Tolerance of high doses of morphine: lack of evidence of learning.
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Biomedical subjects
Publications and source records attributed to Z Amit.
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Male Wistar rats were exposed to a free choice between water and a morphine-sucrose solution. Following stabilization of baseline levels of consumption of morphine, the animals were injected for 5 consecutive days with either FLA-57 (45 or 60 mg/kg i.p.), a non-toxic dopamine-beta-hydroxylase inhibitor or its vehicle. The FLA-57 treated animals significantly attenuated their preference for morphine during the injection and post-injection periods although there were no significant differences related to the dosages used. These treatments produced a concomitant reduction in central norepinephrine levels suggesting that norepinephrine may be involved in the mediation of the reinforcing properties of morphine consumed by laboratory rats. The possibility of common neural mechanisms regulating the pharmacological actions of both morphine and ethanol are discussed.
Rats were trained to run down a runway for food in the goal box, and were then tested with one trial per day for 5 days. After running in the runway and eating in the goal box each rat was injected with a drug and returned to the empty goal box for 50 min. Over the 5 trials, rats that received morphine sulphate increased their running speed approximately 400% while the amount of food they ate in the goal box decreased to about 70% of baseline values. The running speed of rats that received lithium chloride decreased to about 30%, while the amount of food they ate decreased to less than 10% of baseline. These two variables did not change for rats that received saline injections. The large increases in running speed observed in the rats that received morphine injections were attributed to an interaction (but not simple summation) between the positive reinforcing effects of morphine and food. The accompanying paradoxical decrease in amount eaten was discussed in terms of the complex pharmacological properties of morphine and it was suggested that morphine may have a reinforcing effect on behavior that is independent of its affective properties.
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The motor effects produced by intraventricular infusions of morphine were compared to the effects of etonitazene. Despite the similarity in the peripheral actions of these drugs, motor effects of central infusions differed dramatically. Intraventricular morphine infusions resulted in explosive motor behavior whereas etonitazene produced extreme muscular rigidity. The periaqueductal grey (PAG) has been proposed as the substrate of morphine-induced explosive motor behavior. However, considerations of the dose of morphine and the mobility of this drug in tissue suggests that sites other than the PAG may also be involved in explosive motor behavior.
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Ethanol-drinking rats were injected with the dopamine-beta-hydroxylase inhibitor FLA-57, prior to free-choice presentations of ethanol and water either for 5 alternate days (25 or 40 mg/kg i.p.) or for 5 consecutive days (45 mg/kg i.p.). In all cases, the FLA-57 treated animals markedly attenuated ethanol consumption while vehicle-injected controls showed no change from baseline. In the post-injection period ethanol intake gradually returned to baseline levels. Biochemical assays revealed that whole brain norepinephrine levels following injection of FLA-57 (15-60 mg/kg i.p.) were significantly depressed while dopamine and serotonin levels were slightly increased. It is suggested that norepinephrine may be involved in the mediation of the positive reinforcing properties of ethanol regulating its self-administration.
Following stabilization of consumption of a 15% (v/v) ethanol solution in a free-choice with water, rats were presented with a forced-choice of ethanol for 10 consecutive alternate days. Prior to each forced-choice presentation experimental animals were injected with the non-toxic dopamine-beta-hydroxylase inhibitor FLA-57 (30 mg/kg i.p.) while control animals received only vehicle injections. At the termination of the injection phase when ethanol was again made available in a free-choice with water, ethanol consumption for the FLA-57 treated animals was markedly suppressed. These data are interpreted in terms of extinction resulting from the procedure whereby performance of the ethanol drinking response was perpetuated by force with the pharmacological reinforcing properties being blocked by FLA-57-induced depletions of norepinephrine. Applications of these procedures in the treatment of human alcoholics are discussed.
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Male Wistar rats implanted with cannulae aimed at the left lateral cerebral ventricle were individually maintained in Skinner boxes for 11 consecutive days. Animals were neither predependent on morphine nor shaped to press the operant lever. Experimental animals (n = 7) obtained intraventricular infusions of a 1% morphine HCl solution (2 mul per 5-s infusion) for each lever press while control animals (n = 7) received only the vehicle. Four animals were yoked to experimental animals and received equivalent but non-contingent morphine HCl infusions. The mean number of lever presses per day for the experimental group was significantly higher than for the vehicle control or yoked control groups suggesting that naive rats will work for the positive reinforcing properties of morphine when it is infused centrally.
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Infusion of fluids into unrestrained animals requires the use of a flow-thru swivel. A method is described for the construction of a simple efficient swivel assembled from disposable plastic syringes and needles.
This paper critically examines the concept that physical dependence is a necessary attribute for animal models of human alcoholism. On the basis of a review of the literature, it is argued that, since the production of physical dependence requires the presence of continuous high blood-alcohol levels, and since the production of preference for alcohol requires intermittent presentation of alcohol, the two cannot, in principle, be established in the same organism at the same time. It is further argued that physical dependence does not play a role in the development of high alcohol intake in animals. The implications of these observations for human alcoholism are discussed.
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Ventral lateral hypothalamic lesions, made before electrical stimulation, blocked the acquisition of a preference for alcohol by rats; but dorsal lateral hypothalamic lesions did not alter their alcohol consumption. Rats offered alcohol on alternate days, without stimulation, increased their alcohol intake but did not develop a stable preference for alcohol.