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The consequences of pharmacologically evoked augmented serotonin (5-hydroxytryptamine, 5-HT) release on neuronal activity in the brain, as reflected by the cellular expression of the immediate early gene c-fos, were studied. Wistar rats were treated with saline, the 5-HT reuptake inhibitor citalopram (10 micromol/kg s.c.), the 5-HT(1A) receptor antagonist N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)-N-(2-pyridyl)cyclohexane carboxamine trihydrochloride (WAY 100635, 1 micromol/kg s.c.), or the combination of both drugs. At the given dosages, the combination of the drugs has previously been shown to enhance the cerebral release of 5-HT. Two hours and thirty minutes after administration, the brains were fixated, and Fos protein was histologically stained and quantified. The paraventricular nucleus of the hypothalamus, the central nucleus amygdala, the ventromedial hypothalamic nucleus, the dorsolateral striatum, and the nucleus accumbens shell were particularly responsive to increased 5-HT release. The results, illustrating the synergistic consequence of the combined drug treatments, are discussed in terms of activity of the limbic-hypothalamic-pituitary-adrenocortical system., (Copyright 2002 Elsevier Science B.V.)

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.

3,4-Dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) were measured in the corpus striatum, nucleus accumbens and tuberculum olfactorium of the rat brain, 4 antidepressants, 4 anesthetics, dipropylacetate, ethosuximide and metoclopramide induced a rise of DOPAC and HVA levels in the 3 brain regions. No change was observed after carbamazepine, diazepam or propranolol treatment. Combined treatment with a maximally effective dose of haloperidol and morphine, oxotremorine or probenecid produced an additional rise of DOPAC and HVA levels, while no additional rise was seen with chloral hydrate, chlorimipramine, ether, halothane, metoclopramide or sulpiride. The potency of drugs to increase DA metabolism in corpus striatum relative to mesolimbic structures was estimated. Atypical neuroleptics such as sulpiride could be differentiated in this respect from classical neuroleptics such as chlorpromazine, fluphenazine and thioridazine, by their ability to produce a relatively large increase of metabolite levels in the mesolimbic regions. The heterogeneous group of 14 non-neuroleptics however produced regional changes which were very similar to those of the atypical neuroleptics. DA metabolism in mesolimbic regions, in contrast to striatal tissue, seems to respond more to atypical neuroleptics and non-neuroleptics than to typical neuroleptics.

The study concerned the effect of repeated treatment with antidepressant drugs on the elevation of cyclic AMP levels in the rat cerebral cortex following electrical stimulation of the locus coeruleus. Some of the tricyclic and tetracyclic antidepressant drugs inhibited the cyclic AMP response. Desmethylimipramine was the most potent (effective when given 5 mg/kg/day for 2 weeks). Imipramine and nomifensine (daily dose 10 mg/kg for 2 weeks) produced slight decreases, while iprindol and clomipramine were ineffective. After 6 weeks of treatment (daily 10 mg/kg) iprindol, clomipramine and mianserin were without effect. The cyclic AMP response was suppressed by higher doses of the latter two drugs (2 weeks, 20 mg/kg/day). These results indicate that tricyclic and tetracyclic antidepressant drugs are able to decrease cerebral noradrenergic neurotransmission of locus coeruleus neurons, as far as this is mediated by cyclic AMP. It is not clear, however, whether such modification is related to the therapeutic action of antidepressant drugs.

The potential of in vivo spiperone binding as a tool for the detection and quantitative analysis of striatal dopamine (DA) receptor alterations was studied in rat brain lesioned in several ways. Two weeks after kainate (KA) injection a significantly higher radioactivity accumulation was observed in the lesioned striatum than in the contralateral structure after a tracer dose of [3H]spiperone. The difference was maximal 2 days after surgery and it was present for at least 4 weeks while it was reversed 11 weeks after KA injection. The radioactivity uptake (tracer dose of [3H]spiperone) measured 2 weeks after surgery could be specifically prevented in both KA-lesioned and contralateral striatum by haloperidol and N-n-propylnorapomorphine while non-dopaminergic drugs were almost without effect. More than 80% of the radioactivity accumulation was saturable in both contralateral (unlesioned) and KA-lesioned striatum, leaving a slightly higher non-saturable radioactivity level in the latter. One week after unilateral ablation of the cerebral cortex overlying the striatum only minor bilateral differences in striatal radioactivity content were found after a tracer dose of [3H]spiperone. No differences were present after 6-OHDA lesion of the nigrostriatal pathway. Striatal DA receptor densities (Bmax) were determined from the dose-dependency of total striatal spiperone accumulation. This relationship was assessed using cerebellar spiperone accumulation instead of dose. Thus a Bmax of about 75 fmol X mg-1 tissue was found in the striatum of control (unoperated) rats and contralateral to the striatal KA lesion while 2 weeks after surgery it was approximately 33 fmol X mg-1 in the KA-lesioned striatum. One week after unilateral decortication Bmax values of about 50 and 65 fmol X mg-1 were found ipsi- and contralaterally to the lesion respectively.

Intracerebral dialysis in conscious freely moving rats was used to examine the involvement of the N-methyl-D-aspartate (NMDA) receptor in the formation of lactic acid and its consequent appearance in extracellular fluid. Local administration of NMDA in the striatum of conscious, freely moving rats was found to produce a transient increase in extracellular lactate. Alternatively, administration of the NMDA antagonists 2-amino-7-phosphonoheptanoic acid or 2-amino-5-phosphonopentanoic acid delayed the onset of and attenuated the magnitude of the lactate production induced by an electroconvulsive seizure. Pretreatment of the striatum with either of these antagonists reduced the total amount of lactate observed in extracellular fluid following ischemia induced by cardiac arrest, but did not affect the time course of the appearance of lactate in the extracellular space.

The subject of this study was the disappearance of 3, 4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) from the brain of rats treated with pargyline and pargyline in combination with tropolone. The DOPAC decline was exponential after pargyline treatment, while the HVA decline became a first order elimination when in addition to monoamine oxidase, catechol-O-methyl transferase was also inhibited. The turnover of the metabolites was calculated by multiplying the steady state level by the fractional rate constant (k). The DOPAC turnover was found to be 23.3 nmol/g/h in the corpus striatum and 22.6 nmol/g/h in the mesolimbic structures. The HVA turnover was 11.2 nmol/g/h in the corpus striatum and 6.7 nmol/g/h in the mesolimbic structures. The data showed that under control conditions DOPAC is only partially O-methylated to HVA, while the formation of HVA via the methoxytyramine pathway is unlikely. DOPAC turnover therefore probably approximates dopamine turnover.

The accumulation and retention of radioactivity in rat brain were studied after intravenous injection of the dopamine (DA) agonist [3H]N-n-propylnorapomorphine ( [3H]NPA). Dose-dependent saturable accumulation of label was found in the striatum, nucleus accumbens and olfactory tubercle. DA agonists (apomorphine, N,N-dipropyl-5,6-ADTN) and antagonists (haloperidol, cis-flupenthixol) prevented this accumulation. Enhanced accumulation of radioactivity in the striatum was found after 6-OHDA lesions and short- and long-term treatment with reserpine. These results are an indication of specific NPA binding to presumably postsynaptically situated DA receptors. One hour after administration of the drug, the effect of NPA on striatal DA metabolism was not correlated with receptor saturation. Maximal numbers of in vivo NPA binding sites (about 30 and 22 pmol . g-1) in striatal tissue were calculated from independent measurements at 15 and 60 min after NPA injection. Regional distribution of radioactivity after a tracer dose of [3H]NPA was assessed in 35 brain areas and parts of the spinal cord. In addition to the already mentioned DA-rich areas receptor-specific NPA binding was also found in several other brain parts.

A concurrent semi-automatic fluorometric assay technique for 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), is described. The method is based on a rapid manually performed isolation of DOPAC and HVA on small columns of Sephadex G-10 followed by an automated fluorometric detection with a continuous flow system. DOPAC and HVA were measured in the corpus striatum, nucleus accumbens and olfactory tubercle of the rat, under normal conditions and after treatment with amphetamine, apomorphine, clozapine, haloperidol, morphine, oxotremorine, pargyline, probenecid, sulpiride and thioridazine. Clozapine, morphine, sulpiride and oxotremorine induced the most pronounced rise of DA metabolites in the nucleus accumbens. Probenecid produced a DOPAC accumulation in the nucleus accumbens. Striking differences were observed between the DOPAC/HVA ratios in the different structures of control animals. The concurrent assay enables a rapid screening of the action of drugs in regional DA metabolism.

The influence of apomorphine, chloral hydrate, haloperidol, morphine, oxotremorine, pargyline, probenecid and promethazine on DOPAC and HVA levels was studied in the substantia nigra (including the ventral tegmental dopaminergic regions) and corpus striatum of the rat brain. The time--effect curves of changes in HVA levels after pretreatment with apomorphine, haloperidol, morphine, oxotremorine or promethazine are presented. The time--effect curves for the substantia nigra showed an initial rapid HVA rise, which was not observed in the corpus striatum. Promethazine treatment caused a small but significant HVA rise in the substantia nigra only. Chloral hydrate, morphine and oxotremorine induced a similar percentage increase in DOPAC and HVA levels in the substantia nigra as well as in the corpus striatum. Haloperidol, however, caused a small percentage change in the metabolite levels in the substantia nigra when compared to the pronounced rise seen in the corpus striatum. The apomorphine-induced HVA decrease observed in both structures provides evidence for the presence of a dopaminergic receptor in the substantia nigra.

Homovanillic acid (HVA) levels were measured in the eye and the corpus striatum of rats under normal conditions and after different drug treatments. Neuroleptic agents such as clozapine, cis-flupenthixol and haloperidol induced comparable increases in HVA levels, whereas the non-neuroleptic trans-isomer of flupenthixol was inactive in both structures. Apomorphine decreased HVA levels in the retina and the corpus striatum, while amphetamine induced a decreased HVA formation in the retina and did not change levels of HVA in the corpus striatum. Probenecid caused a similar percentage rise of HVA in both structures. Morphine and oxotremorine induced a rise in HVA levels in the corpus striatum but not in retinal samples.

Homovanillic acid (HVA) was measured in the corpus striatum aan the limbic structures nucleus accumbens and olfactory tubercle of the rat, under normal conditions and after different drug treatments. Clozapine, thioridazine, morphine and physostigmine induced a similar percentage HVA increase in the three brain structures studied. Haloperidol and pimozide induced a higher percentage increase of HVA in the corpus striatum and nucleus accumbens when compared with the olfactory tubercle. Oxotremorine induced the highest HVA levels in the nucleus accumbens. Probenecid induced a significantly higher percentage accumulation of HVA in the limbic structures, especially in the olfactory tubercle. The HVA rise seen after haloperidol was suppressed by pretreatment with p-chlorophenylalanine or amino-oxyacetic acid in all structures studied. After atropine or trihexylphenidyl treatment the HVA rise induced by haloperidol was slightly suppressed in the limbic structures only. Our results suggest that not only under normal conditions but also after treatment with various types of drugs, dopamine metabolism as reflected by the HVA levels, is closely related in the different rat brain structures.

The neuronal localization of in vivo N-n-propylnorapomorphine (NPA) binding in the rat striatum was studied using 3 types of lesions. Striatal dopamine (DA) receptor densities (Bmax) were estimated from the relationships between total striatal and cerebellar NPA accumulation. A Bmax of 26.9 +/- 1.6 fmol X mg-1 wet weight tissue was found in the striata of non-lesioned (unoperated) rats. Similar values were obtained for striata with 6-hydroxydopamine-lesioned dopaminergic fibres. Kainate (KA)-lesioned striata contained 4.6 +/- 0.5 fmol X mg-1 saturable NPA binding sites. After unilateral decortication the receptor densities were in both striata resulting in ipsi- and contralateral Bmax values of 23 and 36 fmol X mg-1 respectively. With a tracer dose of [3H]NPA less radioactivity accumulated in the KA-lesioned striatum, while after unilateral destruction of the dopaminergic pathway more radioactivity was found in the ipsilateral striatum and no bilateral differences in striatal radioactivity concentration were found after unilateral cortical ablation. These observations show that all in vivo saturable striatal NPA binding sites are situated on striatal neurons and cortico-striatal afferents and that the effects of lesions on striatal DA receptor densities cannot be predicted from bilateral differences in the accumulation of tracer doses of [3H]NPA.