E. Stefanini

Dopamine receptors: Pharmacological and anatomical evidences indicate that two distinct dopamine receptor populations are present in rat striatum

(3H)-haloperidol and (3H)-spiroperidol binding studies after kainate injection into the striatum indicate the presence of dopamine receptive sites not located on post-synaptic membranes. The majority of these dopamine “receptors” which are not associated to an adenylate cyclase appear to be localized on terminals of cortico-striatal neurons. On the other hand sulpiride, an antipsychotic drug which increases striatal dopamine synthesis, does not inhibit dopamine-stimulated adenylate cyclase either in vitro or in vivo. However sulpiride stereospecifically displaces (3H)-haloperidol from striatal binding sites.

Distribution of GABAB receptor mRNAs in the rat brain and peripheral organs

GABA, the predominant inhibitory neurotransmitter present in the mammalian CNS, is also found in the periphery. GABA actions are mediated by the ionotropic GABA(A)/GABA(C) receptors, as well as the metabotropic GABA(B) receptor. The rat GABA(B) receptor has recently been cloned and two cDNA clones have been isolated encoding two isoforms of the receptor, GABA(B)R1a and R1b. Northern blot analysis revealed the presence of both transcripts in the rat brain using specific cDNA probes for GABA(B)R1a and R1b, respectively. However, Northern blot analysis, hybridized with a probe containing a sequence common to both isoforms, revealed specific RNAs in the rat brain and in testis, but not in other peripheral tissues. In the present study, by using the more sensitive reverse transcriptase-polymerase chain reaction with a specific set of primers for each isoform and Southern blot analysis, we found that both isoforms of the GABA(B) receptor are expressed not only throughout the brain but also in all peripheral organs examined, including heart, spleen, lung, liver, small intestine, large intestine, kidney, stomach, adrenal, testis, ovary and urinary bladder. The peripheral distribution of GABA(B)R1 mRNAs supports the notion of a physiological role for GABA in the control of a wide range of peripheral organs.

Sodium-dependent interaction of benzamides with dopamine receptors

Sulpiride and other benzamide (BM)-displacing activity on [3H]-spiroperidol ([3H]SPIR) binding by rat striatal dopaminergic receptors was found to be uniquely sodium-dependent, while classical neuroleptic (NL) activity was not influenced by NaCl. These results suggest the existence of at least two populations of striatal dopaminergic receptors, sodium-dependent and sodium-independent, through which BM and NL respectively interact.

Selective inhibition of serotonin uptake by trazodone, a new antidepressant agent

Abstract The inhibitory effect of trazodone, a non tricyclic antidepressant, on 5-HT and catecholamine uptake into the synaptosomal preparation from the rat brain was compared with that of chlorimipramine. The inhibition of 5-HT uptake by trazodone is competitive with a K i of 1.6 × 10 −6 M. Trazodone inhibits 3 H-5-HT, 3 H-NE and 3 H-DA uptake with an IC 50 of 1.4 × 10 −6 , 3.1 × 10 −4 and 5.2 × 10 −4 M, respectively. Therefore trazodone is 220 and 370 times more potent in inhibiting 5-HT than NE and DA uptake, respectively. The respective IC 50 values of chlorimipramine were 0.9 × 10 −7 , 3.6 × 10 −6 and 4.0 × 10 −6 M for 3 H-5-HT, 3 H-NE and 3 H-DA.

Differential effect of psychotropic drugs on dihydroxyphenylacetic acid (DOPAC) in the rat substantia nigra and caudate nucleus

Abstract The effect of different psychotropic drugs on DOPAC levels in the caudate nucleus and in the substantia nigra was compared. While pargyline, haloperidol and damphetamine caused parallel changes in both areas, apomorphine and reserpine influenced DOPAC levels in the caudate nucleus and in the substantia nigra differently. In both areas pargyline caused a rapid fall in DOPAC concentrations, while haloperidol caused a marked increase. D-amphetamine was slightly more potent in decreasing DOPAC level in the substantia nigra than in the caudate nucleus. On the other hand, apomorphine was very potent in decreasing DOPAC level in the caudate nucleus but failed to influence it in the substantia nigra. Finally, reserpine, which depleted dopamine stores in both areas, increased DOPAC in the caudate nucleus but decreased it in the substantia nigra.

Prolactin-Releasing Effect of a Novel Anti-Dopaminergic Drug, Domperidone, in the Rat

The prolactin (PRL)-releasing effect of domperidone (DOM), a blocker of dopamine receptors which does not cross the blood-brain barrier, was studied in unanesthetized male rats and compared to that of

[3H]Spiroperidol binding to a putative dopaminergic receptor in rat pituitary gland.

A class of high affinity DA receptor sites has been identified with [3H] SPIR in the anterior and pisterior lobes of rat pituitary gland. Competitive studies with DA receptor antagonists and agonists clearly demonstrated that [3H] SPIR stereospecifically labels a true dopaminergic receptor in both lobes. The physiological significance of these receptors, although still unclear, may be that of controlling the secretion of pituitary hormones and peptides.

[3H]haloperidol and [3H]spiroperidol receptor binding after striatal injection of kainic acid

Abstract [ 3 ]Haloperidol and [ 3 H]spiroperidol binding studies after kainate injection into the striatum indicate the presence of dopamine receptive sites not located on post-synaptic membranes. However, the physiological meaning of these “presynaptic” sites remains to be established.

Different effects of the calcium antagonists nimodipine and flunarizine on dopamine metabolism in the rat brain

The effect of two calcium antagonists, nimodipine and flunarizine, on striatal dopamine (DA) metabolism in rats was compared. Flunarizine (5–20 mg/kg i.p.) caused a dose-dependent increase in the DA metabolite, 3,4-dihydroxyphenilacetic acid (DOPAC) in the caudate nucleus. Following the 20 mg/kg dose, DOPAC levels were maximally elevated by about 50% from 2 to 12 hrs after treatment. On the contrary, nimodipine at the dose of 20 mg/kg i.p. produced a modest decrease in DOPAC levels. Neither calcium antagonist modified DA content. However, both nimodipine and flunarizine, at the dose of 20 mg/kg, markedly reduced the accumulation of DOPAC in the caudate nucleus induced by haloperidol (1 mg/kg). It is suggested that flunarizine, but not nimodipine, has a neuroleptic-like action, whereas the two calcium antagonists have in common the ability to attenuate the hyperactivity of DA neurons.

Neonatal hypothyroidism induces striatal dopaminergic dysfunction

Oral administration of the antithyroid drug methimazole (50 mg/kg per day) to rats during the last six days of pregnancy, and subsequent daily s.c. injection of methimazole (20-30 mg/kg) to their pups from birth to postnatal day 30 provoked hormonal and somatic alterations resembling (with all caution to any association between rodent and human data) those of congenital hypothyroidism. The steady-state concentrations of striatal dopamine were similar in hypothyroid and euthyroid, 32-day-old rats, while the levels of the dopamine metabolites 3,4-dihydroxyphenylacetic and homovanillic acids were markedly decreased in hypothyroidism. The results of this and our earlier study [Vaccari A. and Gessa G. L. (1989) Neurochem. Res. 14, 949-955] show that the maximal synaptosomal uptake of [3H]dopamine, an index for the density of nigrostriatal dopaminergic terminals, and the maximum number of membrane [3H]tyramine binding sites, reflecting the concentration of the vesicular transporter for dopamine, were decreased in the hypothyroid striatum. There was also a loss of those D1-type dopaminergic receptors claimed to be located on neurons intrinsic to the striatum, and, consequently, dopamine-stimulated, D1-regulated adenylate cyclase activity was depressed. It is suggested that individual dopaminergic nerve endings in the neonatal hypothyroid striatum must contain more dopamine, owing to some loss of pertinent innervation and, therefore, to the presence of less vesicular transport sites for dopamine. Hypothyroidism-related decreases in the maximum number of striatal D1- and, reportedly, D2-receptors, plus the impairment of D1-coupled second messenger activity, may play a role in the derangement of those neurobehavioural patterns where a dopaminergic regulation is putatively implied.