Alcohol and drug research最新文献

1-N,N-bis-(Dichloroethyl)carbamate-delta 9-THC (THC carbamate), a nitrogen mustard analog of delta 9-THC, was recently synthesized as a potential anti-tumor agent. The decrease in spontaneous activity, induction of hypothermia, and the antinociceptive properties of THC carbamate and delta 9-THC were compared. THC carbamate and delta 9-THC were administered by a number of peripheral routes as well as intraventricularly (ivt). THC carbamate lacked cannabinoid activity following peripheral administration, with the exception of iv administration which produced very weak cannabimimetic effects. In contrast, THC carbamate was equipotent to delta 9-THC in reducing rectal temperature by 3 degrees C, and 5 times less active in decreasing spontaneous activity following ivt administration. The apparent lack of central effects following peripheral administration might limit the effectiveness of THC carbamate as an anti-emetic agent, but its use as a site-directed alkylator (a receptor probe) holds promise.

Mice have rarely been used for drug discrimination research. A procedure is described for training mice to discriminate sodium pentobarbital (PB) from vehicle and the pharmacological specificity of the PB stimulus was assessed by generalization testing with methohexital, ethanol, chlorpromazine and morphine. Mice were trained to discriminate PB from vehicle using a two-lever procedure with responding maintained under a fixed-ratio 20 schedule of milk presentation. Training was initiated with 10 mg/kg PB or saline given i.p. 20 min prior to the sessions, and stimulus control was assessed every third session during 2-min periods when responding on either lever was reinforced. After 48 training sessions, good stimulus control had not been achieved. The PB dose was increased to 15 mg/kg, and after 12 additional training sessions, a mean accuracy of 93.5% and 88.1% was obtained on PB and saline tests, respectively. Generalization tests for the time course of the PB stimulus indicated that over 90% PB-lever responding occurred with pretreatment times of 5, 10 and 20 min, falling to 25.6% by 40 min and 15.4% by 60 min. Dose-dependent generalization was also obtained with doses of 15, 20 and 30 mg/kg occasioning over 75% and doses of 5 and 10 mg/kg occasioning less than 25% PB-lever responding. The mice also generalized from PB to methohexital and ethanol, although with the latter greater than 90% PB-lever responding was only produced by a dose that substantially decreased overall rates of responding. Generalization was not obtained with morphine nor chlorpromazine. Typical drug discrimination procedures utilized for pigeons, rats and monkeys can also be used with mice.

Dihydroergotoxine (DHET) decreased voluntary ethanol intake in rats selected for their stable ethanol preference (mean daily ethanol intake 8 g/kg). DHET inhibition was markedly potentiated by thioridazine. The potentiation is explained with a synergistic inhibitory effect on dopaminergic transmission: that is, DHET acting on dopamine (DA) autoreceptors and thioridazine preferentially inhibiting postsynaptic DA receptors.

The effects of the anorectics benzphetamine, chlorphentermine, clortermine, mazindol, phendimetrazine, and phenmetrazine on food intake were compared to the effects of d-amphetamine in rhesus monkeys given daily access to food pellets. The ability of these compounds to maintain intravenous self-administration under a fixed-ratio 10 schedule was also determined in rhesus monkeys. All drugs reduced food intake in a dose-related manner. d-Amphetamine was the most potent. Mazindol, chlorphentermine, phenmetrazine, and phendimetrazine were approximately 1/5 to 1/9 as potent as d-amphetamine while benzphetamine and clortermine were 1/14 and 1/20 as potent, respectively. Benzphetamine, mazindol, and phenmetrazine were self-administered above saline levels and were approximately equipotent. Chlorphentermine and clortermine were not self-administered and phendimetrazine was self-administered by only one of four monkeys at one dose. Thus, although all of the compounds were effective anorectics, chlorphentermine, clortermine, and phendimetrazine did not function as positive reinforcers. Since the ability of a drug to function as a positive reinforcer is related to its dependence potential, these three compounds might be less subject to abuse when used therapeutically. Within the group of 3 compounds that was self-administered, benzphetamine was relatively more potent as a positive reinforcer than as an anorectic. Therefore, this drug might be a less desirable compound for therapeutic use.

The ability of ethanol to decrease the duration of sensory neuron action potentials was evaluated at different temperatures. Intracellular stimulation and recordings were made as the drug was perfused onto dorsal root ganglion neurons in vitro. The cells were bathed in a medium which caused the evoked action potentials to have long durations which were calcium dependent. Ethanol decreased the duration of the action potentials in a dose-dependent manner, without altering amplitude, rate of rise, or resting potential. Furthermore, the potency of the drug varied directly with the temperature of the bathing medium. The recovery time for the reversal of ethanol's effect was also found to be temperature dependent. However, moderate temperature changes alone did not significantly alter the action potential waveform. These data are compatible with a boundary lipid or direct effect on the calcium channel for the mechanism of ethanol's action.

The relationship between genetically determined acute ethanol sensitivity and cerebellar phospholipid composition was investigated. Cerebellar phospholipid composition was compared in two lines of mice that have been selected for differential sensitivity to the acute hypnotic actions of ethanol. The relative ethanol sensitivity of the long sleep (LS) and ethanol resistance of short sleep (SS) mice is well established, and was observed in this study. Cerebellar phospholipid and cholesterol concentrations were found to be identical in the two lines. No differences were found in the total cerebellar or synaptosomal plasma membrane phospholipid fatty acid composition between the two lines. Additionally, there was no change in phospholipid composition or cholesterol concentration in the cerebellum of either SS or LS mice following chronic alcohol treatment. This study suggests that neither total cerebellar nor synaptosomal phospholipid composition is a major determinant of the differential response to acute ethanol in the ethanol sensitive and resistant mouse lines.

The effects of morphine and metkephamid were determined on the writhing test in drug-naive mice and mice that had been exposed to morphine solutions as their sole fluid source for a 5- or 7-day period. The average dose of morphine consumed was 435 mg/kg, using either 0.5 mg/ml solution for 7 days or a 1 mg/ml solution for 5 days. The ingestion of these morphine solutions produced a marked tolerance to the analgesic effects of morphine and cross-tolerance to the analgesic effects of metkephamid.

A variety of clinical and animal data suggest that the repeated administration of cocaine and related psychomotor stimulants may be associated with a behavioral sensitization whereby the same dose of the drug results in increasing behavioral pathology. This investigation was designed to determine the effects of chronic cocaine administration on the binding of [3H]sulpiride, a relatively specific ligand for D2 dopaminergic receptors, in the rat brain using in vitro homogenate binding and light microscopic quantitative autoradiographic methodologies. Chronic daily injections of cocaine (10 mg/kg, i.p.) for 15 days resulted in a significant decrease in the maximum concentration of sulpiride binding sites in the striatum and a significant increase in the maximum number of these binding sites in the nucleus accumbens. No significant differences in binding affinity were observed in either brain region. These data suggest that chronic cocaine administration may result in differential effects on D2 receptors in the nigro-striatal and mesolimbic dopaminergic systems.

The principal finding in this study was that imipramine binding to platelet membranes was lower in a group of ten alcoholics abstinent a mean of 11 days than in a group of ten age- and sex-matched controls (p less than 0.004). The mean (std dev, std error) for imipramine binding in the alcoholic subjects was 718 (110, 37) femtomol/mg platelet membrane protein and 931 (173, 58) femtomol/mg protein in the control subjects. Imipramine binding did not correlate significantly with age, severity of alcoholism, days of abstinence from alcohol, or severity of depression in the alcoholic subjects. Severity of depression did, however, correlate with severity of alcoholism (r = 0.678, p less than 0.03) in the alcoholic subjects in this study. The results of this preliminary experiment suggest that chronic ethanol exposure might affect either the synthesis of imipramine binding sites in megakaryocytes or the structural environment of imipramine binding sites in the platelet membrane. The significance of lower imipramine binding in alcoholics, all of whom expressed some depressive symptoms, remains to be established.

The role of brain aldehyde dehydrogenase (ALDH) and acetaldehyde in mediating ethanol-induced locomotor activity was investigated using several enzyme inhibitors. Cyanamide, an ALDH inhibitor elevates blood acetaldehyde levels in the presence of ethanol. Concurrent administration with 4-methylpyrazole, an alcohol dehydrogenase inhibitor, prevents peripheral accumulation of acetaldehyde by cyanamide. Two hr prior to testing locomotor activity in open field boxes, 111 male Long Evans rats were pretreated with i.p. injections of saline (S+S), 4-methylpyrazole (4MP+S), cyanamide (S+C) or 4-methylpyrazole + cyanamide (4MP+C). Subjects then received i.p. injections of one of three doses of ethanol (0.4, 0.8 or 1.2 gm/kg) or saline vehicle one minute prior to testing in the open field and locomotor activity was recorded for a 10 min period. Locomotor activity of animals pretreated with cyanamide (S+C and 4MP+C) was significantly depressed compared to groups S+S and 4MP+S particularly at the two lower doses tested. These effects cannot be attributed to elevated blood acetaldehyde levels since pretreatment with 4MP+C prevented peripheral accumulation of acetaldehyde. A characteristic common to both cyanamide-treated groups was the inhibition of brain ALDH. It is therefore suggested that brain ALDH may play a role in the mediation of locomotor effects produced by ethanol. It is conceivable that ALDH plays this role by regulating the levels of acetaldehyde in brain.