Henri S. Havdala

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.

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.

Acupuncture: An evaluation in the painful crises of sickle cell anaemia

&NA; An evaluation of acupuncture for pain relief was made in 10 patients with sickle cell anaemia during 16 pain crises. A model was developed in which the patient served as his own control and in which both patient and examiner were unaware of whether an acupuncture point or a sham site was treated. The results show (1) that pain relief was obtained in 15 of the 16 painful episodes regardless of whether an acupuncture point or a sham site was treated, demonstrating considerable overlap between the effects of needling acupuncture points and sham sites; (2) that needling at acupuncture points for pain relief is not significantly superior to treatment at sham sites; (3) that needling, per se, whether at acupuncture points or at sham sites can be useful for alleviating pain in sickle cell crises. The model could be useful for evaluation of pain relief by needling in other diseases.

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.

NEUROPEPTIDES AND OTHER DOPAMINE MODULATORS IN THE EXTRAPYRAMIDAL SYSTEM

Evidence is presented comparing the efficacy of two monoamine oxidase inhibitors, deprenyl and harmaline, in two animal models of parkinsonism. Harmaline is shown to more strongly potentiate dopamine mechanisms, whereas deprenyl is shown to more potently affect brain phenylethy1 ami ne. Moreover, phenylethyiamine is shown to reverse reserpine-induced parkinsonism in rats after pretreatment with the catecholamine depleter α-methyl-para-tyrosine, thus suggesting a direct role for phenylethylamine in the striatum. Furthermore, we show that an opiate antagonist, naloxone, and two opiate agonists have differential effects in producing rotation in rats with unilateral 6-hydroxydopamine lesions of the substantia nigra. This evidence suggests dual sites of action for enkephalins in the nigro-striatal pathway. We also report that other brain neuropeptides may modulate dopamine function in the extrapyramidal system.