Dopaminergic Hyperactivity Research Articles

Normalization of cytochrome- c oxidase activity in the rat brain by neuroleptics after chronic treatment with PCP or methamphetamine

Previous studies, primarily involving the use of positron emission tomography (PET), have contributed to the hypothesis that a state of hypometabolism may underlie schizophrenia. The chronic use of methamphetamine (MAP) or phencyclidine (PCP), both of which have been shown to enhance dopaminergic function in the brain, leads to a psychotic state in man which has prompted the suggestion that these compounds may have utility as models of schizophrenia. In the present study, regional alterations in energy metabolism were examined in the rat brain using cytochrome- c oxidase (COX) and succinate dehydrogenase (SDH) histochemistry following chronic treatment with PCP and MAP. PCP and MAP were administered alone or in the presence of fluphenazine or clozapine to animals for 28 days, after which mitochondrial enzyme activities were estimated. Both PCP and MAP produced profoundly similar decreases in COX activity in a broad spectrum of regions. Most prominent in this regard were the caudate-putamen, nucleus accumbens and septum. No changes were noted in sections stained for SDH activity, suggesting that results were dependent upon neither a generalized mitochondrial dysfunction nor mitochondrial loss. Cell counts and TUNEL histochemistry also failed to reveal any significant differences between control and treated animals, implying that reductions were not a result of cell loss. Both clozapine and fluphenazine offered varying degrees of protection from the effects of PCP and MAP. The results provide evidence which implicates dopaminergic hyperactivity in the finding of reduced energy metabolism in the brains of schizophrenics.

Expression of a D 2 dopamine receptor antisense RNA in brain inhibits D 2-mediated behaviors

Drugs currently used to treat disorders of dopamine-mediated behaviors in the central nervous system are non-selective in that they interact not only with more than one isoform of dopamine receptor but also with receptors for other neurotransmitters. A new strategy to inhibit the actions of individuals dopamine receptor subtypes is to inhibit the synthesis of the receptors through the use of oligonucleotides antisense to the transcripts encoding the different receptors. Earlier studies showed that oligodeoxynucleotides antisense to the D 1 or D 2 dopamine receptor messenger RNAs specifically inhibited the biological actions mediated by these individual isoforms of the dopamine receptor. However, these actions were relatively short-lasting. To determine whether one can achieve long-lasting inhibition of dopamine responses, while still taking advantage of the highly selective nature of an antisense strategy, an expression vector was employed that generates antisense RNA to the transcripts encoding the D 2 dopamine receptor. A single intrastriatal injection of this vector generated an antisense RNA to the D 2 dopamine receptor, selectively reduced the levels of D 2 dopamine receptors, and caused selective, long-term inhibition of behaviors mediated by D 2 dopamine agonists. Such an antisense RNA strategy may find use in studying the function of dopaminergic receptors and in disorders associated with dopaminergic hyperactivity.

THE γ-HYDROXYBUTYRATE SIGNALLING SYSTEM IN BRAIN: ORGANIZATION AND FUNCTIONAL IMPLICATIONS

γ-Hydroxybutyrate is a metabolite of GABA which is synthesized and accumulated by neurons in brain. This substance is present in micromolar quantities in all brain regions investigated as well as in several peripheral organs. Neuronal depolarization releases γ-hydroxybutyrate into the extracellular space in a Ca 2+-dependent manner. Gamma-hydroxybutyrate high-affinity receptors are present only in neurons, with a restricted specific distribution in the hippocampus, cortex and dopaminergic structures of rat brain (the striatum in general, olfactory bulbs and tubercles, frontal cortex, dopaminergic nuclei A 9, A 10 and A 12). Stimulation of these receptors with low amounts of γ-hydroxybutyrate induces in general hyperpolarizations in dopaminergic structures with a reduction of dopamine release. However, in the hippocampus and the frontal cortex, it seems that γ-hydroxybutyrate induces depolarization with an accumulation of cGMP and an increase in inositol phosphate turnover. Some of the electrophysiological effects of GHB are blocked by NCS-382, a γ-hydroxybutyrate receptor antagonist while some others are strongly attenuated by GABA B receptors antagonists. Gamma-hydroxybutyrate penetrates freely into the brain when administered intravenously or intraperitoneally. This is a unique situation for a molecule with signalling properties in the brain. Thus, the γ-hydroxybutyrate concentration in brain easily can be increased more than 100 times. Under these conditions, γ-hydroxybutyrate receptors are saturated and probably desensitized and down-regulated. It is unlikely that GABA B receptors could be stimulated directly by GHB. Most probably, GABA is released in part under the control of GHB receptors in specific pathways expressing GABA B receptors. Alternatively, GABA B receptors might be specifically stimulated by the GABA formed via the metabolism of γ-hydroxybutyrate in brain. In animals and man, these GHBergic and GABAergic potentiations induce dopaminergic hyperactivity (which follows the first phase of dopaminergic terminal hyperpolarization), a strong sedation with anaesthesia and some EEG changes with epileptic spikes. It is presumed that, under pathological conditions (hepatic failure, alcoholic intoxication, succinic semialdehyde dehydrogenase defects), the rate of GHB synthesis or degradation in the peripheral organ is modified and induces increased GHB levels which could interfere with the normal brain mechanisms. This pathological status could benefit from treatments with γ-hydroxybutyric and/or GABA B receptors antagonists. Nevertheless, the regulating properties of the endogenous γ-hydroxybutyrate system on the dopaminergic pathways are a cause for the recent interest in synthetic ligands acting specifically at γ-hydroxybutyrate receptors and devoid of any role as metabolic precursor of GABA in brain. © 1997 Elsevier Science Ltd. All Rights Reserved.

Hyperactive behavioural effects induced by intranigral infusion of a pyridinium metabolite of haloperidol in rats

Amphetamine-like behaviours such as sniffing and head movements were observed in rats intranigrally injected with a pyridinium metabolite of haloperidol (HP+). Photobeam interruptions by rats injected with HP+ were over 200 times more frequent than those of control rats 24 h after the operation. This apparent dopamine agonist effect of HP+ may be relevant to some of the clinical side effects of haloperidol such as acute dystonia and chronic tardive dyskinesia, which have been proposed to be the result of dopaminergic hyperactivity.

Neurochemical analysis of the tyrosine hydroxylase expression in methamphetamine-sensitized rats.

To elucidate the expression of TH mRNA in MAP-induced behavioral sensitization, rats were daily injected with MAP (5 mg/kg i.p.) or saline for 14 days. Progressive enhancement was observed in MAP-induced stereotyped behavior. After 7 days of discontinuation of MAP treatment, the rats were decapitated and the brains were prepared for either in situ hybridization or Northern blot hybridization. In situ hybridization revealed that the signals of TH mRNA were localized to the dopaminergic perikarya of substantia nigra and ventral tegmental area in the midbrain, and Northern blot analysis showed that the levels of TH mRNA in these areas decreased by 37% compared to that in the saline-treated controls. These findings indicate that MAP-induced dopaminergic hyperactivity is not associated with enhanced expression of TH gene mRNA.

Regulation of [ 3H]dopamine release from mesolimbic and mesocortical areas of guinea pig brain by sigma receptors

The role of sigma (σ) receptors in brain function is poorly defined. They are located in limbic areas, including nucleus accumbens (NAC) and prefrontal cortex (PFC), both of which are thought to be involved in schizophrenia. Many antipsychotics (APs), including haloperidol, bind with high affinity to σ receptors. Dopaminergic hyperactivity in NAC is thought to underlie positive symptoms of schizophrenia, while dopaminergic hypoactivity in PFC is thought to underlie negative symptoms. Sigma receptors regulate N- methyl- d-aspartate (NMDA)- stimulated [ 3H]dopamine ([ 3H]DA) release in caudate-putamen (CP), the neuroanatomical substrate for extrapyramidal side effects resulting from chronic AP treatment. In the current study, we investigated whether σ receptors could similarly regulate DA release in mesolimbic and mesocortical tissue, and the relative participation of different σ receptor subtypes in this process. We found that, in NAC, regulation of DA release by the prototypical σ agonist (+)pentazocine was mediated predominantly by the σ 1 receptor, whereas in the PFC a portion of the (+)pentazocine effect was likely mediated by the σ 2 receptor. We also observed, in both the NAC and PFC, that regulation of DA release by the σ agonist BD737 was mediated primarily by the σ 1 receptor. In addition, we determined that (+)pentazocine or BD737 effects on DA release were not mediated via opioid receptors, nor the phencyclidine (PCP) binding site within the NMDA receptor-operated cation channel, nor by σ receptor effects upon [ 3H]DA accumulated by noradrenergic terminals in PFC.

Methamphetamine-induced dopaminergic hyperactivity is not accompanied with increase in tyrosine hydroxylase mRNA of the rat midbrain

Tyrosine hydroxylase (TH) mRNA was measured in the midbrain of rats treated repeatedly with methamphetamine (MAP). Male Sprague-Dawley rats were daily injected with MAP (5 mg/kg, i.p., once daily) or saline for 14 days. Progressive augmentation was observed in MAP-induced stereotyped behaviors. After one week of abstinence, the rats were decapitated and the brains were prepared for either in situ hybridization using non-radioactive cRNA probes or Northern blot analysis using 32P-labeled cDNA probes. In situ hybridization showed that the signals of TH mRNA were localized to the dopaminergic perikarya in the midbrain and were reduced in MAP-treated animals compared to the controls. Northern blot analysis revealed that the level of TH mRNA in the midbrain of MAP-treated rats was decreased by 37% compared to the controls, which was close to the statistical significance ( P = 0.053). These results indicate that the dopaminergic hyperactivity caused by repeated MAP treatment is not associated with enhanced transcription of the TH gene.

Midlatency auditory evoked potential habituation in PTSD

+ 4.0; p < 0.001). Paroxetine B(max) (number of serotonin transporter binding sites) was significantly correlated with HA (r =-0.326; p ~ 0.049) and approached significance for NS (r = -0.288; p = 0.084), but not with RD. Combining HA and NS scores yielded a higher correlation than using either score alone (r = -0.375; p = 0.022). Although the data are open to other interpretations, they are generally supportive of the hypothesis that a serotonergicaUy mediated dimension of personality may predispose to the development of FFSD in psychologically traumatized individuals. ously, two with benzodiazepine treatment, and one with neuroleptic treatment. Case histories and possible etiologies for panic disorder with psychosis are discussed. It is suggested that psychotic features in panic disorder could be related to dopaminergic hyperactivity. A dimensional approach is proposed where the axes of anxiety and psychosis overlap, producing a variety of clinical pictures ranging from anxiety symptoms in schizophrenia to panic attacks with psychotic features.

The glycine/NMDA receptor antagonist, L-701,324 reverses isolation-induced deficits in prepulse inhibition in the rat

Previous studies have demonstrated that the glycine/NMDA receptor antagonist, L-701,324 (7-chloro-4-hydroxy-3(3-phenoxy)phenyl-2(H)quinolone) blocks the activation of mesolimbic dopamine systems induced following psychostimulant administration in the rat (Bristow et al. 1994). In the present study, pretreatment with L-701,324 also reversed the deficit in prepulse inhibition (PPI) observed in rats reared in social isolation after weaning. Given that PPI is also attenuated in schizophrenic patients and that isolation rearing induces both neurochemical and behavioural abnormalities suggestive of a physiologically induced state of dopaminergic hyperactivity, these results suggest that blockade of the glycine/NMDA receptor may offer a new strategy for the development of novel antipsychotic agents.

Lateralized interdependence between limbicotemporal and ventrostriatal dopaminergic transmission

The antipsychotic effects of dopaminergic antagonists suggest dopaminergic hyperactivity plays a role in schizophrenia. 4,6,23,29 However, an elevated number of D 2 dopamine receptors in the left putamen of nontreated schizophrenics has been reported 12 which is consistent with a diminution of dopaminergic transmission in the ventral striatum. Morphological and functional studies have shown marked alterations in the left medial temporal lobe (entorhinal cortex, hippocampus, parahippocampus gyrus) of schizophrenics. 3,7,8,10,11,34,35 As the entorhinal cortex and the ventral hippocampus project to the ventral striatum, 14,18,30,33,36 the functional relationship between left temporal structures and the left ventral striatum may be impaired in schizophrenics. To assess the validity of this hypothesis, we investigated the existence of a preferentially left hemispheric interdependency between dopaminergic pathways in male rats. We found that dopaminergic projections in the entorhinal cortex and the ventral hippocampus regulate dopaminergic transmission in the nucleus accumbens, particularly in the left hemisphere. Temporal D 2 dopamine receptors seem to be primarily involved in this effect. This lateralized interdependent functioning appears structurally based. These results may provide new insights into the pathophysiology of schizophrenic psychoses.

A Weighted Nonparametric Procedure for the Combination of Independent Events

AbstractA weighted inverse normal procedure for combining independent events is considered. The procedure is utilized to combine results from six clinical studies on homovanillic acid concentrations in relation to the hypothesis that schizophrenia is the result of dopaminergic hyperactivity.

Catecholamines in Autistic Disorder: Effects of Amisulpride and Bromocriptine in a Controlled Crossover Study

ABSTRACT The biochemical effects on catecholaminergic systems of the dopamine antagonist amisulpride and the dopamine agonist bromocriptine were evaluated in a double-blind, randomized, crossover study in children with autistic disorder. Plasma levels of dopamine, norepinephrine, and epinephrine; urinary concentrations of homovanillic acid (HVA), vanillyImandelic acid (VMA) and 3-methoxy-4-hydroxyphenylethylene glycol (MHPG); and plasma prolactin were measured. At doses of amisulpride and bromocriptine that had the expected opposing effects on plasma prolactin, the drugs' effects on the catecholaminergic systems were similar. Both agents unexpectedly lowered urinary HVA (total, free, and sulfated) although only amisulpride decreased the HVA levels significantly. This paradoxical decrease in HVA levels suggests that both dopamine agonists and antagonists could act on autoreceptors or presynaptic dopaminergic receptors in the central nervous system. There was no significant action of either drug on plasma epinephrine, urinary VMA, or urinary MHPG, suggesting that neither drug altered norepinephrine or epinephrine systems; however, a weak increase of plasma norepinephrine occurred after amisulpride treatment, consistent with effects observed with other neuroleptics. Neither agent altered plasma dopamine, suggesting that peripheral dopamine metabolism was unchanged. The clinical effects of amisulpride and bromocriptine have been reported to be unexpectedly complementary. The complementary clinical effects of a dopamine agonist and dopamine antagonist might speculatively be related to their similar action on dopamine autoreceptors, leading to a correction of the dopaminergic hyperactivity that has been postulated in autistic children.

Alpha-methyl-para-tyrosine pretreatment protects from striatal neuronal death induced by four-vessel occlusion in the rat.

Rats were treated with alpha-methyl-para-tyrosine (AMT, 250 mg/kg, i.p), an hydroxylase inhibitor, in order to decrease brain levels of catecholamines. Six hours later, when cerebral dopamine (DA) and norepinephrine were reduced by about 80%, a transient forebrain ischemia of 30 min duration was induced by four-vessel occlusion technique. Evaluation of brain damage 72 hours after ischemia showed that AMT treatment significantly decreased neuronal necrosis in the striatum but had no cytoprotective effect in the CA1 sector of the hippocampus and in the neocortex. AMT treatment reduced mortality within the ischemic period but did not affect either the mortality within the recirculation period or the postischemic neurologic deficit. These results suggest that the striatal cytoprotective effect of AMT is linked to cerebral DA depletion and that excessive release of DA during ischemia or dopaminergic hyperactivity during recirculation play a detrimental role in the development of ischemic cell damage in the striatum.

Ondansetron--the first highly selective 5-HT3 antagonist in therapy of psychiatric diseases

Ondansetron is a highly selective 5-HT3 antagonist, which has recently become available for the control of chemotherapy-induced emesis. Since 5-HT3 receptors not only have a high density in the area postrema but also in the hippocampal and amygdala region of the limbic system, it has been suspected that 5-HT3 selective agents have psychotropic effects. In animal models of anxiety ondansetron showed a benzodiazepine-like anxiolytic effect without any sedation or withdrawal effects. Other states of withdrawal have been prevented with ondansetron. This agent might also exert neuroleptic effects since dopaminergic hyperactivity in the mesolimbic system was antagonised by ondansetron. In different models of memory and learning a positive effect on basal learning behaviour and on scopolamine-induced memory impairment was noted. This manuscript reviews essential pharmacological and behavioural effects of ondansetron as well as preliminary data from clinical studies. The role of highly-selective ligands for a more differentiated view of serotonergic subsystems are discussed.

Decreased ( 3H) quinuclidinyl benzilate binding to lymphocytes in Gilles de la Tourette syndrome

In spite of an unknown pathophysiology, it has been suggested that central dopaminergic hyperactivity exists in Gilles de la Tourette syndrome (TS). Cholinergic influences have also been postulated as a dopaminergic-cholinergic balance seems to be important in other movement disorders. If TS is due to alterations of cholinergic activity, this may also be expressed at postsynaptic levels. Recently, we showed that circulating lymphocytes may serve as useful peripheral markers reflecting induced alterations or inherent changes in muscarinic receptors in the central nervous system (CNS). In the present study, we compared the muscarinic binding characteristics in peripheral lymphocytes as measured by ( 3H) quinuclidinyl benzilate ([( 3H)-QNB] in 27 umedicated TS patients, against 22 healthy (age and gender-matched) controls. B max and K d values were determined using Lineweaver-Burke plots. The mean B max values in nontreated TS patients was markedly and significantly lower than in controls (10.59 ± 8.4 versus 40.16 ± 9.2 fmole/10 6 cells, p < 10 −6), while K d values were similar in both groups. Our findings suggest that changes in cholinergic receptors may play a role in the pathophysiology of Tourette syndrome.

Effects of pharmacological manipulation of dopaminergic and cholinergic neurotransmission in genetically dystonic hamsters

In an inbred line of Syrian hamsters attacks of sustained dystonic postures of the limbs and trunk can be initiated by handling or mild environmental stimuli (e.g. new cage). The severity of the dystonic syndrome in these mutant hamsters (gene symbol dt SZ) is age-dependent, with a peak at about 30–40 days of age. A scoring system for grading the type and severity of the dystonic attacks can be used to study the activity of drugs against dystonic movements with individual pre- and post-drug vehicle trials as control. The effects of drugs which alter dopaminergic or cholinergic functions in the brain were studied in selectively bred dystonic hamsters and age-matched non-dystonic controls. The dopamine precursor levodopa (injected together with carbidopa) and the dopamine receptor agonist apomorphine increased the severity of dystonia in hamsters when administered prior to the age of maximum severity of dystonia. A very similar effect was observed with the cholinomimetic pilocarpine. In contrast, the dopamine receptor antagonist haloperidol caused a marked overall reduction in dystonic movements. Anticholinergic drugs, i.e. trihexyphenidyl and biperden, increased the latency to onset of the dystonic attack, but did not reduce its severity. No differences were observed between dystonic and non-dystonic hamsters with respect to extent and duration of stereotypies induced by dopaminergic and cholinergic drugs or hypolocomotion and catalepsy produced by haloperidol. The data suggest that dopaminergic hyperactivity might be involved in the pathophysiology of dystonia in dt SZ mutant hamsters.

Altered Secretion of Corticosteroids and Prolactin in Adrenal Regeneration Hypertensive Rats

To assess the possible role of mineralocorticoids in the onset and maintenance of hypertension in adrenal regeneration hypertensive (ARH) rats, the change in plasma mineralocorticoids, with adrenal regeneration after enucleation in ARH rats was investigated and compared with those in unilaterally nephroadrenalectomized, 1% saline-fed (UNA) rats, sham-operated, 1% saline-fed (1% NaCl) rats and water-fed (water) rats. Plasma aldosterone was determined by RIA and the other mineralocorticoids were measured by HPLC. How plasma PRL, a marker of central dopaminergic activity, affected aldosterone secretion was determined by RIA. In ARH, plasma corticosterone (B), 18-OH-DOC and aldosterone levels 2 weeks after operation were as low as 20-30% of corresponding values, but the plasma DOC level was almost 100% of the corresponding value in the other groups. Four weeks after operation plasma B increased to a level comparable with that in the other groups and the plasma aldosterone level remained low. However, plasma DOC and 18-OH-DOC levels 4 weeks after operation were as high as 120-200% of corresponding values in the other groups. Six weeks after operation, the plasma aldosterone level returned to a value comparable with that in UNA and 1% NaCl and plasma DOC and 18-OH-DOC levels returned to corresponding values in the other groups. The plasma PRL level 4 weeks after operation was significantly lower in ARH than in the other groups. These results suggest that transient DOC and 18-OH-DOC increases observed in ARH may be important in the onset of hypertension, while other factors may be involved in its maintenance and that the transient central dopaminergic hyperactivity observed in ARH may be responsible for a delayed return from aldosterone deficiency.

Cyclo(leu-gly) reverses the permanent dopamine receptor up-regulation induced by ovariectomy

Several neuropsychiatric diseases, including tardive dyskinesia and schizophrenia, are thought to involve increased neurotransmission at dopaminergic synapses. Although many animal models of this dopaminergic hyperactivity have been studied, the ovariectomized (OVX) rat model, which we recently developed, appears to be unique. The brain D2 DA receptor up-regulation (increases in receptor number) and the behavioral hypersensitivity to dopamine (DA) agonists that develop in this model after a few months appear to be permanent. Using this model, it is now possible to screen for agents that can reverse a permanent dopaminergic supersensitivity. In this report, we document such a reversal by cyclo(leu-gly) (CLG), a dopaminergic neuromodulator, in the OVX model. Female Fisher rats were ovariectomized and allowed to recover for 3 months. Following a challenge dose of apomorphine (0.45 mg/kg, i.p.) OVX rats showed significantly more stereotypic sniffing (+ 175%) than sham controls. Following lower doses of APO (125 and 150 μ/kg, i.p.), OVX rats showed significantly more locomotor activity (+ 105 and + 365%). CLG (4 daily doses, 8 mg/kg, s.c.) reversed these hypersensitive responses. In parallel, OVX rats showed a significant increase (+ 35%) in [3H]-spiroperidol binding (Bmax) in corpus striatum relative to sham rats; this dopamine receptor up-regulation was also reversed by CLG. We conclude (1) that the long-term OVX rat is useful for modelling the permanent or irreversible aspect of supersensitivity to DA; and (2) CLG may be useful in the treatment of dopaminergic diseases.

Prolactin shifts after neuroleptic withdrawal

Neuroleptic-induced alterations in serum prolactin levels may have important clinical implications. Twenty-two stable schizophrenic patients, taken off medication over a 3-week period, were followed for 40 weeks or until the neuroleptic was reinstituted. Serum prolactin levels were measured during neuroleptic treatment and during the neuroleptic-free period. When serum prolactin levels were plotted over time, 55% of the subjects showed shifting prolactin levels in the shape of a “V” (i.e., a fall in prolactin level preceding an increase in the level) in the early weeks following withdrawal. Subjects with the “V” shape had significantly lower prolactin levels during neuroleptic treatment than those without the “V” shape. The pathophysiological significance of the prolactin “V” pattern is uncertain. It is consistent, however, with transient dopaminergic hyperactivity following neuroleptic withdrawal.

What Is Left of Attention in Schizophrenia?-Reply

<h3>In Reply.—</h3> Dr Bracha's finding of left-ward turning preferences in schizophrenic patients does support our own demonstration of right-sided visual neglect in these patients. The fact that results in both studies were also found in neuroleptic-naive patients and that no patients in either study had an opposite asymmetry adds strong support to the hypothesis of lateralized abnormalities in schizophrenia. We differ in the interpretation of the result. Dr Bracha argues that rightsided dopaminergic hyperactivity¹is responsible and we have suggested elsewhere^2-4that a left-sided dopminergic deficiency (or a similar lesion) is responsible. A dopaminergic-deficiency hypothesis of schizophrenia has been discussed by other authors^5-7and is not incompatible with available data. We base our conclusion on the following: (1) We have also observed hyperactivity of the left globus pallidus in neuroleptic-naive schizophrenic patients,⁸a finding seen following the appearance of selective unilateral dopaminergic lesions.⁹This