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The analgesic effect of caffeine used alone and in combination with dipyrone and butalbital was evaluated after oral administration in mice, using two different pain tests: the hot plate test and the phenylbenzoquinone-induced writhing test. Neither caffeine (5 to 200 mg/kg) nor butalbital (10 and 20 mg/kg) (20 mg/kg was the highest dose that did not induce sleep) produced a significant antinociceptive effect, whereas dipyrone was active from 400 mg/kg in the hot plate test and from 50 mg/kg in the writhing test. The scores obtained with the combinations were not different from those of the dipyrone-treated group, except for the butalbital-dipyrone combination. Thus caffeine is not an analgesic adjuvant in mice; its presence in the combination studied appears to be justifiable only insofar as it inhibited the sedative effect of butalbital.

Behavior of pigeons was controlled by fixed-ratio, fixed-interval and multiple fixed-ratio fixed-interval schedules of reinforcement. When each thirtieth peck on a response key produced food (fixed-ratio schedule) high rates of responding were maintained; low to intermediate doses of ethanol left unchanged or increased those rates. Under the fixed-interval schedule the first response after 5 min produced food and comparatively lower rates of responding were maintained that gradually increased up to food presentation. Low to intermediate doses of ethanol only decreased overall rates of responding under the fixed-interval schedule. When the fixed-ratio and fixed-interval schedules alternated regularly throughout a single experimental session (multiple fixed-ratio fixed-interval schedule), differential effects that depended upon the schedule of reinforcement were still obtained. Ethanol affected local rates of responding within the fixed intervals differently depending upon the rates prior to drug administration; low rates were increased while higher rates were decreased. As with other drugs, the effects of ethanol on schedule-controlled responding depended upon the particular rates and patterns of responding maintained by the schedule of reinforcement.

The effects of pentobarbital and diazepam were compared in a series of tests in squirrel monkeys; the effects of phenobarbital and flurazepam were compared in a second series. Observations were made of gross behavior and on the ECoG; the latter was analyzed by the spectral density technique. The two barbiturates induced sedation,which was occasionally so deep that the monkeys could not be readily aroused. The benzodiazepines induced sedation in some monkeys, but others showed signs of restlessness. The ECoG showed general slowing with the barbiturates, whereas the benzodiazepines produced mixed fast and slow patterns. Spectral density analysis showed that pentobarbital increased activity at frequencies below 40 Hz, with the largest increases occurring below 8 Hz. Phenobarbital increased activity below 8 Hz, but differed from pentobarbital by decreasing activity above 13 Hz. The benzodiazepines increased activity below 8 Hz, decreased it between 8 and 20 Hz, and increased it between 20 and 50 Hz.

Four different convulsant barbiturates and also thiopental, methohexital and pentobarbital were tested for in vitro contractor effects on rabbit jejunal segments, aortic strips and tracheal chains. The two convulsants that elicited lethal, tonic seizures in vivo contracted all three types of isolated preparation; however, two other convulsants that elicited intense but nonlethal, clonic seizures lacked contractor effect. Methohexital and pentobarbital also lacked contractor effect. In aortic strips, contractions induced by the two convulsants were not impaired by concentrations of phenoxybenzamine (10(-5) M) that blocked all contractor response to 10(-4) M norepinephrine, acetylcholine or histamine. Thiopental also contracted aortic strips but the effect differed from that of the convulsants in that it was much less intense, was partially antagonized by pretreatment with phenoxybenzamine, and was greatly potentiated by the presence of norepinephrine. Intense contractor effects, independent of adrenergic mechanisms, seem characteristic of a particular group of convulsant barbiturates; there are also similar with respect to structure, stimulant potency, and seizure pattern.

Rats, whose behavior was maintained under a multiple fixed-ratio fixed-interval schedule of food presentation, were given delta 9-tetrahydrocannabinol (delta 9-THC), pentobarbital, barbital, and d-amphetamine before, during and after chronic delta 9-THC administration. Low doses of the barbiturates and d-amphetamine increased rates of responding, especially under the fixed-interval component. Higher doses of all four drugs decreased rates of responding under both schedule components. Tolerance developed to the rate-decreasing effects of delta 9-THC and there was cross tolerance to the rate-decreasing effects of pentobarbital and to a lesser extent barbital, but not to the rate-decreasing effects of d-amphetamine. During chronic delta 9-THC administration, rate-increasing effects of pentobarbital and barbital continued to occur, but the rate-increasing effects of d-amphetamine were attenuated. A second group of rats whose behavior was maintained under a variable-interval schedule of food presentation were given delta 9-THC and barbital before and during chronic barbital administration. Low doses of barbital increased rates of responding and higher doses of both drugs decreased rates. Tolerance developed to the rate-decreasing effects of barbital and there was cross tolerance to delta 9-THC. No tolerance developed to the rate-increasing effects of barbital. Thus, there is cross tolerance between barbiturates and delta 9-THC for rate-decreasing effects on schedule-controlled behavior, but neither tolerance nor cross tolerance occurs for rate-increasing effects.

The disposition kinetics of antipyrine after a single i.v. dose (75 mg/kg) of [14C]antipyrine were examined in control rats and in rats pretreated with butalbital and phenobarbital. Blood antipyrine data indicated that daily administration of phenobarbital (50 mg/kg) for 14 days resulted in significantly more rapid elimination of antipyrine than that observed after equal doses of butalbital, which was in turn significantly faster than the control values. Results of additional antipyrine tests after phenobarbital pretreatment for 2 and 5 days showed considerable enzyme induction after only 2 days of exposure to phenobarbital; the mean antipyrine clearance after the 2-day pretreatment was not significantly different from those after the 5- and 14-day pretreatments. The data suggested that the maximum increase in antipyrine clearance, ca. 190% of the control value, was achieved after approximately 5 daily doses of phenobarbital and maintained until the end of the 14-day pretreatment period. The subsequent decline in the induced enzyme activity, assessed by the antipyrine clearance values on days 1, 3, 6, and 9 post-phenobarbital treatment, appeared to be mono-exponential with a half-time of 3.8 days. Thus, the enzyme activity would return to baseline at ca. 15 days after the last dose of phenobarbital. In these studies, consistent increases in liver weight with increasing antipyrine clearance were observed, while no apparent relationship between antipyrine distribution volume and barbiturate pretreatment was found.

Tertiary butylurea has been investigated neuropharmacologically in mice and rats, and the results indicate that the compound possesses a marked CNS activity. It exhibited a pronounced activity against pentetrazole-induced convulsions and lethality, but the protection against strychnine-induced convulsions and lethality, was only partial. A significant prolongation of pentobarbital sleeping time by a subsedative dose of tert-butylurea was also observed. Protection afforded by tert-butylurea against tremorine-induced tremors and the intensity of its analgesic activity were both of moderate degree. In a subsedative dose range, tert-butylurea exhibited motor incoordination and behavioral effects with a decrease in the minor and the major movements of animals, as apparent from the treadmill and activity meter experiments respectively. The compound, however, does not seem to be a potent sedative-hypnotic agent, although there is a fairly good margin of safety between the hypnotic and the lethal dose orally. The anti-pentetrazole activity of tert-butylurea suggests its possible effectiveness against 'petit mal' seizures and, therefore, calls for additional studies to evaluate the anticonvulsant activity of tert-butylurea.

The mortality caused by barbiturate poisoning in mice is reduced by the combined action of the DNA pyrimidines thymine and 5-hydroxymethylcytosine (5-HMC) and the structurally related vitamins, pyridoxal, nicotinamide and thiamine, given intraperitoneally. The acute hypnotic effect of sodium pentobarbital at moderate to high dosages is also antagonized by these compounds. All five compounds are required for activity. The structural similiarity between these antagonist components and the barbiturates had suggested that the former's reactions as cofactors or as the constituents of more complex molecules might be points of drug inhibition. It therefore appeared that this inhibition might be reversed by administration of these cellular constituents. The obligatory requirement for both thymine and 5-HMC as components of this antagonist raises the possibility that a metabolically reactive DNA species in brain may be one site of barbiturate action. At the dosages employed, this antagonist produces no behavioral or symptomatic response in non-narcotized animals and may thus provide a basis for treatment of barbiturate poisoning.

The aporphine alkaloids bulbocapnine, corytuberine, boldine and glaucine were studied in mice and compared with haloperidol, phenobarbital and morphine. All aporphines inhibited the exploratory rearing activity and elicited palpebral ptosis, catalepsy, hypothermia, and prolonged anesthesia by thiopental. They also reduced nociception (hot plate; phenylquinone-induced writhing) and (except for corytuberine) were anticonvulsant against harman and picrotoxin, but not against bicuculline and pentetrazol; corytuberine was proconvulsant. The aporphines (except for corytuberine) antagonized the apomorphine- and methylphenidate-induced stereotyped gnawing and also the apomorphine-induced climbing activity; corytuberine was prostereotypic. The antignawing effects (including those of haloperidol) were stronger when the antagonists were administered after the agonists (gnawing full-fletched) rather than before them: this led to the speculation of a metaphilic interaction at central site(s). Clonazepam inhibited the antistereotypic effect (vs apomorphine) more potently with the aporphines than with haloperidol. The antinociceptive effect (writhing) of the aporphines was, in contrast to that of morphine, resistant to both naloxone and yohimbine. The latter applied also to the antilicking action in the hot plate test; the antijumping effect of boldine was (like that of morphine) antagonized by both yohimbine and naloxone, whereas that of corytuberine was inhibited only by naloxone and that of bulbocapnine preferentially by yohimbine. Hence, opioid and adrenergic mechanisms are unequally involved in the antinociceptive effects of the aporphines. The present results also showed that licking and jumping (in the hot plate test) are pharmacologically different phenomena. In low doses, the aporphines and haloperidol antagonized the antinociceptive effect of morphine (hot plate); hence, these drugs may be considered partial agonists or partial antagonists, respectively.

The effects of galanthamine, an alkaloidal anticholinesterase agent whose chemical structure bears similarity to codeine, was studied in various animal and isolated organ tests. Antinociceptive activity of galanthamine given subcutaneously was detected and compared to physostigmine and morphine in the rat hot plate test. Naloxone partially blocked the effect of galanthamine but not that of physostigmine. Both cholinesterase inhibitors provided analgesia in the mouse acetic acid writhing test. They potentiated the effect of morphine in the rat hot plate test but inhibited the barbiturate anaesthesia potentiation of morphine in the rat. While galanthamine provided analgesia in the intact animal, it failed to produce opiate-like activity in such isolated organs as longitudinal muscle strip of the guinea-pig ileum, mouse vas deferens, and cat nictitating membrane.

At 3 X 10(-5) M concentratons, 5-(2-cyclohexylideneëthyl)-5-ethyl barbituric acid (CHEB) causes a contraction of rabbit aortic strips that is equivalent to about half of the maximal response to norepinephrine. If a calcium-free medium is substituted for normal bathing solution and drug is added immediately thereafter, there is no response to the convulsant barbiturate but a nearly normal response to norepinephrine. When calcium is replaced in stepwise increments, the contractor response to CHEB appears in corresponding increments. The prompt influence of changes in external calcium-concentration suggests that CHEB-induced contraction occurs as a result of calcium influx into cells rather than a release of free calcium from previously accumulated intracellular stores. CHEB effect, like that of potassium, is prevented by pretreatment with lanthanum (5 X 10(-3)M). CHEB differs from potassium in that its effects are even more sensitive to changes in extracellular calcium concentration. Nevertheless, CHEB can contract aortic strips in the presence of iproveratril at a concentration (10(-4)M) that blocks all response to potassium (100 mM).

Pentobarbial, thiopental and the convulsant 5-ethyl-5-(2-cyclohexylideneëthyl) barbituric acid (CHEB) were tested for contractor effect on the isolated lung of the fullfrog at pH 7.0 (7% CO2 and 20 mM HCO3-) and pH 8.4 (0.3% CO2 and 20mM HCO3-). CHEB was a potent contractor, thiopental a feeble contractor, and pentobarbital lacked contractor effect. The contractor potencies of both CHEB and thiopental were greater at the more acid pH. The potencies of formally charged agonists such as acetylcholine and K+ were not altered by the pH differences employed in these experiments. The pKa of CHEB was found to be 8.18 at 15 degrees C and 8.03 at 27 degrees C. Calculation of concentration-effect relationships of ionized and nonionized CHEB showed that only the nonionized CHEB was responsible for the contractor effect.

This study deals with the interactions of cocaine with barbital, pentobarbital and ethanol in nontolerant and tolerant male Sprague-Dawley rats. Cocaine hydrochloride (50 mg) pellets implanted s.c. in rats prior to the i.p. injections of sodium barbital (150 mg/kg dose once daily for 4 days) potentiated the hypothermic response 2 hr after the barbital injection, when maximum hypothermia occurred. The s.c. implantation of the same type of pellets prior to the i.p. injections of sodium pentobarbital (75 mg/kg dose once daily for 5 days) potentiated the pentobarbital hypnosis as measured by the duration of loss of the righting reflex in animals. Cocaine pellets (12.5 mg) implanted s.c. in rats potentiated the hypnosis induced by ethanol (3.2 g/kg i.p.) and the implantation of the same type of pellets (12.5, 25 mg) in ethanol-tolerant rats restored the ethanol hypnosis to levels observed in acutely treated animals. The course of tolerance development to barbital-induced hypothermia or pentobarbital hypnosis did not appear to be affected by cocaine. The possible role of central monoamines in the potentiation of barbital hypothermia and pentobarbital and ethanol hypnosis by cocaine is discussed.