Renato Gaggi

Effects of calcium antagonists on biogenic amines in discrete brain areas

Discrete brain sections were obtained from rats given i.p. verapamil, nifedipine, diltiazem or flunarizine (0, 10, 20 or 40 mg/kg). The biogenic amines and metabolites in the hypothalamus, brainstem hippocampus, striatum, thalamus-midbrain and cortex were determined by high-performance liquid chromatography with electrochemical detection. The treatments induced several changes in the levels of neurotransmitters and metabolites, displaying regional specificity and differences according to the various compounds. It was speculated that some effects could have been due to indirect actions and/or to interactions of the compounds with receptors other than the voltage-sensitive calcium channels. However blockade of these channels could account for the following effects. (a) The nifedipine-induced increases in the 5-hydroxy-3-indoleacetic acid levels and, in general, the signs of activation of the serotonergic systems. (b) The fall in the 3,4-dihydroxyphenylacetic acid levels and, in general, the signs of attenuation of dopaminergic neurotransmission induced by nifedipine, verapamil and diltiazem. (c) The fall in the norepinephrine levels induced by all the compounds studied.

Effects of the selective 5-HT receptor agonists 8-OHDPAT and DOI on behavior and brain biogenic amines of rats

1. The behavioral responses, as well as the biogenic amines and metabolite contents in discrete brain areas were determined in male rats subcutaneously treated with a 5-HT1A (8-OHDPAT) or 5-HT2A (DOI) agonist at doses (0.5-2 mg/kg) sufficient to produce the typical effects of the stimulation of these brain receptor subtypes. 2. Besides the expected effects (i.e., forepaw treading, flat body posture and inhibition of 5-HT release and turnover), 8-OHDPAT displayed signs of increased dopaminergic transmission. 3. DOI increased dopamine turnover and provoked stereotypical behavior, in addition to head shakes and body twitches. 4. Moreover, DOI induced both forepaw treading and flat body posture, which are believed to be typical responses to the stimulation of brain 5-HT1A receptors. 5. This finding cannot be explained on the basis of actual knowledge, because the affinity of DOI for 5-HT1A receptor has been found to be very low, whereas indirect mechanisms of activation of this receptor subtype triggered by stimulation of 5-HT2A receptor are actually unknown.

Antidepressant versus neuroleptic activities of sulpiride isomers on four animal models of depression

The atypical neuroleptic sulpiride is also prescribed for depression because of its activating effect. However, such an effect does not necessarily imply an action identical to that of classical antidepressants, and a laboratory comparison of the neuroleptic and antidepressant activities of sulpiride may contribute to a better definition of its psychotherapeutic profile. Sulpiride isomers were studied in the rat in four behavioural models of depression which are thought to be influenced by neuroleptics in different ways. Desipramine (imipramine) and haloperidol were employed in each test as a standard antidepressant and neuroleptic, respectively. The four tests were: 1) prevention of apomorphine-induced sedation: 2) antagonism of apomorphine-induced hypothermia; 3) behavioural despair (swim test); 4) learned helplessness (FR2 lever pressing escape). Desipramine ameliorated behaviour in all tests; haloperidol ameliorated the response to test 1, influenced that to test 2 in a neuroleptic-like way and worsened the responses to tests 3 and 4.(-)-Sulpiride worked in a similar way to haloperidol in all tests.(+)-Sulpiride significantly and dose-dependently ameliorated the responses to test 3 and was inactive in the others. No conclusion was drawn from test 1 owing to its lack of specificity; the results of the remaining tests indicated a neuroleptic profile of (-)-sulpiride and suggested a potential “antidepressant” activity of (+)-sulpiride which merits further investigation.

Comparison among the effects of nifedipine, nimodipine and nisoldipine on the brain biogenic amines of normal or haloperidol treated rats

1. Previous studies have shown that dihydropyridine calcium antagonists affected the metabolism of the brain biogenic amines more extensively than the non-dihydropyridine ones. The effects of three dihydropyridines (nifedipine, nimodipine or nisoldipine, 0.05-0.10 mmol/kg i.p.) on brain monoamines and metabolites have been evaluated on both normal and haloperidol treated rats. 2. The small changes induced by the drugs on normal rats were markedly increased in the haloperidol treated rats, clearly showing an inhibition of dopaminergic systems. 3. These effects were selective for the striatum and cerebral cortex, with nisoldipine being more effective than nimodipine or nifedipine. 4. The effects of the three drugs on serotonergic systems were similar or more marked on haloperidol treated rats than on normal rats. These effects, showing activation of serotonergic systems, displayed some regional specificity and different potency of the three compounds. Nisoldipine also appeared to be the most effective drug on serotonergic systems. 5. In conclusion nisoldipine, as well as other calcium antagonists, may have a place in the treatment of some mood disorders.

The activation of serotonin receptors prevents glutamate-induced neurotoxicity and NMDA-stimulated cGMP accumulation in primary cortical cell cultures.

In the present study, we performed experiments on primary cell cultures from rat neocortex to assess the effects of the selective serotonergic 5HT(1A), 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) or 5HT(2), (+/-)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) agonists on neuronal death induced by 15min exposure to (-)glutamate (300 microM) as measured by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT). The results show that both drugs attenuated (-)glutamate-induced neurotoxicity and this effect was fully antagonized by the selective antagonists of 5HT(1) (NAN-190) or 5HT(2) (ketanserin) receptors.The effects of the selective serotonergic agonists on the production of cyclic GMP (cGMP) accumulation induced by N-methyl-D-aspartate (NMDA) in the same neuronal preparation were also evaluated. Only the 5HT(2) agent, but not 8-OH-DPAT, per se, decreased basal cGMP levels. In contrast, both drugs attenuated the NMDA-induced cGMP accumulation in this cell preparation. The unexpected similar behavior of 5HT(1) and 5HT(2) agonists towards glutamate-induced neurotoxicity and NMDA-induced cGMP accumulation in primary cell cultures is discussed. It is concluded that primary cell cultures from rat cerebral cortex could represent a suitable experimental model to search novel neuroleptics which exert their effects via 5HT receptors.

Effects of nitrendipine and nisoldipine on biogenic amines in discrete areas of rat brain

1. Biogenic amines and metabolites were determined in discrete brain sections obtained from rats once or repeatedly treated with nitrendipine or nisoldipine. 2. The increase in both the 5-HIAA levels and the 5-HIAA/5-HT ratio suggested that the drugs activated the serotonergic system in various brain areas. 3. Moreover, nisoldipine decreased the HVA content and the HVA/DA ratio in the striatum. 4. This suggested that nisoldipine, but not nitrendipine, inhibited dopaminergic neurotransmission in this brain area. 5. The effects induced by repeated treatment with nitrendipine or nisoldipine were reduced as compared to those caused by a single administration of these drugs. 6. All these facts could be explained on the basis of the pharmacokinetic properties of nitrendipine and nisoldipine and by the ability of these drugs to interact with the brain VSCC.

Actions of nimodipine on the serotonergic systems of rat brain

1. The effects of the serotonin (5-HT) precursor, L-5-hydroxytryptophan (L-5-HTP), or the selective 5-HT1A receptor agonist, 8-OHDPAT, on behavior or brain 5-HT metabolism or both were evaluated in rats IP pretreated with nimodipine at doses ranging from 0.31 to 40 mg/kg. 2. Nimodipine, in a wide dose range (0.6-20.0 mg/kg) potentiated the head-twitch response to L-5-HTP. 3. The effects of nimodipine on the 5-HT metabolism of rats treated with L-5-HTP did not comply with the increase in the behavioral response to this 5-HT precursor. 4. Nimodipine antagonized the effects on 5-HT metabolism induced by 8-hydroxy-2-(di-N-propyl-amino)-tetralin through stimulation of 5-HT1A autoreceptors. 5. It was concluded that the effects of nimodipine on brain 5-HT metabolism appeared to be linked to activation of serotonergic neurotransmission likely due to inhibition of the back-regulation mechanism mediated by presynaptic 5-HT1A receptors.

Effects of isradipine and darodipine on serotonergic system of the rat brain.

Isradipine and darodipine are dihydropyridine calcium antagonists that easily pass into the brain, showing high affinity for cerebral L-type voltage-sensitive calcium channel (VSCC). These drugs were IP administered to rats to study their effects on serotonergic systems of discrete brain areas. Isradipine (0.05-5.0 mg/kg) and darodipine (0.3-20 mg/kg) increased the 5-HIAA/5-HT ratio, mostly enhancing the metabolite (5-HIAA) content in various brain areas, suggesting that serotonin (5-HT) turnover was increased. This increase appeared to depend on facilitation of serotonergic neurotransmission, because low doses of isradipine (< 0.075 mg/kg) or darodipine (< 0.6 mg/kg) enhanced the number of head twitches induced by L-5-hydroxytryptophan (L-5-HTP). However, higher doses of isradipine (1.5 mg/kg) or darodipine (5 mg/kg) also appeared to stimulate a negative feedback mechanism, which predominated over the facilitation when the serotonergic neurotransmission was strongly activated. Thus, higher drug doses decreased both the serotonin turnover and the number of head twitches on rats treated with L-5-HTP. It was speculated that the observed effects were due to brain VSCC blockade, although the studied compounds showed a peculiar profile of properties when compared to other previously studied calcium antagonists. Moreover, it was concluded that darodipine appeared to be more effective and selective than isradipine regarding the effects on brain serotonergic systems.

Calcitonin enhances the effects of nimodipine on biogenic amines of rat brain

1. Nimodipine affects the brain biogenic amines suggesting both inhibition of the striatal dopaminergic system and activation of serotonergic systems in various brain areas. 2. Salmon calcitonin affects serotonergic systems as nimodipine does. 3. It was hypothesized that these effects could be more than additive since they all have been ascribed to inhibition of neuronal calcium influx. 4. Biogenic amines and metabolites were determined in brain areas obtained from rats pretreated with saline or salmon calcitonin (10 MRC U/kg, s.c.) and treated with nimodipine (2.5-20 mg/kg, i.p.). 5. The effects of nimodipine and salmon calcitonin appeared to be merely additive.

Dialysable and non‐dialysable hydroxyproline in the rat's urine: age related and diurnal variations

1. Urinary dialysable and non‐dialysable hydroxyproline, which are considered good indices of bone resorption and neoformation respectively, were determined in rats under conditions that modify skeleton metabolism, such as body growth and parathyroid or calcitonin administration. It was also investigated whether dialysable and non‐dialysable hydroxyproline excretions showed significant circadian fluctuations in rats of different ages.