Alcohol and drug research最新文献

The effect of several doses of morphine (0, 0.5, 2, 5 or 10 mg/kg, i.v.) on heart rate was assessed in restrained and freely-moving rats. Morphine produced a dose-dependent bradycardia followed by tachycardia. The magnitude and duration of bradycardia were greater in restrained rats, whereas the magnitude and duration of tachycardia were greater in unrestrained rats. Naltrexone (5 mg/kg) pretreatment completely blocked the biphasic heart rate response to morphine (8 mg/kg). When naltrexone was given after the bradycardic portion of the response, tachycardia declined to baseline levels. These results suggest that one or both components of the biphasic response are mediated by opioid receptors.

The effect of chronic maternal ethanol ingestion on the ontogenetic development of rat hepatic ethanol-oxidizing systems was investigated. Alcohol dehydrogenase (ADH) activity was first detected at day 19 of gestation. It then increased rapidly to reach adult levels by day 14 postnatally. The ontogenetic pattern, the specific activity and the affinity of the enzyme for its substrate or cofactor were not affected by chronic maternal ethanol consumption. Hepatic microsomal cytochrome P-450 content was first detected in trace amounts just prior to birth. It then increased rapidly in the first 10 days postnatally. Chronic maternal ethanol ingestion did not affect the developmental pattern but induced an increase in the total amount of P-450 detected throughout the postnatal period studied. Fat accumulation was found in fetal and postnatal livers and appeared to correlate with the emerging ability to oxidize ethanol by fetal ADH. The late appearance of the ADH and microsomal ethanol-oxidizing systems indicates that the fetal liver would be entirely dependent on maternal mechanisms to oxidize in-utero ethanol.

Female Long-Evans rats (N = 30) were tested for individual preference for beer for a 24 h period and then assigned to beer (BR) (N = 15) or control (CT) (N = 15) groups according to preference. BR animals were allowed ad libitum access to beer, food and water; while CT animals were allowed ad libitum access to food and water for a 21 day period. Beer, food and water consumption levels were recorded daily. Animals were weighed every other day. Blood alcohol levels and pattern of drinking (comparison of beer consumption in light versus dark cycles) were measured in a separate set of animals. At the end of 21 days of drinking, beer was withdrawn from the BR group and all animals were observed for withdrawal symptomology. BR animals ate more food than CT animals days 2 through 13, and then ate less than CT on days 17 through 21. BR animals drank more "total water" (drinking water plus water in beer) than CT. Body weights were not affected. Changes in body temperatures and tail flick latency, and notation of hyperactivity, shivering and tremoring during 8 hours of withdrawal indicated that BR animals were dependent on alcohol.

Cyclo(Leu-Gly) (CLG), a diketopiperazine analog of Pro-Leu-Gly-NH2 (MIF), has direct effects on dopamine (DA) mediated behaviors as well as on D-2 DA receptors. Endogenous opioids, as well as morphine have also been implicated as neuromodulators of dopaminergic function. We studied these interactions in an animal model in which chronic morphine administration induces a dopaminergic supersensitivity that can be detected during the 48 hour (h) period following withdrawal of morphine. At 24 h following morphine withdrawal, there was a 3.5-fold increase in stereotypic behavior in rats following a challenge dose of apomorphine (APO) (0.5 mg/kg). By 48 h this effect had disappeared. Co-administration of CLG (8 mg/kg s.c.) with morphine attenuated the development of the behavioral supersensitivity to APO. D-2 DA receptor binding analysis indicated that parallel molecular changes occurred. There was a morphine-induced increase in the affinity (+167 percent) in antagonist (i.e. 3H-spiroperidol displaced by butaclamol) binding at 24 h after withdrawal. Co-administration of CLG with morphine attenuated these DA receptor changes at 24 hours which is consistent with the peptide's effect on stereotyped behavior. However, antagonist binding parameters did not parallel changes in behavior at 48 h. Agonist binding was then studied by examining DA displaceable 3H-spiroperidol (75 pM) binding to the D-2 DA receptor. Two receptor subpopulations D-2-HI and D-2-LO were revealed. Morphine caused an increase in the affinity for agonist binding to the D-2-HI site (83-fold increase). Affinity changes at the D-2-HI site correlated positively and strongly with the behavioral changes in all groups at both 24 and 48 h. We conclude that changes in agonist binding to D-2 DA receptors rather than antagonist binding is more consistent with the behaviors induced by morphine and CLG.

The psychoactive cannabinoids, delta 9-tetrahydrocannabinol (delta 9-THC), delta 8-tetrahydrocannabinol (delta 8-THC), 11-hydroxy-delta 9-tetrahydrocannabinol (11-OH-delta 9-THC) and 9-nor-9 beta-hydroxyhexahydrocannabinol (beta-HHC), as well as the nonpsychoactive cannabinoids, cannabinol (CBN), cannabidiol (CBD), abnormal CBD, delta 8-THC methyl ether (1-OCH3-delta 8-THC) and 9-nor-9 alpha-hydroxyhexahydrocannabinol (alpha-HHC), were used to assess the role of cholinergic mechanisms in the different behavioral actions of these cannabinoids. Their effects on mouse brain choline and acetylcholine (ACh) levels and on ACh turnover were determined in cortex, hippocampus, striatum, midbrain and medulla-pons. delta 9-THC (30 mg/kg) caused a significant elevation of ACh in all five brain areas. 11-OH-delta 9-THC (30 mg/kg) increased ACh in hippocampus, striatum and midbrain. delta 8-THC (30 mg/kg) increased ACh in cortex and hippocampus. delta 9-THC and 11-OH-delta 9-THC increased choline in midbrain and cortex, whereas beta-HHC increased choline in all areas, except hippocampus, at a dose of 30 mg/kg. Also at this dose, delta 9-THC, 11-OH-delta 9-THC, delta 8-THC and beta-HHC decreased ACh turnover in the hippocampus, as did CBN (10-30 mg/kg), 1-OCH3-delta 8-THC (100 mg/kg) and alpha-HHC (100 mg/kg). ACh turnover was also decreased in midbrain by 1-OCH3-delta 8-THC and in the striatum by alpha-HHC. Thus, the most consistent effects of cannabinoids, both psychotomimetic and nonpsychotomimetic, were to increase ACh and decrease ACh turnover in the hippocampus.(ABSTRACT TRUNCATED AT 250 WORDS)

An animal model of human reaction time was used to assess the effects of ethanol on reactive capacity (RC) as a function of age. Three doses of ethanol (0.5, 1.0 & 1.5 g/kg of 20% v/v, i.p.) were confirmed by gas chromatographic analysis of blood samples taken immediately following every behavioral test. Fisher 344 rats were trained to use their forepaws to hold down a lever until the onset of a buzzer and light that signalled impending foot shock, which occurred within 200-1000 msec of the stimulus. All rats were shaped to release the lever faster than 200 msec, which permitted them to avoid all shock under saline treatment. In the first experiment, only young adult rats (3-4 mos) were tested. Ethanol caused a dose-dependent impairment of RC. In a second experiment, rats aged 4, 12 and 24 mos were tested. As in previous work, RC was reduced by age. Ethanol caused a dose-dependent impairment of response speed (as indicated by the average of the fastest five RTs) that was exaggerated in the 24 mo-old rats. Ethanol also appeared to amplify the trial-by-trial variability in RC that was typical of the old rats under saline conditions. Nevertheless, if given enough time (1000 msec) most rats (except for a few in the oldest group) were able to avoid shock under ethanol as reliably as under saline conditions, even at the highest dose. Thus, ethanol specifically slowed reaction time while sparing memory and motivational and motor capacities required for success in this task. Both extensive practice and pre-test warm up sessions modified the effects of ethanol; however they did not do so differentially across ages.

A review of the literature indicates that a number of food constituents, e.g., dietary sugar, neurotransmitter amino acid precursors and food deprivation, may modulate the development of tolerance and physical dependence as well as influence the self-administration of several drugs of abuse in animals. In particular, the role of palatability of food, involvement of the autonomic nervous system, exposure to cold and nutritional status as well as seasonal cyclical changes is discussed. The effect of the above factors may in part be mediated by precursor modulation of monoaminergic neurotransmitters, modulation of endogenous opioid neurotransmitters in the neuronal terminals of the brain or modulation of endogenous peptides. This paper points to the need of conducting additional research to address this complex and potentially important area of research.

The present experiments demonstrated that the within session patterns of ethanol consumption of animals given unrestricted access to both food and water can be controlled by altering the schedule of access to ethanol. The first experiment demonstrated that the number of ethanol responses emitted per bout was inversely related to the number of one hour access periods presented per session. In a second experiment, ethanol access was limited to only the dark period of a 12 hour light-dark cycle. Total daily ethanol responding was similar to that of animals that had access to ethanol 23 hours a day. Further restrictions on ethanol availability by restricting access to the last 20 minutes of each hour of the dark period, resulted in an increase in the number of responses emitted per bout.

Because male Syrian hamsters demonstrate greater preference for ethanol than female hamsters, we compared them with regard to ethanol sensitivity and hepatic alcohol and aldehyde dehydrogenase activities. Male hamsters were slower to recover righting response and had lower blood alcohol levels upon recovery than did females. Hepatic alcohol dehydrogenase activity was approximately twice as high in females as males, but gender differences were not found for either cytosolic or non-cytosolic aldehyde dehydrogenase activities. The results suggest that the reduced ethanol sensitivity of female hamsters is due to more rapid metabolism. However, the finding that female hamsters have higher blood alcohol concentrations upon recovery also suggests the possibility of reduced CNS sensitivity.