Psychopharmacology communications最新文献

A single injection of fenfluramine (100 mumol/kg) produced evidence of neurotoxicity in cresyl violet or silver stained sections of rat brain which was restricted to the serotonergic (B-9) cell group located in the ventromedial midbrain tegmentum. Reacting cells throughout this region exhibited an irregular shape and an intense staining of the cytoplasm, while in the caudal 1/4 of this region the reacting cells also exhibited a perineuronal space. These effects were greatly reduced in the rostral 3/4 of B-9 at 14 and 30 days after fenfluramine. In the caudal 1/4 of B-9 the neurotoxic actions remained prominent and included signs of cellular dissolution. These signs of an irreversible degenerative effect of fenfluramine on cells in the caudal 1/4 of the B-9 region were identical to those seen after p-CA, while the effects in the rostral 3/4 of B-9 were not as prominent. The differential neurotoxic effects of fenfluramine and p-CA on cells in the rostral 3/4 of B-9 were associated with a differential effect on serotonin content of hippocampus and amygdala.

The effect of molindone on the activity of dopaminergic (DA) neurons in the rat midbrain and on DA metabolism in the striatum and olfactory tubercles was studied using extracellular single unit recording and biochemical techniques respectively. Molindone in low intravenous doses (0.4-0.8 mg/kg) was found to reverse d-amphetamine and apomorphine induced depression of DA neurons and to block apomorphine induced depression of these cells. Molindone was also found to increase dopamine synthesis and dihydroxyphenylactic acid levels in the striatum and olfacotry tubercles. In all of these respects molindone behaves identically to most classical neuroleptics. However, unlike most antipsychotic drugs previously tested, molindone failed to increase the baseline firing rate of DA cells and blocked haloperidol induced increases in DA neuron activity. In this regard molindone most closely resembles thioridazine and clozapine. Possible mechanisms of action of molindone are discussed based on these findings.

Behavioral and mood changes were measured for 8 normal male subjects after oral administration of sodium pentobarbital (3 mg/kg body weight). This procedure was repeated on three occasions: firstly a drug-free condition; then a condition following two weeks of maintenance 0.7 to 1.2 MEQ/L lithium carbonate; and then another drug-free condition. Intial analyses indicated a lowering of the level of euphoria reached in the lithium pentobarbital condition below that achieved after pentobarbital alone. Examination of this effect showed that the reduction after pentobarbital plus lithium was mirrored by a reduction in the baseline for the same response items due to lithium alone. The lessening of euphoria appeared to result from a general lowering of affect due to lithium maintenance. More detailed analyses showed that the quantitative response to pentobarbital was in no case reduced by lithium condition. Certain reversal effects were also discovered in which lithium plus pentobarbital acted in the opposite direction from pentobarbital alone.

1. The effects of lithium on electrolyte metabolism can be demonstrated in man in acute as well as in long-term lithium treatment. 2. It seems feasible to integrate these lithium effects with effects on biogenic amines to form an integral hypothesis for lithium action in manic-malancholic man. 3. The results are consistent with one of the following two hypotheses: a) that lithium acts by membrane stabilization and/or b) that lithium acts by interplay with magnesium or one or more enzymes. 4. The above findings and hypotheses direct attention to membrane dyfunction as the basic defect in manic-melancholic states. This may find support in preliminary findings of special HL-A profiles in unipolar and bioplar manic-melancholic patentis. 5. A four-type pump-defect model may theoretically account for the various clinical types of affective disorders.

Elevation of the media potassium concentration results in an immediate, but transient increase in the rate of respiration in cerebral cortex slices of the rat. As the respiratory burst decrease in intensity, a transient oxidation of the tissue respiratory intermediates is followed by a net reduction. The burst of respiration is accompanied by a large decrease in tissue ATP and phosphocreatine concentrations. ATP and phosphocreatine concentrations are essentially fully recovered within 5-6 min. The apparent increase in ATP hydrolysis during the peak of the respiratory response was not, however, accompanied by increases in the tissue content of ADP and 5'-AMP. Increased deamination of the adenine nucleotides is discussed as a possible mechanism in the large contraction of the total adenine pool observed during the course of the metabolic response to elevated potassium concentrations.

SU-23397 is a unique new hybrid molecule, the animal profile being characteristic of neuroleptic activity. Although the trial was uncontrolled, there appears to be no doubt that SU-23397 exerts antipsychotic activity between 20 mg and 250 mg daily in severely ill schizophrenic patients. Seven of the ten subjects required at least transient antiparkinson medication. Two patients demonstrated premature ventricular contractions. One patient had infrequent PVCs at baseline which increased in frequency with rising dosage. The other patient developed frequent premature ventricular contractions only after active and medication was initiated and was subsequently withdrawn from the study.

During a four month period, 20 rats treated with subcutaneous injections of chlorpromazine (CPZ), at any dose tested, gained less weight than saline treated controls. However, increased feeding did occur on the first day of CPZ treatment if the animal was drug free for at least two days prior to treatment. The "first day" hyperphagia was a time limited response that did not occur until 8 hours after CPZ injection and lasted only one day. During the period of hyperphagia, treated animals showed increased motivation to obtain food. Although sedation is a marked effect of CPZ and may be the reason for the delayed onset of hyperphagia, sedation with a different drug does not cause hyperphagia. It is suggested that accumulation of a metabolite of CPZ may interfere with the feeding response and cause the hyperphagia to disappear after the first day of treatment.

In previous studies we have shown that perphenazine inhibits the metabolism of nortriptyline and imipramine. In this study the metabolism of 14C-imipramine and 14C-desipramine was studied before and during treatment with perphenazine. Studies on the imipramine and desipramine metabolites in urine showed that the major effect of perphenazine is an inhibition of the 2-hydroxylation of imipramine and desipramine. This causes a decreased formation and excretion of non-conjugated and glucuronide bound hydroxy metabolites and accumulation of imipramine and desipramine. There was some relationship between the dose of perphenazine and the decrease in total urinary excretion but the individual variations in response were pronounced (2-3-fold).

Phencyclidine produces a dose-dependent ipsilateral rotation in rats with unilateral substantia nigra lesions. This ipsilateral turning is decreased 41% by pretreatment with AMPT and 81% by prior administration of haloperidol. Ipsilateral turning elicited by phencyclidine can also be altered by treatment with cholinergic agents. These findings suggest that phencyclidine may be acting by increasing the availability of dopamine on the intact side of a unilaterally-lesioned substantia nigra rat and that the response can be modulated by alterations in the cholinergic system.

A method for the assay of 7-hydroxychlorpromazine in biological fluids is described. The stages of the method are extraction into ether, back extraction into acid, alkalinisation and further extraction into ether, evaporation of the extract to dryness, and gas-chromatography of the extracted material as a silylated derivative using conditions previously described for chlorpromazine. The method is applicable to certain other hydroxylated chlorpromazines, but it is not superior to existing methods for the assay of nonhydroxylated analogues. Only small quantities of 7-hydroxychlorpromazine were detected in the plasma of schizophrenics showing a satisfactory clinical response, even when the compound was present in urine, providing strong evidence that the presence of 7-hydroxychlorpromazine in blood is not a pre-requisite of successful therapy.