Dopamine Receptor Supersensitivity Research Articles

Hypophysectomy does not prevent development of striatal dopamine receptor supersensitivity induced by repeated neuroleptic treatment

Hruska et al. (1980) reported that hypophysectomy prevented the onset of dopamine receptor supersensitivity. We have repeated this investigation administering haloperidol (0.75 mg/day) or sulpiride (2×15 mg/day) or saline for 17 days, followed by a 3 day drug washout period, to sham-operated or hypophysectomised rats. Haloperidol or sulpiride pretreatment caused an enhancement of apomorphine-induced stereotyped behaviour and increased the number of specific striatal [ 3H]spiperone binding sites (B max) in both hypophysectomised and sham -operated animals compared to their respective saline controls. We conclude that hypophysectomy does not prevent the onset of striatal dopamine receptor supersensitivity induced by repeated neuroleptic treatment in the rat.

Enhanced response to apomorphine in rats treated with multiple injections of human beta endorphin and its blockade by Pro-Leu-Gly-NH 2 and cyclo (Leu-Gly)

Repeated intraventricular injections of human β-endorphin to rats every eight hours for three days resulted in the development of super-sensitivity of brain dopamine receptors as evidenced by an enhanced locomotor activity response to apomorphine, a dopamine receptor agonist. Daily subcutaneous injections of Pro-Leu-Gly-NH 2 or its cyclic analog, cyclo (Leu-Gly) blocked the enhanced apomorphine-induced stimulation of locomotor activity in β-endorphin treated rats. Thus, the development of brain dopamine receptor supersensitivity induced by chronic β-endorphin administration may be regulated by the hypothalamic peptides.

Increase in rat striatal acetylcholine content by bromocriptine: Evidence for an indirect dopaminergic action

Bromocriptine, at the optimal dose and time of 4 mg/kg, 90 min, increased the content of acetylcholine in the rat striatum by about 30% without affecting the acetylcholine content in other brain regions. Striatal choline acetyltransferase and acetylcholinesterase activities and sodium-dependent high affinity choline uptake were not affected by the in vivo administration or the in vitro incubation with even high amounts of the drug. The increase in striatal acetylcholine by bromocriptine was mediated through the dopaminergic system since pretreatment with pimozide or penfluridol, powerful dopamine receptor antagonists, completely prevented the effect while parachlorophenylaline and phenoxybenzene pretreatment were ineffective. The action of bromocriptine, differently from that of apomorphine, was also blocked upon inhibition of tyrosine hydroxylase by alphamethylparatyrosine, suggesting that intact catecholamine synthesis is necessary for the drug to act. The requirement of dopamine by bromocriptine was further indicated when no potentiation of the cholinergic response to bromocriptine occurred following induction of dopamine receptor supersensitivity by long-term 6-hydroxydopamine lesion of the nigroneostriatal pathway. On the other hand, evidence is presented to show that bromocriptine acts in synergism with dopamine as the latency period for the onset of bromocriptine's cholinergic action was significantly decreased when it was administered in combination with a subthreshold dose of L-dopa, the dopamine precursor. There also was no summation of bromocriptine's increase with apomorphine's increase in striatal acetylcholine content at supramaximal doses possibly indicating that the same population of intrastriatal cholinergic neurons is the common target of both drugs. It is proposed that bromocriptine exerts an inhibitory effect on the striatal cholinergic neurons through a stimulation of the dopaminergic system but, differently from apomorphine, it requires the presence of endogenous dopamine for its action.

Transplanted adrenal chromaffin cells in rat brain reduce lesion-induced rotational behaviour.

Rats with unilateral lesions of substantia nigra pars compacta (SN), the area of the brain containing most dopamine-containing neurones, are a widely recognized animal model of Parkinson's disease1–4. When given dopamine agonists such as apomorphine, such rats rotate in a direction contralateral to the lesion, presumably because of the development of supersensitive dopamine receptors in the striatum ipsilateral to the lesion. When grafts of embryonic SN are placed in the lateral ventricle5,6, or into a transplant cavity7 adjacent to the striatum in animals with SN lesions, this rotational behaviour has been shown to decrease. Histochemical examinations have shown that axons from the grafts have grown into the striatum5–7, and biochemical measurements indicate that dopamine concentrations are increased in areas of the striatum adjacent to the SN grafts6. Nevertheless, an obvious problem with this technique, both for basic research and possible clinical applications, is the requirement for fetal central nervous donor tissue. We now describe how grafts of adrenal medulla can be used with similar effects, involving chromaffin cells.

Drug withdrawal in chronic schizophrenic patients: in search of neuroleptic-induced supersensitivity psychosis.

As a test of the hypothesis that neuroleptics can induce a psychosis secondary to dopamine receptor supersensitivity, we examined the behavioral ratings of 20 symptomatic chronic schizophrenic patients who were withdrawn from neuroleptic drugs and maintained drug free for 4 wk. We hypothesized that, if supersensitivity existed, it might be reflected in a drug-free course characterized by an initial phase of exacerbation followed by improvement (a "hump"). Four patients had such a course. No patient had the inverse of this hypothesized course (improvement followed by relapse). The implications of this finding and problems inherent in testing the supersensitivity psychosis hypothesis are discussed.

Increased central 5-hydroxytryptamine receptor mechanisms in rats after chronic neuroleptic treatment.

1 The behavioural responses of drugs known to act through central 5-hydroxytryptamine (5-HT) mechanisms have been investigated in rats receiving a neuroleptic (trifluoperazine) in their drinking water for 4 to 6 months.2 5-Hydroxytryptophan (5-HTP) induced 5-HT-dependent behaviours including head bobbing and lateral head weaving, reciprocal forepaw treading, tremor, backward walking, body writhing and ;wet-dog' shakes. In doses of 50 to 150 mg/kg, 5-HTP induced more intense behavioural effects in neuroleptic-treated rats than in the control animals.3 Similarly the putative 5-HT agonist, quipazine (1 to 20 mg/kg) and the 5-HT releasing drug, fenfluramine (5 to 20 mg/kg), both induced significantly greater motor responses in the chronically neuroleptic-treated rats.4 A 5-HT uptake inhibitor (femoxetine, 2.5 to 10 mg/kg) had little behavioural effect in either control or trifluoperazine-treated rats.5 Total specific high-affinity binding of radiolabelled 5-HT was significantly increased in crude membrane fractions prepared from the cortex, striatum and substantia nigra of neuroleptic-treated rats compared to control animals.6 High-affinity uptake of radiolabelled 5-HT into striatal slices was similar in experimental and control animals.7 Behavioural and biochemical data would indicate that postsynaptic 5-HT mechanisms are enhanced in rats treated chronically with trifluoperazine. Chronic neuroleptic therapy may thereby induce cerebral 5-HT receptor supersensitivity in addition to the well-documented cerebral dopamine receptor supersensitivity.

Relationship between functional supersensitivity and extent of denervation of dopamine receptors

To investigate the relationship between extent of denervation and development of functionally significant striatal DA receptor supersensitivity rats were given unilateral 6-hydroxydopamine lesions with a range of concentrations (1–9 μg/4 μl) of the neurotoxin. From the wide range of resulting contralateral rotational responses to apomorphine (50 μg/kg SC) and their associated depletions of striatal dopamine, a linear relationship between these parameters was found that indicated 70% depletion of striatal dopamine content as a minimum requirement for the development of functionally significant dopamine receptor supersensitivity in the rotating rat model. Parallels with human neurological disorders are discussed.

Characterization of normal and supersensitive dopamine receptors: effects of ergot drugs and neuropeptides.

Dopamine receptors have been characterized by the use of radiolabelled dopamine agonists and antagonists. Using ibotenic acid induced lesions of the striatum, evidence was obtained that 3H-N-propylnorapomorphine (3H-NPA) binding sites and 3H-bromocriptine binding sites are located both on intrastriatal nerve cells and on extrinsic nerve terminals probably mainly originating in the cerebral cortex. Development of dopamine receptor supersensitivity as evaluated in 6-hydroxydopamine lesioned rats was associated with an 50% increase in the number of 3H-NPA binding sites in the striatum. Furthermore, one year following the 6-hydroxydopamine induced lesion of the dopamine pathways two binding sites for 3H-NPA could be demonstrated in the striatum. However, at this time interval the total number of 3H-NPA binding sites was not increased. The functional significance of these two binding sites for 3H-NPA in the striatum is unknown, but they are probably coupled to the biological effector in view of the marked behavioural supersensitivity demonstrated in these old animals. The dopamine receptor agonists and especially the dopaminergic ergot derivatives have been characterized by studying their affinities for 3H-bromocriptine, 3H-spiperone, 3H-ADTN and 3H-NPA binding sites in vitro. It is suggested that the Ki ratios for agonist and antagonist radioligands may be one useful way to characterize the agonist-antagonist character of the drug. Another important method is to study the effects of dopamine receptor agonists on the specific in vivo binding of 3H-spiperone and 3H-NPA. The correlation analysis of DA agonist affinities for the four radioligands of DA receptors used in the present study give evidence for the existence of at least 3 types of DA receptors. Actions of dopaminergic ergot drugs have been evaluated at supersensitive dopamine receptors. The findings suggest that the shift to the left of the threshold dose to activate supersensitive dopamine receptors could be due to a lowering of the stereoselectivity of agonist interaction at the dopamine agonist sites of supersensitive dopamine receptors. Such a change may explain the highly preferential action of CF 25-397 at supersensitive dopamine receptors, since its affinity for 3H-NPA binding sites was not increased in the present experiments. In agreement with previous work, evidence have also been presented that prolonged treatment with a potent dopaminergic drug, pergolide, can produce a down regulation of normal dopamine receptors by reducing the density of such receptors. Evidence has also been presented that CCK-8 and the desulphated CCK-8 (10(-6) M) can in vitro reduce the number of 3H-NPA binding sites in the striatum. These results indicate that cholecystokinin peptides via activation of cholecystokinin receptors can regulate the movements of the 3H-NPA binding sites across the plane of the membrane in such a way as to make them less available to the external surface of the membrane...

Tardive dyskinesia: Two-year recovery

Tardive dyskinesia has been studied and reported with increasing frequency since the initial paper by Schönecker 1 in 1957. The classical symptoms of tardive dyskinesia (TD) are involuntary movements of the lips, jaws, and tongue. In addition, there may be choreiform (quick, jerking) movements or athetoid (arhythmic, wormlike) movements of the extremities. Characteristically, these movements are inhibited by self-conscious awareness; 2 they are aggravated by anxiety and disappear during sleep. 3,4 In 1973, after several years of controversy, the American College of Neuropsychopharmacology declared that TD was unquestionably linked to neuroleptic administration and suggested that prolonged use of these drugs must be approached with caution. 3 It is postulated that the etiological mechanism is a hyperdopaminergic state resulting from dopamine receptor supersensitivity induced by long-term receptor blockade by neuroleptics. 5 Clinically, symptoms become manifest after neuroleptic withdrawal or dose reduction; symptoms disappear for a time when neuroleptic dose is increased; anticholinergic drugs worsen the symptoms. 3,5 Prevalence of TD in neuroleptic-treated patients varies with the population studied and depends on several factors, notably age. 6,7 Once TD has been discovered in a chronic schizophrenic patient, the clinician needs to make a difficult decision. Should maintenance therapy be continued? 8 What is the natural progression of TD under conditions of clinically appropriate neuroleptic maintenance? In order to answer this question, we did a 2-year follow-up of patients whose TD had been diagnosed in an outpatient survey 2 years previously. 6

Swim-induced grooming in mice is mediated by a dopaminergic substrate.

Grooming induced in mice after a period of swimming was potently and dose-dependently blocked by neuroleptics. The order of potency of the neuroleptics was spiroperidol greater than haloperidol greater than cis-flupenthixol greater than pimozide greater than chlorpromazine greater than thioridazine. The trans isomer of flupenthixol was inactive at 40 microM/kg. The alpha-adrenergic receptor antagonists, phentolamine and phenoxybenzamine, and the catecholamine synthesis inhibitor, alpha-methyl-p-tyrosine were essentially without effect on the grooming behaviour. Amitriptyline inhibited grooming behaviour only in doses which severely affected the animals motor function. Fluoxetine was without effect. Cis-flupenthixol was less active in inhibiting grooming in animals chronically treated with haloperidol than in control animals, indicating the presence of supersensitive dopamine receptors. The data indicate that swim-induced grooming in mice is mediated via dopaminergic systems.

Dopamine receptor supersensitivity and schizophrenia: a review.

Advances in knowledge of brain neurochemistry have lent impetus to the biological study of schizophrenia. A prominent example is the dopamine hypothesis. Increasing additions to and refinements of neurochemical knowledge, particularly the study of receptors, have continued to support biological hypotheses of schizophrenia. A recently proposed hypothesis is that schizophrenic patients suffer from dopamine receptor supersensitivity at certain phases of their illness. The present article selectively reviews data that are relevant to this refinement of the dopamine hypothesis.

Long-term d-amphetamine in rats: Lack of change in post-synaptic dopamine receptor sensitivity

Treatment of rats with d-amphetamine (5 mg/kg) once daily for 25 days did not change locomotor responses, on day 7 of withdrawal, to dopamine (DA) or d-amphetamine into the nucleus accumbens. Nor was there a change in 3H-spiperone binding of caudate nucleus membranes. There was no effect of treatment on the locomotor response of rats to 1.0, 1.5 or 2.0 mg/kg d-amphetamine IP. However, d-amphetamine-treated rats were significantly less sensitive to 0.5 mg d-amphetamine. Although 1, 2 or 3 mg/kg apomorphine produced in same degree of stereotypy in both treatment groups, there was a significant difference in the response of the two groups to 0.5 mg apomorphine, d-amphetamine-treated animals being less sensitive than vehicle-treated animals. No change was found in brain DA levels with or without synthesis inhibition. The present data do not support the hypothesis that chronic treatment of rats with d-amphetamine can produce supersensitive post-synaptic DA receptors.

Long-term application of haloperidol: effects on dopamine and acetylcholine receptors.

Rats were injected daily with haloperidol, 0.5 mg/kg i.p., or pimozide, 2 mg/kg i.p., for a period of 8 or 16 days, respectively. 24 h after the last injection of haloperidol, these rats were challenged with gamma-butyrolactone (GBL) in doses of 200-750 mg/kg i.p. In haloperidol-treated rats, higher doses of GBL are needed in order to increase the rate of dopa accumulation. This finding demonstrates the development of supersensitivity of dopamine (DA) autoreceptors towards endogenously released DA. Pimozide had no effect on the increased rate of dopa accumulation induced by increasing doses of GBL. From this data it is concluded that pimozide in our model is mainly active on postsynaptic DA receptors and haloperidol is active on pre- and postsynaptic DA receptors. In rats treated chronically with daily injections of haloperidol, benztropine, in a dose of 50 mg/kg, induced a decrease in dopa accumulation which was more marked than the decrease seen with benztropine, 50 mg/kg in animals treated with a single injection of haloperidol only. The opiate antagonist, naloxone at a dose of 10 mg/kg, had no effect on these results. Benztropine, 50 mg/kg i.p., had no effect on the increased rate of dopa accumulation induced by GBL, 400 mg/kg. The data support the hypothesis that in parallel to the development of supersensitive postsynaptic DA receptors, there is a development of subsensitivity in cholinergic receptors within the nigro-neostriatal system. Further the results show that a new DA-acetylcholine equilibrium is reached during long-term haloperidol treatment. The implications of these findings in regard to extrapyramidal side effects during long-term neuroleptic treatment are briefly discussed.

The effect of cyclo (Leu-Gly) on chemical denervation supersensitivity of dopamine receptors induced by intracerebroventricular injection of 6-hydroxydopamine in mice

Chemical denervation supersensitivity of postsynaptic dopamine receptors was induced in mice by intracerebroventricular injection of 6-hydroxydopamine. Fourteen days after the 6-hydroxydopamine injection, mice exhibited greater spontaneous locomotor activity and hypothermic response when challenged intraperitoneally with apomorphine. Whole brain levels of dopamine were reduced by 80%. Daily subcutaneous administration of cyclo (Leu-Gly) (50 μg/mouse/day) for 14 days inhibited the development of dopamine receptor supersensitivity induced by 6-hydroxydopamine as evidenced by the blockade of an apomorphine induced locomotor and hypothermic effect. Cyclo (Leu-Gly) did not alter the depletion of brain dopamine induced by 6-hydroxydopamine. These data suggest that cyclo (Leu-Gly) can block the development of dopamine receptor supersensitivity induced by 6-hydroxydopamine without protecting the neurons from dopamine depletion.

PROCEEDINGS OF THE AUSTRALASIAN SOCIETY OF CLINICAL AND EXPERIMENTAL PHARMACOLOGISTS

PROCEEDINGS OF THE AUSTRALASIAN SOCIETY OF CLINICAL AND EXPERIMENTAL PHARMACOLOGISTS

Inhibition of neuroleptic-induced dopamine receptor supersensitivity by cyclo (Leu-Gly)

Behavioral supersensitivity of dopamine receptors was induced in mice by chronic administration of haloperidol (1 mg/kg/day for 21 days) and its subsequent withdrawal for 48 hr. This was evidenced by enhanced spontaneous locomotor activity and hypothermic responses to a dopamine agonist, apomorphine. Concurrent administration of cyclo (Leu-Gly), the enzymatically resistant diketopiperazine, an analog of melantropin release inhibiting factor, blocked haloperidol-induced dopamine receptor supersensitivity as evidenced by the blockade of apomorphine induced responses. Since many studies have linked the development of neuroleptic induced tardive dyskinesias with enhanced sensitivity of brain dopamine receptors, and the latter was blocked by cyclo (Leu-Gly), this agent may be of value in preventing the development of symptoms of neuroleptic-induced tardive dyskinesias.

Effect of long-term L-dopa administration on the dopaminergic and cholinergic (muscarinic) receptors of striatum in 6-hydroxydopamine lesioned rats

L-Dihydroxyphenylalanine (L-Dopa) (200 mg/kg/day) was administered for 30 days to the rats whose nigrostriatal dopamine pathway was lesioned unilaterally with 6-hydroxydopamine and the receptor binding of 3H-spiperone and 3H-quinuclidinyl benzilate ( 3HQNB) was measured in the dopaminergic and muscarinic cholinergic receptors of the striatum. 3H-spiperone binding increased by 73% and 3HQNB binding decreased by 14% in the lesioned side when compared to the control side of L-Dopa-non-treated rats. 3H-spiperone binding was measured in the lesioned sides of L-Dopa-treated and L-Dopa-non-treated rats and was found to have decreased by 21% in the former. In the control side of the L-Dopa-treated lesioned rats, however, 3H-spiperone binding increased by 27% when compared to the opposite striatum of the same rats. 3HQNB binding in the lesioned side of L-Dopa-treated rats was not significantly different from that of the control side statistically. These results suggest that changes in functional equilibrium between the dopaminergic and cholinergic mechanisms influence the muscarinic cholinergic receptors and that supersensitivity of dopamine receptors after lesion of the nigrostriatal pathway also remains after long-term L-Dopa treatment.

Characterization of the striatal dopamine receptor supersensitivity produced by estrogen treatment of male rats

Estrogen treatment of male rats produced an increase in the number of striatal dopamine receptors, without altering their affinity. This effect only occurs in vivo and has a slow onset. Only the β-diastereomer of 17-estradiol was active. Other striatal receptors appeared to be unchanged as was the presynaptic uptake of dopamine. Hypophysectomy completely blocked the response to estrogen as measured on striatal dopamine receptors and on stereotypy, a behavior associated with striatal dopamine receptor stimulation. These results are relevant to the clinical observations of chorea associated with the use of oral contraceptives or with pregnancy.

Hypophysectomy prevents the striatal dopamine receptor supersensitivity produced by chronic haloperidol treatment

Hypophysectomy prevents the striatal dopamine receptor supersensitivity produced by chronic haloperidol treatment

Cyclo (leucylglcine) inhibits the development of morphine induced analgesic tolerance and dopamine receptor supersensitivity in rats

Intraperitoneal administration of cyclo (leucylglycine) (2 and 4 mg/kg of body weight) prior to and during chronic morphinization in male Sprague-Dawley rats inhibited the development of tolerance to the analgesic effect of morphine. Rats were rendered tolerant to morphine by subcutaneous implantation of four morphine pellets, each containing 75 mg of morphine free base, over a 3-day period. The development of tolerance was evidenced by decreased response to morphine and inhibition of tolerance by the greater analgesic response. Cyclo (leucylglycine) also antagonized the decrease in motor activity (sedation) during morphine withdrawal. Dopamine receptor sensitivity was enhanced in morphine tolerant rats as measured by apomorphine (2 mg/kg) induced increases in spontaneous motor activity. Cyclo (leucylglycine) administration also blocked dopamine receptor supersensitivity induced by chronic morphinization. It is concluded that development of tolerance to opiates may be associated with enhanced dopamine receptor sensitivity since both the phenomena were blocked by cyclo (leucylglycine).