Effect of carbidine, sulpiride and haloperidol on levels of monoamines and their metabolites in the brain structures of rats

Haloperidol (1 mg/kg) was shown to increase significantly the dopamine (DA) turnover in n. accumbens and striatum and to a lesser degree in frontal cortex and hypothalamus of the rat brain; to decrease the noradrenaline content in hypothalamus. Sulpiride (50 mg/kg) slightly increased DA turnover in striatum and hypothalamus and lowered the serotonin (5-HT) content in frontal cortex. Carbidine (25 mg/kg) was found to increase DA turnover in frontal cortex, striatum and hypothalamus to a greater degree than haloperidol; 5-HT turnover was increased in all the cerebral regions. The results obtained indicated that the atypical neuroleptic drug carbidine exerts the predominant effect on the frontal cortex, the serotoninergic component being clearly pronounced.     

Apomorphine-induced behaviour during the oestrous cycle of the rat

The effect of various doses of apomorphine (APO) (25, 250, 400 and 750 micrograms/kg, s.c.) on open field behaviour, stereotyped behaviour, body temperature and concentrations of serum oestradiol was studied in cycling females and in ovariectomized rats. With the exception of grooming, the hormonal variations during the cycle, or the ovariectomy, did not have an effect on behaviour related to stimulation of presynaptic dopamine (DA) receptors. The endocrine status on proestrus (PE), characterized by an increase in serum oestradiol, did influence hyperlocomotion and hypothermia induced by apomorphine; the former being attenuated and the latter increased, as compared to the other phases of the cycle. Ovariectomy resulted in an increase in the stimulatory effect of apomorphine on locomotion. Stereotypy induced by apomorphine was unaltered by hormonal variations during the cycle and it was slightly attenuated by removal of the ovaries. During phases of low levels of oestrogen (oestrus, metestrus) apomorphine significantly increased the levels of serum oestradiol, determined 30 min after the administration of drug. It is concluded that the various DAergic mechanisms in brain are differentially affected by hormonal variations during the cycle and by ovariectomy.     

Regional effects of amphetamine, cocaine, nomifensine and GBR 12909 on the dynamics of dopamine release and metabolism in the rat brain.

1. The effects of single-dose regimens of amphetamine, cocaine, nomifensine and GBR 12909 on the dynamics of dopamine (DA) release and metabolism were evaluated in the frontal cortex, hypothalamus, nucleus accumbens and striatum. The regimens selected are known to produce substantial behavioural effects. 2. 3-Methoxytyramine (3MT) and 3,4-dihydroxyphenylacetic acid (DOPAC) rates of formation were used to assess DA metabolism by catechol-O-methyltransferase and monoamine oxidase respectively. The rate of formation of 3MT was used as an index of synaptic DA. The ratio and sum, respectively, of 3MT and DOPAC rates of formation were used to assess DA reuptake inhibition and turnover. 3. The effects of amphetamine on 3MT production and DOPAC steady-state levels were similar in all regions, suggesting similar pharmacodynamic actions. Amphetamine increased 3MT formation and steady-state levels, and reduced DOPAC steady-state levels. DOPAC formation was significantly reduced only in the nucleus accumbens and striatum. Total DA turnover remained unchanged except in the nucleus accumbens. Apparently, the amphetamine-induced increase in DA release occurred at the expense of intraneuronal DA metabolism and did not require stimulation of synthesis. 4. Nomifensine elevated 3MT formation in all regions. A similar effect was produced by cocaine except in the nucleus accumbens. GBR 12909 elevated 3MT production only in the hypothalamus, the striatum and the nucleus accumbens. 5. Cocaine selectively reduced DOPAC formation in the frontal cortex. Nomifensine increased and reduced, respectively, DOPAC formation in striatum and hypothalamus. GBR 12909 elevated DOPAC formation in all regions except the cortex, where pargyline did not reduce DOPAC levels in GBR 12909-treated rats.(ABSTRACT TRUNCATED AT 250 WORDS)     

Differential regional development of tolerance to increase in dopamine turnover upon repeated neuroleptic administration

Repeated treatment with haloperidol and sulpiride induced tolerance to the increases in homovanillic and dihydroxyphenyl acetic acids in the striatum, nucleus accumbens, tuberculum olfactorium and frontal cortex of the rat. The threshold dose inducing this effect appeared to be lower in the striatum than in the limbic regions. Similar results were found in the frontal cortex by measuring dopamine utilization. Moreover, tolerance developed earlier in the striatum than in the limbic areas. The possible reasons are discussed for the differential development of tolerance in the various DA areas investigated.     

Effects of Amantadine on Dopaminergic Neurons in Discrete Regions of the Rat Brain

The effect of a dopamine agonist, amantadine, on dopaminergic neurons was investigated in rat brains. Amantadine (40 mg/kg, i.p.) tended to increase DA (16%) and DOPAC (24%) levels. Further, amantadine (40 mg/kg, i.p.) significantly increased HVA levels in frontal cortex (44% above baseline after 40 mg/kg, i.p.) but not in corpus striatum and nucleus accumbens. Amantadine significantly increased DA levels at doses of 10, 20 and 40 mg/kg, i.p., in corpus striatum. On the other hand, amantadine decreased the L-DOPA accumulation by 30% in frontal cortex. This decreasing effect of amantadine may be attributable to a negative feedback mechanism by DA autoregulation. Our findings, therefore, suggest that amantadine may accelerate dopaminergic neurotransmission by increasing DA release from the frontal cortex and may possibly improve senile dementia.     

Sensitization versus tolerance to the dopamine turnover-elevating effects of haloperidol: the effect of regular/intermittent dosing

Recent clinical research suggests that particular patterns of changes in presynaptic dopamine (DA) turnover accompany the therapeutic response to neuroleptics. We sought to determine whether daily versus weekly dosing of haloperidol for 3 weeks produced distinct effects on DA, dihydroxyphenylacetic acid (DOPAC), and homovanillic acid (HVA) concentrations in multiple brain areas. Daily dosing favored the development of tolerance to the DA-turnover elevating effects of haloperidol in the striatum and nucleus accumbens. Weekly dosing favored the development of sensitization in the striatum, posterior olfactory tubercle, and ventral tegmental area. These results suggest that dosing schedules may determine, at least in part, the effects of chronic neuroleptic administration on presynaptic DA function.     

Ontogenetic changes in dopaminergic pre and postsynaptic elements in rat brain: effects of quinpirole and sulpiride.

The effects of quinpirole and sulpiride on dopamine (DA), dihydroxyphenylacetic acid (DOPAC) and accumulation of dihydroxyphenylalanine (DOPA) after inhibition of DOPA decarboxylase were determined for the striatum and tegmentum of 11- and 17-day-old rat pups. In both 11- and 17-day-olds, sulpiride enhanced striatal DOPAC and DOPA accumulation; whereas, quinpirole decreased DOPAC levels and increased DA levels. In the tegmentum, sulpiride enhanced DOPA accumulation in the 11-day-olds only. 3H-spiroperidol binding sites were also measured in the striatum, nucleus accumbens, tegmentum, medial frontal cortex, and the hippocampo-entorhinal area of 11- and 17-day-old pups. Age-dependent increases in binding site density were found in the striatum and nucleus accumbens.     

Definition of the in-vivo accumulation of [3H]spiperone in brain using haloperidol and sulpiride to determine functional dopamine receptor occupation

The in-vivo administration of [3H]spiperone caused an accumulation of radioactivity in the substantia nigra, tuberculum olfactorium, nucleus accumbens, striatum and frontal cortex when compared with cerebellar levels. Haloperidol (0.01-1.0 mg kg-1 i.p.) dose-dependently prevented the accumulation of [3H]spiperone in the substantia nigra, tuberculum olfactorium, striatum and nucleus accumbens. Sulpiride (10-160 mg kg-1 i.p.) dose-dependently prevented the accumulation of [3H]spiperone only in the substantia nigra. The effects of sulpiride on other areas were not consistent; there was a suggestion of a reduction in the accumulation of [3H]spiperone in tuberculum olfactorium and striatum, but not in nucleus accumbens. Neither haloperidol (0.01-1.0 mg kg-1 i.p.) nor sulpiride (10-160 mg kg-1 i.p.) caused displacement of [3H]spiperone from the frontal cortex. Both haloperidol (0.01-0.5 mg kg-1) and sulpiride (10-80 mg kg-1) increased striatal and mesolimbic HVA concentrations. Haloperidol potently blocked apomorphine-induced stereotypy but sulpiride was only effective at the highest dose employed. The functional effect produced by haloperidol correlated with its ability to define [3H]spiperone binding in-vivo to dopamine receptors in the substantia nigra, striatum and tuberculum olfactorium. In contrast, there was no correlation between functional effect of sulpiride and its ability to define [3H]spiperone binding in-vivo.     

A TRH analog (DN-1417). Effects on the levels of monoamines and the metabolites in the various brain regions in rats

The effects of a TRH (thyrotropin-releasing hormone) analog, DN-1417 (gamma-butyrolactone-gamma-carbonyl-L-histidyl-L-prolinamide citrate), on the levels of norepinephrine (NE), dopamine (DA), serotonin (5-HT) and the metabolites in the various brain regions of rats were determined by means of high performance liquid chromatography with electrochemical detection. DN-1417 (20 mg/kg, i.p.) produced marked decreases in the levels of NE, DA and 5-HT, especially in the nucleus accumbens, striatum and hypothalamus. The maximum effect was observed at 15 min after the administration. DA metabolites, 3,4-dihydroxyphenylacetic acid and homovanillic acid, increased significantly in the nucleus accumbens, striatum and hypothalamus, whereas 3-methoxy-4-hydroxyphenylglycol and 5-hydroxyindoleacetic acid remained unchanged. 3-Methoxytyramine increased significantly in the nucleus accumbens and striatum. Two week chronic administration of DN-1417 (20 mg/kg, i.p.) increased the levels of DA and NE in the nucleus accumbens and DA in the striatum. These results suggest that DN-1417 stimulates the turnover of the cerebral monoamines, especially the release of DA from the nucleus accumbens and striatum in the mesolimbic and nigro-striatal DAergic systems.     

Caffeine mimics dopamine receptor agonists without stimulation of dopamine receptors

The purpose of this study was to examine whether caffeine stimulates dopamine (DA) receptors. The effects of caffeine on the binding of [3H]spiperone to membranes from the striatum, accumulation of L-DOPA in the striatum in mice receiving gamma-butyrolactone, and regional levels of 3,4-dihydroxyphenylacetic acid in the brain of the rat were investigated and compared with those elicited by DA receptor agonists. Caffeine did not inhibit the binding of [3H]spiperone to membranes or the accumulation of L-DOPA in the striatum, produced by gamma-butyrolactone. Caffeine decreased the levels of 3,4-dihydroxyphenylacetic acid significantly in the striatum, olfactory tubercle and nucleus accumbens and slightly in the frontal cortex of rats, whereas it delayed utilization of DA in all those regions except the frontal cortex. Taken together these results suggest that caffeine fails to stimulate pre- or postsynaptic DA receptors. The possible mechanism by which caffeine mimics DA receptor in DA metabolism and behavior are discussed.     

Effects of acute ethanol administration on monoamine and metabolite content in forebrain regions of ethanol-tolerant and -nontolerant alcohol-preferring (P) rats

The contents of dopamine (DA), serotonin (5-HT) and their metabolites in the frontal cortex, anterior striatum, nucleus accumbens and hypothalamus of alcohol-tolerant and -nontolerant rats of the alcohol-preferring P line were determined one hour after the IP administration of 2.5 g ethanol/kg body wt. Compared with saline-injected controls, nontolerant P-rats injected with ethanol had (a) 60% higher levels of 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) in the frontal cortex; (b) 30-60% higher levels of DOPAC and HVA in the anterior striatum and nucleus accumbens; and (c) 20% higher levels of 5-HIAA in all three forebrain regions. In the tolerant group, the effects of IP ethanol on DOPAC and HVA were markedly attenuated or completely eliminated in these three forebrain regions. However, in the case of 5-HIAA, an attenuated response was observed only in the nucleus accumbens of the tolerant group. The IP administration of ethanol had little effect on the contents of DA or 5-HT in any of these three forebrain regions, with the exception that 5-HT levels were elevated in the anterior striatum of both the tolerant and nontolerant groups. In the hypothalamus, there were no significant differences for the contents of DA, 5-HT or their metabolites between the nontolerant or tolerant P rats after IP ethanol. The data indicate that both acute ethanol administration and chronic alcohol intake by the P line of rats alters certain DA and 5-HT systems that may be involved in the brain reward circuitry and in DA pathways involved in motor functions.     

Risperidone: a novel antipsychotic with many “atypical” properties?

The acute and chronic administration effects of risperidone (Ris), a mixed 5HT₂/D₂ receptor antagonist, versus haloperidol (Hal) on dopaminergic and serotoninergic activity were investigated in the rat prefrontal cortex (Pfc), and the whole striatum (Str) as well as separately, in dorsal striatum (StrD) and nucleus accumbens (Acb). During acute administration, Hal was found to be more potent than Ris in increasing DA turnover rate in StrD. In contrast, during chronic administration, Ris but not Hal, continued to increase DA turnover activity in StrD. Moreover, in contrast to Hal, chronic Ris treatment continued to increase DA and 5-HT turnover rate in Pfc. These differential effects reveal that Hal does not share common characteristics with Ris with respect to its neurochemical profile in the Str and Pfc.     

Risperidone: a novel antipsychotic with many “atypical” properties?

The acute and chronic administration effects of risperidone (Ris), a mixed 5HT₂/D₂ receptor antagonist, versus haloperidol (Hal) on dopaminergic and serotoninergic activity were investigated in the rat prefrontal cortex (Pfc), and the whole striatum (Str) as well as separately, in dorsal striatum (StrD) and nucleus accumbens (Acb). During acute administration, Hal was found to be more potent than Ris in increasing DA turnover rate in StrD. In contrast, during chronic administration, Ris but not Hal, continued to increase DA turnover activity in StrD. Moreover, in contrast to Hal, chronic Ris treatment continued to increase DA and 5-HT turnover rate in Pfc. These differential effects reveal that Hal does not share common characteristics with Ris with respect to its neurochemical profile in the Str and Pfc.     

Dopamine in the basal ganglia and benzodiazepine-induced sedation

The effects of the anxiolytic benzodiazepine flurazepam on motor activity and the turnover of dopamine were measured in rats. Changes in motor activity were measured using a doppler-shift device; changes in extracellular homovanillic acid (HVA), monitored by linear sweep voltammetry with carbon paste electrodes implanted in the striatum and nucleus accumbens and ex vivo measurements of changes in 3,4-dihydroxyphenylacetic acid/dopamine (DOPAC/DA) ratios in the striatum and nucleus accumbens were used as indices of changes in the turnover of dopamine. Injection of vehicle increased the nocturnal rise in the concentration of HVA and the ex vivo DOPAC/DA ratio in the nucleus accumbens. Injection of flurazepam decreased the nocturnal rise in HVA and DOPAC/DA ratio in the nucleus accumbens below control levels. There was also a decrease in the nocturnal rise in motor activity. Neither injection of vehicle nor injection of flurazepam caused changes in either the concentration of HVA or the DOPAC/DA ratio in the striatum. The correlation coefficient for motor activity compared to concentration of HVA remained high for the nucleus accumbens but was reduced for the striatum after administration of flurazepam. The results suggest that the sedative effect of flurazepam may be due to an action on the mesolimbic but not the nigrostriatal dopaminergic pathway.     

In vivo receptor occupancy of NRA0045, a putative atypical antipsychotic, in rats.

We have previously reported that (R)-(+)-2-amino-4-(4-fluorophenyl)-5-[1-[4-(4-fluorophenyl)-4-oxobutyl]+ ++pyrrolidin-3-yl]thiazole (NRA0045) is a novel antipsychotic agent with affinities for dopamine D4, 5-hydroxytryptamine 2A (5-HT2A) and alpha1 receptors. In the present study, in vivo receptor occupancy of 5-HT2A, alpha1, dopamine D2 and D3 receptors by NRA0045 was assessed, based on in vivo and ex vivo receptor binding, and findings were compared to reference antipsychotic drugs (haloperidol, risperidone, clozapine). Intraperitoneal administration of haloperidol highly occupied the dopamine D2 receptor in the striatum and nucleus accumbens, and alpha1 adrenoceptors in the frontal cortex. Occupation of the 5-HT2A receptor in the frontal cortex and the dopamine D3 receptor in the nucleus accumbens and islands of Cajella was moderate. By contrast, atypical antipsychotics such as risperidone and clozapine dose-dependently occupied the 5-HT2A receptor in the frontal cortex, with moderate to negligible occupancy of the D2 receptor in the striatum and the nucleus accumbens. Clozapine and risperidone also occupied the alpha1 adrenoceptor in the frontal cortex, and clozapine did not occupy the dopamine D3 receptor. As seen with other atypical antipsychotics, intraperitoneal administration of NRA0045 dose-dependently occupied the 5-HT2A receptor and the alpha1 adrenoceptor in the frontal cortex, while it was without effect on dopamine D2 and D3 receptors in the striatum, nucleus accumbens and islands of Cajella. Thus, the strong occupancy of 5-HT2A and alpha1 receptors is involved in the pharmacological action of NRA0045.     

Regional effects of neuroleptics on dopamine metabolism and dopamine-sensitive adenylate cyclase activity.

The effect of haloperidol, chlorpromazine, thioridazine and sulpride on the levels of DOPAC and HVA, as an index of DA turnover, and on the activity of DA-stimulated adenylate cyclase was investigated inthe striatum, the nucleus accumbens and the tuberculum olfactorium of the rat brain. Haloperidol, chlorpromazine and thioridazine caused a more marked increase in DA turnover in the striatum than in the mesolimbic areas, while the reverse was true for sulpiride. In contrast, although the relative potency of these compounds varied greatly, the Ki of each drug for the DA-sensitive adenylate cyclase was similar in three structures of rat brain. The results indicate that in the three brain structures investigated there was no correlation between the differential effects of neuroleptics on dopamine turnover in vivo and the blockade by these drug of the DA-sensitive adenylate cyclase activity in vitro.     

Effects of cocaine and the cocaine analog CFT on glutamatergic neurons

The effects of cocaine and the cocaine analog methyl-3β-(p-fluorophenyl)-1H,5H-tropane-2b-carboxylate (CFT) on glutamate turnover rate were studied in the nucleus accumbens, striatum, frontal cortex, and parietal-cingulate cortex of the rat, using neurotransmitter turnover rate as an estimate of the activity of the glutamatergic neurons. Both cocaine [15 or 30 mg/kg, intraperitoneally (IP)] and CFT (2.2 mg/kg, IP) increased glutamate turnover in the nucleus accumbens, although the time course of their actions differed. These effects on glutamate turnover appeared at times after maximal motor activation of the animals had occurred. On the other hand, neither cocaine nor CFT affected glutamate turnover in the frontal cortex, parietal-cingulate cortex, or striatum. Neither cocaine nor CFT affected the content of glutamate or glucose in any brain region studied. Thus, although cocaine and CFT affect glutamatergic neurons in the CNS, these actions are not generalized across the CNS, but are restricted to a specific brain region.     

Regional neurotransmitter responses after acute and chronic electroconvulsive shock

Regional neurotransmitter changes after acute and chronic electroconvulsive shock (ECS) were studied using the technique of repeated microdialysis. Microdialysis was carried out on alternate sides of the brains of anaesthetised rats before and during the first and the eighth ECS or sham (control) treatments. Extracellular fluid release of monoamines and their metabolites was measured in the frontal cortex, striatum and nucleus accumbens using HPLC with electrochemical detection. The first ECS produced selective regional responses, shown by increased concentrations of noradrenaline (NA) and dopamine (DA) in frontal cortex, by unchanged DA content in striatum, and by a small rise in NA and a fall in DA concentrations in nucleus accumbens. Concentrations of metabolites increased after ECS in all regions studied, and for homovanillic acid and dihydroxyphenylacetic acid, the temporal pattern of these changes did not resemble that of DA. Comparison of neurotransmitter responses as per cent of baseline release after the first and eighth ECS treatments showed they were identical. Basal release of monoamines and metabolites before the first ECS or sham treatment was similar in all regions studied. Prior to the eighth treatment, basal release of NA in the frontal cortex and DA in the striatum was elevated in the ECS-treated animals, while basal release of NA in the nucleus accumbens was reduced in both ECS-and sham-treated animals. These data suggest that acute and chronic ECS have different and region-specific effects on neurotransmitter release, although the overall pattern of these responses is not changed by chronic treatment. The catecholamine-releasing actions of ECS, and the changes in basal release of neurotransmitters seen after chronic treatment may contribute to its therapeutic effects.     

Acute scopolamine treatment decreases dopamine metabolism in rat hippocampus and frontal cortex

The aim of the present study was to correlate the impairment of cognitive function induced by scopolamine with the activity of dopaminergic synapses in brain areas which are innervated by the mesocortical limbic system (e.g. hippocampus and frontal cortex) or by the mesostriatal system (e.g. striatum and nucleus accumbens). The results indicate that acetylcholine receptor blockade induced by the intraperitoneal injection of 0.5 mg/kg scopolamine resulted in a selective decrease in the content of the dopamine metabolites 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA). This effect appeared to be specific for the hippocampus and frontal cortex. Indeed, dopamine turnover in striatum and nucleus accumbens was not affected by scopolamine treatment. The scopolamine-induced decrease of dopamine turnover in both hippocampus and frontal cortex paralleled in terms of both time- and dose-dependence the drug-induced amnesic effects, as measured by a passive avoidance behavioral test.     

Modulation by dopaminergic and serotonergic systems of cholinergic interneurons in nucleus accumbens and striatum

The acetylcholine turnover rate and the enzymatic activity of choline acetyltransferase were determined in the nucleus accumbens and striatum. Whereas both apomorphine and a serotonin agonist MK 212 led to a decrease in acetylcholine turnover rate, haloperidol showed the opposite effect in the nucleus accumbens and striatum, respectively. Dopamine and serotonin agonists induced a depression of the enzymatic activity but this effect was less pronounced than the effect on acetylcholine turnover rate. It is concluded that in the nucleus accumbens and striatum the cholinergic interneurons appear to be modulated by dopaminergic and serotonergic systems in an inhibitory manner.