A. L. Misra

Effect of caffeine on cocaine locomotor stimulant activity in rats

The effect of caffeine on the locomotor stimulant activity induced by intravenous cocaine in rats was investigated. Low doses of caffeine (20 mg/kg IP) potentiated the locomotor activity induced by 1, 2.5 mg/kg intravenous doses of cocaine and higher doses of caffeine (50, 100 mg/kg IP) had no significant effect. The locomotor stimulant effect of 20 mg/kg IP dose of caffeine per se in vehicle was significantly higher and that with 100 mg/kg dose significantly lower than that of the vehicle control. Thus caffeine produced dose-dependent effects on cocaine-induced locomotor stimulant activity, with low dose potentiating and higher doses having no significant effect on such activity. Pharmacokinetic or dispositional factors did not appear to play a role in potentiation of cocaine locomotor stimulant activity by caffeine.

Stereospecific potentiation of opiate analgesia by cocaine: predominant role of noradrenaline

&NA; Cocaine hydrochloride (50 mg) pellets implanted subcutaneously in male Wistar rats potentiated the analgesia of morphine, levorphanol, methadone and buprenorphine as measured by the tail‐withdrawal test. Potentiated opiate analgesia was abolished by naloxone and further enhanced by desipramine and phenoxybenzamine. Yohimbine, &agr;‐methyl p‐tyrosine, haioperidol, zimelidine, methysergide, p‐chlorophenylalanine produced no significant effect on potentiated opiate analgesia. Pseudococaine (dextro‐cocaine), which is several‐fold less potent than cocaine as an inhibitor of noradrenaline and dopamine reuptake in the CNS, had no significant effect on opiate analgesia. Analgesia produced by low doses of baclofen, a GABA agonist, was also not potentiated by cocaine. This study suggests a predominant role for noradrenaline in the Stereospecific potentiation of opiate analgesia by cocaine.

Cocaine: tolerance to its convulsant and cardiorespiratory stimulating effects in the monkey.

Abstract Repeated daily I.V. injections of cocaine in the monkey at a minimal convulsant dosage (MCD) produced tolerance resulting in a marked increase in the MCD of cocaine. The repeated daily I.V. injections of cocaine at subconvulsant doses (2.0–4.0 mg/kg) produced a marked decrease in the cardiorespiratory stimulating effect and apparent plasma half-tife of cocaine in the monkey.

Disposition in the rat of buprenorphine administered parenterally and as a subcutaneous implant

Disposition of [15, 16(n)-3H]buprenorphine in the rat has been investigated after a single 0.2 mg/kg i.v. bolus dose and continuous administration via a s.c. implantable long-acting delivery system. After the i.v. injection, the tri-exponential decay of drug from brain occurred with t1/2 values of 0.6, 2.3 and 7.2 h, respectively (plasma t1/2 0.5, 1.4 h, third phase not estimated due to sustained concn.) Decay of drug from another high-affinity binding site in brain occurred with t1/2 values of 1.1 and 68.7 h, respectively. Fat and lung had higher concn. than other tissues and plasma. No metabolites of drug were detected in brain. Unmetabolized drug excreted in urine and faeces one week after i.v. injection were 1.9 and 22.4% of dose, respectively, and 92% of the dose was accounted for in one week. Urinary metabolites (%) were: conjugated buprenorphine 0.9; norbuprenorphine (free 9.4, conjugated 5.2); tentative 6-O-desmethylnorbuprenorphine (free 5.4, conjugated 15.9). Peak plasma concn. of buprenorphine occurred four weeks after s.c. implantation of a long-acting 10 mg 3H-buprenorphine pellet, and apparent dissociation half-lives of drug from low- and high-affinity binding sites in brain were 4.6 and 6.8 weeks, respectively. Fat, spleen and skeletal muscle had higher concn. than other tissues and plasma. No significant difference in brain morphine concn. was observed in placebo and nonlabelled buprenorphine-pelleted animals after a 2 mg/kg i.v. challenge dose of 3H-morphine. This study emphasizes the importance of high-affinity binding of buprenorphine in brain and subsequent slow dissociation as a prime factor in its prolonged agonist/antagonist effects and higher potency than other narcotic agonists.

Intracellular disposition of [3H]-cocaine, [3H]-norcocaine, [3H]-benzoylecgonine and [3H]-benzoylnorecgonine in the brain of rats

Abstract [ 3 H]-cocaine, [ 3 H]-norcocaine, [ 3 H]-benzoylecgonine and [ 3 H]-benzoylnorecgonine were administered i.c. in equi-potent pharmacologic doses and the intracellular disposition and metabolism of each drug determined. Norcocaine and cocaine rapidly entered and egressed from the brain so that 4.8–6.1% of the radioactivity present in brain at one minute was observed at 30 minutes. The highest levels of subcellular radioactivity were generally found in the microsomal plus supernatant, followed by the nuclear and shocked mitochondrial fractions. No apparent localization of the radioactivity occured in synaptic membranes. The brain/plasma (B/P) ratio curves for cocaine and norcocaine were similar; however, the norcocaine values were considerably higher at each time interval. Benzoylecgonine and benzoylnorecgonine had higher comparative B/P ratios than cocaine or norcocaine and persisted in brain for a longer period of time so that 0.6–2.1% of the radioactivity present in brain at 1 hour was detected at 24 hours. Cocaine and norcocaine were extensively metabolized to the benzoylmetabolites. Benzoylecgonine was metabolized to benzoylnorecgonine and benzoylnorecgonine was unmetabolized. The brain disposition data and B/P ratios agreed quite well with the overall pharmacologic action of cocaine and its metabolites.

Cocaine: Distribution and Metabolism in Animals

The abuse potential of cocaine primarily initiated through the intense euphoric effect of the drug with subsequent inducement of psychic dependence (Deneau, Yanagita, and Seevers, 1969) has prompted us to study the physiological disposition and metabolism of this drug in acutely- and chronically-treated animals. Although several reports have appeared in the literature (Woods, McMahon, and Seevers, 1951; Ortiz, 1966; Montesinos, 1965; Fish and Wilson, 1969), there is a paucity of data on the general pharmacodynamics of cocaine, especially in regards to disposition, metabolism, psychic dependence, tolerance, and the central mechanisms of action of this drug.

Disposition and Metabolism of [3HCocaine in Acutely and Chronically treated Dogs

1. Beagle dogs were chronically treated with cocaine, 5 mg/kg subcutaneously twice daily for 6 weeks, followed by same dose of [3H]cocaine given intravenously. 2. The t1/2 values of cocaine in plasma, liver, spleen and heart, in acutely and chronically treated dogs, were: 1-2, 1-1; 2-2, 1-8; 1-8, 1-3; 2-0, 1-2 h, respectively. In both groups, cocaine disappeared from all areas of the central nervous system 12-24 h after injection but significant amounts of radioactivity due to benzoylnorecgonine and benzoylecgonine persisted in the CNS even 1 week after administration of cocaine. Brain-to-plasma ratios of cocaine were lower in chronically-treated than in acutely-treated dogs 2 and 4 h after injection. 3. Norcocaine, benzoylnorecgonine, benzoylecgonine and ecgonine were metabolites of cocaine in dog brain in both groups. Norcocaine and benzoylnorecgonine were present in higher amounts in brains of chronically treated dogs. Rate of disappearance of norcocaine was similar to cocaine in both groups. 4. The amounts of cocaine excreted in urine and faeces as percentage of dose were 0-9-5-0, 1-1-6 in the acute and 2-2-3-3 and 0-2-0-3 in the chronically treated dogs. Major excretion of radiactivity occurred in urine within 24 h in both groups. Total radioactivity (65% of dose) in urine plus faeces was similar in both groups. 5. Norcocaine, benzoylnorecgonine, benzoylecgonine, ecgonine, norecgonine, ecgonine methyl ester and unidentified compounds were urinary metabolites of cocaine in both groups. Benzoylnorecgonine and ecgonine were excreted in higher amounts and benzoylecgonine and norecgonine in lower amounts in the acute than in the chronically treated dogs. 6. The possible role of persistence of benzoylnorecgonine and benzoylecgonine (which possessed potent stimulant activity intracisternally) in the CNS is discussed.

Pharmacokinetics and Metabolism of [3H] Thebaine

1. A method is described for determination of [3H]thebaine in biological materials with sensitivity of 10–20 ng.2. Following a 5 mg/kg subcutaneous dose of [3H]thebaine to rats, max. brain and plasma concns. were 937 ng/g and 1076 ng/ml at 0.5 and 1 h, respectively; these declined to non-detectable levels at 24 h. The corresponding half-lives of thebaine in rat plasma and brain were 1.1 and 1.5 h, respectively.3. Free thebaine excreted in 96 h urine and faeces following a 5 mg/kg subcutaneous dose was 16.7 and 4.3% and total radioactivity was 43.4 and 8.4%, respectively.4. Extensive metabolism of thebaine occured in rat; several metabolites were identified by chromatography, and metabolites were also shown to be present in the brain.5. Rat plasma proteins and human albumin bound thebaine (1–100 µg/ml) to the extent of 66.7 and 27.3%, respectively; binding to plasma proteins was independent of thebaine concentration.6. Rapid metabolism and elimination of thebaine prevents its persistance in brain. These fi...

Disposition of [3H] phencyclidine in the rat after single and multiple doses

After a 2.5 mg/kg i.v. bolus injection of [3H] PCP to male Wistar rats, the half-lives (α and β phases) in plasma were 0.25 and 2.0 hr respectively. PCP was barely detectable in plasma 16 hr after inj. Decay of PCP from brain provided half-lives of 0.25, 3.3, 101 hr respectively. The brain to plasma and adipose tissue to plasma conc. ratios of PCP ranged between 7 to 15 and 31 to 100 respectively. The excretion of PCP (% dose) in urine and feces was 4,0.7 and with 25 mg/kg i.p. injection 2.7, 1.5 respectively; cumulative excretion with these 2 doses 71, 42 respectively. Oxidative hydroxylation in all 3 rings, conjugation, N-dealkylation, N-oxidation, dihydroxylation were the metabolic pathways of PCP. PCP and metabolites persisted for prolonged periods in adipose tissue and brain. On multiple dosing of PCP (25 mg/kg i.p.), brain and plasma levels were significantly lower in chronic as compared to the acute group. Concurrently higher values of metabolites and higher ratios of total metabolites to free drug conc. in plasma occurred in chronic as compared to the acute group. Data suggest that chronic treatment of rats with PCP enhanves its metabolism by induction of hepatic microsomal enzymes.

Comparative effects of cocaine and pseudococaine on EEG activities, cardiorespiratory functions, and self-administration behavior in the rhesus monkey.

The effects of cocaine and pseudococaine on the EEGs, heart and respiratory rates, and self-administration behavior were studied in rhesus monkeys. An intravenous injection of cocaine (2.5 and 4.0 mg/kg) in the monkey produced low-voltage fast waves (LVFWs) in the EEGs and behavioral hyperexcitation accompanied by marked increases in the heart and respiratory rates with mydriasis and excessive salivation. In contrast, pseudococaine produced high-voltage slow waves (HVSWs) in the EEGs and behavioral depression accompanied by the same symptoms of the autonomic functions as those produced by cocaine. Both isomers were self-administered by the monkeys. During cocaine self-administration sessions, the animals showed hyperexcitation in their overall behavior, while with pseudococaine thay showed almost normal behavioral responses. These results suggest that cocaine produced excitatory effects and pseudococaine inhibitory effects on the EEGs and behavior. Both isomers stimulate the heart and respiratory rates, and were self-administered by the monkeys.