An experimental model of tardive dyskinesias

Rats treated continually and chronically with trifluoperazine (ca 3 mg/kg/day) for six months initially developed mild catalepsy and an inhibition of spontaneous locomotor activity; both effects disappeared by three months. An initial increase in dopamine turnover (as measured by levels of homovanillic acid and dihydroxyphenylacetic acid) also disappeared by three months. Apomorphine-induced stereotypy was completely inhibited in drug-treated animals at two weeks, but progressively returned to normal after three months of drug intake. An exaggerated response to apomorphine developed in animals after six months of drug administration. Inhibition of striatal dopamine-stimulated adenylate cyclase found during the first month of drug intake was reversed at three months, a trend exaggerated after continuous drug administration for six months. Specific striatal ³H-spiperone binding affinity decreased acutely, but was increased after six months drug intake; no change in number of receptor sites occurred.These changes suggest that at least striatal dopamine receptors may become “supersensitive” during chronic neuroleptic treatment.     

Prolactin increases the density of striatal dopamine receptors in normal and hypophysectomized male rats

Administration of prolactin to adult male rats, by s.c. injection, significantly increases the density of the striatal dopamine (DA) receptors, without altering the apparent affinity of the receptors for [³H]spiroperidol. Larger doses of prolactin are required to increase the density of the striatal DA receptors in hypophysectomized rates compared to normal rats. These results suggest that prolactin might be the common mediator of the increase in striatal DA receptor density produced by either estrogen or haloperidol administration. Monitoring and/or altering prolactin levels might be informative in neurologic or psychiatric disorders involving striatal DA neurotransmission.     

The effect of chronic levodopa on haloperidol induced behavioral supersensitivity in the guinea pig

The effect of chronic levodopa-carbidopa administration (200 mg/kg for 21 days) on guinea pigs rendered behaviorally supersensitive by the prior administration of haloperidol (.5 mg/kg for 21 days) was examined. Animals who showed an increased behavioral response to apomorphine after chronic haloperidol administration were treated with levodopa-carbidopa and then apomorphine - induced stereotypy was reexamined. Although the chronic levodopa control groups and the chronic haloperidol control remained supersensitive to the behavioral effect of apomorphine, the haloperidol-levodopa group's behavioral response to apomorphine returned to normal. Both chronic dopaminergic antagonist and agonist administration have been demonstrated to induce heightened apomorphine-induced stereotypy and this has been interpreted as a reflection of altered striatal dopamine receptor site sensitivity. The finding that the serial administration of a chronic dopaminergic antagonist followed by a chronic dopaminergic agonist results in a return to normal of a striatal dopamine receptor-dependent behavior suggests that these chronic treatments affect dopamine receptor sites by different mechanisms of action. Since neuroleptic induced dopaminergic supersensitivity in animals is an accepted model of tardive dyskinesia, levodopa may also reverse dopaminergic supersensitivity in patients and might be a potential therapeutic agent in tardive dyskinesia.     

Tyrosine administration decreases serum prolactin levels in chronically reserpinized rats

The injection of tyrosine, 200 mg/kg, decreased serum prolactin levels and elevated hypothalamic (and striatal) concentrations of two dopamine metabolites, dihydroxyphenylacetic acid and homovanillic acid, in chronically reserpinized rats. Tyrosine administration had none of these effects in otherwise untreated rats, and did not block the increase in serum prolactin that occurred 4 hours after a single injection of reserpine. As anticipated, the injection of dopa decreased serum prolactin in all rats. Valine, another large neutral amino acid, did not modify serum prolactin in chronically reserpinized animals. Since prolactin secretion is normally inhibited by dopamine released from the hypothalamus, reserpine treatment probably elevates serum prolactin by depleting the hypothalamus of dopamine. Our data suggest that tyrosine injection suppresses serum prolactin levels in chronically reserpinized rats by enhancing the synthesis and release of hypothalamic dopamine. Thus, administration of tyrosine, dopamine's dietary precursor, can alter physiologic functions that depend on dopamine.     

Comparison of the effects of substituted benzamides and standard neuroleptics on the binding of 3H-spiroperidol in the rat pituitary and striatum with in vivo effects on rat prolactin secretion.

The abilities of sulpiride, metoclopramide, clozapine, loxapine, chlorpromazine, thioridazine, fluphenazine, haloperidol, (+)-butaclamol and RMI 81,582 to displace ³H-spiroperidol from rat pituitary and striatal membranes in vitro were compared to their abilities to stimulate rat prolactin secretion in vivo. There was a significant correlation between the abilities of clozapine, chlorpromazine, thioridazine, fluphenazine, RMI 81,582, haloperidol and (+)-butaclamol to bind to pituitary and striatal spiroperidol binding sites and to stimulate rat prolactin secretion. Loxapine was somewhat more potent and sulpiride and metoclopramide were markedly more potent in their abilities to stimulate prolactin secretion than would be predicted on the basis of their abilities to bind to pituitary dopamine receptors as measured by antagonism of ³H-spiroperidol binding. The abilities of metoclopramide and sulpiride to increase prolactin secretion and to produce anti-psychotic and extrapyramidal effects may be mediated by action at dopamine receptors which differ from those at which classical neuroleptics act, and they may also be mediated by non-dopaminergic mechanisms. Potency as inhibitors of ³H-neuroleptic binding in the rat pituitary or striatum appears to have heretofore unappreciated limitations to predict physiological functions such as prolactin stimulation and anti-psychotic activity.     

Mesolimbic and striatal dopamine receptor supersensitivity: prophylactic and reversal effects of L-prolyl-L-leucyl-glycinamide (PLG)

Functional supersensitivity of mesolimbic and striatal dopamine receptors has been suggested to contribute to the pathogenesis of schizophrenia and tardive dyskinesia. Using the rodent model of chronic administration of the neuroleptic haloperidol, we investigated the possible desensitizing effects of a tripeptide structurally unrelated to dopamine agonists, L-prolyl-L-leucyl-glycinamide (PLG) on mesolimbic and striatal dopaminergic receptor supersensitivity. Administration of PLG either prior to or after chronic haloperidol, inhibited the supersensitivity of dopamine receptors. The results have implications for pharmacological intervention in preventing tardive dyskinesia and relapse psychosis of schizophrenia.     

Narcotic dependence, narcotic action and dopamine receptors.

Acute systematic administration of narcotic analgesics increases the firing rate of nerve cells in the zona compacta of the substantia nigra, causes an increase in the rate of dopamine turnover in striatal and mesolimbic areas of the brain, stimulates prolactin release, inhibits brain self-stimulation and discriminated shock-avoidance, blocks cardiovascular effects of systemically injected dopamine, blocks aggression as well as compulsive jumping in mice treated with DOPA and amphetamine, antagonizes stereotypy induced by apomorphine or amphetamine, and blocks apomorphine-induced vomiting in dogs. Chronic administration of narcotic analgesics results in withdrawal signs upon the cessation of the drug administration. These signs include, tolerance to the increase in striatal dopamine turnover caused by narcotic analgesics or haloperidol, aggressive behaviors which are further stimulated by directly or indirectly acting dopamine-receptor agonists and are blocked by dopamine-receptor blockers, facilitation of recovery from the “lateral hypothalamic syndrome”, an increase in basal levels of striatal adenylate cyclase which shows greater sensitivity to dopamine, and, an enhanced sensitivity to apomorphine-induced reduction of dopamine turnover. It is therefore, concluded that acute administration of narcotic drugs results in an inhibition of dopamine-receptor activity while chronic administration of these drugs results in an increased response of these dopamine receptors to dopamine agonists. Recent experiments on the interaction of other drugs with narcotic analgesics suggest that, unlike the direct action of neuroleptics on the dopamine receptors, the narcotic action on dopamine receptors is indirect.     

Role of estrogens on striatal dopaminergic activity

Studies were undertaken to evaluate the effects of estradiol and prolactin on striatal dopamine receptor activity. Dopamine receptors were quantified in partially purified striatal membranes by equilibrium binding using [3H]spiroperidol. When we investigated whether the D-2 dopamine receptor activity changes during the estrous cycle, the results suggest an increase in dopamine receptor density in diestrous, without modifications in the affinity. The finding that in ovariectomized rats the dopamine receptor binding parameters remained unchanged, suggests that gonadal steroids are not essential in the mechanism of action of this receptor. Results of activity of D-2 dopamine receptors showing that hyperprolactinemia fails to increase the number of these receptors do not support the hypothesis that circulating prolactin regulates the activity of these striatal dopamine receptors. Administration of estradiol benzoate (250 micrograms/kg per day) to hyperprolactinemic rats, by s.c. injection, significantly decreased both the density and the affinity of the striatal dopamine receptors. The present data indicate that, although prolactin does not seem to modify the activity of striatal dopamine receptors, it could modulate the estrogen-induced hypersensitivity of these receptors.     

Dopaminergic supersensitivity in striatum and olfactory tubercle following chronic administration of haloperidol of clozapine

Mice were maintained on diets containing haloperidol or clozapine for 8–10 days. Two days after these drug-containing diets were withdrawn the effects of apomorphine were determined on locomotor activity and on the retardation of dopamine depletion produced by synthesis inhibition with α-methyltyrosine. After either neuroleptic the effects of apomorphine were enhanced when compared with mice maintained on a control diet, suggesting the development of supersensitive dopamine receptors.     

Increase in striatal acetylcholine levels in vivo by piribedil a new dopamine receptor stimulant

Piribedil, (1–2″-pyrimidyl)-4-piperonyl piperazine), an agent proposed for the treatment of Parkinson's disease, was found to increase acetylcholine levels in the rat striatum and diencephalon but not in the mesencephalon, cerebellum or hemispheres. The effect was most marked in the striatum (greater than 100%) and long-lasting (at least 8 hours after a single administration of 60 mg/kg i.p.). Striatal choline levels were also increased by piribedil but did not parallel at all times and doses the effect on acetylcholine. Furthermore, choline levels were increased in all brain regions except the hemispheres. Striatal choline acetyltransferase and acetylcholinesterase were not affected by $\text{in vitro}$ or $\text{in vivo}$ treatment with even high doses of piribedil. α-Methyl-p-tyrosine was ineffective in blocking piribedil while pimozide, a blocker of dopamine receptors, completely antagonized the action of piribedil on striatal acetylcholine. It is concluded that piribedil produced the increase in striatal acetylcholine by directly stimulating dopamine receptors.     

Repeated Reserpine Increases Striatal Dopamine Receptor and Guanine Nucleotide Binding Protein RNA

Abstract: In the present study the effects of repeated administration of reserpine on striatal dopamine receptor and guanine nucleotide binding protein mRNAs were determined. Twenty-four hours after seven consecutive daily injections of reserpine—a treatment that is known to produce functional sensitization of D₁ and D₂ dopamine receptors—the level of striatal D₁ dopamine receptor mRNA was unchanged. However, the level of mRNA for the G protein G_sα was increased by 127%. After extended reserpine treatment for 14 days, levels of both striatal D₁ DA receptor and G_sα mRNAs were elevated by 99 and 78%, respectively. Seven days of reserpine treatment also increased levels of mRNA of the striatal D₂ dopamine receptor and of G proteins G_i2α and G_oα by 200, 79, and 32%, respectively. After 14 days of reserpine treatment the level of striatal D₂ dopamine receptor mRNA was increased by twofold. In contrast, levels of the mRNAs coding for the G proteins G_i2α and G_oα were unchanged. These data suggest that dopamine receptors and their respective G proteins play important roles in the development of sensitization of striatal dopamine receptors during repeated reserpine treatment. Furthermore, the persistent increase in level of striatal G_sα mRNA suggests that this G protein is necessary to maintain supersensitivity of the striatal D₁ dopamine receptor system following long-term dopamine depletion.     

Choline chloride in animal models of tardive dyskinesia

Rats treated chronically with haloperidol show evidence of supersensitive dopamine receptors by increased stereotypy when challenged with apomorphine. When such animals are treated acutely with choline chloride at the time of challenge, no changes in stereotypy were observed. Chronic treatment, either during or after induction of supersensitivity, mitigated stereotypy after challenge. This model of dopaminergic supersensitivity is pertinent to the development of tardive dyskinesia in man after treatment with neuroleptic drugs. Our results with choline chloride in the animal model are consistent with their therapeutic action in tardive dyskinesia.     

The effect of thioridazine on haloperidol induced behavioral hypersensitivity

Behavioral Hypersensitivity (BH) to dopamine agonists occurs following chronic treatment with most neuroleptics including haloperidol. In the present study we observed that the concurrent administration of thioridazine and haloperidol prevented the development of BH. In contrast, another neuroleptic, fluphenazine, coadministered with haloperidol, potentiated the degree of BH relative to animals treated with haloperidol only. In rats already made hypersensitive by chronic treatment with haloperidol, a 4 week subsequent treatment with normal saline, thioridazine alone of thioridazine in combination with haloperidol, produced normal behavioral responsiveness. These results suggest that thioridazine prevents the development of BH and can reverse the expression of haloperidol-induced BH.     

Effect of prolactin and estradiol on rat striatal dopamine receptors

Chronic estrogen treatment has been found to increase the level of rat striatal dopamine receptors. Since it is well known that estrogen treatment increases circulating prolactin levels, we have investigated the possibility that the stimulatory effect of estrogens on dopamine receptors is exerted via prolactin. Ovariectomized female or intact male rats were implanted with three adenohypophyses under the kidney capsule or treated with 17 β-estradiol (10 μg, twice daily) for 2 weeks. In animals of both sexes, the pituitary-implanted and estradiol-treated rats showed higher levels of [³H]spiperone binding to striatal dopamine receptors. This effect of estradiol or pituitary implants on dopamine receptors was further investigated in ovariectomized rats. The pituitary-implanted and estradiol-treated rats had elevated plasma prolactin levels and an increased density of striatal dopamine receptors without alteration of their affinity. The role of the pituitary in the effect of estradiol was next investigated using hypophysectomized female rats treated with 17 β-estradiol (10 μg, twice daily), o-prolactin (500 μg, twice daily) or bearing three anterior pituitary implants. The implants as well as the treatment with estradiol or prolactin increased the level of striatal dopamine receptors in hypophysectomized rats while, as expected, the estradiol-treated animals did not have elevated plasma prolactin levels. The present data indicate that high prolactin levels lead, as observed with chronic estradiol treatment, to an increased density of striatal dopamine receptors. However, the effect of estradiol may not be explained exclusively by increased prolactin levels since a similar stimulatory effect is observed in hypophysectomized animals.     

Enhancement of Hypophysectomy-Induced Dopamine Receptor Hypersensitivity in Male Rats by Chronic Haloperidol Administration

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.     

BRAIN ACETYLCHOLINE AND CHOLINESTERASE: EFFECT OF PHENOTHIAZINES AND PHYSOSTIGMINE INTERACTION IN RATS1

Abstract— The effect of phenothiazines either alone or in combination with physostigmine on whole brain acetylcholine concn and cholinesterase activity has been investigated in male rats. Phenothiazines (chlorpromazine, trifluperazine and thioridazine) when injected alone had no significant effect on brain acetylcholine concentration. Pretreatment with chlorpromazine and thioridazine significantly enhanced the physostigmine-induced increase in brain acetylcholine concn and inhibition of cholinesterase activity. However, trifluperazine had no significant effect on the physostigmine-induced increase in brain acetylcholine concentration and inhibition of cholinesterase activity. The potentiation of the physostigmine-induced increase in brain acetylcholine concn by phenothiazines may be due to (1) increased acetylcholine turnover secondary to the blockade of dopamine receptors by neuroleptic drugs and.     

Effects of cyclo (Leu-Gly) on neurochemical indices of striatal dopaminergic supersensitivity induced by prolonged haloperidol treatment

The effects of a prolonged treatment with cyclo (Leu-Gly) and/or haloperidol on biochemical parameters indicative of striatal dopamine target cell supersensitivity have been investigated in the rat. When given acutely, cyclo (Leu-Gly) (2 mg/kg sc) did not affect striatal homovanillic acid, dihydroxyphenylacetic acid and acetylcholine levels both under basal conditions or after acute haloperidol (1 mg/kg ip) treatment. When given concomitantly with haloperidol (infused by means of osmotic minipumps at a rate of 2.5 μg/h sc) for 14 days, cyclo (Leu-Gly) (2 mg/kg sc once daily) failed to prevent the fall of striatal dopamine metabolites observed 2 days following withdrawal and the tolerance to the elevation of dopamine metabolites which occurs in response to challenge with the neuroleptic during withdrawal. Prolonged treatment with cyclo (Leu-Gly) also failed to affect the tolerance to the decrease of striatal acetylcholine levels which occurs under chronic haloperidol treatment. These data suggest that the mechanism whereby cyclo (Leu-Gly) inhibits the development of neuroleptic-induced dopaminergic supersensitivity does not involve an action of the peptide on nigro-striatal dopaminergic and striatal cholinergic neurons and is probably exerted distally to both dopaminergic and cholinergic synapses.     

Evidence for a peripheral dopaminergic mechanism in the antihypertensive action of lergotrile

Lergotrile (0.5 mg/kg, i.p.) lowered blood pressure significantly in spontaneously hypertensive rats. This effect was antagonized by pretreatment with haloperidol, pimozide, or domperidone. In normotensive rats, administration of haloperidol or domperidone rapidly increased serum prolactin levels. Haloperidol also increased striatal levels of dihydroxyphenylacetic acid and homovanillic acid; however, domperidone did not, which confirms that this latter blocker probably acts primarily as a $\text{peripheral}$ dopamine antagonist. Taken together, these data suggest that lergotrile lowers blood pressure in hypertensive rats mainly by stimulating $\text{peripheral}$ dopamine receptors.     

Tyrosine availability and dopamine synthesis in the striatum: studies with gamma-butyrolactone

The administration of tyrosine (200 mg/kg) to adult male rats significantly enhanced the increase in striatal dopamine (DA) levels that followed gamma-butyrolactone (GBL) injection. Tyrosine injection also stimulated the rise in striatal dihydroxyphenylalanine (DOPA) accumulation after injection of m-hydroxybenzylhydrazine dihydrochloride (NSD-1015) that resulted from GBL administration. These results identify a new paradigm in which an increase in the brain levels of tyrosine enhances the rate of formation of dopamine. In addition, They support the notion that tyrosine hydroxylase must be “activated” in order for tyrosine availability to influence DA synthesis.     

Adaptive changes in sigma and phencyclidine receptors during the long-term use of haloperidol and raclopride in rats

The experiments on male albino rats have shown that 15 days haloperidol (0.5 mg/kg) and raclopride (1 mg/kg) treatment, but not acute administration, causes the increase of density of sigma receptors in the brain. The number of phencyclidine receptors was also elevated, but this increase was not statistically evident. The behavioral effects of ketamine (5 mg/kg) were evidently decreased after long-term haloperidol and raclopride treatment. The motor stimulation and stereotyped behavior induced by apomorphine (0.15 mg/kg) were increased only after treatment of haloperidol, but not raclopride. It seems probable that repeated neuroleptic (haloperidol and raclopride) treatment causes the hyposensitivity of sigma and phencyclidine receptors, despite the increase of their number. It is possible that this change is related to the depolarization inactivation of dopamine neurons caused by repeated neuroleptic administration.