Arnold J. Friedhoff

Induction of oral dyskinesias in naive rats by D1 stimulation.

Repetitious opening and closing of the mouth and high frequency clonic jaw movements were observed in rats challenged with dopamine agonists after acute treatment with sulpiride or a low dose of spiroperidol. SKF 38393, a specific D1 receptor agonist, alone, also induced these behaviors and cis-flupenthixol blocked them, evidence suggesting D1 dopamine receptor mediation.

Selective dopamine D2 receptor reduction enhances a D1 mediated oral dyskinesia in rats

We have previously shown, through the use of selective D1 and D2 dopamine receptor interactive drugs, that repetitive jaw movements in rats can be produced by activation of the D1 system or blockade of the D2 system. In the present study we have shown that genetic or developmental factors resulting in a lesser number of D2--relative to D1--receptors is associated with repetitive jaw movements. We have found in two strains of rats with different striatal D2 to D1 ratios, the strain with fewer D2 sites had more jaw movements. We also found that experimental reduction of D2 receptors via prenatal intervention resulted in an increase in spontaneous jaw movements, as did aging, which is accompanied by a decrease in the number of D2 receptors. The findings of these studies carried out in rats, parallel, in a number of ways, findings in human oral dyskinesia associated with either aging or neuroleptic treatment.

Selective D2 dopamine receptor agonists prevent catalepsy induced by SCH 23390, a selective D1 antagonist

SCH 23390, an apparently selective antagonist of central D1 dopamine receptors, produced profound catalepsy at low doses (0.1 mg/kg, s.c.). Pretreatment with the selective D2 receptor agonists LY 141865, RU 24213 or LY 171555, the active (-) enantiomer of LY 141865, elicited a dose-dependent inhibition of the cataleptic response. Pergolide and apomorphine were also effective. This effect was not due to altered disposition or penetration of SCH 23390 into the brain since pretreatment with a dose of LY 171555 which completely blocked catalepsy had no effect on the ID50 of SCH 23390 to inhibit 3H-cis-piflutixol binding to D1 receptors measured ex vivo. Alternative mechanisms are considered to explain the results, which offer new insights into striatal dopaminergic regulation of motor activity.

3,4-Dimethoxyphenylethylamine and Other Amines in the Urine of Schizophrenic Patients

THE preceding communication confirming the presence of 3,4-dimethoxyphenylethylamine in the urine of schizophrenic patients1,2 is of considerable interest. The fact that their procedure differed in some respects from ours adds further support to our identification of this compound.

INTERLEUKIN-1 STIMULATES THE BETA-AMYLOID PRECURSOR PROTEIN PROMOTER

Summary1.Amyloid plaques found in the brains of Alzheimers diseased patients are composed of the 42 amino acid beta-amyloid peptide (BAP) which is processed out of the larger amyloid precursor protein (APP).2.To study the regulation of the APP gene expression, we have isolated the promoter region of this angle of this single-copy gene and produced a reporter gene system to determine if the promoter is responsive to agents that may cause the overproduction of APP leading to the abnormal accumulation of plaques in AD.3.The promoter contains sequences homologous to heat shock elements, AP-1 binding sites, and phorbol ester-inducible sequences as well as GG-rich regions found in other constitutively expressed genes.4.We show here that this promoter is inducible in cultured cells by interleukin-1 (IL-1) in a transient assay system and that the HSE and AP-1 binding site are required for this inducibility.5.This induction of transcription from the APP promoter implies that this gene is responsive to tropic and/or trophic agents which may be present in the diseased brain.

Receptor reserve at striatal dopamine autoreceptors: Implications for selectivity of dopamine agonists

The dose response curve for apomorphine reversal of gamma-butyrolactone (GBL)-induced L-DOPA accumulation in rat striatum was shifted almost 6-fold to the right after partial irreversible blockade (83%) of dopamine (DA) autoreceptors with N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ); however, the maximal response was not reduced. In contrast, the major effect of a similar degree of irreversible blockade (86%) on the dose-response curve for the autoreceptor-selective agent EMD 23,448 was a reduction in maximal response (60% of control), indicating that EMD 23,448 is a partial agonist. A large receptor reserve therefore exists at the DA autoreceptor, which may explain in part why many DA agonists are more potent in models pre- than postsynaptic receptor activation.

BIOCHEMICAL AND BEHAVIORAL CHANGES IN RATS EXPOSED TO ETHANOL IN UTERO

Long-lasting behavioral and biochemical modifications have been found in animals exposed to various psychotropic substances during the neonatal period. Certain drugs, such as amphetamine, meprobamate, chlorpromazine, or morphine, administered to pregnant animals have been found to produce enduring changes in their offspring. Pertinent literature has been reviewed by Kornetsky I and Branchey and Friedhoff.? Little is known about the effects of prenatal exposure to ethanol. Changes in tyrosine hydroxylase (TH), believed to be the rate-limiting enzyme in catecholamine biosynthesis, were found in this laboratory in the brains of pups exposed to ethanol in uiero.i The enzyme determinations were made in the caudates of pups aged 8, 15. and 22 days. TH was found to be increased in all age groups (TABLE I ) . Most experiments that study the offspring of animals exposed to psychotropic drugs during the gestational period investigate either behavioral or biochemical changes. To investigate a possible relationship between behavioral and biochemical parameters, we studied open field behavior, in addition to brain TH, in pups treated prenatally with ethanol.

TETRAHYDRO-β-CARBOLINES: SPECIFIC INHIBITORS OF TYPE A MONOAMINE OXIDASE IN RAT BRAIN1

Abstract— A series of serotonin and phenethylamine analogs were tested for their ability to differentially inhibit type A or B monoamine oxidase (EC 1.4.3.4) in rat hypothalamus. The most specific and potent effects were shown by several tetrahydro‐β‐carbolines which competitively inhibited the oxidative deamination of serotonin at micromolar concentrations. In contrast, effective inhibition of phenethylamine deamination was observed only at or near millimolar concentrations of these drugs. Significant reductions of type A but not type B MA0 activity were also observed after administration of 25–100 mg/kg, i.p., of tetrahydro‐β‐carboline and its 6‐methoxy derivative.

A dopamine-dependent restitutive system for the maintenance of mental normalcy.

The exact nature of biological and psychological or behavioral interrelationships has been the substance of many theories. Ideas have ranged from the strict mechanistic, in which a biological event determines every psychological phenomenon, to dualistic proposals in which ideas or other psychological events are guided by their own laws, biological events being only the means by which these other-determined events are generated. A parallel situation exists in the area of adaptation and coping, in that the exact role that psychological coping strategies play in relation to biological adaptive mechanisms has not been well defined. The uncertain nature of these relationships is also partly responsible for the controversy between those “believing in” biological or pharmacological treatment for mental disturbances and those with a commitment to psychotherapy or related psychological treatments, although most would acknowledge that both psychological or behavioral repertoires (e.g., fight or flight) as well as certain brain biological systems play a significant role in human adaptation. It is the relationship between behavioral coping strategies and the adaptations that occur in biological systems that have been little explored in a systematic manner.’ In that regard it would be expected that systems with a high degree of plasticity would be candidates to mediate sustained changes in demands of the external world, and the central dopaminergic system is one such system. It has the capacity to up and down regulate the number of dopamine receptors in response to prolonged changes in the amount of dopamine impacting on the receptor recognition sites. This plasticity has generally been demonstrated through the use of drugs. Antipsychotic drugs that block dopamine receptors produce a compensatory increase in receptor number, while 1-dopa produces a down-regulating effect.u Despite the fact that drugs have the capacity to induce compensatory modification in the system, it is likely that the primary role of the u p and down-regulating system is to mediate a physiological process rather than a pharmacological one. In this report I will present evidence that the physiological function of the adaptive regulation of the dopaminergic system is in the mediation of a restitutive system in the brain that maintains or restores mental stability in the face of changing environmental contingencies. This system can also be fine tuned to the maternal chemical environment by a process of accommodation during prenatal life so as to enhance chances for survival after birth! In contrast to the prenatal state during which physiology accommodates to the environment, in postnatal life homeostatic adaptations are made to prevent sustained environmental changes from changing pre-existing physiological adaptations.

Factors affecting the delay of antidepressant effect in responders to nortriptyline and phenelzine

Seventy-six elderly depressed patients who had responded to either nortriptyline or phenelzine after a trial of up to 3 months were examined. The mean week of response was nearly 6 weeks. Patients who were more severely depressed took longer to respond. Patients with endogenous depression responded sooner on nortriptyline than did patients with nonendogenous depression. For patients on nortriptyline, lower plasma levels in the early weeks of treatment may delay response while differences in platelet monoamine oxidase inhibition in the early weeks of treatment do not appear to affect week of response for patients on phenelzine.