevail over extraneuronal ones. Thus, most of the metabolites of 3H-NA formed during incubation with the amine (including the O-methylated products) were of neuronal origin. The acid deaminated metabolite 3,4-dihydroxymandelic acid (DOMA), tended to be much better retained by the tissue than the neutral deaminated metabolite, 3,4-dihydroxyphenylethyleneglycol (DOPEG). While neuronal uptake exhibited no stereoselectivity, a pronounced stereoselectivity was found for monoamine oxidase (MAO) [(-)NA> (+)NA] as well as for the enzymes which are in series with MAO, namely, aldehyde reductase and aldehyde dehydrogenase [(-)DOPEG> (+)DOPEG; (-)DOMA <(+)DOMA]. 3. After about 2 h of washout, the efflux of radioactivity from the tissue [which was previously incubated for 30 min with 1.2 μM of either 3H-(-)- or 3H-(±)NA] originated from one neuronal compartment with no stereoselectivity of the rate constant for the efflux of total tritium. The rate-limiting step for the neuronal efflux of tritium resided either in the net efflux of amine from the storage vesicles (normal tissues) or in the net efflux across the axonal membrane (tissues with the amine metabolizing enzymes inhibited). The effects of cocaine and phenoxybenzamine on the neuronal efflux of tritiated compounds strongly depended on the intraneuronal distribution of the 3H-amine. The results indicate that cocaine has only one site of action (neuronal uptake), while phenoxybenzamine exerts reserpine-like as well as cocaine-like effects. 4. The neuronal efflux of tritium from normal tissues preloaded with 3H-(-)- or 3H-(±)NA consisted mainly of amine metabolites (90% of the total; most of this was DOPEG). Since after 2 h of washout the tissue contained hardly any metabolites, these metabolites did not represent pre-formed metabolites (formed during the period of preloading) but newly formed metabolites resulting from the catabolism of the neuronally stored amine. This catabolism was brought about through the activity of presynaptic enzymes and was stereoselective in that more DOPEG, less DOMA and less O-methylated metabolites were formed from (-)-than from (+)NA.

Effects of Chlorpheniramine and Pyrilamine on the Atrial Actions of Acetylcholine, Tyramine, and Ephedrine

The experiments described herein were performed on isolated, spontaneously beating rabbit atria. The muscarinic actions of acetylcholine in the presence of physostigmine were antagonized by pyrilamine, chlorpheniramine and procaine which demonstrates that these drugs have an “antimuscarinic” action. The nicotinic (positive inotropic and chronotropic) actions of acetylcholine in the presence of atropine were also antagonized by pyrilamine and chlorpheniramine. Cocaine, pyrilamine, and chlorpheniramine inhibited the atrial stimulation by tyramine and ephedrine. The fact that the antimuscarinic and antinicotinic effects of pyrilamine and chlorpheniramine show similar slopes may indicate that similar receptors are involved. Cocaine and pyrilamine also have parallel slopes indicating that pyrilamine has a cocaine-like effect which is not related to local anesthesia.

THE EFFECT OF GUANETHIDINE, COCAINE, AND RESERPINE ON THE HYPOTENSIVE ACTION OF THIOPENTAL

The effects of reserpine, guanethidine and cocaine on the amount of thiopental required for a 50-mm decrease in mean arterial blood pressure have been investigated. The dose of thiopental required for the hypotensive response was less in animals pretreated with reserpine (0.1 mg/kg/day for 2 days) than in control dogs. In contrast, guanethidine (10 mg/kg/day for 2 days) did not alter the dose of thiopental necessary for the hypotensive effect and cocaine (5 mg/kg, administered acutely) actually increased the dose required. It was found that the animals receiving guanethidine or cocaine were supersensitive to exogenous norepinephrine but those receiving this particular schedule of pretreatment with reserpine were not. Previous work has suggested that the increased sensitivity to hypotension induced by thiopental as seen in animals receiving reserpine is due to marked depletion of norepinephrine from the myocardium. It is suggested that the susceptibility to hypotension produced by thiopental in the dogs receiving guanethidine is unchanged in spite of depletion of norepinephrine because the small amounts of still releasable norepinephrine are potentiated by the cocaine-like effect of guanethidine.

Interaction of antihistaminics with norepinephrine uptake: A cocaine-like effect

Interaction of antihistaminics with norepinephrine uptake: A cocaine-like effect