Dopamine Receptor Supersensitivity Research Articles

Modulation of CNS dopamine receptors by peptides

1. 1. L-prolyl-L-leucyl-glycinamide (PLG), when administered concurrently with neuroleptic drug, blocked the development of dopamine receptor supersensitivity both at the behavioral and biochemical level. 2. 2. Chronic administration of haloperidol resulted in development of cholecystokinin (CCK) receptor supersensitivity in the mesolimbic regions of the brain. There was no change in equilibrium dissociation constant (KD) for CCK binding. 3. 3. The results are discussed in relation to modulation of dopamine receptor by peptides and possible models of Interaction of peptides with dopamine receptors are proposed.

Long-term adaptive changes in striatal dopamine function in response to chronic neuroleptic intake in rats.

Chronic neuroleptic drug administration to rats reverses initial dopamine receptor blockade so that animals exhibit striatal dopamine receptor supersensitivity. This effect may be of functional significance in the whole animal for it is accompanied by increased striatal acetylcholine content and by reversal of the acute increase in striatal acetylcholine release. Continuous drug intake may increase the number of striatal 3H-spiperone binding sites while decreasing the number of 3H-N, n-propylnorapomorphine binding sites. While D-2 adenylate cyclase independent dopamine receptor binding sites increase in number, no change occurs in the number of D-1 sites labelled by 3H-piflutixol despite increased adenylate cyclase activity. Haloperidol and sulpiride differentially alter striatal 3H-acetylcholine and 3H-glutamate release in a manner suggesting selective changes in dopamine receptors lying on striatal cell bodies and on the terminals of corticostriate glutamate terminals. In summary, neuroleptic drugs induce a series of adaptive changes on chronic administration consistent with the development of functional striatal dopamine receptor supersensitivity.

Effects of putative dopamine autoreceptor agonists in pharmacological models related to dopaminergic and neuroleptic activity

The pharmacological profile of 2 proposed selective dopamine (DA) autoreceptor agonists 3-PPP and 3-phenethyl-PP was compared with that of apomorphine in test systems for detection of dopaminergic and antidopaminergic activity. In vitro 3-PPP and 3-phenethyl-PP showed preferential affinity for D-2 DA receptors and only very low affinity for D-1 DA receptors. Accordingly, and in contrast to apomorphine, no stimulation of DA-sensitive adenylate cyclase was observed. A weak to moderate inhibitory activity of all 3 compounds was shown in uptake systems for DA, NA and 5-HT. A weak or no effect on α 1-or α 2-adrenergic receptors was observed. 3-PPP, 3-phenethyl-PP and apomorphine inhibited spontaneous locomotor activity in mice and rats, induced contralateral circling behaviour in 6-hydroxy-DA-lesioned rats and induced emesis in dogs. The DA involvement in these effects was confirmed by antagonistic effects of neuroleptics in all three test systems. Apomorphine was the only compound inducing stereotyped behaviour in normal rats and neuroleptically induced supersensitive mice and inducing ipsilateral circling behaviour in hemitransected rats. 3-PPP did not show activity in several tests for neuroleptic effects in vivo, including inhibition of apomorphine- and methylphenidate-induced stereotyped gnawing, cataleptogenic effect, inhibition of conditioned avoidance response and inhibition of 6,7-ADTN-induced hyperactivity after injection into the nucleus accumbens. In contrast 3-PPP and 3-phenethyl-PP antagonized d-amphetamine-induced stereotyped licking/gnawing and hyperactivity. 3-PPP did not influence the cateleptogenic or methylphenidate antagonistic effect of cis-(Z)-flupentixol or haloperidol. 3-PPP increased the methylphenidate antagonistic effect of spiroperidol and the apomorphine antagonistic effect of cis-(Z)-flupentixol, cis-(Z)-clopenthixol and spiroperidol. It is concluded that 3-PPP and its more potent derivative 3-phenethyl-PP show high selectivity for DA receptors mediating sedation in rodents but that these compounds activate DA receptors mediating emesis and activate denervation supersensitive DA receptors, while not affecting neuroleptic supersensitive DA receptors. The neuroleptic-like activity of 3-PPP and 3-phenethyl-PP is only shown as a d-amphetamine antagonistic effect, indicating a presynaptic site of action. The increase of some neuroleptic effects may have clinical relevance for treatment of diseases associated with DA hyperactivity.

Noneatecholaminergic Treatments of Tardive Dyskinesia

We review the results of more than 120 studies of the treatment of tardive dyskinesia with noncatecholaminergic agents. The disorder is thought to arise from dopamine receptor supersensitivity brought on by long term neuroleptic-induced receptor blockade. Ironically, neuroleptics are the most consistently effective treatment of tardive dyskinesia. Nevertheless, it would be desirable to treat it with other compounds. The most intensively studied drugs are the cholinergics, including physostigmine, deanol, choline, and lecithin, but their efficacy has been equivocal. Anticholinergics, opiates, and tryptophan appear to worsen the syndrome or have no effect. Trials of gamma-aminobutyric acid agonists, lithium, and amantadine also produced mixed results. Effectiveness has been claimed for benzodiazepines, estrogens, and pyridoxine,, but the evidence is scant. A small number of preliminary reports on other treatments are also summarized. We discuss briefly the implications of these studies, but methodological problems limit interpretation.

Demonstration of a new type of dopamine receptor agonist: an indolyl-3-butylamine. Actions at intact versus supersensitive dopamine receptors in the rat forebrain.

Demonstration of a new type of dopamine receptor agonist: an indolyl-3-butylamine. Actions at intact versus supersensitive dopamine receptors in the rat forebrain.

The effect of opioids on striatal calmodulin levels

Phosphorylation of proteins in synaptic membranes of rat striatum by endogenous kinases was quantified by scanning the optical density on radioatograms made from gels after electrophoresis of assay samples. Neither the decreased phosphorylation found in samples from morphine-tolerant rats could be raised to control levels, nor could samples from untreated rats be raised to those found after acute opioid administration by the addition of Ca++ and calmodulin to the assay. However, the addition of opioids in vitro to the assay was able to inhibit the stimulation of protein kinase activity by Ca++ and camodulin. Calmodulin seemed to be transported from membranes to cytosol of striatal synaptosomes from morphine tolerant rats. This phenomenon has been related to striatal dopamine receptor supersensitivity (5, 10), a condition suggested by many kinds of evidence in tolerant animals. After acute administration of etorphine or methionine-enkephalin, the levels of calmodulin were increased in both compartments of striatal synaptosomes. The increased membranal levels may be related to its ease of extraction from the membranes and thus to a physical change in calmodulin.

Antagonizing effect of lithium on the development of dopamine supersensitivity in the tuberoinfundibular system

We investigated wether receptor supersensitivity occurs in the tuberoinfundibular dopaminergic system, as reported in the nigrostriatal and mesolimbic areas. Animals received either haloperidol or saline for 2 weeks. Five days after the last injection of haloperidol, animals pretreated with haloperidol showed a significantly longer lasting inhibition of prolactin (PRL) secretion by apomorphine, compared with the controls. This dopamine receptor supersensitivity was also observed on the 12th, but not the 33rd day after the cessation of haloperidol administration. The effect of lithium on this dopamine supersensitivity in PRL release was investigated. All rat were treated with haloperidol and fed either a diet containing lithium carbonate or a diet without lithium for 2 weeks. Lithium administration with haloperidol resulted in the inhibition of PRL-lowering action of apomorphine at 5 days of withdrawal from haloperidol, indicating that the supersensitivity of dopamine receptors on pituitary lactotrophs were decreased by lithium. This action of lithium may be related to the prophylactic effect of the drug on the manic-depressive disease.

Chronic lithium administration has no effect on haloperidol-induced supersensitivity of pre- and postsynaptic dopamine receptors in rat brain

We have studied the effect of chronic lithium administration on haloperidol-induced dopaminergic supersensitivity in rat brain. Lithium had no effect on haloperidol-induced increases in apomorphine inhibition of dopamine synthesis in the striatum and mesolimbic regions. Similarly, lithium was without effect on haloperidol-induced increases in density of [ 3H]spiperone binding sites in the striatum. These results indicate that lithium has no effect on haloperidol-induced supersensitivity of presynaptic dopamine receptors in the striatum and mesolimbic regions and on postsynaptic dopamine receptors in the striatum.

A second generation catecholamine hypothesis.

The catecholamine hypothesis proposed an increase in functional brain norepinephrine in the manic phase of manic-depressive illness. This paper reviews a secondary hypothesis suggesting that dopamine may be involved in the manic process. Increases in functional dopamine may result from the release of dopamine which is amplified by a supersensitive dopamine receptor that has developed during the depressive phase prior to the onset of mania. Lithium may act, in part, by blocking the development of supersensitive dopamine receptors. Evidence compatible with this hypothesis is reviewed.

Increased striatal acetylcholine after 14 months cis-flupenthixol treatment in rats suggests functional supersensitivity of dopamine receptors

Rats received continuous administration of cis -flupenthixol (0.8–1.2 mg/kg/day) or trans -flupenthixol (0.9–1.2 mg/kg/day) in drinking water for 14 months. The administration of cis -flupenthixol, but not trans -flupenthixol, caused apparent cerebral dopamine receptor supersensitivity. Thus, animals receiving cis -flupenthixol, but not trans -flupenthixol, showed enhanced apomorphine-induced stereotyped behaviour. Dopamine concentration in striatum was not altered by drug treatment but striatal HVA and DOPAC concentrations were reduced in animals receiving cis -flupenthixol, but not trans -flupenthixol. No consistent change in Bmax or K D for specific striatal 3H-spiperone binding was observed after 14 months drug intake. However, in cis -flupenthixol treated animals a 40% increase in Bmax was observed following 2 weeks drug withdrawal. Continuous cis -flupenthixol intake increased striatal acetylcholine concentrations; trans -flupenthixol was without effect. This suggests the apparent increase in cerebral dopamine receptor supersensitivity caused by continuous long-term cis -flupenthixol administration is of functional importance in the intact animal.

The effect of chronic L-DOPA administration on supersensitive pre- and postsynaptic dopaminergic receptors in rat brain

Chronic administration of haloperidol induced supersensitivity of the pre- and postsynaptic dopaminergic receptors in rat brain. The response of the presynaptic receptors was determined by an enhanced inhibitory effect of apomorphine on dopamine synthesis after gamma-butyrolactone injection. This change in the receptor function was detected both in the nigrostriatal and mesolimbic pathways. Haloperidol also increased the 3H-spiperone binding sites in striatal membranes, indicating supersensitivity of the postsynaptic receptors. Subsequent prolonged treatment with high doses of L-DOPA/carbidopa resulted in a decrease in 3H-spiperone binding sites, but had no effect on the supersensitive presynaptic receptors. It is suggested that tardive dyskinesia may be a state of both pre- and postsynaptic dopamine receptor supersensitivity and that chronic L-DOPA treatment may have a differential effect on these sites.

Neuronal mechanisms regulating ethanol effects on the dopaminergic system

Chronic ethanol consumption induces an increase in striatal 3H-Spiroperidol and 3H(−) Sulpiride specific binding by enhancing the affinity between the different dopaminergic recognition sites and the labelled ligands. Dopamine (DA) receptor supersensitivity is also suggested by the enhanced effect of neuroleptics in inducing hypomotility in rats treated with ethanol. The results, obtained by means of the administration of neuroleptics in comparison to ethanol treated rats, indicate a lack of cross tolerance between ethanol and other drugs acting on the dopaminergic recognition sites. These data suggest that ethanol effects on the dopaminergic system are mediated by events involving other neurotransmitter systems.

Differential enhancement of behavioral sensitivity to apomorphine following chronic treatment of rats with (−)-sulpiride and haloperidol

Rat exploratory activity as well as apomorphine-induced hypermotility and stereotyped behavior were assayed following acute (60 min before) or chronic (21 days) administration of sulpiride stereoisomers and haloperidol. Parallel groups of rats were assayed for their hypermotility and stereotyped responses to challenging doses of apomorphine 7 and 21 days after discontinuation of chronic treatments. Following its acute administration, (−)-sulpiride fully antagonized apomorphine-induced hypermotility without affecting the level of animal spontaneous activity and partially counteracted stereotyped behavior. Haloperidol completely suppressed both apomorphine responses and also depressed exploratory activity. Some tolerance to the anti-apomorphine effect of (−)-sulpiride, was observed following chronic administration. After discontinuation of the chronic treatments, the (−)-sulpiride groups exhibited enhanced behavioral sensitivity to apomorphine only with respect to hypermotility, whereas haloperidol groups were supersensitive with respect to both hypermotility and stereotyped responses. The results are discussed in terms of differential dopamine receptor supersensitivity arising from prolonged administration of butyrophenone and substituted benzamide.

Repeated administration of sulpiride for three weeks produces behavioural and biochemical evidence for cerebral dopamine receptor supersensitivity

Administration of sulpiride (2 × 100 mg/kg i.p.) or haloperidol (5 mg/kg i.p.) to rats for 3 weeks with subsequent withdrawal for 3 or 4 days induced cerebral dopamine receptor supersensitivity. Apomorphine-induced stereotyped behaviour after drug withdrawal was enhanced by pretreatment with either haloperidol or sulpiride both of which increased the number of specific striatal binding sites ( B max) for [ 3H]spiperone, [ 3H] N, n-propylnorapomorphine and [ 3H]sulpiride. Neither drug altered the dissociation constant ( K D ) for the ligand binding assays. Striatal dopamine sensitive adenylate cyclase activity was unaltered by such a pretreatment with either haloperidol or sulpiride. The data show that sulpiride, like haloperidol, is capable of inducing behavioural and biochemical supersensitivity of cerebral dopamine receptors.

The effect of chronic bromocriptine and L-dopa on spiperone binding and apomorphine-induced stereotypy.

Chronic treatment with dopamine (DA) agonists has been reported in various paradigms to cause supersensitivity of DA receptors or, contradictorily, subsensitivity of DA receptors. The present study administered 15 mg/kg bromocriptine for 7 days and measured both striatal spiperone binding and apomorphine (AP)-induced stereotypy. A significant decrease in AP-induced stereotypies was observed after chronic bromocriptine treatment, but without a significant parallel decrease in striatal spiperone binding. These results probably do not represent a true agonist-induced subsensitivity, but possibly show that residual bromocriptine in vivo may antagonize AP-induced stereotypy. Since some reports have suggested that L-Dopa may specifically reverse the increases in DA receptor number induced by chronic haloperidol, we also studied the effect of 7 days of L-Dopa treatment after 6-week chronic haloperidol treatment of mice. While chronic haloperidol significantly increased striatal spiperone binding, subsequent L-Dopa treatment did not reverse this biochemical supersensitivity. It is concluded that agonist induction of subsensitivity in the DA system is difficult to reproduce and may depend on highly specific dosage conditions and treatment schedules.

Effects of chronic lithium treatment on dopamine receptors in the rat corpus striatum. II. No effect on denervation or neuroleptic-induced supersensitivity

The influence of chronic dietary lithium administration was evaluated on dopamine receptor supersensitivity in the rat corpus striatum. Supersensitivity was induced with either unilateral destruction of dopamine-containing fibers in the nigrostriatal pathway or with 3 weeks of treatment with haloperidol (HAL). Both treatments elevated [ 3H]spiroperidol binding sites, but in neither case was this increase in ligand binding affected by chronic dietary Li (brain levels 0.8 to 1.2 mEq/l tissue). Our rats receiving 21 daily injections of HAL did show a behavioral supersensitivity to the dopamine agonist, apomorphine, and this effect was attenuated by concurrent treatment with dietary Li (accompanying paper). However, in contrast to previous data 20, this behavioral attenuation could not be linked to the prevention of increased [ 3H]spiroperidol binding in the corpus striatum. Furthermore, co-administration of dietary Li to subjects injected with HAL for 3 weeks did not reverse the increased density of [ 3H]spiroperidol binding sites which developed in the corpus striatum. Neither HAL nor Li treatment altered the affinity of the radioligand for its binding site. In the same animals, neostriatal dopamine-sensitive adenylate cyclase was not affected by either long-term dietary Li or chronic neuroleptic treatment, supporting the view that membrane antagonist and agonist sites differentially adapt to chronic alterations of synaptic input. Taken together, the results are incompatible with the hypothesis that the anti-manic action of Li is related to its ability to prevent dopamine receptor supersensitivity.

Chronic haloperidol treatment increased calcium-dependent phosphorylation in rat striatum

In previous studies, we observed that when rats were chronically treated with haloperidol, there was a significant increase of calmodulin activity in their striatal membranes. Calmodulin is knwon to modulate calcium-dependent protein phosphorylation in neural membranes. In the present study, we found that the total 32P-incorporation in the striatal proteins from chronic haloperidol-treated rats was significantly increased in comparison to saline-treated rats. A majority of the phosphorylation was attributed to the calcium-mediated activity, since it could be blocked by a calcium chelating agent (EGTA). By using EGTA to inhibit phosphorylation, the results indicated that the haloperidol-treated rats had approximately 3.5-fold greater Ca ++-dependent protein kinase activity than the saline-treated rats. Exogenous calcium alone was insufficient to stimulate phosphorylation in the haloperidol-treated rats to the same magnitude as in the saline-treated rats. Calmodulin may be required. 32P-incorporation of two striatal proteins at molecular weight 40 and 52 kilodaltons were markedly stimulated by calcium. Cyclic AMP-mediated phosphorylation seemed to take only a small part in the alteration of total phosphorylation. Therefore, the increase of calmodulin activity and calcium-dependent phosphorylation appears to play a major role in the drug-induced dopamine receptor supersensitivity in rat striatum.

Neuroleptic drug-induced dopamine receptor supersensitivity: antagonism by L-prolyl-L-leucyl-glycinamide.

An animal model of tardive dyskinesia was used to evaluate the potential antidyskinetic properties of the neuropeptide L-prolyl-L-leucyl-glycinamide (PLG). In rats, PLG administered concurrently with the neuroleptic drug haloperidol or chlorpromazine antagonized the enhancement of specific [3H]spiroperidol binding in the striatum that is associated with long-term neuroleptic treatment. The results are discussed in relation to a possible functional coupling of the putative PLG receptor with neuroleptic-dopamine receptor complex and clinical implications for tardive dyskinesia.

Cocaine-induced supersensitivity of striatal dopamine receptors: role of endogenous calmodulin

The effect of cocaine on the binding of specific radioligands to rat striatal dopamine (DA) receptors and on the activation by DA of striatal adenylate cyclase activity was studied in vivo and in vitro. As early as 60 min after an injection of cocaine (20 mg/kg. i.p.) the apparent B max of [ 3H]spiroperidol and [ 3H] N-propylnorapomorphine binding was increased by 37%. In contrast, the affinity of the receptor for the labelled ligands remained unchanged. The injection of cocaine (20 mg/kg. i.p.) also increased the content of membrane-bound calmodulin and the responsiveness of adenylate cyclase to DA stimulation. The activation of adenylate cyclase by sodium fluoride (NaF) or choleratoxin was similar in saline and cocaine-treated rats, indicating that cocaine did not modify the guanosine triphosphate (GTP)-binding protein which couples the cyclase with the DA recognition site. An increase in DA stimulation of adenylate cyclase and B max for the binding of radioligands was also obtained in vitro after a 60 min incubation of striatal slices with cocaine (10 −6 M), but not with lidocaine (10 −6 M). The present data suggest that cocaine may interact with post-synaptic membrane constituents and thereby increase the availability of membrane-bound calmodulin. This mobilization of calmodulin may be the cause for the supersensitivity of adenylate cyclase to activation by DA.

Growth hormone and prolactin stimulation by Madopar in Parkinson's disease.

Madopar, a combination of levodopa with benserazide, induced an inconsistent rise in plasma growth hormone in unmedicated patients with Parkinson's disease and in controls, and a greater growth hormone rise in Parkinsonian subjects on chronic Madopar therapy. In subjects on chronic therapy with levodopa and carbidopa (Sinemet), the growth hormone releasing effect of Madopar was blunted. Madopar increased plasma prolactin (PRL) in controls, unmedicated patients and patients on Madopar therapy while in patients on Sinemet therapy the PRL-releasing effect of Madopar was strikingly reduced. Since these data were interpreted as due to a defective dopamine tone in the hypothalamus of Parkinsonian subjects on Madopar but not Sinemet therapy, a direct dopamine receptor agonist, lisuride was administered. Lisuride, however, elicited a blunted growth hormone response both in patients on Madopar and Sinemet therapy, without revealing a state of supersensitivity of dopamine receptors for growth hormone control in Parkinsonian subjects on Madopar therapy. No difference was present in the PRL-lowering effect of lisuride in the different experimental groups. These findings suggest that: (1) hypothalamic dopamine function is impaired in Parkinsonian subjects on Madopar therapy, preserved in unmedicated patients and enhanced in patients on Sinemet therapy; (2) the endocrine effects observed in Parkinsonian subjects on chronic Madopar therapy may be due to some penetration of benserazide across the blood brain barrier in the region of the hypothalamus; (3) since Madopar and Sinemet are in essence equally effective antiparkinsonian remedies, penetration of benserazide does not occur across the blood brain barrier surrounding the nigrostriatal system.