Neuroleptic-induced striatal dopamine receptor supersensitivity in mice: Relationship to dose and drug

Clozapine and molindone administered to mice for 21 days did not elevate the density of striatal ³H-spiperone binding sites at doses clinically equivalent to 1.5 mg/kg haloperidol, which elevated binding by 29%. Thioridazine (25 mg/kg) elevated binding by 25%. It appears that clinically equivalent doses of clozapine and molindone have reduced ability to induce striatal D-2 dopamine receptor supersensitivity. These data are discussed in relationship to in vitro potencies and toxicity. The dose-response relationship of chronic haloperidol treatment and specific striatal ³H-spiperone binding was complex, i.e., binding was elevated at all doses, but the dose-response curve was concave upward. These data suggest that supersensitization is a complex interactive phenomenon comprised of elevation of striatal D-2 dopamine receptor density and other compensatory mechanisms. Present address: Department of Psychiatry, Medical College of Pennsylvania 3200 Henry Avenue, Philadelphia, PA 19129     

Differential effects of continuous administration for 1 year of haloperidol or sulpiride on striatal dopamine function in the rat

Administration of haloperidol (1.4–1.6 mg/kg/day) for up to 12 months or sulpiride (102–109 mg/kg/day) for between 6 and 12 months increased the frequency of purposeless chewing jaw movements in rats. N,n-propylnorapomorphine (NPA) (0.25–2.0 mg/kg SC) did not induce hypoactivity in haloperidol-treated rats at any time; sulpiride treatment for 9 and 12 months caused a reduction in the ability of NPA to induce hypoactivity. Haloperidol, but not sulpiride, treatment enduringly inhibited low dose apomorphine effects (0.125 mg/kg SC). After 12 months, sterotypy induced by high doses of apomorphine (0.5–1.0 mg/kg) was exaggerated in haloperidol-, but not sulpiride-treated rats.B_max for specific striatal ³H-spiperone binding was increased by haloperidol, but not sulpiride, treatment throughout the study. B_max for ³H-NPA binding was elevated only after 12 months of both haloperidol and sulpiride treatment. B_max for ³H-piflutixol binding was not alfered by chronic haloperidol or sulpiride treatment. Striatal dopamine-stimulated adenylate cyclase activity was inhibited for the 1st month of haloperidol treatment, thereafter returning to control levels; dopamine stimulation was increased after 12 months of sulpiride treatment. Striatal acetylcholine content was increased after 3 and 12 months of treatment with haloperidol, but was not affected by sulpiride.Chronic administration of sulpiride does not induce identical changes in striatal dopamine function to those caused by haloperidol.     

Effects of ethanol on turnover and function of striatal dopamine

Acute oral administration of ethanol increased the rate of depletion of dopamine in the striata of rats injected with -methyl-p-tyrosine. This effect was eliminated by pretreatment with atropine or by lesioning of the striato-nigral tract. Ethanol also attenuated the inhibitory effect of apomorphine on turnover of striatal dopamine. Unilateral injection of ethanol into the neostriatum of rats followed by intraperitoneal injection of either apomorphine or amphetamine elicited marked ipsilateral head-to-tail body turning. This turning was blocked by pretreatment with haloperidol. Chronic intubation of ethanol to rats enhanced contralateral body turning elicited by unilateral intrastriatal injection of dopamine. Injection of 6-hydroxydopamine into the substantia nigra led to denervation supersensitivity of dopaminergic functions in the neostriatum. This effect was not seen in rats that were given ethanol postinjection of 6-hydroxydopamine. These results suggested that ethanol has an inhibitory effect on the nigrostriatal dopaminergic system.     

A comparison of striatal and mesolimbic dopamine function in the rat during 6-month trifluoperazine administration

Previous work has shown that 6–12 months continuous trifluoperazine (TFP) administration to rats causes striatal dopamine receptor supersensitivity. We have now replicated our original findings in the striatum and report concurrent changes in mesolimbic dopamine function during chronic TFP (2.8–4.0 mg/kg/day) administration for 6 months. Initial inhibition of apomorphine-induced stereotyped behaviour, which lasted for 2 weeks after the beginning of drug administration, was replaced by an exaggerated response to apomorphine (0.5 mg/kg SC) after 6 months drug intake. Striatal dopamine sensitive adenylate cyclase activity was inhibited at 1 and 3 months, but by 6 months was enhanced compared to control values. Mesolimbic adenylate cyclase activity was inhibited after 2 weeks and thereafter returned to control levels. Dopamine-identified ³H-spiperone binding sites (B_max) in the striatum were increased by 2 weeks, reduced at 1 month and increased again at 6 months. In mesolimbic areas B_max was increased at 2 weeks and 1 month but thereafter returned to control levels. The dissociation constant (k _D) of specific ³H-spiperone binding was increased in the striatum and mesolimbic areas at 1 month and 2 weeks respectively. The results show differential changes in dopamine function in striatal and mesolimbic brain areas during 6 months continuous TFP administration to rats.     

Dopamine-receptor binding and adenylate-cyclase activity in mouse striatal tissue in the supersensitivity phase after neuroleptic treatment

The specific binding of ³H-labelled haloperidol (³H-Hal) and the basal and dopamine-stimulated adenylate-cyclase activity in vitro were investigated in mice treated with a single dose or with repeated doses of neuroleptic drugs. These dose regimens are known to induce behavioural supersensitivity and to decrease dopamine synthesis and release a few days after cessation of dosage.Shortly after a single dose of teflutixol (5 mg/kg i.p.) the binding of ³H-Hal was reduced to very low levels. Four and five days later the apparent number of receptor-binding sites was slightly reduced. The binding returned to normal levels after 6 days. The reduced binding most likely reflects the receptor blockade induced by teflutixol. Four days after treatment both basal and dopamine-stimulated adenylate cyclase were within normal limits. Six days following a single dose of piflutixol (0.08 mg/kg i.p.) a light increase in dopamine-stimulated adenylate cyclase activity was observed. Three days after repeated doses of haloperidol (1.25 mg/kg p.o. daily for 5 days), both basal and dopamine-stimulated adenylate cyclase were unchanged. After 3 weeks treatment with teflutixol (5 mg/kg i.p. daily), the specific binding of ³H-Hal was slightly reduced 5 days after, but almost equal to controls 8 days after the last dose.The data presented neither support nor reject the hypothesis of an increased number of DA receptors in the supersensitivity phase after neuroleptic treatment of mice.     

Brain tyrosine depletion attenuates haloperidol-induced striatal dopamine release in vivo and augments haloperidol-induced catalepsy in the rat

Rationale There are conflicting reports as to whether alterations in tyrosine levels affect functional indices of striatal dopamine (DA) transmission. Since the DA antagonist haloperidol (HAL) increases striatal DA release and induces catalepsy through its actions on striatal DA systems, it provides a useful paradigm to assess both neurochemical and behavioral effects of lowering brain tyrosine levels.Objectives To determine how brain tyrosine depletion affects HAL-induced catalepsy and striatal DA release in awake, freely moving rats.Methods In male rats, a control or tyrosine- and phenylalanine-free neutral amino acid solution NAA(–) (IP) was administered 30–60 min prior to HAL (IP). In one cohort, striatal microdialysate was assayed for DA levels. In a parallel cohort, catalepsy was measured using the bar test.Results NAA (–) reduced striatal tyrosine levels by 60%. The latter did not affect basal striatal DA release, but consistently delayed the attainment of maximal HAL-induced (0.19 mg/kg and 0.25 mg/kg SC) striatal DA release; the latter was abolished by administration of tyrosine. NAA(–) also potentiated HAL-induced catalepsy.Conclusions Acute brain tyrosine depletion attenuates HAL-induced striatal DA release and potentiates haloperidol-induced catalepsy. Both effects can be reversed by administration of tyrosine. Overall, the data indicate that tyrosine depletion affects both neurochemical and behavioral indices of striatal DA release.     

Hypophysectomy fails to affect the supersensitivity of striatal dopamine target cells induced by prolonged haloperidol treatment

The influence of hypophysectomy on biochemical indices of striatal dopamine target cell supersensitivity induced by prolonged haloperidol treatment was investigated in the rat. Hypophysectomy itself did not modify dihydroxyphenylacetic acid (DOPAC) levels but slightly enhanced acetylcholine concentrations in the striatum. Hypophysectomy failed to affect the ability of haloperidol, apomorphine and pergolide to alter these biochemical parameters after acute administration. Prolonged administration of haloperidol (by means of osmotic minipumps delivering 2.5 micrograms/h) for 14 days caused a decrease in DOPAC and an increase in acetylcholine levels in the striatum during withdrawal; these effects were of a similar magnitude in sham-operated and hypophysectomized rats. Moreover, there was a similar degree of tolerance to the elevation of DOPAC and to the diminution of acetylcholine concentrations in striatum in response to challenge with haloperidol during withdrawal in sham-operated and hypophysectomized animals. Finally, a similar supersensitive biochemical response to pergolide (decrease in DOPAC and increase in acetylcholine levels) was observed in both hypophysectomized and sham-operated animals after prolonged haloperidol treatment. These data suggest that hypophyseal factors do not affect the development of striatal dopamine target cell supersensitivity caused by prolonged haloperidol treatment.     

Changes in dopamine synthesis rate in the supersensitivity phase after treatment with a single dose of neuroleptics

The changes in ¹⁴C-dopamine accumulation formed from ¹⁴C-tyrosine in mice after treatment with three neuroleptics, cis (Z)-flupenthixol, fluphenazine, and haloperidol, were followed for 6 days. The neuroleptics all changed DA synthesis rate in the same way, initially causing an increase which was followed by a decrease after approximately 3 days. The results are compared with pharmacological results (Christensen et al., 1976) and there seems to be a very close correlation between receptor blockade and increase in DA synthesis on the one hand and on the other hand receptor supersensitivity and decrease in DA synthesis, as was also shown previously for teflutixol (Hyttel, 1975). It is concluded that the changes in receptor activity are always followed by compensatory changes in DA synthesis rate.     

Chloroethylnorapomorphine,a proposed long-acting dopamine antagonist: Interactions with dopamine receptors of mammalian forebrain in vitro

N-Chloroethylnorapomorphine (NCA) interacts with homogenates of rat corpus striatum to block subsequent stimulation of cyclic AMP synthesis by 50 μM dopamine (DA) (IC₅₀ 30 μM). The 10-O-methylated (12-monophenolic) analog of NCA is weaker; an O,O′-diester of NCA is inactive. The NCA-induced inhibition is counteracted by coincubation with DA or apomorphine, but not norepinephrine. Blockade by NCA is non-competitive vs. DA and not readily reversed by washing. NCA also competes for binding of ³H-apomorphine to subsynaptosomal calf caudate membranes (IC₅₀ 285 nM) with greater potency than the monophenolic or diester analogs. NCA may represent a unique long-acting antagonist of DA receptors.     

Differences in the time course of dopaminergic supersensitivity following chronic administration of haloperidol,molindone, or sulpiride

The onset and persistence of changes in 3H-spiroperidol binding to dopamine (DA) D2 receptors were examined in rat mesolimbic and striatal regions following daily administration of haloperidol, molindone, or sulpiride for 3, 7, 14, or 28 days. Neuroleptic dose equivalencies were determined by inhibition of 3H-spiroperidol in vivo binding in several rat brain regions. Changes in locomotor and stereotyped responses to the specific DA D2 agonist quinpirole were examined 3 days after the last treatment dose. Haloperidol or molindone administration increased mean stereotypy scores and striatal DA D2 receptor densities throughout the 28-day treatment period. In contrast, mesolimbic DA D2 receptor densities were transiently increased and returned to control values after 28 days of haloperidol or molindone treatment. Sulpiride treatment increased mean stereotypy scores and striatal B_max values, but had no effect on locomotion or mesolimbic dopamine receptor density. Additionally, the magnitude of change in the various measures of brain DA function varied among the three neuroleptic treatment groups. Results from this study suggest that mesolimbic and striatal brain regions differ in their response to long-term neuroleptic administration and that drug choice may influence the magnitude of neuroleptic-induced dopaminergic supersensitivity.     

Hyperprolactinemia fails to increase striatal dopamine receptors in male and female C57BL/6J mice

Mice were administered prolactin by either homotypic anterior pituitary grafts (4 weeks) or subcutaneous osmotic pumps containing ovine prolactin (1 week). The pituitary grafts produced considerably greater elevations of circulating prolactin than the osmotic pumps. In neither case was any change detected in striatal [3H]spiperone binding to dopamine receptors. These results are discussed in the context of contradictory evidence obtained with rats.     

On the involvement of a tonic dopamine D2-autoinhibition in the regulation of pulse-to-pulse-evoked dopamine release in the rat striatum in vivo

The dopamine overflow evoked by trains of electrical stimulation pulses applied to the ascending dopaminergic pathway was measured with continuous amperometry in the striatum of anesthetised rats. As previously observed in in vitro studies, a pulse by pulse analysis showed a fall in dopamine overflow evoked by pulses 2 to 6, compared to the response evoked by pulse 1. However, in contrast with in vitro findings, the present in vivo data showed that the dopamine receptor antagonist haloperidol i) completely reverses the fall in dopamine overflow between pulse 1 and subsequent pulses, ii) enhances the dopamine overflow elicited by pulse 1. These results suggest that in vivo, both basal and pulse-evoked dopamine overflow results in stimulation of dopamine D2-type autoreceptors and therefore in regulation of dopamine release. Received: 2 December 1996 / Accepted: 28 February 1997     

Chronic haloperidol during development attenuates dopamine autoreceptor function in striatal and mesolimbic brain regions of young and older adult rats

The effects of chronic haloperidol administration during the prenatal and preweanling periods on dopamine autoreceptor function were examined in striatum, olfactory tubercles, and nucleus accumbens of young (2–3 month) and older (12–13 month) adult rats. In striatum of young and older adult rats that had been chronically treated with haloperidol early in life, as well as in the nucleus accumbens of older adults receiving early chronic haloperidol, gamma-butyrolactone (GBL) did not induce significant increases in dopamine levels. In olfactory tubercles of young adults that had received early chronic treatment with haloperidol, apomorphine pretreatment failed to reverse the observed GBL-induced increase in dopamine levels. Thus, dopamine autoreceptor function appears to be attenuated in rats chronically treated with haloperidol during early development, in contrast to reports of autoreceptor supersensitivity following neuroleptic treatment in adulthood.This research was supported in part by National Institute of Mental Health Grant R01MH35761 and a BRSG Grant S07RR07149-09 awarded by the Biomedical Research Support Grant Program, Division of Research Resources, National Institutes of Health.     

Unilateral striatal dopamine denervation: Reduced motor inhibitory effects of dopamine antagonists revealed in models of asymmetric and circling behaviour

Summary Circling and asymmetric behaviours to apomorphine (dopamine agonist/antagonist) challenge were studied in rats with unilateral striatal electrolesions or 6-hydroxydopamine (6-OHDA) lesions, each induced by combined lesions at 3 striatal locations, to allow an assessment of drug action on normal receptors in the intact striatum or supersensitive receptors in the lesioned striatum respectively. The minimally effective dose of 6-OHDA (given in the presence of DMI and tranylcypromine) to cause functional change was 3×8 g, with 3×32 g providing maximal change. Electrolesions were shown histologically to be confined to striatal tissue, and dopamine depletions caused by 6-OHDA were selective for the striatum.Temporal differences were recorded for onset of asymmetry and circling behaviour, both between behaviours and between lesions. Thus, asymmetry developed during the 2nd–4th days after 6-OHDA lesion but circling developed more abruptly on postoperative days 10–12. In contrast, both asymmetry and circling behaviours were apparent from the first day following electrolesion. The dose-dependent effects of apomorphine were apparent at much lower doses in 6-OHDA lesioned than electrolesioned rats. This potency difference was also demonstrated for two further dopamine agonists, 2-di-n-propylamino-5,6-dihydroxytetralin and SK & F 38393. In contrast, the agonist-induced asymmetric and circling behaviours of electrolesioned rats were some 9–44 times more sensitive than those of 6-OHDA lesioned rats to antagonism by the neuroleptic agents haloperidol, -flupenthixol and oxiperomide, although tiapride antagonism was very similar in both the electrolesioned and 6-OHDA-lesioned rats. Thus, selective striatal denervation techniques are used to show that asymmetric and circling behaviours can be differentially induced and manipulated, and that the increased sensitivity (over electrolesions) of 6-OHDA lesioned rats to dopamine agonist action to induce these behavioural effects is associated with a reduced sensitivity to neuroleptic activity to reduce the asymmetric and circling responses.     

Effect of apomorphine and nigrostriatal lesions on aggression and striatal dopamine turnover during morphine withdrawal: Evidence for dopaminergic supersensitivity in protracted abstinence

Reliable aggression was seen in rats which were grouped 30 days after undergoing continuous withdrawal from morphine. This withdrawal aggression, associated with long-lasting effects of morphine dependence, was blocked by morphine or lesions of the nigrostriatal bundle, but not by lesions of the median forebrain bundle. When the nigrostriatal lesioned rats were treated with a small dose of apomorphine, the aggression was reinstated. Apomorphine reduced the turnover of dopamine in the 30-day withdrawn rats at doses which were ineffective in similarly housed non-dependent rats. These results suggest that animals undergoing protracted morphine abstinence show aggression due to a latent dopaminergic supersensitivity, similar to that previously reported during acute narcotic withdrawal.     

8-OH-DPAT, a 5-HT1A agonist and ritanserin, a 5-HT2A/C antagonist, reverse haloperidol-induced catalepsy in rats independently of striatal dopamine release

In this study, both catalepsy and changes in extracellular levels of striatal dopamine (DA) and dihydroxyphenyl acetic acid (DOPAC) induced by the typical neuroleptic haloperidol (HAL) were simultaneously assessed, using intracerebral microdialysis in freely moving rats, in the presence of either the 5-HT_1A agonist 8-OH-DPAT or the 5-HT_2A/C antagonist ritanserin. HAL (1 mg/kg, SC) elicited a strong cataleptic state, reaching its maximal intensity (about 240 s) 2 h after the drug administration. This effect was paralleled by a long-lasting enhancement of striatal DA and DOPAC extracellular levels, reaching 230 and 350% of basal values, respectively. 8-OH-DPAT (0.1 mg/kg, SC) given 2.5 h after, and ritanserin (0.63 and 1.25 mg/kg, IP), given 15 min prior to HAL, significantly reduced the neuroleptic-induced catalepsy. However, both 5-HT agents failed to modify basal DA and DOPAC striatal outflow as well as the stimulatory effect of HAL on these parameters. It can thus be concluded that the anticataleptic effect of these compounds is not related to an alteration of DA release within the striatum. Received: 29 August 1996/Final version: 25 November 1996     

Effects of estrogen on striatal dopamine receptor function in male and female rats

The present study compares, biochemically and behaviorally, the effect of estrogen on central dopamine (DA) function in male and female rats. Estrogen has no direct effect in vitro on DA receptors from striatal tissue of male or female rats. In vivo administration of 17β-estradiol valerate to male or long-term ovariectomized female rats significantly increases the density of the striatal DA receptors by about 20 percent. Behaviorally, normal female rats have more intense stereotypy produced by apomorphine (APO stereotypy), regardless of the phase of their estrous cycle, than normal male rats, while the density of striatal DA receptors is equal. Estrogen administration to male rats increases their APO stereotypy. Normal intact female rats have no changes in APO stereotypy after the administration of estrogen. However, ovariectomy of female rats increases APO stereotypy, and estrogen administration decreases APO stereotypy back to the levels observed in normal intact female rats. In the male rat there is a good correlation between the increased striatal DA receptor density and the increased APO stereotypy, but in the female rat factors other than striatal DA receptor density appear to the important in the regulation of APO stereotypy.     

Effects of amphetamine and amfonelic acid on the disposition of striatal newly synthesized dopamine

A comparison of the in vivo biochemical actions of the psychotomimetic central stimulants, d-amphetamine (d-AMPH) and amfonelic acid (AFA), on the metabolism of rat striatal newly synthesized [3H]dopamine (DA) was made by pulse labeling with [3H]tyrosine. No evidence for the formation of the alcoholic DA metabolites [3H]3-methoxy-4-hydroxyphenylethanol (MOPET) or [3H]3,4-dihydroxyphenylethanol (DOPET) was found in control or drug-treated animals. Both [3H]3,4-dihydroxyphenylacetic acid (DOPAC) and [3H]homovanillic acid (HVA) concentrations were increased by AFA in the presence of haloperidol, while [3H]DA content was decreased. In contrast, d-AMPH, in the presence of haloperidol, decreased [3H]DOPAC and increased [3H]DA, even in monoamine oxidase-blocked rats. Thus monoamine oxidase inhibition did not appear to be a major factor in the action of amphetamine to increase [3H]DA, but cannot be excluded as a contributing factor to the lowering of [3H]DOPAC. Similar actions of d-AMPH were seen on preformed DA. Amphetamine may release newly synthesized DA in such a way that some of the released DA enters the neuronal storage system.     

An involvement of dopamine in higher order choice mechanisms in the monkey

Low doses of amphetamine induce choice perseveration in an object discrimination task under conditions where such perseveration either increases or decreases the number of rewards obtained as compared to chance performance. Neither stereotyped motor actions nor repetitive choice of position contributed to this effect which could be blocked by pre-treatment with the neuroleptic haloperidol. These results demonstrate that higher order choice mechanisms may involve dopamine systems in the primate.