Dopamine Receptor-blocking Drugs Research Articles

Dopamine 1-like receptor in the brain holds key to zombie cockroach transformation

It's a grizzly scene; a female jewel wasp (Ampulex compressa) wrestles an American cockroach (Periplaneta americana) to the ground. But what follows is a masterclass in neurosurgery. Following a precise sting aimed at the first bundle of nerves in the body, immobilising the cockroach's front legs, the wasp then deals its coup de grâce through the neck, aiming a second sting directly into a region of the brain known as the central complex, transforming the cockroach into a zombie-incubator for her egg. ‘Biochemical analysis of the venom shows the presence of [the neurotransmitter] dopamine’, says Frederic Libersat from Ben Gurion University of the Negev, Israel, adding that the neurotransmitter is entirely responsible for the initial stage of the transformation, when the cockroach begins to groom obsessively. However, it wasn't clear which of the two possible dopamine receptors (D1-like receptor or D2-like receptor) in the cockroach brain could be mediating the neurotransmitter's gruesome effect. So, Stefania Nordio (Ben Gurion University of the Negev) and Libersat set about bamboozling the cockroach's nervous system with drugs to identify which receptors are responsible for the deadly transformation that robs the insects of free will.‘These experiments require some technical skill and lots of practice’, says Libersat, who chose a series of drugs that selectively activate or disable the dopamine receptors in the cockroach's brain, to identify which receptors are targeted by the wasp's mind-bending venom. Injecting a drug that specifically activates the D1-like receptor into the central complex, Nordio and Libersat watched the insects as they ceased ambling around the arena and settled down to grooming, as if they'd been stung. However, the cockroaches that were injected with a drug that activates the D2-like receptor did not behave as if they had been stung and continued wandering around. The D1 receptor is the key receptor that controls the cockroaches’ urge to settle down and groom.The duo then injected cockroaches with a drug that blocks both dopamine receptors and waited a few hours before releasing jewel wasps in with the cockroaches to see if the drugs could prevent the wasps’ venom cocktail from disabling the cockroaches. Sure enough, the cockroaches were protected from the wasps’ stings, continuing to stroll around the arena even after being stung 6 h after the drug was applied. In addition, selectively blocking the D2 receptor with a drug, leaving the D1 receptor responsive, left the cockroaches vulnerable to the wasps’ stings, while the cockroaches treated to prevent the D1 receptor from responding to the toxic venom continued moving around the arena unaffected, providing more evidence that the D1 receptor is essential for initiating the transformation.Finally, the team tested the protective powers of the dopamine receptor blocking drugs to find out whether the dopamine receptors are targeted by wasp venom later in the cockroach's zombie transformation. Treating the cockroaches with a drug before letting the wasps loose, the team kept an eye on the stung insects for 2 days to find out whether they lost the ability to flee. Initially the cockroaches were unable to make a run for it. However, a day after being stung, when most cockroaches can no longer walk independently, the cockroaches that had been pre-treated with the drug had regained their free will and could make a dash for it; the wasp venom was targeting both dopamine receptors to rob the zombies of the ability to walk independently.So, jewel wasp venom specifically targets the D1 receptors in the cockroach brain to trigger the first stage of the zombie transformation, while both receptors rob the cockroach of the ability to walk unaided as the mind-altering venom takes hold.

Tardive dyskinesia

Tardive dyskinesia is a group of hyperkinetic and hypokinetic movement disorders, following the administration of dopamine receptor-blocking drugs. The severity of these syndromes varies from soft forms to the development of life-degrading situations. Phenomenologically tardive dyskinesia can be represented both in isolation and in various combinations. Recognition of these syndromes early in the development of tardive dyskinesia can optimize therapeutic treatment and reduce the risk of severe complications. As a means of treatment, deutetrabenazine or valbenazine are used as first-line drugs, with resistance to therapy and in severe cases, drugs of other groups are used (amantadine, baclofen, botulinum toxin type A, clonazepam, donepezil, gabapentin, ginkgo biloba, levetiracetam, melatonin, pregabalin, thiamine, verapamil, vitamin B6, vitamin E). Our own experience of 12 patients with tardive dystonia showed the effeciency of local injections of botulinum toxin.

Constructing the Immune Signature of Schizophrenia for Clinical Use and Research; An Integrative Review Translating Descriptives Into Diagnostics.

Schizophrenia is considered a syndrome comprised by several disease phenotypes, covering a range of underlying pathologies. One of these disease mechanisms seems to involve immune dysregulation and neuroinflammation. While the current dopamine receptor-blocking antipsychotic drugs decrease psychotic symptoms and prevent relapse in the majority of patients with schizophrenia, there is a huge need to explore new treatment options that target other pathophysiological pathways. Such studies should aim at identifying robust biomarkers in order to diagnose and monitor the immune biophenotype in schizophrenia and develop better selection procedures for clinical trials with anti-inflammatory and immune-modulating drugs. In this focused review, we describe available methods to assess inflammatory status and immune disturbances in vivo. We also outline findings of immune disturbances and signs of inflammation at cellular, protein, and brain imaging levels in patients with schizophrenia. Furthermore, we summarize the results from studies with anti-inflammatory or other immune-modulating drugs, highlighting how such studies have dealt with participant selection. Finally, we propose a strategy to construct an immune signature that may be helpful in selecting and monitoring participants in studies with immune modulating drugs and also applicable in regular clinical work.

Tardive Dyskinesia-like Syndrome Due to Drugs that do not Block Dopamine Receptors: Rare or Non-existent: Literature Review

<strong>Background:</strong> Although tardive dyskinesia (TD) is most commonly defined as a movement disorder caused by chronic exposure to dopamine-receptor-blocking drugs (DRBDs), it has also been thought to result from exposure to some non-DRBDs. <strong>Methods:</strong> We critiqued many reviews making the association between non-DRBDs and a TD-like syndrome and almost all case reports. We checked whether cases met criteria for the diagnosis of TD-like syndrome and whether DRBDs had been excluded. <strong>Results:</strong> We found that both tricyclic antidepressants and selective serotonin reuptake inhibitor antidepressants may unmask or exacerbate TD after prior exposure to or with concurrent use of DRBDs. We found support for its existence outside of this context to be extremely weak. <strong>Discussion:</strong> There is little evidence that drugs other than DRBDs by themselves cause a TD syndrome; most reported cases appear to occur as a result of a ‘‘priming’’ effect induced by a DRBD, which is later unmasked.

Dropped Head Syndrome after Minor Trauma in a Patient with Levosulpiride-Aggravated Vascular Parkinsonism.

Dropped Head Syndrome after Minor Trauma in a Patient with Levosulpiride-Aggravated Vascular Parkinsonism.

A phase 2, placebo-controlled, randomized, double-blind trial of tozadenant (Syn-115) in patients with Parkinson's disease with wearing-off fluctuations on levodopa

A phase 2, placebo-controlled, randomized, double-blind trial of tozadenant (Syn-115) in patients with Parkinson's disease with wearing-off fluctuations on levodopa

Drug Therapies for Tardive Dyskinesia: Part 2

Tardive dyskinesia (TD) is a serious complication associated with the long-term use of dopamine receptor-blocking drugs. No drugs are approved by the U.S. Food and Drug Administration for treating TD. A number of drugs appear to have some benefit for its treatment, including branched-chain amino acids, piracetam (Nootropil(®), Nootrop(®), Nootropyl(®)), clonazepam (Klonopin(®)), levetiracetam (Keppra(®)), propranolol (Inderal(®)), and clonidine (Catapres(®)), and they would be clinically reasonable to try. Gabapentin (Neurontin(®) and others) has a good safety profile and would be appropriate to consider, although no controlled trials confirm its efficacy. The efficacy of ginkgo biloba should be balanced against its safety concerns. Essential fatty acids have not been shown to be effective. Antioxidant therapies, including vitamin E, melatonin, and vitamin B₆, could conceivably be used together with other drug therapies for the treatment of TD.

Tardive dyskinesia and withdrawal emergent syndrome in children

Tardive dyskinesia (TD) is a well-recognized and sometimes permanent adverse effect of treatment with dopamine receptor-blocking drugs (DRBDs), also referred to as neuroleptics. This iatrogenic disorder has been well characterized in adults, but not extensively studied in children. Withdrawal emergent syndrome (WES) is another pediatric movement disorder related to the use of DRBDs. TD and WES are among the most feared adverse effects of DRBD treatment, and have important medical and legal implications. We review published studies of children under the age of 18 years who were exposed to DRBD to determine the clinical spectrum and estimate the possible prevalence of TD and WES. We particularly wish to draw attention to the phenomenology, clinical course and treatment of these childhood-onset disorders. Although avoiding DRBDs is the best strategy for minimizing the risk of TD and WES, physicians who evaluate children exposed to DRBDs must be vigilant and recognize the early symptoms and signs of these syndromes to provide appropriate clinical management.

Sydenham’s chorea

Sydenham's chorea (SC) is a manifestation of acute rheumatic fever (ARF). Although the incidence of SC has declined significantly, particularly in developed areas, it remains the most common cause of acute chorea in children worldwide. Recent data show that SC accounts for almost all cases of chorea in children in the United States. As there is no specific laboratory marker of this condition, the diagnosis relies on a careful clinical history and laboratory assessment to rule out alternative causes. Morbidity is primarily related to cardiac lesions in ARF. It is recommended that all patients with suspected SC submit to a cardiologic evaluation. Neurologic features encompass motor signs, among which chorea is the most prominent, and nonmotor symptoms such as obsessive-compulsive behavior and attention-deficit/hyperactivity disorder. The first-line treatment of SC is valproic acid. Patients who do not respond to this drug or who present with severe chorea (particularly chorea paralytica, in which the muscle tone is so decreased that patients are bedridden) should be treated with risperidone. Other dopamine receptor-blocking drugs, such as haloperidol, may also be useful. There is growing evidence that immunosuppressive treatment, such as intravenous methylprednisolone followed by a tapering course of oral prednisone, is effective. This option has been used in patients who failed to respond to (or did not tolerate) the previously mentioned therapies. Plasmapheresis and intravenous immunoglobulin are regarded as experimental treatments. Obsessive-compulsive behavior associated with SC is not usually as severe as in other conditions such as Tourette's syndrome. Finally, because at least 20% of patients with SC experience recurrent attacks of ARF, they carry a high risk of developing severe cardiac lesions. These patients require prophylaxis against streptococcus infection, using penicillin or sulfa drugs.

Metabotropic glutamate receptor agonists for schizophrenia

A drug acting at metabotropic glutamate receptors has recently been reported to be an effective antipsychotic, breaking the rule that only dopamine receptor-blocking drugs have this property. The finding complements accumulating evidence that glutamatergic abnormalities are important in the pathophysiology of schizophrenia.

Tardive gait

Tardive dyskinesia (TD) is a hyperkinetic movement disorder induced by dopamine receptor blocking drugs (DRBDs). TD typically presents with stereotypy or dystonia, but may also cause akathisia, myoclonus, or tremor. However, no detailed reports of gait abnormalities have been documented. We report three patients exposed to DRBDs who developed “tardive gait” and conclude that gait dysfunction may be part of the TD spectrum.

Emerging drugs in Tourette syndrome

Proper education of the patient is the first step in the treatment of Tourette syndrome (TS). Before deciding how to treat the patient, it is important to decide whether to treat the TS-related symptoms. Counselling and behavioural modification may be sufficient for those with mild symptoms. Medications, however, may be considered when symptoms begin to interfere with peer relationships, social interactions, academic or job performance, or with activities of daily living. Therapy must be individualised and the most troublesome symptoms should be targeted first. Antidopaminergic agents are clearly the most effective drugs in the treatment of tics. Although haloperidol and pimozide are the only drugs currently approved by the FDA for the treatment of TS, other dopamine receptor-blocking drugs and tetrabenazine, a dopamine depleting drug, as well as botulinum toxin injections, have been used to treat tics associated with TS. Carefully designed, comparative, longitudinal trials assessing the efficacy and adverse-effect profiles of these drugs, including tardive dyskinesia, are lacking. Selective serotonin reuptake inhibitors are recommended for the treatment of obsessive-compulsive behaviour: a common comorbidity. Psychostimulants, such as methylphenidate, are the treatment of choice for attention deficit hyperactivity disorder. Even though these drugs may transiently increase tics, this does not necessarily constitute a definite contraindication to the use of these drugs in patients with TS. Here, existing and emerging medical treatments in patients with tics and comorbid behavioural disorders associated with TS are reviewed.

Dyskinesias Subside off All Medication in a Boy with Autistic Disorder and Severe Mental Retardation

A boy with autistic disorder and severe mental retardation developed severe dyskinesias, including objective akathisia (probable) and tics, a month after discontinuation of at least two years of treatment with drugs block dopamine receptors. These dyskinesias greatly subsided during a 17-wk. open-label nonblind clinical trial of clomipramine, and returned transiently when the parents abruptly discontinued clomipramine. However, the dyskinesias gradually subsided during two and a half years of follow-up with the boy being off all medication. A few stereotypies remain. We believe this suggests the hypothesis that movement disorders, such as withdrawal and tardive akathisia and tics, occurring in boys with autistic disorder treated with dopamine receptor-blocking drugs may subside months or years after discontinuation of the agents and that clomipramine may facilitate this process. We also hypothesize that some boys with autistic disorder and mental retardation exhibit fewer movement disorders, fewer psychiatric symptoms, and better over-all functioning after they have received no dopamine receptor-blocking drugs for several months, and this improvement continues years after the medication has ceased.

Differential effects of neuroleptic agents on hepatic cytochrome P-450 isozymes in the male rat

We report the effects of various dopamine receptor-blocking drugs on gene and protein expression, as well as the activity of several hepatic cytochrome P-450 (CYP) enzymes in the male Sprague-Dawley rat. At equipotent doses (with respect to receptor blockade and behavioural tests), the dopamine D 2-receptor selective sulpiride and remoxipride gave a conspicuous down-regulation of CYP2C11 and its associated androstenedione 16α-hydroxylation activity as well as of the CYP2C11-specific mRNA. The average immunoidentified CYP2C11 levels correlated with the CYP2C11-specific mRNA levels in all treatment groups ( r=0.994), indicating a transcriptional mechanism. The CYP3A protein was also selectively down-regulated. In contrast, androstenedione 5α-reduction was significantly increased. Clozapine, a non-selective neuroleptic, gave the same effects on the steroid metabolism as sulpiride and remoxipride. In contrast, diverging effects were observed for clozapine, compared to sulpiride and remoxipride, on the immunoidentified CYP1A2, CYP2B1, and CYP3A. These proteins were elevated by clozapine, and down-regulated by sulpiride and remoxipride. Our results are of interest for the interpretation of preclinical dose ranging toxicity tests of neuroleptic agents in rats. They may also be relevant in relation to certain interactions and adverse reactions observed in the clinical use of these drugs. The down-regulation of certain CYP enzymes is most likely mediated by an interaction with the growth hormone secretion.

Tardive dyskinetic syndrome in rats infected with Borna disease virus

Tardive Dyskinesia (TD) is a hyperkinetic movement disorder caused by chronic treatment of psychiatric patients with dopamine (DA) receptor blocking drugs (Stacy & Jankovic 1991). Although TD is one of the most important and frequently encountered iatrogenic disorders in clinical medicine, its pathophysiology is poorly understood. We have observed a hyperkinetic movement disorder in rats experimentally infected with a neurotropic RNA virus, Borna disease virus, that may provide important insights into the pathophysiology of TD. Like TD patients, infected rats show prominent orofacial dyskinesias. In keeping with the dopamine (Goetz & Klawans 1982) and anatomic (Fibiger & Lloyd 1984) hypotheses of TD, the Borna disease rat model shows enhanced behavioural sensitivity to DA agonists and selective striatal cell damage. There is also evidence of DA deafferentation and heterogeneous reduction of D2 binding in the caudate-putamen, particularly from sites implicated in oral behaviour. These observations on a virus-induced movement disorder offer novel approaches to TD pathogenesis.

Tardive stereotypy and other movement disorders in tardive dyskinesias.

We reviewed the medical records and videotapes of 100 patients with tardive dyskinesia (TD) referred to our movement disorders clinic to characterize the spectrum of hyperkinetic movement disorders caused by dopamine receptor blocking drugs (DRBD). Tardive stereotypy, present in 78 patients, was the most common type of TD, followed by tardive dystonia, akathisia, tremor, chorea, and myoclonus. Sixty-four had a combination of these hyperkinesias. In a second study, a "blind" review of videotapes of patients with a variety of movement disorders found that DRBD were the cause of stereotypic movements in 89.3% of patients, and 96.1% of patients with TD had stereotypy. We conclude that stereotypy can be readily differentiated from other hyperkinetic movement disorders and that its presence in an adult is highly suggestive of prior exposure to DRBD.

Effect of 3-PPP, a putative dopamine autoreceptor agonist, on rat serum prolactin levels

3-(3-hydroxyphenyl)-N-n-propylpiperidine (3-PPP) has been reported to be a relatively selective agonist for dopamine (DA) auto-receptors in the striatal and limbic region. We have examined the effect of 3-PPP on rat plasma or serum prolactin levels. 3-PPP produced a non-significant decrease in baseline plasma prolactin levels. It produced a dose-dependent inhibition of the increase in serum prolactin levels produced by gamma-butyrolactone. Both doses of 3-PPP tested completely reversed the increase in serum prolactin levels.produced by reserpine and alpha-methylparatyrosine. These results strongly indicate that 3-PPP directly stimulated DA receptors on pituitary lactotrophes. 3-PPP only weakly inhibited the ability of 3H-spiroperidol to bind to pituitary or striatal membranes, suggesting that it may act at a different DA receptor than classical DA receptor blocking drugs. This DA receptor could have properties in common with the autoreceptors of the mesolimbic and nigrostriatal DA neurons.

The dopamine receptor of the rat mammotroph in cell culture as a model for drug action

Dopamine can act directly on pituitary cells to inhibit prolactin release. This action can be blocked by dopamine receptor blocking drugs such as haloperidol, sulpiride and other neuroleptic agents. Comparison of the properties of the mammotroph dopamine receptor with the adenylate cyclase linked dopamine receptor of the limbic forebrain reveals some obvious differences. For example, dopamine receptor stimulants such as S-584 and lergotrile mesylate are inactive in stimulating the adenylate cyclase preparations but are potent in inhibiting pituitary prolactin secretion. Such inhibition of prolactin secretion can be reversed by haloperidol or sulpiride. In contrast to these observations, sulpiride does not block dopamine stimulation of cAMP formation. In addition, dopamine, apomorphine or lergotrile mesylate have no effect on a pituitary adenylate cyclase preparation and dopamine fails to elevate cAMP in the intact cells in culture. Despite the similarity between these two dopamine sensitive systems with respect to a number of agonists and antagonists, the exceptions described suggest that the pituitary system with further study may offer some greater reliability as a predictive test for clinically useful agents. These results also suggest that the receptors for dopamine, like that for norepinephrine, are of two types, only one of which is coupled to adenylate cyclase.

ON THE RELEVANCE OF PREFERENTIAL INCREASES OF MESOLIMBIC VERSUS STRIATAL DOPAMINE TURNOVER FOR THE PREDICTION OF ANTIPSYCHOTIC ACTIVITY OF PSYCHOTROPIC DRUGS

Abstract— Drugs possessing (chlorpromazine, haloperidol, clozapine, thioridazine and sulpiride) or lacking (benzoctamine and perlapine) antipsychotic activity were compared with respect to their ability to enhance x‐methyl‐p‐tyrosine‐induced dopamine disappearance from the mesolimbic area and corpus striutum of rat brain. In addition, their effects on the endogenous concentrations of homovanillic (HVA) and 3.4‐dihydroxyphenylacetic (DOPAC) acids in these two brain areas were determined.Some of the drugs enhanced dopamine disappearance in the mesolimbic area more than in the striatum. The most active in this respect were sulpiride. perlapine and chlorpromazine. By contrast, haloperidol was slightly more active in the striatum than in the mesolimbic area.None of the drugs was more efficient in elevating HVA levels in the mesolimbic area than in the striatum. However, there were large differences in the relative extent of the HVA increases in the two regions. Benzoctamine, perlapine and chlorpromazine increased HVA concentrations in the mesolimbic area nearly as much as in the striatum. Thioridazine and haloperidol, however, elevated striatal HVA much more effectively.Haloperidol and clozapine increased the DOPAC concentration in both areas to about the same extent. The other drugs were more active in the striatum. The largest difference between both regions was shown by chlorpromazine.Perlapine and benzoctamine, both lacking antipsychotic activity, produced much larger increases of HVA than of DOPAC. This is in contrast to the results obtained with true neuroleptics and may reflect an involvement of release phenomena in the action of these two drugs on dopamine metabolism.These results suggest that a preferential increase of dopamine turnover in the mesolimbic area is not necessarily linked to a better ratio of antipsychotic activity vs. extrapyramidal side effects. Moreover, an antiacetylcholine component of dopamine receptor blocking drugs does not seem to be a prerequisite for preferential activity on dopamine turnover in the mesolimbic system.