GM1 ganglioside attenuates the development of vacuous chewing movements induced by long-term haloperidol treatment of rats

Tardive dyskinesia (TD) is a serious side-effect of long-term treatment with neuroleptics. To investigate if TD may be a result of neuroleptic-induced excessive stimulation of striatal glutamate receptors, the effect of the anti-excitotoxic GM1 ganglioside was studied in a rat model of TD. In an acute experiment each of four groups of rats was treated with GM1 20 mg/kg SC+saline IP, saline SC+haloperidol 1.2 mg/kg IP, GM1 SC+haloperidol IP, or saline SC+saline IP. In a subsequent long-term experiment lasting 16 weeks, each of the four groups was treated as in the acute experiment, with the exception that haloperidol was injected IM as decanoate 38 mg/kg every 4 weeks, and the controls received vehicle injections. The behavior was videotaped and scored at intervals during both experiments, including 16 weeks after cessation of the long-term treatment. Haloperidol induced a significant increase in vacuous chewing movements (VCM) and immobility both in the acute and in the long-term experiment. Other categories of behaviour (rearing, moving, sitting) were significantly affected only in the acute experiment. GM1 did not affect any of the acute behavioural effects of haloperidol, but significantly reduced VCM in the long-term experiment. The effects on VCM of haloperidol and GM1 persisted for at least 8 weeks after cessation of the long-term treatment. These results suggest that long-lasting changes in striatal function induced by excessive glutamate receptor stimulation may be a mechanism for the development of VCM in rats and perhaps also for TD in humans.     

Oral Dyskinesias and striatal lesions in rats after long-term co-treatment with haloperidol and 3-nitropropionic acid

The pathophysiologic basis of tardive dyskinesia remains unclear. It has been proposed that tardive dyskinesia may be a result of excitotoxic neurodegeneration in the striatum caused by a neuroleptic-induced increase in striatal glutamate release and impaired energy metabolism. To investigate this hypothesis, haloperidol decanoate (38 mg/kg/four weeks intramuscularly) and the succinate dehydrogenase inhibitor 3-nitropropionic acid (8 mg/kg/day via subcutaneous osmotic mini-pumps), were administered alone or together for 16 weeks to four-months-old rats. Control rats received sesame oil intramuscularly and had empty plastic tubes subcutaneously. Vacuous chewing movements, a putative analogue to human tardive dyskinesia, were recorded during and after drug treatment. Haloperidol alone, 3-nitropropionic acid alone, and 3-nitropropionic acid+haloperidol treatments induced an increase in vacuous chewing movements. However, vacuous chewing movements were more pronounced and appeared earlier in rats treated with 3-nitropropionic acid+haloperidol. After drug withdrawal, increases in vacuous chewing movements persisted for 16 weeks in the haloperidol alone and 3-nitropropionic acid+haloperidol group and for four weeks in the 3-nitropropionic acid alone group. Brains from each group were analysed for histopathological alterations. Bilateral striatal lesions were present only in rats with high levels of vacuous chewing movements in the 3-nitropropionic acid+haloperidol-treated rats. Nerve cell depletion and astrogliosis were prominent histopathologic features. There was selective neuronal sparing of both large- and medium-sized aspiny striatal neurons. These results suggest that mild mitochondrial impairment in combination with neuroleptics results in striatal excitotoxic neurodegeneration which may underlie the development of persistent vacuous chewing movements in rats and possibly irreversible tardive dyskinesia in humans.     

A hemagglutinin-based multipeptide construct elicits enhanced protective immune response in mice against influenza A virus infection

The effect of the muscarinic antagonist, scopolamine, was examined for a change in the increase in extracellular dopamine, dihydroxyphenyl acetic acid (DOPAC), homovanillic acid (HVA) and 5-hydroxyindolacetic acid (5-HIAA), induced by haloperidol or clozapine in the striatum and nucleus accumbens of anaesthetised and awake rats, monitored using in vivo cerebral microdialysis. Rats received scopolamine (1 mg kg(-1); s.c.) or vehicle followed by haloperidol (1 mg kg(-1); s.c.) or clozapine (20 mg kg(-1); s.c.). Dopamine, DOPAC, HVA and 5-HIAA overflow into striatal or accumbens perfusates was determined using high performance liquid chromatography with electrochemical detection (HPLC-ECD). Scopolamine failed to modify the clozapine- or haloperidol-induced efflux of dopamine or its metabolites in either the striatum or nucleus accumbens following systemic administration in anaesthetised or awake rats. Although pretreatment with scopolamine tended to produce a smaller increase in the clozapine-induced efflux of DOPAC in striatal perfusates than following clozapine treatment alone, this was not statistically significant. Furthermore, local infusion of scopolamine (100 microM) with clozapine (1 mM) via the microdialysis probe did not attenuate the elevated efflux of dopamine observed following clozapine alone, in either the striatum or nucleus accumbens, in anaesthetised rats. This treatment did prevent the clozapine-induced increase in DOPAC and HVA in the striatum but not the nucleus accumbens. Carbachol (50 microM) infused into the dorsolateral striatum or nucleus accumbens raised extracellular dopamine levels 200% and 150%, respectively above baseline. Our data suggest that the increased efflux of dopamine and its metabolites in the rat basal ganglia following clozapine administration is not significantly dependent upon the interaction of clozapine with muscarinic receptors.     

Effect of antidepressant drugs on dopamine D1 and D2 receptor expression and dopamine release in the nucleus accumbens of the rat

This study examined the effect of repeated treatment with the antidepressant drugs, fluoxetine, desipramine and tranylcypromine, on dopamine receptor expression (mRNA and binding site density) in sub-regions of the nucleus accumbens and striatum of the rat. The effect of these treatments on extracellular levels of dopamine in the nucleus accumbens was also measured. Experiments using in situ hybridisation showed that the antidepressants caused a region-specific increase in D2 mRNA, this effect being most prominent in the nucleus accumbens shell. In contrast, none of the treatments increased D1 mRNA in any of the regions examined. Measurement of D2-like binding by receptor autoradiography, using the ligand [3H]YM-09151-2, revealed that both fluoxetine and desipramine increased D2-like binding in the nucleus accumbens shell; fluoxetine had a similar effect in the nucleus accumbens core. Tranylcypromine, however, had no effect on D2-like binding in the nucleus accumbens but decreased binding in the striatum. In micro-dialysis experiments, our data showed that levels of extracellular dopamine in the nucleus accumbens were not altered in rats treated with either fluoxetine or desipramine, but increased by tranylcypromine. From our findings, we propose that the antidepressant drugs tested enhance dopamine function in the nucleus accumbens through either increased expression of post-synaptic D2 receptors (fluoxetine and desipramine) or increased dopamine release (tranylcypromine).     

Effect of scopolamine on the efflux of dopamine and its metabolites after clozapine, haloperidol or thioridazine

The extracellular concentrations of dopamine (DA) and its metabolites, dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), in the striatum and the nucleus accumbens were measured in awake, freely-moving rats. Clozapine (20 mg/kg, i.p.) increased extracellular DA and HVA in both regions but increased DOPAC only in the striatum. Scopolamine (1 mg/kg), although it had no effect by itself in the striatum or nucleus accumbens, inhibited the ability of clozapine to increase extracellular DA, DOPAC and HVA concentrations in the striatum. The clozapine-induced increase in DA in the frontal cortex was not blocked by scopolamine. Haloperidol (1 mg/kg, i.p.) and thioridazine (10 mg/kg, i.p.) also increased extracellular DA, DOPAC and HVA in the striatum, but scopolamine pretreatment did not inhibit these increases. The results suggest that clozapine differs from haloperidol and thioridazine in that the effect of clozapine, but not that of the two neuroleptic drugs, to increase DA release in the striatum acutely depends on muscarinic receptor stimulation. These results suggest that clozapine, despite its strong muscarinic antagonist properties, does not produce full blockade of muscarinic receptors in vivo in the striatum. The interaction of clozapine with the cholinergic system in the striatum could be relevant to its lack of ability to produce extrapyramidal symptoms or tardive dyskinesia.     

Spatial learning and performance in the radial arm maze is impaired after N-methyl-{d}-aspartate (NMDA) receptor blockade in striatal subregions.

These experiments addressed the role of striatal N-methyl-{d}-aspartate (NMDA) receptors in spatial behavior in the radial arm maze. Rats treated with the NMDA antagonist D-2-amino-5-phosphonopentanoic acid (AP-5) in the nucleus accumbens core, medial caudate, and posterior caudate were all significantly impaired in acquiring the correct spatial responses. In contrast, rats infused with AP-5 in the nucleus accumbens shell showed little impairment. When rats in all groups had learned the maze and were performing at similar levels, AP-5 had relatively little effect except in the posterior caudate group, where errors and trial times were again increased. These findings demonstrate the importance of NMDA receptor-dependent activity within the accumbens and caudate in spatial learning and performance. The neural processes necessary for adaptive spatial learning in complex environments may recruit multiple cortical systems having specialized functions, which in turn are integrated in widespread striatal regions. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Effect of chronic haloperidol treatment on synaptic protein mRNAs in the rat brain

Chronic haloperidol treatment caused significant decreases in the levels of synaptotagmin I and IV, synaptobrevin II, syntaxin 1A and Rab 3A mRNAs in the nucleus accumbens but not in the prefrontal cortex medial field, striatum, substantia nigra and ventral tegmental area. No significant changes in SNAP 25 and synaptophysin mRNA levels were observed in any brain region examined. The reduced expression of synaptic proteins may be related to haloperidol-induced depolarization block of mesolimbic dopamine neurons.     

Modification of haloperidol-induced pattern of c-fos expression by serotonin agonists

Acute challenge with clozapine and haloperidol produce different anatomical patterns of c-fos expression in the forebrain. The pharmacological profile of atypical antipsychotics suggests that serotonin might contribute to the unique therapeutic benefits of these drugs. In order to test this possibility, we examined the abilities of 5-HT1A and 5-HT2A/2c agonists to modify the pattern of c-fos expression induced by haloperidol and clozapine. Various groups of rats were pretreated with either saline, DOI, 8-OH-DPAT, and 8-OH-DPAT + DOI 30 min prior to haloperidol or clozapine administration. Rats were killed 90 min after antipsychotic administration. In saline-pretreated rats, haloperidol produced intense Fos-LI in all four striatal quadrants while the effect of clozapine was restricted to the medial part of the striatum. Prior administration of 8-OH-DPAT significantly reduced haloperidol-induced Fos-LI in all four striatal quadrants while DOI and 8-OHDPAT + DOI significantly reduced Fos-LI only in dorso- and ventrolateral quadrants. In the nucleus accumbens, haloperidol induced intense Fos-LI in the core and the shell regions whereas clozapine induced c-fos expression only in the shell. Pretreatment with 8-OHDPAT in haloperidol treated rats reduced Fos-LI in the core region yielding to a c-fos pattern similar to that induced by clozapine. In the prefrontal cortex of saline-pretreated rats, haloperidol produced a moderate c-fos expression compared with the intense expression produced by clozapine. Pretreatment with serotonin agonists before haloperidol brought the number of FOS-positive neurons to the same level as in clozapine treated rats. These results show the ability of 5-HT agonists to transform the typical pattern of c-fos expression induced by haloperidol into a pattern resembling that of clozapine.     

Behavioral sensitization to cocaine, but not cocaine-conditioned behavior, is associated with increased dopamine occupation of its receptors in the nucleus accumbens.

Rats had repeated treatments with cocaine associated with a specific context (paired group). Evidence for classical conditioning of cocaine's motor-activity effects and context-specific behavioral sensitization to cocaine was obtained, relative to vehicle-treated (control) and pseudoconditioned (unpaired) groups. Only the paired group exhibiting context-specific behavioral sensitization had more dopamine bound to both D?-like and D?-like receptors in the nucleus accumbens than did rats in the control group receiving cocaine on the test day. No effects on receptor occupation were found in rats showing a classical conditioned response to a context previously paired with cocaine. Thus, sensitization to cocaine, but not classical conditioning of cocaine's behavioral effects, was associated with greater dopaminergic neurotransmission selectively in the nucleus accumbens. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

S 16924 ((R)-2-[1-[2-(2,3-dihydro-benzo[1,4] dioxin-5-Yloxy)-ethyl]-pyrrolidin-3yl]-1-(4-fluoro-phenyl)-ethanone), a novel, potential antipsychotic with marked serotonin (5-HT)1A agonist properties: I. Receptorial and neurochemical profile in comparison with clozapine and haloperidol

S 16924 showed a pattern of interaction at multiple (>20) native, rodent and cloned, human (h) monoaminergic receptors similar to that of clozapine and different to that of haloperidol. Notably, like clozapine, the affinity of S 16924 for hD2 and hD3 receptors was modest, and it showed 5-fold higher affinity for hD4 receptors. At each of these sites, using a [35S]GTPgammaS binding procedure, S 16924, clozapine and haloperidol behaved as antagonists. In distinction to haloperidol, S 16924 shared the marked affinity of clozapine for h5-HT2A and h5-HT2C receptors. However, an important difference to clozapine (and haloperidol) was the high affinity of S 16924 for h5-HT1A receptors. At these sites, using a [35S]GTPgammaS binding model, both S 16924 and clozapine behaved as partial agonists, whereas haloperidol was inactive. In vivo, the agonist properties of S 16924 at 5-HT1A autoreceptors were revealed by its ability to potently inhibit the firing of raphe-localized serotoninergic neurones, an action reversed by the selective 5-HT1A receptor antagonist, WAY 100,635. In contrast, clozapine and haloperidol only weakly inhibited raphe firing, and their actions were resistant to WAY 100,635. Similarly, S 16924 more potently inhibited striatal turnover of 5-HT than either clozapine or haloperidol. Reflecting its modest affinity for D2 (and D3) autoreceptors, S 16924 only weakly blocked the inhibitory influence of the dopaminergic agonist, apomorphine, upon the firing rate of ventrotegmental area-localized dopaminergic neurones. Further, S 16924 only weakly increased striatal, mesolimbic and mesocortical turnover of dopamine (DA). Clozapine was, similarly, weakly active in these models, whereas haloperidol, in line with its higher affinity at D2 (and D3) receptors, was potently active. In the frontal cortex (FCX) of freely moving rats, S 16924 dose-dependently reduced dialysate levels of 5-HT, whereas those of DA and NAD were dose-dependently increased in the same samples. In contrast, although S 16924 also suppressed 5-HT levels in the striatum and nucleus accumbens, DA levels therein were unaffected. Clozapine mimicked this selective increase in DA levels in the FCX as compared to striatum and accumbens. In contrast, haloperidol modestly increased DA levels in the FCX, striatum and accumbens to the same extent. In distinction to S 16924, clozapine and haloperidol exerted little influence upon 5-HT levels. Finally, the influence of S 16924 upon FCX levels of 5-HT, DA (and NAD) was attenuated by WAY 100,635. In conclusion, S 16924 possesses a profile of interaction at multiple monoaminergic receptors comparable to that of clozapine and distinct to that of haloperidol. In addition, S 16924 is a potent, partial agonist at 5-HT1A receptors. Correspondingly, acute administration of S 16924 decreases cerebral serotoninergic transmission and selectively reinforces frontocortical as compared to subcortical dopaminergic transmission. In line with these actions, S 16924 shows a distinctive profile of activity in functional (behavioral) models of potential antipsychotic activity (companion paper).     

Atypical antipsychotic drugs selectively increase neurotensin efflux in dopamine terminal regions

Typical antipsychotic drugs, such as haloperidol and chlorpromazine, increase synthesis of the neuropeptide neurotensin (NT) in both the striatum and the nucleus accumbens, whereas atypical antipsychotic drugs, such as clozapine and olanzapine, do so only in the nucleus accumbens. By using in vivo microdialysis, we now report that acute administration of haloperidol, clozapine, or olanzapine failed to alter the release of NT in either the striatum or nucleus accumbens. In contrast, chronic administration of haloperidol for 21 days increased NT release in both the striatum and nucleus accumbens, whereas treatment for 21 days with the atypical antipsychotic drugs, clozapine or olanzapine, increased NT release selectively in the nucleus accumbens. These findings suggest that (i) increased NT mRNA expression and NT tissue concentrations are associated with increases in the extracellular fluid concentrations of the peptide and (ii) atypical antipsychotic drugs may exert their therapeutic effects and produce fewer side effects by virtue of their selectivity in limbic compared with striatal, target neurons.     

Differential regulation, by MK-801, of dopamine receptor gene expression in rat nigrostriatal and mesocorticolimbic systems

Glutamate agonists have been shown to stimulate striatal dopamine release, but less is known about dopamine-glutamate interactions at the receptor level. We treated rats with 0.3, 1.0, or 3.0 mg/kg of MK-801, an NMDA antagonist, daily for 1 week and, using in situ hybridization, measured dopamine receptor mRNA levels in cortical and subcortical structures. MK-801 caused a significant increase of D1 and D2 mRNA in the dorsal and ventral striatum, a significant decrease of D3 mRNA in the nucleus accumbens, and a significant decrease of D1 mRNA in the limbic cortex. Dopamine autoreceptor expression, reflected by D2 mRNA in the midbrain, was increased in the ventral tegmental area, but not in the substantia nigra. Thus, MK-801 appears to differentially regulate the mesocorticolimbic and nigrostriatal dopamine systems.     

Dopaminergic and glutamatergic blocking drugs differentially regulate glutamic acid decarboxylase mRNA in mouse brain

Dopaminergic and glutamatergic inputs play an important role in regulating the activity of GABAergic neurons in basal ganglia. To understand more fully the biochemical interactions between these neurotransmitter systems, the effects of blocking dopamine and glutamate (N-methyl-D-aspartate) (NMDA) receptors on the expression of glutamic acid decarboxylase (GAD) mRNA were examined. Persistent blockade of dopamine receptors was achieved by daily injections of EEDQ, a relatively non-selective irreversible D1 and D2 dopamine receptor antagonist, or FNM, a relatively selective irreversible D2 dopamine receptor antagonist. Persistent blockade of NMDA receptors was achieved by continuously infusing dizocilpine (MK-801), a non-competitive NMDA receptor antagonist. The levels of GAD mRNA in mouse brain were measured by in situ hybridization histochemistry following treatment with these agents. Repeated administration of EEDQ increased the levels of GAD mRNA in corpus striatum and frontal and parietal cortex; the first significant effects were seen after 4 days of treatment. Treatment with FNM elicited effects similar to those produced by EEDQ, except FNM also significantly increased GAD mRNA in nucleus accumbens. Neither EEDQ nor FNM produced significant effects on GAD mRNA in olfactory tubercle or septum. Infusion of MK-801 produced a rapid and marked decrease in the levels of GAD mRNA in corpus striatum, nucleus accumbens, olfactory tubercle, septum and frontal and parietal cortex; significant changes were seen as early as 2 days of treatment. No significant effects were seen in globus pallidus. Cellular analysis of emulsion autoradiograms from corpus striatum revealed that MK-801 reduced the amount of GAD mRNA in individual cells as well as the proportion of cells expressing high levels of GAD mRNA. These results suggest that dopamine, though its interaction with D2 dopamine receptors, exerts an inhibitory effect on the expression of GAD mRNA, and that glutamate, though its interaction with NMDA receptors, exerts a stimulatory effect on GAD mRNA expression. They show further that the regulation of gene expression by dopamine receptors or NMDA receptors is different in different regions of the brain.     

The role of striatal glutamate receptors in models of Parkinson's disease

The aim of the study was to examine the effect of antagonists of the NMDA receptor on the parkinsonian-like muscle rigidity in rats. Reserpine and haloperidol increased the muscle resistance of the hind foot to passive movements, as well as the reflex electromyographic (EMG) activity in the gastroenemius and tibialis anterior muscles. MK-801 (0.32-1.28 mg/kg s.c.), an uncompetitive antagonist of the NMDA receptor, and L-701,324 (5-40 mg/kg i.p.), an antagonist of the glycine site, reduced the muscle tone and the reflex EMG activity enhanced by reserpine or haloperidol. AP-5 (2 and 5 micrograms/0.5 microliter), a competitive antagonist of the NMDA receptor, and 5,7-dichlorokynurenic acid (1.0-4.5 micrograms/0.5 microliter), the glycine site antagonist injected bilaterally into the rostral striatum, inhibited the muscle rigidity induced by haloperidol. In contrast, AP-5, injected alone bilaterally into the intermediate-caudal striatum induced muscle rigidity. The present results suggest that: (1) the inhibitory effect of the NMDA receptor antagonists on the parkinsonian-like muscle rigidity depends, at least partly, on their action on the rostral striatum; (2) the blockade of NMDA receptors in the intermediate-caudal striatum may reduce the beneficial impact of these compounds.     

3H](+)-7-OH-DPAT and [3H]pramipexole binding in the striatum and nucleus accumbens of Sprague-Dawley and Fischer-344 rats

The binding of the D2-like agonists, (+)-7-hydroxy-N,N-di-n-[3H]propyl-2-aminotetralin (7-OH-DPAT) and [3H]pramipexole (2-amino-4,5,6-tetrahydro-6-propylaminobenzthiazole; MIRAPEX) were determined in membranes from adult male Sprague-Dawley and Fischer-344 rats. Saturation analysis, which optimized binding to D3 receptors, revealed 3-6 fold differences in Bmax values between the two radioligands with no change in affinity. [3H](+)7-OH-DPAT labeled 41.4+/-4.1 to 61.8+/-3.0 fmol/mg protein in nucleus accumbens and striatal homogenates, yet [3H]pramipexole labeled only 7.0+/-1.2 to 18.9+/-5.3 fmol/mg protein. Regional differences with both radioligands were observed in Fischer-344 rats; the striatum exhibited a 52%-69% greater density of sites in comparison to the nucleus accumbens. These data suggest that D3 receptor density can vary significantly between animal strains depending on the radioligand used, and [3H]pramipexole identifies a different ratio of sites in the striatum and nucleus accumbens compared to [3H](+)7-OH-DPAT.     

BIMG 80, a novel potential antipsychotic drug: evidence for multireceptor actions and preferential release of dopamine in prefrontal cortex

In radioligand binding studies, BIMG 80, a new putative antipsychotic, displayed good affinity at certain serotonin (5-HT1A, 5-HT2A, 5-HT6), dopamine (D1, D2L, D4), and noradrenergic (alpha1) receptors. The effect of acute subcutaneous BIMG 80, clozapine, haloperidol, risperidone, amperozide, olanzapine, and Seroquel was then investigated on dopamine release in medial prefrontal cortex, nucleus accumbens, and striatum in freely moving rats using the microdialysis technique. Four different neurochemical profiles resulted from the studies: (a) Systemic administration of BIMG 80, clozapine, and amperozide produced greater percent increases in dopamine efflux in medial prefrontal cortex than in the striatum or the nucleus accumbens. (b) Haloperidol induced a similar increase in dopamine concentrations in the striatum and nucleus accumbens with no effect in the medial prefrontal cortex. (c) Risperidone and olanzapine stimulated dopamine release to a similar extent in all brain regions investigated. (d) Seroquel failed to change significantly dopamine output both in the medial prefrontal cortex and in the striatum. Because an increase in dopamine release in the medial prefrontal cortex may be predictive of effectiveness in treating negative symptoms and in the striatum may be predictive of induction of extrapyramidal side effects, BIMG 80 appears to be a potential antipsychotic compound active on negative symptoms of schizophrenia with a low incidence of extrapyramidal side effects.     

The power of support groups: influence on infant feeding trends in New Zealand

The effect of streptozotocin (STZ)-induced diabetes and a combination of chronic treatment with haloperidol (HPD) on dopamine (DA)D2, serotonin (5-HT) 5-HT1A and 5-HT2A receptors was investigated in rat brain. Rats were randomly assigned to one of four groups: vehicle-vehicle, STZ-vehicle, vehicle-HPD, and STZ-HPD groups. Four weeks after single administration of STZ (65 mg/kg IV) or vehicle (citrate buffer), rats received depot HPD (4 mg/kg IM) or vehicle (sesame oil) once a week for 4 weeks. Sixteen days after the last injection of HPD or vehicle, rats were sacrificed, and the density of binding sites was determined using [3H]spiperone as ligand in the striatum (D2),[3H]8-hydroxy-2-(di-n-propyl)-aminotetraline in the hippocampus (5-HT1A), and [3H]ketanserin in the frontal cortex (5-HT2A). The density of D2 receptors was significantly increased in the vehicle-HPD compared to vehicle-vehicle controls. However, striatal D2 receptor density of the STZ-HPD and the STZ-vehicle were not significantly different from the vehicle-vehicle group. A significant increase in cortical 5-HT2A receptor density was observed only in the group of STZ-vehicle. Treatment with STZ, HPD, or the combination thereof, did not affect the density of 5-HT1A receptors. The affinity constants for D2, 5-HT1A, and 5-HT2A receptors were not affected by any treatment. These results suggest that diabetic state may affect brain serotonergic activity via an increase in the density of 5-HT2A receptors. This may indicate an increased vulnerability to major depression in patients with diabetes. The lack of an effect of the combined chronic treatment with STZ and HPD on the D2 receptor density may correspond to the increased risk to develop tardive dyskinesia in patients with diabetes.     

Role of the nucleus accumbens and the striatum in the production of turning behaviour in intact rats

Recent knowledge of the mechanisms underlying turning or circling behaviour in intact rats is reviewed. Most interest has been directed towards the striatum because of the classical hypothesis that turning behaviour results from lateral differences in the activity of the bilateral nigrostriatal pathway. However, the assumption that asymmetrical activation of the striatum is a necessary condition for dopamine-dependent turning behaviour has been questioned by several studies showing that unilateral injection of amphetamine or dopamine receptor agonists into the nucleus accumbens, a target of the mesolimbic dopaminergic system, also produces reliable circling away from the side of injection. Apart from discussing differences in stepping patterns of turning and discussing the role of the dopamine D1/D2 receptor interaction, the present survey focuses attention upon the two-component hypothesis, especially in relation to our recent studies in which activities of dopamine D1 and D2 receptors in the striatum and the nucleus accumbens have been manipulated separately in intact rats. It is hypothesized that turning behaviour is produced by asymmetry within nucleus accumbens circuits which involve neuronal connections from the nucleus accumbens to the A9 cell area, which in turn projects to the ventrolateral striatum that determines the direction of turning.