Pharmacological blockade of brain alpha1-adrenoceptors as measured by ex vivo [3H]prazosin binding is correlated with behavioral immobility.

The present studies examined the relationship between the blockade of central alpha1-adrenoceptors, as measured by ex vivo binding of [3H]prazosin in the cerebral cortex and the inhibition of behavioral activation to a mildly novel environment (cage change). It was found that intraventricular (i.v.t.) terazosin, a saline-soluble alpha1-adrenoceptor antagonist, dose dependently inhibited both ex vivo cortical binding and behavioral activation and that there was a highly significant positive correlation between the two with a slope near unity. Prazosin, a nonsaline soluble antagonist which had to be given intraperitoneally (i.p.), was much less potent at blocking both behavioral activity and cortical ex vivo binding, although it blocked ex vivo binding in the lung, indicating that it was effective peripherally but did not readily enter the brain. Despite this, however, the inhibition of cortical binding and behavioral activation that i.p. prazosin did produce were highly correlated with each other and had a slope near unity as with terazosin, whereas the more potent inhibition of lung binding was less well correlated with behavioral inhibition and had a slope significantly less than one. These results confirm our earlier studies, which have shown that alpha1-adrenoceptor activity is essential for gross and fine motor behavior in the mouse and that prazosin, which is used extensively in behavioral research, has difficulty entering the mouse brain.

Brain alpha 1-adrenergic neurotransmission is necessary for behavioral activation to environmental change in mice.

Terazosin, a water-soluble alpha 1 antagonist that can be administered in high doses intraventricularly was used to study the relationship between brain alpha 1 adrenoceptor neurotransmission and behavioral activation in the mouse. The antagonist was found to produce a dose-dependent, complete inhibition of motor activity and catalepsy which were reversed preferentially by coinfusion of an alpha 1 agonist (phenylephrine) compared to a D1 (SKF38393) or a D2 agonist, (quinpirole). Blockade of central beta-1 (betaxolol), alpha-2 (RX821002) or beta-2 (ICI 118551) adrenoceptors had smaller or non-significant effects. Terazosin's selectivity for alpha 1 receptors versus dopaminergic receptors was verified under the present conditions by showing that the intraventricularly administered antagonist protected striatal and cerebral cortical alpha 1 receptors but not striatal or cortical D1 receptors from in vivo alkylation by N-ethoxycarbonyl-2-ethoxy-1, 2-dihydroxyquinoline. That its effect was due to blockade of brain rather than peripheral receptors was shown by the finding that intraperitoneal doses of terazosin three to 66 times greater than the maximal intraventricular dose produced less behavioral inhibition. Intraventricular terazosin also produced hypothermia and a reduced respiratory rate suggestive of a reduced sympathetic outflow. However, external heat did not affect the inactivity, and captopril, a hypotensive agent, did not mimic it. Terazosin did not impair performance on a horizontal wire test or the ability to make co-ordinated movements in a swim test suggesting that its activity-reducing effect was not due to sedation and may have a motivational or sensory gating component. It is concluded that central alpha 1-noradrenergic neurotransmission is required for behavioral activation to environmental change in the mouse and may operate on sensorimotor and motivational processes.

The effect of novel antipsychotics in rat oral dyskinesia.

1. The effect of the D1 agonist SKF38393 and the 5HT2C agonist m-CPP on repetitive jaw movements (RJM) was studied in rats. Acute administration of SKF38393 and/or m-CPP induced RJM in a dose dependent manner. In rats treated with both drugs, RJM responses were about equal to the sum of those obtained with each drug alone. 2. The induction of RJM by SKF38393 was somewhat lower in rats pretreated with 5HT2C receptor antagonist, mianserin, whereas mianserin severely reduced RJM induced by m-CPP alone. 3. D1 antagonist SCH23390 inhibited SKF38393 induced RJM but had no effect on m-CPP induced chewing behavior. 4. The present study confirms earlier evidence that D1 agonists used at optimal doses for the induction of RJM do not involve the serotonergic system in a significant way. It does, however, implicate the system in the emergence of drug induced oral behavior in rats. 5. The effect of the atypical antipsychotics, clozapine, olanzapine and risperidone was studied on SKF38393 and m-CPP induced RJM. Pretreatment with the atypical antipsychotics clozapine and olanzapine inhibit SKF38393 and m-CPP induced RJM. Pretreatment with risperidone inhibits m-CPP induced oral behavior in rats while increases dose dependently SKF38393 induced RJM.

A phosphoinositide-linked dopamine D1 receptor mediates repetitive jaw movements in rats.

BACKGROUND: We have demonstrated that rats injected with D1 agonists SKF 38393 or A68930 demonstrate repetitive jaw movements (RJM). These agonist-induced movements in rats are similar in their appearance to those induced in rats by long-term treatment with antipsychotic drugs. Over recent years D-1 receptors were discovered which showed linkage not only to c-AMP but also to PI hydrolysis. We examined the effect of EEDQ inactivation of D1 receptors on D-1 mediated PI hydrolysis and RJM. METHODS: Twenty four hours following EEDQ or vehicle administration D-1 agonists or vehicle were administered. The number of RJM episodes was assessed in EEDQ and vehicle treated rats. D-1 receptor density and inositol phosphate formation were determined in the striata. RESULTS: EEDQ administration resulted, 24 hours later, in 70-80% selective depletion of D-1 receptors in the striata but did not modify the rate of RJM induced by D-1 agonists. There was no significant difference in D-1 mediated PI hydrolysis in EEDQ treated rats when compared to vehicle treated group. CONCLUSIONS: The present data support the earlier demonstration of D-1 agonist induced RJM, an effect mediated by a subpopulation of a D-1 receptor subtype and constitute the first behavioral evidence for the existence of a behavioral response mediated by D-1 like dopamine receptors linked to an alternate second messenger system-PI hydrolysis.

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.

A subpopulation of dopamine D1 receptors mediate repetitive jaw movements in rats.

Repetitive jaw movements (RJM) in rats, a potentially useful animal model of tardive dyskinesia, appears to be mediated by the dopamine D1 receptor as evidenced in part by their induction and inhibition with D1 agonists and D1 antagonists, respectively. Selective destruction of 60-90% of D1 receptors by EEDQ, measured in several CNS dopaminergically innervated areas, preceded by protection of D2, 5-HT2, alpha 1 and alpha 2 receptors, however, failed to reduce D1 agonist-augmentable RJM. Further, the affinity of dopamine toward displacement of 3H-SCH-23390 binding from striatal D1 receptors was significantly decreased by administered EEDQ, a counter-intuitive result in relation to D1 responsitivity and RJM. Thus, at present it is suggested that an EEDQ-resistant D1 receptor subpopulation may exist.

A mechanism underlying neuroleptic induced oral dyskinesias in rats.

Previously we have found that spontaneous repetitive jaw movements (RJM) in rats can be augmented by dopamine D1 receptor stimulation and attenuated by D2 stimulation or by D1 blockade. We now report that high and low RJM responders can be inbred and that RJM responses in such rats are further augmented during washout from eight months of treatment with fluphenazine, a time when N-propyl-apomorphine induced stereotypy is severely depressed. Moreover, selective D1 receptor inactivation by N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ) fails to reduce RJM. Therefore, D2 blockade by neuroleptics is deemed to be the most important mechanism for RJM enhancement. In conclusion, our studies show that oral behaviors are under genetic control, perhaps suggesting that the appearance of tardive dyskinesia in only some patients under neuroleptic therapy is due to a genetic disposition. Furthermore, tardive dyskinesia may be less likely to develop if the neuroleptics used are less potent against D2 receptors, as has been reported for some of the atypical antipsychotic drugs.

A full repetitive jaw movement response after 70% depletion of caudate D1 receptors.

Repetitive jaw movements (RJM in the rat can be produced in a dose-dependent manner with the selective D1 agonist, SKF 38393. Administration of the protein coupling agent, N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ) to rats pretreated with a D2 receptor blocker resulted in a 70-30% reduction of D1 dopamine receptors, but only a 10% reduction of D2 receptors in the rat caudate. Twenty-four hours following EEDQ, the RJM response to SKF 38393 was assessed. The massive selective reduction of the D1 receptor density was found not to modify the rate of RJM induced by SKF 38393 in that dose response curves in control and EEDQ-treated rats were essentially identical. These data provide evidence to indicate that there is a functional D1 receptor reserve for D1-mediated RJM behavior.

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.

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.

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.

Chronic haloperidol does not increase specific dopamine receptor binding in rat frontal cortex.

The specific D2 dopamine receptor antagonist sulpiride was used to quantitate the minor component of [3H]spiroperidol binding (at 0.1 nM) to dopamine receptors in rat frontal cortex. Chronic treatment of rats with haloperidol, 0.5 mg/kg for 3 weeks or 2.5 mg/kg for 5 weeks, did not alter the specific binding of [3H]spiroperidol to dopamine receptors in frontal cortex, whereas both treatments significantly increased binding to striatal dopamine receptors. These findings may be relevant to previous studies demonstrating that the frontal cortex, but not the striatum, is resistant to the development of tolerance to the dopamine metabolite-elevating effects of chronic neuroleptic treatment.

Enduring changes in dopamine receptor cells of pups from drug administration to pregnant and nursing rats.

A decrease in specific [3H]spiroperidol binding to rat caudate tissue and a parallel decrease in sensitivity to apomorphine in eliciting stereotyped behavior was observed in the offspring of rat mothers treated with either haloperidol or alpha-methyl-p-tyrosine-methyl ester during pregnancy. In contrast, evidence of increased dopamine-receptor sensitivity was observed in the pups if haloperidol was administered to their mothers postpartum during nursing rather than during pregnancy.