ATPase activities were studied in brain, kidney and liver (13,000 X g pellet) fraction from the mouse. Dopamine and norepinephrine added in vitro showed a dose-dependent stimulation of Na+ and K+ activated and oligomycin sensitive Mg2+ ATPase activities in brain but not kidney and liver tissue fractions. GABA and serotonin had no effect on ATPase in brain, but inhibited oligomycin sensitive Mg2+ ATPase activities in kidney and liver. The relationship between the enhancement of ATPase activity by neurotransmitters in brain and the neuronal excitation is discussed.

Adenosine Triphosphatases↗

PubMed1976

Effect of pargyline on morphine tolerance and physical dependence development in mice.

The effects of single and repeated pargyline administration on morphine antinociception in both naive and morphine-tolerant mice and on naloxone-precipitated withdrawal in morphine tolerant-dependent animals were investigated. Adult, male Swiss-Webster mice were rendered tolerant to and dependent on morphine by the s.c. pellet implantion technique. Morphine analgesia, as assessed by the tail-flick antinociceptive test, was potentiated in tolerant animals by acute adminstration of pargyline but antagonized by repeated pargyline administration; pargyline produced similar effects in non-tolerant mice and to the same relative degree. Repeated pargyline treatment during morphine pellet implantation enhanced the withdrawal jumping response precipitated by naloxone in dependent mice. Pargyline also, after a single injection, exacerbated jumping in mice undergoing abrupt withdrawal. Neither acute nor chronic pargyline administration altered the brain distribution of injected morphine in non-tolerant mice. It was concluded that pargyline may modify acute morphine actions and withdrawal without materially altering the process(es) involved in the development of tolerance and physical dependence.

Animals↗

PubMed1976

Precipitation of abstinence-like syndrome in morphine-dependent mice by pargyline.

In mice rendered morphine-dependent by pellet implantation for 3 days, the administration of pargyline 6 hours after pellet removal intensified narcotic abstinence behavior, particularly the narcotic withdrawal jumping response. Pargyline, 75 mg/kg i.p., caused a 6- to 9-fold increase in the incidence of jumping in mice withdrawing from morphine 6 hours after removal of the pellet, whereas this effect was not observed: 1) 1 hour after the injection of pargyline or 2) in animals still implanted with the morphine pellet. The median effective dose (ED50) of pargyline required to elicit withdrawal jumping in mice implanted with morphine decreased with increasing physical dependence. The ED50 for 72 hours was about one-sixth that after 24 hours of implantation. Additionally, pargyline potentiated naloxone-precipitated withdrawal jumping as evidenced by a reduction of the naloxone ED50 by approximately one-half. Administration of other monoamine oxidase inhibitors such as pheniprazine, iproiazid or tranylcypromine failed to alter the indicence of jumping in dependent mice undergoind abrupt morphine with drawal. Further, dopamine receptor stimulation by amphetamine, pheniprazine or amantadine antagonized the pargyline-induced jumping response. These data suggest that the increased incidence of withdrawal jumping observed after pargyline in morphine-dependent mice is not related to monoamine oxidase inhibition but rather to a possible pargyline-induced decrease in dopaminergic activity.

Amantadine↗

PubMed1976

Systematic assessment of tolerance to pentobarbital by pellet implantation.

Rapid tolerance development to pentobarbital by pentobarbital pellet implantation was evidenced by a decrease in sleeping time after challenge with different doses of sodium pentobarbital ranging from 37.5 to 100 mg/kg i.p. or a fixed dose of 75 mg/kg i.p. of the drug. The sleeping time produced by sodium pentobarbital decreased by 50% after 1 day. After 2 or 3 days of implantation, the sleeping time was generally further decreased to 15 to 20% of the placebo control group. Tolerance to pentobarbital was still evident 72 hours after pellet removal. The tolerance development to pentobarbital by pentobarbital pellet implantation also was demonstrated by other pentobarbital-induced responses such as hypothermia and lethality. In mice implanted with a 75-mg pentobarbital pellet for 3 days, the degree and duration of pentobarbital-induced hypothermia by intraperitoneal or intracerebral administration of the drug was attenuated. The chronic administration of pentobarbital by three days of pellet implantation reduced the effect of sodium pentobarbital on lethality as evidenced by an increase in the LD50 of sodium pentobarbital after intraperitoneal or intracerebral administration of the drug.

Animals↗

PubMed1975

A model for the rapid development of dispositional and functional tolerance to barbiturates.

The s.c. implantation of a 75 mg pentobarbital pellet in the back of a conscious mouse resulted in a much more rapid development of tolerance to barbiturates than that produced in mice receiving daily i.p. injections of 75 mg/kg sodium pentobarbital. Acceleration in tolerance development by pentobarbital pellet implantation was evidenced by a decrease in sleeping time after the challenge with either sodium pentobarbital or sodium barbital. The degree of hepatic microsomal drug enzyme induction after pentobarbital pellet implantation also was found to be significantly higher than that produced by the injection technique. Further studies demonstrated that the threshold for pentylenetetrazol-induced seizures was significantly reduced compared to that of the sodium pentobarbital daily injected and control groups. These studies provide an animal model for studying the mechanism of barbiturate tolerance and dependence.

Animals↗

PubMed1975

Influence of L-tryptophan on morphine analgesia, tolerance and physical dependence.

Four hours after the acute administration of L-tryptophan (75 mg/kg) to either, nontolerant or morphine-tolerant mice, the antinociceptive effect of morphine was partially and significantly antagonized. Daily tryptophan administration to rats and mice during a 3-day morphine pellet implantation period increased the rates of both morphine tolerance development and development of physical dependence. The accelerating effect of tryptophan on tolerance and dependence development in mice was antagonized by pretreatment with the tryptophan hydroxylase inhibitor, p-chlorophenylalanine. Acute tryptophan administration (75 mg/kg) significantly increased mouse brain 5-hydroxytryptamine levels for at least 4 hours. Although chronic tryptophan treatment increased 5-hydroxytryptamine turnover in morphine-treated mice, no effect of chronic morphine or tryptophan treatment on the particulate tryptophan hydroxylase activity of whole mouse brain was observed. Slight increases in tryptophan hydroxylase activity were observed in the caudate-putamen and septal areas of rat brain 3 and 6 days, respectively, after s.c. morphine pellet implantation. These and previous studies from our laboratory indicate that the development of morphine tolerance and dependence can be modified by agents affecting serotonergic mechanisms.

Analgesia↗

PubMed1975