James L. Marini

Effect of anesthetic doses of γ-hydroxybutyrate on the acetylcholine content of rat brain

SummaryGamma-hydroxybutyrate administered in anesthetic doses produces a time dependent increase in the levels of rat brain acetylcholine. A maximal increase in whole brain and subcortical levels of acetylcholine is observed about 15 min after administration of the lactone form of the drug. A similar GHB-induced increase in acetylcholine is observed in the striatum and a 75% increase in the hippocampus 15 min after administration of the drug. A good temporal correlation was not obtained between the increase in acetylcholine and the depth of anesthesia produced by the drug. Gamma-hydroxybutyrate did not cause a significant change in the striatal or hippocampal levels of choline. Possible mechanisms involved in the production of this increase in acetylcholine are discussed.

Effects of chronic dietary lithium on activity and regulation of (Na+,K+)-adenosine triphosphatase in rat brain.

Abstract Chronic dietary administration of lithium appeared to reduce (Na + ,K + )-adenosine triphosphatase in rat brain by at least two mechanisms. Selective inhibition of the enzyme form with high affinity for ouabain occurred in hippocampus. Nonselective inhibition, manifested by decreased V max for activation by Na + . occurred in hippocampus, cortex and corpus striatum. There was no effect on Na + affinity. Because lithium administration decreased shock-elicited fighting behavior in the presence of moderate tissue lithium levels and in the absence of changes in weight or gross appearance or behavior, the effects on adenosine triphosphatase were pharmacologic rather than toxic.

Activity of a non-hallucinogenic ergoline derivative, lisuride, in an animal behavior model for hallucinogens.

The behavioral effects of IP administration of lisuride, a non-hallucinogenic iso-lysergic acid amide analog structurally related to d-lysergic acid diethylamide (LSD), were examined in 15 cats. Ten animals were given saline or 6.25, 12.5, 25, 50, or 100 μg/kg of lisuride and observed for 1 h by a rater blind to dose. There was a statistically significant effect of lisuride dose on the frequency of occurrence of the behaviors limb flicking, grooming, and abortive grooming. A time-course study with five cats at the most effective lisuride dose, 50 μg/kg, revealed that the frequencies of occurrence of these behaviors reached a maximum during the first 2 h post dose, and were comparable to frequencies after saline by 6 h post dose. An acute tolerance study with four cats scored for 90 min post dose revealed no significant tolerance to a 50 μg/kg lisuride test dose administered 6, 24, or 72 h after an initial 50 μg/kg dose. Acute cross tolerance studies with four cats scored for 90 min after an initial dose of 50 μg/kg of LSD or of lisuride, followed 24 h later by 50 μg/kg of lisuride or LSD, revealed no significant cross tolerance. The potency of lisuride relative to LSD was evaluated in six cats that were scored for 60 min following 25 and 50 μg/kg of LSD and of lisuride. On a molar basis, scores after lisuride were 51% and 67% those after LSD for limb flicking and grooming. These results indicate that lisuride, a non-hallucinogenic iso-lysergic acid derivative, is a false positive in the animal behavior model for hallucinogens.

Antiaggressive effect of lithium ion in man

In studies of the psychopharmacology of human aggression, ‘aggression’ should be related to easily identifiable behavior: angry threats or actual assaults. Aspects of behavior not meeting these criteria but relevant to a study of aggression should be described using appropriate terms such as social dominance, initiative, etc. With these conventions, examination of the heterogeneous literature on lithium treatment of aggression demonstrates that lithium ion exerts an antiaggressive effect in man. A number of hypotheses for the antiaggressive effect are examined using previous studies and new behavioral and biochemical data. It is concluded that the antiaggressive effect is not due to any of the following: lithium toxicity or side effects; subjective or objective weakness; increased reaction time; reduced coordination or motor performance; frank cognitive deficits; hypothyroidism; reduction of serum testosterone; placebo effect; or underlying manic‐depressive illness. Putative “thymoleptic” properties of lithium are too ambiguous to constitute an explanation of lithiums actions in man.

Sustained‐Release Lithium Carbonate in a Double‐Blind Study: Serum Lithium Levels, Side Effects, and Placebo Response

The utility and side effects of sustained-release lithium carbonate (Priadel) in a once-per-day dose regimen was investigated with 66 male delinquents, ages 17-24 years, in a double-blind study comparing the antiaggressive effect of lithium carbonate with placebo. Serum lithium levels and symptoms were determined weekly for up to eight drug-free and 12 on-medication weeks. Average daily doses of 1500-1700 mg Priadel gave 24-hour serum lithium levels in the range 0.7-0.9 mEq/liter. Principal side effects were polyuria and shakiness, with other important side effects bring hand tremor, dryness of mouth, nausea, and weakness. No lithium toxicity was observed, and diarrhea was reported infrequently. Placebo response data are presented.

AN EVALUATION OF THE DOUBLE-BLIND DESIGN IN A STUDY COMPARING LITHIUM CARBONATE WITH PLACEBO

As part of a study of drug treatment of aggressive behavior to be reported separately, we have evaluated the double‐blind procedure in a recently completed comparison of the efficacy of lithium carbonate versus placebo in modifying aggressive behavior in nonpsychotic incarcerated delinquents. We conclude that the side effects of lithium carbonate are sufficient to reveal the medication to most subjects receiving it. Thus, while the study staff could not identify lithium‐receivers at better than chance levels, and while subjects who received placebo could not identify their medication at better than chance levels, subjects who received lithium could accurately identify it. On a weekly symptom check list there was no difference between lithium and placebo groups on average lithium target symptoms reported during 4‐week pre‐ and postmedication control periods; however, lithium‐receivers reported significantly more target symptoms every week medication was administered. Of 16 subjects who quit the study, 14 had received lithium and nearly all of those who gave reasons for quitting specified side effects, most often nausea. The methodological problems of using lithium in a double‐blind design might be overcome by employing a “discontinuation” design, or, speculatively, a double‐blind, cross‐over design utilizing an “active placebo”.

On the specificity of a cat behavior model for the study of hallucinogens.

LSD is the prototype for a cat behavior model for the study of hallucinogens. The models specificity was tested with the nonhallucinogen methysergide, a d-lysergic acid amide derivative structurally similar to LSD. The frequencies of occurrence of the model behaviors limb flicking, grooming, and head plus body shaking show statistically significant dose dependency after i.p. methysergide (62.5-1000 micrograms/kg), and the maximum frequencies of the methysergide-elicited behaviors occur between 1-3 h post-dose. Methysergide produces statistically significant tolerance to limb flicking and grooming 24 h following an acute dose, and there is statistically significant methysergide-LSD and LSD-methysergide cross tolerance to limb flicking at 24 h. In addition, pretreatment with methysergide 15 min before LSD or lisuride antagonizes their elicitation of model behaviors. The dose-response, time course, and tolerance results with methysergide are analogous to those observed after LSD, showing that methysergide has all of the key properties of the models prototype and, therefore, that the cat behavior model is not specific for hallucinogens.

Treatment of human aggressive behavior: Four case studies of the effect of lithium

Abstract In the past five years there has been a steady accumulation of evidence that lithium inhibits aggressive behavior in man. 1–4 The most recent and complete study employed a double-blind design and reported the effect of lithium versus placebo on 16–24 year old incarcerated male delinquents. 5 A significant reduction in threatening or assaultive behavior was found in the lithium-treated group. We now describe in detail four individual case studies from the lithium-treated group in the double-blind study. We feel these four cases exemplify representative types of lithium responsive subjects. For the purposes of this paper a “lithium responder” is defined as a subject who received at least two institutionally-administered penalties for threatening or violent behavior (“major infractions”) during the predrug control period, and had a reduction of at least two major infractions while on lithium. Of 34 lithium subjects, 11 met the control period criterion, and 9 of these met the responder criterion; of 32 placebo subjects, 7 met the control period and 1, the responder criterion. The 4 individuals discussed here showed an unambiguous improvement in their overall ability to control overt violent aggressive behavior while on lithium. The literature contains several individual case studies of the effects of lithium on “aggressive” behavior. Some of the features of these cases taken together with those found in our study serve as a basis for identifying clinical criteria which warrant a trial of lithium in certain types of exaggerated aggressive behavior in man.

Lithium effects on high-affinity tryptophan uptake: evidence against a stabilization mechanism

Abstract Acute effects of lysergic acid diethylamide (LSD) and chlorimipramine on tryptophan uptake into rat brain synaptosomes were studied in rats treated chronically with dietary lithium and in control rats. The acute drug treatments did not change V max or K m for trytophan uptake in control rats. In lithium-treated rats, chlorimipramine increased and LSD decreased V max . These results indicate that, rather than stabilizing serotonin production through tryptophan uptake changes, chronic lithium treatment may increase the responsiveness of tryptophan uptake to changes in serotonin utilization.

Serotonergic and dopaminergic effects on yawning in the cat

The serotonergic agents LSD (0.01-0.05 mg/kg) and lisuride (0.025 and 0.05 mg/kg) elicited a high frequency of limb flicking in the cat after IP doses; LSD, but not lisuride, elicited a significantly increased frequency of yawning as well. In combination, LSD plus lisuride (0.025 mg/kg each) gave additive frequencies of limb flicking, but the frequency of yawning was half that after LSD alone. The dopamine agonist apomorphine had no significant effect on either yawning or limb flicking over the dose range 0.006 to 3.2 mg/kg. Pretreatment of cats with 1.0 mg/kg of apomorphine (but not with 0.05 mg/kg) significantly reduced the frequency of yawning elicited by 0.01 or 0.025 mg/kg of LSD, but had no effect on limb flicking. The dopamine antagonist haloperidol had no effect on limb flicking at doses from 0.008 to 0.512 mg/kg, but produced a significantly increased frequency of yawning at 0.256 mg/kg, an effect antagonized by lisuride administration. Given that lisuride has more potent dopamine agonist properties than LSD, these results are consistent with serotonergic elicitation of yawning, dopaminergic inhibition of yawning, and with their concomitant interaction in the expression of drug-induced yawning in the cat. The behavioral pharmacologies of limb flicking and yawning are different in this species.