Bruce I. Diamond

A comparison of venlafaxine, trazodone, and placebo in major depression.

A double-blind, placebo-controlled trial was undertaken to compare the safety and efficacy of venlafaxine and trazodone in patients with major depression. Two hundred twenty-five patients entered an initial 6-week treatment phase, and 149 completed it. Ninety-six patients who were responders continued in a 1-year, double-blind, long-term phase during which they received the same medication and doses they had during the short-term phase. Both active treatments were significantly more effective than placebo on some measures during the short-term study, but venlafaxine produced more improvement in the cognitive disturbance and retardation factors on the Hamilton Rating Scale for Depression. Trazodone was more effective against the sleep disturbance factor. Patients on venlafaxine were most likely to enter the long-term phase and to remain in the trial longest. The side effect profiles of the three treatment groups were compared. Venlafaxine was most likely to cause nausea, whereas trazodone was associated with the most dizziness and somnolence.

Chronic phenylethylamine stereotypy in rats: a new animal model for schizophrenia?

Abstract The chronic administration of phenylethylamine (50 mg/kg) or d-amphetamine (3.75 mg/kg) produces stereotyped behavior in rats. This chronic administration induces a behavioral sensitization consisting of an increase in intensity of stereotypies and a decrease in their latency to onset. The substitution of phenylethylamine for d-amphetamine, or vice versa, maintains not only stereotypies but also the sensitization effect. Acute pretreatments with the anti-psychotic dopamine blockers haloperidol and pimozide block stereotypy induced by both phenylethylamine and d-amphetamine, whereas antipsychotics with fewer extrapyramidal effects, thioridazine and clozapine, preferentially block phenylethylamine-evoked behavior. The fact that stereotypy induced by phenylethylamine, unlike that induced by d-amphetamine, does not depend so greatly upon neostriatal actions suggests that it may therefore represent a better animal model for schizophrenia.

Enkephalins and nigrostriatal function

Unilatera1 lesions of the substantia nigra were made with 6-hydroxydopamine in rats. In this model, drugs such as naloxone, which block endogenous enkephalin receptors, potentiated agents with postsynaptic dopaminergic actions, while antagonizing agents with presynaptic dopaminergic actions. Drugs which increase brain enkephalin content (d-phenylalanine or methionine-enkephalin) antagonized postsynaptically active agents and potentiated presynaptic agents. Naloxone also reversed reserpine-induced parkinsonism in rats. Separate pre-and postsynaptic enkephalinergic neurons thus seem to modulate nigrostriatal function.

Lithium prevention of amphetamine-induced ‘manic’ excitement and of reserpine-induced ‘depression’ in mice: Possible role of 2-phenylethylamine

Repeated treatment of mice with lithium chloride (45 mg/kg, i.p., daily for 8 days) reduced the jumping, fighting, stereotypies, and hyperactivity induced by d-amphetamine (5 mg/kg, i.p.). Lithium also reduced the hypoactivity observed 1–3 h after reserpine (0.75 mg/kg, i.p.). In biochemical studies we found that 8-day treatment with lithium markedly reduced (to 45% of control) the recovery from brain of labelled 2-phenylethylamine (PEA) following i.p. injection of labelled L-phenylalanine, while decreasing recovery from brain of labelled PEA following its i.p. injection to 63% of control. In saline-treated mice, d-amphetamine appeared to increase PEA synthesis and to accelerate its disposition, whereas reserpine enhanced PEA synthesis and reduced disposition; all of these effects were antagonized by lithium pretreatments. Since PEA appears to be one of the most powerful behavioral stimulants among endogenous neuroamines, and because its deaminated metabolites are behavioral depressants, such antagonism of brain PEA metabolism may significantly contribute to the prophylactic action of lithium against both manic and depressive behavior.

Estrogen in experimental tardive dyskinesia

Postmenopausal women have the highest incidence of tardive dyskinesia, suggesting that loss of ovarian function may predispose to this condition. Moreover, reports have indicated that estrogens could reduce abnormal movements in tardive dyskinesia. To test the effects of estrogen in tardive dyskinesia, ovariectomized rats were treated daily for 16 days with haloperidol alone (0.5 mg per kilogram) or haloperidol plus estradiol benzoate (EB; 8μg per kilogram). Rats were then challenged with apomorphine (0.25 mg per kilogram) 4 and 10 days after cessation of the chronic treatments. Chronic treatment with haloperidol alone enhanced the response to apomorphine, whereas the combined treatment produced a synergistic response. Rats treated chronically with haloperidol and then treated daily with EB after the haloperidol treatment showed an attenuation of drug-induced stereotypy. These data indicate that estrogen may mask development of tardive dyskinesia.

A NEW ANIMAL MODEL FOR SCHIZOPHRENIA: BEHAVIORAL AND RECEPTOR BINDING STUDIES

We present evidence that five week daily administration to rats of either phenylethylamine, d-amphetamine, or cocaine produce qualitatively and quantitatively similar stereotyped behavior. Haloperidol and pimozide block all drug-induced stereotypy, whereas clozapine antagonizes only phenylethylamine stereotypy. In membrane receptor binding studies using 3H-dopamine, we found that no chronic pretreatment significantly affected striatal dopamine receptor affinity, whereas cocaine and d-amphetamine, but not phenylethylamine, increased the density of striatal dopamine receptors. These results are discussed in light of formulating a representative animal model for schizophrenia.

Differential Membrane Effects of General and Local Anesthetics

The authors studied the effects of varying Na++ and Ca++ concentrations and of replacing H2O with D2O in Ringers solution upon the actions of general and local anesthetics on isolated frog sciatic nerves. This experimental model was used to study whether general anesthetics affect excitable membranes in a manner similar to that of typical membrane stabilizers (local anesthetics). Procaine (2.5–7.5 mM), halothane (9, 18, and 36 mM), enflurane (8 mM), and ketamine (0.15 and 0.73 mM) raised threshold and lowered spike amplitude, and their effects were facilitated by reducing Na++ concentration in the Ringers solution. The local anesthetic effects of procaine (2.5–7.5 mM) and ketamine (0.73 mM) were antagonized by Ca++, while the axonal depressant effect of halothane was facilitated by increasing Ca++ concentration in the Ringers solution, indicating a different mode of action. General anesthetics also differed from local anesthetics in their interaction with water: replacement by D2O of H2O in the Ringers solution selectively increased the axonal depressant effects of halothane and enflurane but not those of ketamine or procaine. Since D2O differs from H2O in its greater icelikeness, these results are consistent with the view that general anesthetics stabilize excitable membranes via stabilization of the water-biopolymer lattice, as predicted by the hydrate-microcrystal theory of anesthesia. In contrast, local anesthetics may stabilize excitable tissues by binding to the same fixed negative charges of the membrane to which Ca++ is normally bound.

Enhancement of hypophysectomy-induced dopamine receptor hypersensitivity in male rats by chronic haloperidol administration.

Abstract: It has been reported that hypophysectomy (HYPOX) would antagonize the development of a neuroleptic‐induced dopamine receptor hypersensitivity, and suggested that the neuroleptic‐induced dopamine receptor hypersensitivity may be mediated by the neuroleptic‐induced hyperprolactinemia. Conversely, we and others have reported on the ability of HYPOX animals to develop a neuroleptic‐induced dopamine receptor hypersensitivity. The present study was undertaken to define the possible role(s) of prolactin in the modulation of striatal dopamine receptor sensitivity. The data from these studies indicate: that HYPOX alone will result in the development of a striatal dopamine receptor hypersensitivity; that the HYPOX‐induced dopamine receptor hypersensitivity could be increased by the chronic administration and withdrawal of haloperidol; that administration of prolactin to HYPOX rats would partially antagonize the development of the neuroleptic‐induced dopamine receptor hypersensitivity; and that the administration of prolactin alone had minimal effects on the apomorphine‐induced behavior or neurochemistry of the HYPOX animals. These results suggest that the neuroleptics do not require the presence of a pituitary secretion (specifically, prolactin) to induce a striatal dopamine receptor hypersensitivity; however, they do indicate that a pituitary secretion, perhaps prolactin, may have the ability to modulate striatal dopamine sensitivity.

A new putative neuroregulator of the extrapyramidal system.

A putative neurotransmitter, 2-phenylethylamine, which is most highly concentrated in the extrapyramidal system of human brain, is able to reverse reserpine-induced parkinsonism in animals and elicit stereotypy. This action is only partially antagonized after catecholamine depletion by pretreatment with a-methyl-para-tyrosine, and fully blocked by pretreatment with haloperidol, a dopamine receptor blocker. Therefore, via direct and/or indirect actions, 2-phenylethylamine may serve a neuroregulatory role in the extrapyramidal system.

DURATION OF DRUG-INDUCED DYSKINESIAS: A PHARMACOLOGIC DISTINCTION

The induction of stereotyped behaviors in animals has been used to serve as models for neuropsychiatric disease states. We present evidence that the pharmacology of these stereotypies induced by either d-amphetamine (d-AMPH) or 2-phenylethylamine (PEA) is a function of the chronicity of the model, thus suggesting the evolution of tolerance or sensitization to the actions of certain monoamines involved in this behavior, and providing insight into the refractoriness to treatment of certain chronic neuropsychiatric diseases. Moreover, the fact that acutely and chronically induced stereotyped behaviors differ in their pharmacology suggests that caution be exercised in extrapolating acute and chronic animal models to chronic progressive neurological disease.