Potency Of Cocaine Research Articles

Magnesium alters the potency of cocaine and haloperidol on mouse aggression

Magnesium has been shown to have certain behavioral effects similar to the stimulants cocaine and amphetamine, particularly on mouse resident-intruder aggression. Consequently, it was hypothesized that magnesium should interact with the indirect agonist cocaine and the antagonist haloperidol to alter their potency in the mouse resident-intruder model. Acute and chronic drug effects were compared. Results demonstrate an enhancement of cocaine potency by 30 and 125 mg/kg MgCl2 and a lowering of cocaine potency by a 15% required-Mg2+ deficient diet as measured by shifts in the dose response to acutely administered cocaine. Following chronic 0.5 mg/kg cocaine for 15 days, a dose of 125 mg/kg acutely administered MgCl2 prevented the disruptive effects of chronic cocaine on mouse aggression. Acutely administered haloperidol was influenced by Mg2+ treatments in a manner opposite from the effects on cocaine, while the chronic effects of haloperidol were affected in the same manner by Mg2+ treatments as those shown for chronic cocaine. Several mechanisms are suggested to explain these interactions.

Modification of the response to opioid and monopioid drugs by chronic opioid antagonist treatment

Chronic exposure to opioid antagonists increases the analgesic actions of opioids such as morphine. In the present studies, morphine's analgesic potency was increased (supersensitivity) following an 8 day subcutaneous naltrexone implant in mice, but not following a 1 day implant. Supersensitivity was maximal 24hr following the 8 day implant and declined linearty and had returned to control levels by 120hr. Implantation of naltrexone pellets for 8 days was found to increase the relative analgesic potency of methadone by 120%, while the lethal potency of cocaine was slightly (19%), but significantly, decreased. In contrast, identical treatment did not alter the potency of the benzodiazepine alprazolam to induce ataxia.

Intravenous self-administration of cocaine and norcocaine by dogs.

The potency of cocaine, relative to d-amphetamine, to initiate and maintain intravenous self-administration behavior by dogs (n = 5) was determined. Response-contingent infusions of cocaine (at unit doses of 0.15, 0.30 and 0.60 mg/kg/infusion) and d-amphetamine (at unit doses of 0.05 and 0.10 mg/kg/infusion) were available during daily 4-h sessions on a FR1 reinforcement schedule. By comparing the dose-response curves of the two drugs, it was found that 1 mg of amphetamine is equivalent to 5.3 mg of cocaine (95% confidence limits = 3.8--9.1 mg). In a second experiment, pretreatment with the alpha-adrenergic antagonist phenoxybenzamine (in doses ranging from 0.125--2.0 mg/kg, IV) did not produce any appreciable changes in responding for cocaine (0.2 mg/kg/infusion) by dogs (n = 9). In contrast, when the same animals were pretreated with the dopaminergic antagonist pimozide (in doses ranging from 5--40 mg/kg, IV), subsequent responding for cocaine was increased in a dose-dependent manner. In a third experiment it was determined that norcocaine, the N-demethylated metabolite of cocaine, would maintain self-administration behavior by dogs (n = 4) when it was substituted for cocaine. As expected, when saline was substituted for cocaine, responding was not maintained.

The pharmacological relevance of the cocaine binding site in mouse brain

The potencies of cocaine and various cocaine analogs in inhibiting the specific binding of ( 3H)cocaine to mouse brain membranes were compared with their pharmacological effects (locomotor stimulation, behavior, and local anesthesia). It is suggested that the cocaine binding site in brain mediates central actions but not local anesthesia.

The effects of psychomotor stimulants on single-spatial alternation behavior in dogs.

Dogs were trained to pedal press for drinking water in a noncued, single-spatial alternation task. After the dogs were exhibiting stable performance at or above predetermined criteria levels, they were given three doses of four different drugs (methylphenidate, 0.2, 0.4, and 0.8 mg/kg; d-amphetamine, 0.15, 0.3 and 0.6 mg/kg; cocaine, 0.5, 1, and 2 mg/kg; and phenmetrazine, 0.6, 1.2 and 2.4 mg/kg). In general, all four drugs produced similar changes in performance. The number of correct responses was an especially sensitive indicator of drug effects. All four drugs also produced significant increases in both the average response latency and total session duration, but there were few significant changes in either the total number of responses or number of intertrial interval responses. Relative to d-amphetamine, the potencies of cocaine and phenmetrazine, but not methylphenidate, were generally higher for the measures of single-spatial alternation than for self-administration.

Cocaine-induced conditioned taste aversions in rats

In two separate studies cocaine hydrochloride at doses between 10–36 mg/kg was found to induce a dose-related conditioned taste aversion (C.T.A.) to saccharin, and to be an effective conditioning agent even when injections of the drug were delayed 90 min after saccharin intake. These data contrast with an earlier report [3] which suggested that cocaine was totally devoid of aversive properties. However, they do indicate that cocaine is only a weak aversion-inducing agent. In contrast to other drugs, the doses of cocaine which are required to induce a C.T.A. are very large relative to those commonly employed in behavioural studies. The weak potency of cocaine in inducing C.T.A. may be related to the drug's marked potency in the self-administration paradigm. Some possible determinants of cocaine's weak effects are discussed.

Effect of (+)-amphetamine on the retention of 3H-catecholamines in slices of normal and reserpinized rat brain and heart.

The effect of reserpine on the inhibition by (+)-amphetamine and cocaine of the accumulation of 3H-dopamine (DA) in striatal slices and 3H-noradrenaline (NA) in slices of cerebral occipital cortex and heart atrium of rats and the release of 3H-amines from these tissues were examined. Reserpine (5 mg/kg intraperitoneally) was injected 18 hours before the experiments. It was found that reserpine markedly enhanced the in vitro potency of amphetamine in the striatum and heart but only slightly in the cortex. After administration in vivo (+)-amphetamine was about 10 time more potent in reducing the amine accumulation in the cortex as in the striatum. Reserpine enhanced the effect in both regions. The inhibitory potency of cocaine in vitro was unchanged by reserpine in the striatum but was reduced in the cortex and heart. Reserpine did not change the inhibitory potency of desipramine in the cortex and heart. The release of the 3H-amines by (+)-amphetamine was enhanced by reserpine in the striatum and heart but the small release produced in the cortex was not increased. The release produced by cocaine was similarly enhanced by reserpine but cocaine was much less active than (+)-amphetamine. The results indicate that (+)-amphetamine and cocaine inhibit the amine accumulation by different mechanisms.

Potentiation of morphine analgesia by cocaine in mice

The interaction between morphine and cocaine in producing analgesia in mice has been studied. To investigate the mechanism of this interaction, some other local anaesthetics and amphetamine and imipramine were tested in combination with morphine. The effect of pretreatment with reserpine, or of treatment with the antiadrenaline drug phentolamine, was examined. The potency of each local anaesthetic in potentiating noradrenaline was assessed. Cocaine potentiated morphine analgesia. Procaine and lignocaine, though less potent, were also effective, but cinchocaine was not. Hence, ability to potentiate morphine was not related to local anaesthetic activity. Involvement of the sympathomimetic action of cocaine was indicated because (1) the potencies of cocaine, procaine and lignocaine in potentiating morphine were related to their potencies in potentiating noradrenaline, (2) reserpine antagonized the actions of morphine and morphine-cocaine combinations and (3) amphetamine potentiated morphine. However imipramine did not increase and phentolamine did not reduce the action of morphine.

Acute and chronic toxicity of oxethazaine: A highly potent local anesthetic

Oxethazaine, an N-substituted bis-acetamide, represents a new series of powerful local anesthetics exceeding by far the potency of either cocaine, procaine, lidocaine, or dibucaine. Acute toxicity studies establish that it is not a primary skin irritant; neither does it cause corneal damage nor conjunctival erythema and hyperemia. Further, there is a considerable margin of safety for intragastric, subcutaneous, intramuscular, intrarectal and intravesical administration. Toxicity following intravenous and intrapulmonary administration, however, is high, and deaths occur quickly from depression of myocardial contractility and impaired conduction. Rats and dogs can ingest oxethazaine daily for months without evidence of either toxicity, effect on weight, peripheral blood picture, bone marrow, viscera or kidney, and liver function. The tendency for increased deposition of glycogen in the liver is probably a reversible storage phenomenon. Absorption of intragastrically administered oxethazaine in water or alumina gel occurs rapidly and is detectable within 30 minutes. The amounts absorbed, however, differ and are greater from the water vehicle. Detoxication probably is chiefly in the liver and involves the metabolism of hydroxyethylamine and mephentermine.

Oxethazaine and related congeners: a series of highly potent local anesthetics.

1. Oxethazaine and several N-substituted bis-acetamide congeners constitute a new series of powerful local anesthetics, exceeding by far the potency of either cocaine, procaine, lidocaine or dibucaine. 2. All are effective by topical application to the cornea, cutaneous infiltration or intraspinally. 3. Since oxethazaine is highly effective topically and has a large margin of safety when administered intragastrically, it has proven to be useful clinically for control of pain due to a variety of gastric disorders. 4. Its effectiveness at the acidity of the gastric environment is due to the fact that oxethazaine, a weak base, is relatively non-ionized at pH 1.