Alcohol and drug research最新文献

The pharmacologic properties of phencyclidine were assessed in adult, male rats using a three-chambered, place-conditioning apparatus. Phencyclidine hydrochloride (PCP), at doses of 0.5 to 4 mg/kg, produced a dose-related place-aversion after three drug/environment pairings. During the place-conditioning procedure, 4 mg/kg of PCP significantly increased spontaneous locomotor activity compared to saline-control. Tolerance to PCP-induced place-aversion developed after four daily administrations of 4 mg/kg of PCP. d-Butaclamol, 0.4 mg/kg, given 1 min before each of the three conditioning-doses of PCP decreased the development of the place-aversion induced by PCP. 1-Butaclamol was without significant effect. Spiroperidol, 0.06 mg/kg, completely blocked the development of PCP place-aversion. Spiroperidol and the stereoisomers of butaclamol did not have significant place-conditioning activity when administered alone in the place-conditioning paradigm. The data suggest that PCP induces place-aversion in rats in the place-conditioning model, and that tolerance to this effect develops within 4 days. Furthermore, since d-butaclamol or spiroperidol, but not 1-butaclamol, antagonized this effect of PCP, PCP-induced place-aversion may be mediated in part by a dopaminergic mechanism.

The role of ethanol in phencyclidine-related death and loss of motor co-ordination was studied in male ICR albino mice. LD50s, and ED50s for loss of righting reflex, and for the "rotarod" test were determined for each drug in the presence of various doses of the other. Isobolograms (plots of equieffective dose combinations) of these LD50s and ED50s showed that low doses of ethanol reduced the LD50 of phencyclidine (PCP) by about 20%, while higher doses (1-3 g/kg) of ethanol were without further effect. In contrast to effects on lethality, there was synergism (potentiation) of loss of motor co-ordination. Doses of ethanol above 1 g/kg reduced the ED50 of PCP for loss of righting from about 60 mg/kg to 1-3 mg/kg. Similarly, low doses of PCP (less than 40 mg/kg) reduced the ED50 of ethanol from 3 g/kg to 1 g/kg. There was a slight but consistent synergism between the drugs in the rotarod test over the range of effective doses (0.25-2.0mg/kg PCP and 0.1-1.2 g/kg ethanol). It is concluded that consumption of ethanol does not greatly increase the risk of death from PCP overdose; however the severe adverse effects on motor co-ordination of moderate doses of PCP together with moderate doses of ethanol are greatly potentiated by doses of the other drug. It is estimated that commonly used doses could result in total loss of motor ability, which could explain the prevalence of accidental deaths (especially drowning) when PCP and ethanol have been consumed together.

An improved method for the measurement of erythrocyte aldehyde dehydrogenase (ALDH) activity was developed and used to determine the enzyme activity in 38 male Caucasian patients admitted to this VA Medical Center for alcohol detoxification. Patients who had been treated within a year prior to the study with any drug known to inhibit ALDH, such as disulfiram, were excluded from the study. In agreement with previous reports, the erythrocyte ALDH levels were decreased relative to non-alcoholic controls. However, no useful correlation was found between the erythrocyte ALDH levels and any of 35 standard clinical chemical and hematological parameters including those that indicated alcoholic liver disease.

Urine samples were collected before breakfast from 94 normal volunteers (41 males and 53 females) aged 25-70 years. Salsolinol (SA) was analyzed by gas chromatography-mass spectrometry (GC/MS), and dopamine, norepinephrine and epinephrine were determined using high performance liquid chromatography (HPLC). SA levels were significantly higher in the urine of male moderate drinkers (MDs) than in male seldom or non drinkers (SNDs). In females, however, a significant difference of urinary SA levels was not observed between MDs and SNDs. There was a sex difference of urinary SA levels among SND subjects, i.e., females showed a higher SA than males. Urinary catecholamines were not significantly altered by long-term moderate alcohol drinking in either sex. There was no correlation between urinary levels of dopamine and SA. These results indicate that urinary SA can be increased by long-term drinking even in normal, not alcoholic subjects.

Ethanol alters equilibrium between neurotransmitter availability, receptor systems and biological responsiveness. This action may contribute to the accelerating effects of ethanol on the aging process. On this line, the interaction between age and ethanol consumption was studied at laboratory and clinical levels.

Ligand binding techniques are widely used to measure drug, hormone, and neurotransmitter receptors. Despite its wide application, quantitative methods of data analysis have not been widely adopted. This paper reviews some of the problems associated with semiquantitative methods of data analysis, and describes a mathematically based approach to the design and analysis of ligand binding experiments. Widely spaced concentrations of radiolabeled ligand are displaced by concentrations of cold drug. Analysis of these curves, which describe a "binding surface," with computer curve-fitting programs significantly increases the power of the ligand-binding technique.

Consensus of the literature points towards a neuropsychogenetic model of alcoholism. Evidence in both animals and humans tends to support the proposed "genotype" theory of alcohol-seeking behavior, whereby a predisposition to alcohol preference may be mediated in part by either innate (genetic) or environmentally (stress and/or alcohol) induced brain opioid peptide dysfunction. Potential therapeutic rationale involving the utilization of novel inhibitors of carboxypeptidase A (enkephalinase) which raise endogenous enkephalin levels and possess anti-alcohol seeking effects is emphasized.

The diverse behavioral and biochemical effects induced by ethanol suggest that ethanol exerts differential effects on the CNS. When the neuroactive amino acids, glycine, glutamate, aspartate, GABA and taurine, were measured in the cortex, striatum, hippocampus, midbrain, and brain stem of acute or chronic ethanol-treated rats, site specific changes were observed for glutamate, glycine, and aspartate. No changes were found for GABA or taurine. Upon in vivo application, it was found that the microinjection of thyrotropin-releasing hormone (TRH, 500 ng) into the medial septum significantly shortened ethanol's impairment of the righting reflex, while microinjection of muscimol (30 ng) markedly potentiated ethanol's impairment of the righting reflex. When these studies are combined with previous work showing that microinjection of muscimol (30 ng) into the inferior colliculus blocks audiogenically induced seizures in ethanol-withdrawn rats, the convergence implies that specific sites in the CNS may modulate certain actions of ethanol. Therefore, we propose that the medial septum and inferior colliculus can be used as in vivo models to study the acute and chronic actions of ethanol, respectively.