Jack W. Schweitzer

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.

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.

Possible genetic factors underlying the pathophysiology of tardive dyskinesia

Rates of spontaneous and drug-induced repetitive jaw movements (RJM) in rats vary widely. Low and high RJM responders were isolated and genetically selected. At each generation mean RJM responses (spontaneous or SKF 38393-induced) of the two types of rats were found to differ significantly, whereas neither apomorphine-induced stereotypic responses nor D1 and D2 receptor numbers and affinities differed. A significant increase in cAMP production was evident in SKF 38393-stimulated striatal homogenates of high RJM responders as compared with low responders. Animals subjected to 8-months exposure to fluphenazine exhibited RJM that were about twice as great as that of controls, 2 months after the last treatment, with a prevalence of about 75%. Similarities between RJM observed in rats and neuroleptic-induced tardive dyskinesia suggest that the two are strongly related.

N-Ethoxycarbonyl-2-Ethoxy-1, 2-Dihydroquinoline (EEDQ): A New Tool to Probe CNS Receptor Function

In 1968 Belleau and associates (Belleau et al., 1968) reported that the peptide coupling agent N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ) was a potent and irreversible α-adrenergic receptor antagonist. Subsequent in vitro studies in peripheral tissues by Chang et al. (1970) and Kalsner (1973) revealed that it could also irreversibly inactivate muscarinic cholinergic and serotonergic receptors, respectively. There was relatively little interest in this agent, however, until Hamblin and Creese (1983) demonstrated its ability to irreversibly block central dopamine (DA) receptors as well. In this article we will review the growing number of studies which have successfully utilized this agent to generate important new insights into the function of several CNS receptors, with special emphasis on dopamine (DA) receptors. Pertinent examples from our own studies on DA receptors will be presented, and its application to the determination of the relationship between receptor occupancy and response for agonists at CNS receptors mediating various functional effects will be highlighted.

Clinical and treatment effects on 3H-clonidine and 3H-imipramine binding in elderly depressed patients.

3H-clonidine and 3H-imipramine binding were measured in depressed patients, 55 years and older. There was no significant difference in either 3H-clonidine or 3H-imipramine binding between depressed patients and age- and sex-matched controls. There was no significant correlation between 3H-clonidine or 3H-imipramine binding and severity of depression before treatment. There was a significant negative correlation between the KD of 3H-imipramine binding sites and Hamilton score over seven weeks of antidepressant treatment. There was no significant difference between receptor data of responders and nonresponders to antidepressant treatment.

Role of maternal biochemistry in fetal brain development: effect of maternal thyroidectomy on behaviour and biogenic amine metabolism in rat progeny.

Few studies have addressed the role of biochemicals of maternal origin on fetal neurodevelopment and behavioural outcome. Thyroid deficiency in the thyroidectomized pregnant rat provides an excellent model to study fetal effects of maternal chemistry, as this condition is known to be associated with deficits in motor and cognitive behaviour in human offspring. Based on evidence that thyroid hormone of maternal origin may be an important determinant in regulating these behaviours, we assessed neurobehaviours and regional brain biogenic amine levels in offspring of rats thyroidectomized (Tx) prior to conception. Cross-fostering techniques were used to isolate fetal effects of maternal thyroid deficiency from possible neonatal effects during nursing by thyroid-deficient dams. The progeny of Tx dams showed significant deficits in maze learning, were less cautious in emotionality testing, and were more active in open-field exploration. Tx females appeared to be more vulnerable to the effects on learning. Learning in Tx males was only slightly impaired. Serotonin and dopamine metabolism was also affected in a brain region-specific manner in Tx progeny. Levels of 5-HIAA were reduced in the olfactory tubercle and cortex. HVA levels were lower in olfactory tubercle, but were elevated in the hippocampus. As these neurotransmitters play a functional role in activity, mood and learning, the findings may be pertinent to the observed behavioural impairments. The results are consistent with the hypothesis that an adequate in utero thyroid hormone environment may be essential for early fetal neurodevelopment even if the fetus is euthyroid.

Diminished D2 dopamine receptor function and the emergence of repetitive jaw movements.

Oral movements in rats, repetitive jaw movements (RJM), can be induced in a dose dependent manner by a specific D1 agonist, SKF 38393, and decreased by D2 receptor stimulation with a specific D2 agonist, LY 141865. Irreversible D1 receptor inactivation by N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline severely reduced oral responses induced by SKF 38393, whereas such blockade of D2 receptors greatly augmented the D1 mediated behavior. Further, we found that chronic prolonged D2 receptor blockade following administration of fluphenazine decanoate facilitated repetitive jaw movements.

Repeated inescapable stress produces a neuroleptic-like effect on the conditioned avoidance response.

This study tests the hypothesis that the dopaminergic system mediates a restitutive response by decreasing its own activity in the face of events like persistent inescapable stress that threaten to interrupt organized mental activity. It is well established that neuroleptic drugs inhibit the conditioned avoidance response (CAR), but not the escape response, probably via a reduction in subcortical dopaminergic activity. We trained rats to perform the CAR and then subjected them to acute and chronic stress to determine whether this would result in inhibition of the CAR. Rats subjected to twice daily tailshock stress for 8 days showed inhibition of the CAR and a reduction in dopamine (DA) utilization in the nucleus accumbens. These findings are compatible with the hypothesis that an endogenous DA-dependent mechanism exists that mimics neuroleptic effects in the face of repeated stress. In humans this response may serve as a protection against psychotic decompensation from chronic endogenous or exogenous insult.

The metabolism of α-14C-3,4-Dimethoxyphenethylamine

Abstract α-14C-Dimethoxyphenethylamine hydrochloride was administered to rats, i.p., and the metabolites were isolated and identified from the 0–2.5 hr urine. The following compounds were positively identified (percentages of urinary 14C are given in parentheses): dimethoxyphenylacetic acid (77), unchanged amine (15.5), and N-acetyl-3-methoxytyramine glucuronide (6.0). Tentative identification was also made for N-acetyl-3-methoxytyramine (ca. 0.2) and for trace amounts of N-acetyldimethoxyphenethylamine, 3-methoxy-4-hydroxyphenethanol glucuronide, and dimethoxyphenethanol. Pretreatment of rats with aldehyde and amine oxidase inhibitors resulted in anticipated increases or decreases in the excretion of some of the metabolites. One of the metabolites, N-acetyldimethoxyphenethylamine, was found to be physiologically active, producing hypokinesis within 5 min. Administration of the 14C-labeled compound resulted m the excretion of N-acetyl-3-methoxytyramine glucuronide only. These results, in conjunction with the failure to detect homovanillic acid and methoxytyramine after administering 14C-dimethoxyphenethylamine, indicate that N-acetylation precedes O-demethylation.