Mechanisms of hyperglycemic response to chlorpromazine administered into lateral ventricle in rats. II. Secretion of epinephrine from adrenal medulla

An injection of chlorpromazine(CPZ) into the lateral ventricle caused hyperglycemia in intact rats, but not in adrenal-demedullated rats. However, the hyperglycemic response to CPZ was not blocked by hypophysectomy or pretreatment with dexamethasone. Beta-adrenergic blocking and ganglionic blocking both prevented CPZ-induced hyperglycemia. Furthermore, injection of CPZ did not potentiate the hyperglycemic response to exogenous epinephrine in demedullated rats. From these results, it is suggested that CPZ causes hyperglycemia mainly by the release of epinephrine from adrenal medulla stimulated by impulses from the central nervous system.     

Alterations in the thermic response to chlorpromazine in rats exposed prenatally to central nervous system depressants

The thermic response to acute administration of chlorpromazine (5 mg/kg, i.p.) was assessed in rats exposed prenatally to haloperidol (0.1 mg/kg), phenobarbital (10 mg/kg), nitrazepam (2 mg/kg), propylene glycol (1 ml/kg) or saline, once daily from days 1-21 or 15-21 of gestation. The response in all animals was tested only once. The administration of chlorpromazine to 8- or 13-week-old male and female rats treated with saline (1-21 d) induced marked hypothermia for a 6-hr period of observation. Male and female rats treated with haloperidol (1-21 d) showed a delayed hyperthermic response to chlorpromazine at 8 weeks of age; the males showed an increase in rectal temperature at 3 hr and the females from 3 to 6 hr. Thirteen-week-old males but not females treated with haloperidol (1-21 d) showed a hyperthermic response to chlorpromazine during the first 2 hr. Eight-week-old male and female rats treated with phenobarbital (1-21 d) showed hypothermia, whereas 13-week-old male rats of another group treated with phenobarbital (1-21 d) showed significant hyperthermia after the administration of the chlorpromazine. The hypothermic response of the rats treated with nitrazepam (1-21 d) to chlorpromazine was similar to that in the vehicle (propylene glycol)-treated controls. The male rats treated with phenobarbital (15-21 d) responded to chlorpromazine with significant hyperthermia from 30 min to 1 hr. There was no alteration in thermic response to chlorpromazine in rats born to mothers treated with one tenth of the dose of phenobarbital, haloperidol or nitrazepam.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of maternal chlorpromazine on offspring nervous system development.

Administration of chlorpromazine (7 mg/kg/day) to rat dams from day 8 of pregnancy until the pups were weaned produced small but statistically significant decreases in litter size and birth weight. The difference in pup weight was no longer present at the time of weaning. The offspring of chlorpromazine-treated dams were less able to maintain body temperature in response to restrained cold stress as determined when they were 60–65 days of age. They also incorporated significantly less¹⁴C from tyrosine into heart norepinephrine during acute cold exposure. No differences in incorporation of ¹⁴C into norepinephrine from tyrosine were evident when the animals were not subjected to cold stress. Similarly treated offspring did not have an increase in superior cervical ganglion tyrosine hydroxylase activity after 48 hr of cold exposure while the offspring of control dams did have a significant increase in the activity of this enzyme. These data suggest that maternal administration of chlorpromazine produces a permanent alteration in the ability of the offspring to respond to cold stress and that this deficit is related to an alteration in nervous system development.     

Behavioural and neurochemical effects of cholinergic and dopaminergic agonists administered into the accumbal core and shell in rats.

The first goal of this study was to investigate whether turning behaviour elicited by unilateral injections of the cholinergic agonist carbachol into the shell of the nucleus accumbens differs from that elicited by similar injections into the core of this nucleus, and to compare the behavioural effects with the known effects of such injections of the mixture of the dopamine D1 and D2 receptor agonists SKF 38393 (5 microg) and quinpirole (10 microg). The second goal was to investigate whether these injections of carbachol produce neurochemical alterations in the ventrolateral striatum that differ from similar injections of the mixture of the dopamine D1 and D2 receptor agonists into these brain regions. Injections of carbachol into the shell produced predominantly (a) contralateral circling marked by normal stepping and running in wide circles during the initial 50 min and (b) postural asymmetry during the following 75 min; similar injections into the core produced (a) contralateral pivoting, namely pathological head-to-tail turning marked by abnormal hindlimb stepping during the initial 50 min and (b) postural asymmetry during the next 75 min. The postural asymmetry seen after the carbachol injections was closely associated with the drug-induced increase in the dopamine release measured by microdialysis in the ipsilateral striatum. Injections of the mixture of dopamine agonists into the shell, but not core, also produced pivoting. These shell injections increased the dopamine release in the ipsilateral striatum, and decreased it in the contralateral striatum. The relative increase in the ipsilateral striatum was closely associated with the drug-induced pivoting. The data show that stimulation of cholinergic and dopaminergic receptors in the shell and core elicit effects that vary according to the subregion of the nucleus accumbens. It is concluded that the accumbens-specific, cholinergic effects are mediated via substrates that differ from those involved in the shell-specific, dopaminergic effects.     

The role of the sympathetic nervous system in oestrogen-induced hypertension in rats.

Albino rats of either sex received chronic ethinyl oestradiol (EO) treatment (1.5 mg kg-1 daily, i.m.) for 3 weeks. Untreated control rats received arachis oil vehicle alone. Chronic EO treatment resulted in elevation of blood pressure in both sexes. Female rats exhibited significantly greater elevation in blood pressure than males. In chronic EO-treated rats pressor responses to low doses (0.5 micrograms kg-1) of noradrenaline were significantly increased, while those to angiotensin II, acetylcholine and isoprenaline were unaltered. Chronic EO treatment also sensitized the vascular bed of the rats' hindquarters to noradrenaline. EO-induced hypertension was associated with significant increase in dopamine-beta-hydroxylase activity of adrenal glands. Complete bilateral adrenalectomy or chemical sympathectomy prevented the development of EO-induced hypertension. It is suggested that chronic treatment of rats with EO induces and maintains hypertension. The peripheral sympathetic system plays an important role in this phenomenon.     

Inhibitory effect of centrally administered atrial natriuretic polypeptide on the brain dopaminergic system in rats

The effects of intracerebroventricular injection of atrial natriuretic polypeptide (ANP) and angiotensin II (AII) on the concentration of dopamine, noradrenaline, serotonin and their primary metabolites in the rat brain were studied using high performance liquid chromatography with electrochemical detection. ANP (2 and 5 micrograms) decreased the level of dopamine and its metabolite in the septum and hypothalamus. In contrast, AII (100 ng) increased their levels in these brain regions. The simultaneous administration of ANP (5 micrograms) with AII (100 ng) resulted in a marked reduction of the AII-induced increase of dopamine and its metabolite. No significant changes were observed in the concentrations of noradrenaline and serotonin throughout the brain. These results suggest that the central action of ANP is mediated in part via the dopaminergic system.     

The possible role of metabolites in therapeutic response to chlorpromazine treatment

Eight male adult schizophrenic patients undergoing chronic treatment with chlorpromazine were investigated. Clinical assessments were made weekly by a psychiatrist who was unaware of the biochemical findings. Blood samples were drawn 3 h after the first daily dose and the plasma concentrations of chlorpromazine and 11 of its metabolites were assessed by a direct scan technique employing quantitative thin layer chromatography.Patients that responded well to treatment had high plasma levels of chlorpromazine and 7-hydroxychlorpromazine; whereas non-responders had high plasma levels of chlorpromazine sulphoxide. These preliminary findings support the hypothesis that chlorpromazine metabolites play an important role in determining clinical response to treatment, which arose from the failure of previous investigators to show a statistically significant relationship between plasma levels of the parent compound and clinical response.Recipient of Ciba-Geigy Fellowship in Clinical Psychopharmacology.     

Possible involvement of a dopaminergic pathway in the depressant effe ts of ouabain on the central nervous system

Small doses of ouabain given by intracerebroventricular (i.c.v.) injection in the conscious mouse and rat produce both catalepsy and hypothermia. In addition, pimozide, which can selectively inactivate dopamine receptors in the brain, produces similar pharmacological effects to ouabain when given by the same route of administration in the mouse, although a significant degree of sedation and catalepsy can be induced using doses of pimozide that have little effect on body temperature. Further observations involving the interaction of ouabain with the dopamine receptor stimulant apomorphine suggest that the catalepsy and hypothermia produced by ouabain both involve central dopaminergic pathways. Whereas the production of catalepsy appears to be the result of a dopamine receptor blockade, possibly in the corpus striatum, the production of hypothermia, although associated with increased brain dopamine levels, is not.     

Possible role of central α1-adrenoceptors in the control of the autonomic nervous system in normotensive and spontaneously hypertensive rats

The cardiovascular effects of AR-C 239, a new and selective α₁-adrenoceptor blocking drug were studied in normotensive and spontaneneously hypertensive rats (SHR). AR-C 239 (300 μg/kg i.v.) did not change the heart rate in control (without pretreatment) and bilaterally vagotomized normotensive rats, but induced significant bradycardia in rats pretreated with a β-adrenoceptor blocking drug. This bradycardic effect was inhibited by atropine or bilateral vagotomy. In SHR, the administration of AR-C 239 reduced heart rate in the control, bilaterally vagotomized and β-blocked rats. Blood pressure was decreased in the same way in the two rat strains. It is suggested that central α₁-adrenoceptors could participate in the control of vagal tone in normotensive and SH rats, and of sympathetic activity in the SHR only.     

Modification of the behavioral response to drugs in rats exposed prenatally to chlorpromazine

Female rats exposed prenatally to low levels of chlorpromazine were less susceptible as adults to the rate-reducing effects of chlorpromazine and pentobarbital on fixed-interval performance of a food-reinforced operant. Males were not significantly affected by prenatal treatment.Supported by NIMH grant MH 12568 and Research Scientist Award (Conan Kornetsky) MH 01759. We thank John Rizzo for carrying out the behavioral testing.     

Folate induced-hypermotility response after bilateral injection into the nucleus accumbens of the rat. Possible mediation through dopaminergic mechanisms

Folic acid (FA) and certain of its reduced congeners produce excitatory effects when applied to neuronal tissue. Recent evidence has suggested that folates have other biological properties in common with the excitatory amino acids. The purpose of this study was to determine the activity of folate compounds in a system sensitive to excitatory amino acids. Bilateral injection of folic acid into the nucleus accumbens resulted in a marked increase in locomotor activity at doses of 2.5 and 5 micrograms. Larger doses resulted in behavioral responses, such as body tremor and labored breathing, which interfered with the locomotor response. Similarly, 5-formyltetrahydrofolic acid (FTHF) produced a marked hypermotility response after bilateral injection into the nucleus accumbens (2.5-25 micrograms), while dihydrofolic acid, tetrahydrofolic acid, and 5-methyltetrahydrofolic acid were ineffective. Pretreatment with reserpine (10 mg/kg, i.p.) markedly reduced the hypermotility response elicited by folic acid and FTHF as did pretreatment with haloperidol in both peripheral (0.8 mg/kg) and direct (5 micrograms) injection into the nucleus accumbens. In addition, injection of muscimol (30 ng), which depresses hypermotility induced by dopamine and amphetamine, produced a significant decrease in the hypermotility response produced by folic acid. In contrast, pretreatment with phentolamine (5 mg/kg, i.p.) or propranolol (4 mg/kg, i.p.) did not decrease folic acid or FTHF-induced responses. These results suggest that folic acid and FTHF produce an increase in locomotor activity by facilitating dopaminergic neurotransmission in the nucleus accumbens, possibly by inducing the release of dopamine from the nerve terminals. Thus, these folates have effects similar to those of the excitatory amino acids when injected into the nucleus accumbens.     

Changes of response to dopaminergic drugs in rats submitted to REM-sleep deprivation

Platelet monoamine oxidase activity was determined in 52 unipolar depressive patients, 26 patients with bipolar affective disorder and 48 controls using phenylethylamine as substrate. Unipolar depressive patients of either sex and bipolar depressive women showed significantly higher platelet MAO activity than controls. Women had higher activity than men. Neither age nor serum lithium level correlated with enzyme activity and there was no significant change in activity after the institution of lithium treatment.     

Role of nitric oxide and beta-adrenoceptors of the central nervous system on the salivary flow induced by pilocarpine injection into the lateral ventricle

Our studies have focused on the effect of L-NG-nitroarginine methyl ester (L-NAME), an inhibitor of nitric oxide synthase (NOS), and L-arginine, the substrate of NOS, on salivary secretion induced by the administration of pilocarpine into the lateral cerebral ventricle (LV) of rats. The present study has also investigated the role of the beta-adrenergic agonists and antagonist injected into LV on the salivary secretion elicited by the injection of pilocarpine into LV. Male Holtzman rats with a stainless-steel cannula implanted into the LV were used. The amount of salivary secretion was studied over a 7-min period after injection of pilocarpine, isoproterenol, propranolol, salbutamol, salmeterol, L-NAME and L-arginine. The injection of pilocarpine (10, 20, 40, 80 and 160 microg/microl) into LV produced a dose-dependent increase in salivary secretion. The injection of L-NAME (40 microg/microl) into LV alone produced an increase in salivary secretion. The injection of L-NAME into LV previous to the injection of pilocarpine produced an increase in salivary secretion. L-Arginine (30 microg/microl) injected alone into LV produced no change in salivary secretion. L-Arginine injected into LV attenuated pilocarpine-induced salivary secretion. The isoproterenol (40 nmol/microl) injected into LV increased the salivary secretion. When injected previous to pilocarpine at a dose of 20 and 40 microg/microl, isoproterenol produced an additive effect on pilocarpine-induced salivary secretion. The 40-nmol/microl dose of propranolol injected alone or previous to pilocarpine into LV attenuated the pilocarpine-induced salivary secretion. The injection of salbutamol (40 nmol/microl), a specific beta-2 agonist, injected alone into LV produced no change in salivary secretion and when injected previous to pilocarpine produced an increase in salivary secretion. The 40-nmol/microl dose of salmeterol, a long-acting beta-2 agonist, injected into LV alone or previous to pilocarpine produced no change in salivary secretion. The results have shown that central injections of L-NAME and L-arginine interfere with the salivary secretion, which implies that might participate in pilocarpine-induced salivary secretion. The interaction between cholinergic and beta-adrenergic receptors of the central nervous system (CNS) for the control of salivary secretion can also be postulated.     

Effect of haloperidol treatment on immunoreactive neuropeptide Y secretion into lateral cerebral ventricle of rats

The study aimed to evaluate the effect of acute and 14-day haloperidol treatment (2 mg/kg ip) on release of neuropeptide Y-like immunoreactivity (NPY-LI) in non-anesthetized, freely moving rats by means of push-pull perfusion of the lateral cerebral ventricle. Twenty four hours after a single haloperidol injection NPY-LI release decreased by 15% (p < 0.05). No alterations were detected after 14-day haloperidol treatment. The study has confirmed that haloperidol alters the activity of neuropeptide Y system in the rat brain and suggested that acute haloperidol treatment inhibits the activity of the neuropeptide Y system at least in some brain structures surrounding the cerebral ventricles. The presented results have been discussed in view of our previous findings describing the haloperidol-induced changes in NPY-LI and NPY mRNA levels in the rat brain.     

The hemodynamic response of conscious normotensive rats to atriopeptin III: Lack of a role of the parasympathetic nervous system

The influence of the parasympathetic nervous system on the cardiovascular response to a synthetic atrial peptide (atriopeptin III) was examined in conscious normotensive rats by utilizing radiolabelled microspheres. Atriopeptin III was infused intravenously for 30 min at a rate of 1 microgram/min per rat in animals pretreated with a bolus intravenous injection of atropine, (150 micrograms/rat, n = 8) or of its vehicle (n = 8). Additional animals (n = 9) received the vehicle of both atropine and atriopeptin III. The atrial peptide decreased mean blood pressure to a similar extent in rats pretreated with atropine (from 124 +/- 4.5 to 108 +/- 5.3 mm Hg, mean +/- S.E.M., P less than 0.05) and in the controls (from 123 +/- 3.8 to 105 +/- 3.8 mm Hg, P less than 0.05). Heart rate rose significantly after administration of atropine. After the 30 min infusion, the cardiac index was significantly lower (P less than 0.05) in both groups infused with atriopeptin III (23.7 +/- 2.3 after atropine pretreatment and 25.1 +/- 2.2 ml X min-1 X 100 g-1 without atropine) than in the group of rats given only the vehicle of both atropine and atriopeptin III (32.4 +/- 2.8 ml X min-1 X 100 g-1). Calculated systemic vascular resistance tended to be higher in the former two groups than in the latter. There was no significant difference in regional blood flow distribution within the three groups of rats. These data therefore indicate that in conscious rats atriopeptin III reduces blood pressure and cardiac output without concomitantly diminishing total peripheral vascular resistance.(ABSTRACT TRUNCATED AT 250 WORDS)     

The activation of the renin--angiotensin system in the dog after injection of noradrenaline into the lateral brain ventricle.

Experiments were made on 15 mongrel dogs of either sex. Biologically active substances circulating in the blood after administration of noradrenaline (NA) into the left lateral brain ventricle of the dog were detected using the blood bathed organ technique of Vane. Plasma renin activity was also estimated. NA injected intraventricularly (ivc) in doses of 50-500 mug activated the renin--angiotensin system. Phentolamine prolonged the effect of NA. Propranolol abolished this central effect of NA. The increase in the concentration of endogenous NA in the brain by desmethylimipramine and RO 4-1284 also caused an activation of renin--angiotensin system.     

Kinin receptors of the central nervous system of spontaneously hypertensive rats related to the pressor response to bradykinin.

1. Kinin analogues bradykinin (BK), T-kinin, Met-Lys-BK, Lys-Lys-BK, Des-Arg9-BK with agonist activity and D-Arg0-Hyp3-Thi5,8-D-Phe7-BK (DAHTDBK) and Arg9-Leu8-BK with antagonist activity were injected into the posterior portion of the fourth cerebral ventricle of unanaesthetized rats implanted with permanent cannulae and arterial pressure was measured directly from the abdominal aorta. 2. The spontaneously hypertensive rats (SHR) were more sensitive than normotensive Wistar rats (NWR) to the pressor effect of BK and other kinin analogues. The SHR did not differ in sensitivity of the pressor response to centrally administered angiotensin II or endothelin-1. 3. Experiments with selective kinin agonists and antagonists revealed that in the SHR, as in the NWR, the receptors which mediated the central pressor response are of the BK2 subtype. 4. Measurements of the pressor activity of kinins with different degrees of susceptibility to degradation, as well as experiments with kininase inhibitors, enalaprilat and CPP-Ala-Ala-Phe-pAB, suggest that the kininase activity in the central nervous system of SHR is reduced in comparison to that of NWR. 5. The SHR also showed increased sensitivity to BK and Lys-Lys-BK, compared with the NWR, when the kinins were injected following the administration of a mixture of the kininase inhibitors, suggesting that mechanisms other than kininase activity may play a role in the increased sensitivity of the SHR to the central pressor action of kinins. 6. An in vivo characterization of the kinin receptors which mediate the central pressor response showed that the interaction with DAHTDBK was reversible and of competitive nature.(ABSTRACT TRUNCATED AT 250 WORDS)     

Mechanisms involved in the pressor response to noradrenaline injection into the cingulate cortex of unanesthetized rats

The cingulate cortex (CC) is involved in cardiovascular modulation. CC electrical or chemical stimulation may evoke either pressor or depressor responses, depending on the stimulated site and experimental conditions such as anesthesia. Noradrenaline (NA) is involved in cardiovascular regulation and it is present throughout the cortex. However, there is no report on the cardiovascular effects of intracortical injections of NA. We attempted to verify the effect of NA injection into the CC and to identify possible receptor and peripheral mechanisms involved. NA injection caused pressor responses accompanied by bradycardia, in unanesthetized rats. These responses were markedly reduced under urethane anesthesia. The pressor response was blocked by intracortical pretreatment with phenoxybenzamine or the selective alpha(1)-antagonist WB4101, and it was not affected by pretreatment with the selective alpha(2)-antagonist RX821002, suggesting that alpha(1)-adrenoceptors mediate the response. The pressor response was potentiated by pretreatment with the ganglion blocker mecamylamine and it was abolished by pretreatment with the vasopressin antagonist, dTyr(CH(2)) (5)(Me)AVP or by hypophysectomy. Circulating vasopressin levels were increased after NA injection into the CC. The present results indicate that the pressor response to local injection of NA within the CC is independent of sympathetic nerve activation and is mediated by vasopressin release.     

Repeated chlorpromazine administration increases a behavioural response of rats to 5-hydroxytryptamine receptor stimulation.

1 The hyperactivity syndrome produced in rats by administration of tranylcypromine (20 mg/kg i.p.) followed 30 min later by L-tryptophan (50 mg/kg i.p.) is generally considered to be due to increased 5-hydroxytryptamine (5-HT) functional activity. It is inhibited by chlorpromazine (30 mg/kg i.p.) injected 60 min before the tranylcypromine. However, chlorpromazine injection for 4 days either at a dose of 30 mg/kg once daily or 5 mg/kg twice daily results in an enhanced hyperactivity response to tranylcypromine and L-tryptophan administration 24 h after the final dose of chlorpromazine. 2 One injection of chlorpromazine (30 mg/kg) did not produce enhancement 24 h later and the inhibition of the tranylcypromine/L-tryptophan hyperactivity observed after acute chlorpromazine injection was seen if the rats were given tranylcypromine and L-tryptophan 1 h after the fourth chlorpromazine (30 mg/kg) dose. 3 Chlorpromazine (30 mg/kg) once daily or 5 mg/kg twice daily for 4 days resulted in rats displaying enhanced behavioral responses to the suggested 5-HT agonist 5-methoxy N,N-dimethyltryptamine (2 mg/kg) on day 5. 4 Chlorpromazine (30 mg/kg) once daily for 4 days produces a slight increase in brain 5-hydroxytryptamine (5-HT) concentration on day 5, but no difference in the rate of brain 5-HT synthesis or the rate of 5-HT accumulation after tranylcypromine and L-tryptophan administration. 5. There is some evidence that chlorpromazine blocks 5-HT receptors. It has also been observed that several other neuroleptic drugs do not produce enhanced 5-HT responses after repeated administration. It is suggested therefore that the enhanced behavioural response to 5-HT receptor stimulation following repeated chlorpromazine administration may be because this drug blocks 5-HT receptors.