Effects of calcium channel blockers and hydralazine on plasma glucose levels in streptozotocin-induced diabetic rats in vivo

Effects of calcium channel blockers from structurally different classes and hydralazine on plasma glucose levels were examined in streptozotocin-induced diabetic rats in vivo. Non-dihydropyridine calcium channel blockers (verapamil, diltiazem, 1.0-10 mg/kg, i.p.) did not significantly affect the basal plasma glucose level, and dihydropyridine calcium channel blockers (nifedipine, 0.1-0.3 mg/kg, i.p,; nicardipine, 0.35-0.70 mg/kg, i.p.) caused mild hyperglycemia, which was blocked by the administration of the beta-adrenoceptor antagonist propranolol. In contrast, hydralazine markedly produced hyperglycemia, which was also inhibited by the combined administration of propranolol. The selective alpha 1-adrenoceptor antagonist prazosin greatly potentiated the hydralazine-induced hyperglycemia. Isoproterenol alone showed hyperglycemia similar to that of hydralazine. Hexamethonium (40 mg/kg, i.p.), a ganglionic blocker, blocked the hydralazine-induced hyperglycemia. There was a negative correlation between the hyperglycemic effect and the blood pressure lowering effect by different doses of hydralazine in streptozotocin-diabetic rats, but not in normal rats. These results suggest that endogenous catecholamines are involved in the hydralazine-induced hyperglycemia through the interaction with beta-adrenoceptors in streptozotocin-diabetic rats in vivo.     

The influence of divalent cations on the analgesic effect of opioid and non-opioid drugs

It is generally accepted that divalent cations are involved in the nociceptive pathway. The effect of systemic co-administration of magnesium sulfate and calcium channel blockers (nifedipine, verapamil) on the analgesic effect of opioid (mixed mu/kappa: butorphanol) and non-opioid drugs (paracetamol) was investigated. Albino mice and rats were used as experimental animals. Magnesium sulfate and calcium channel blockers were given i.p., 30 min before the administration of butorphanol tartrate and paracetamol. Analgesia was measured using "hot-plate" ( 52.5( composite function)C), "tail-flick" (radiant heat source), "writhing" (acetic acid, 1%, i.p.) and "tail-clip" tests. The pain threshold was evaluated before and after the administration (i.p.) of the different agents. The effect of the combined administration of different agents on behavior, blood pressure and heart rate, was also determined. Nifedipine (5 mg kg(-1), i.p.) and verapamil (10 mg kg(-1), i.p.) potentiated the analgesic effect of butorphanol tartrate (0.25-2 mg kg(-1), i.p.) in all tests (synergism) and enhanced analgesic effect of paracetamol (50-125 mg kg(-1), i.p.), only in acetic acid writhing and tail-clip tests. Magensium sulfate (2.5 mg kg(-1), i.p.) potentiated the analgesic effect of butorphanol, but not that of paracetamol. Co-administration of nifedipine and verapamil with either of butorphanol (0.25-2 mg kg(-1)) or paracetamol (50-125 mg kg(-1), i.p.) produced no significant effects on motor coordination, motor performance, locomotor activity, long-term memory or on the blood pressure and heart rate of experimental animals. Co-administration of magnesium sulfate, however, significantly induced sedation, inhibition of locomotor activity, motor performance and coordination, as well as impairing of long-term memory, as compared with butorphanol and paracetamol, administered alone. We conclude that the systemic co-administration of calcium channel blockers potentiated the analgesic effect of butorphanol against thermal, mechanical and chemical pain but enhanced that of paracetamol only against mechanical and chemical pain. Magensium sulfate enhanced the analgesic effect of butorphanol, but not that of paracetamol. These findings, merit further studies in animals and humans to evaluate the potential therapeutic benefits of such interactions.     

Effects of chlordiazepoxide, nicotine and d-amphetamine in the rat potentiated startle model of anxiety

The effects of acute administration of chlordiazepoxide (2.5 and 5.0mg/kg, i.p.), nicotine (0.05, 0.1 and 0.4mg/kg, s.c.) and d- amphetamine (0.5 and 1.0mg/kg, i.p.) on rat potentiated startle were investigated. Chlordiazepoxide, 2.5 and 5.0mg/kg, attenuated potentiation of startle, indicating an anxiolytic profile, although the effect of the higher dose was less marked and was accompanied by a reduction in overall startle response, probably reflecting drug-induced sedation. Nicotine at doses of 0.05 and 0.4mg/kg had no significant effects in this test. However, 0.1mg/kg nicotine eliminated potentiation of startle (in two separate experiments), an action comparable to that of 2.5mg/kg chlordiazepoxide. d-Amphetamine at doses of 0.5 and 1.0mg/kg did not significantly influence potentiation of startle. The results suggest that nicotine has an anxiolytic profile in the potentiated startle paradigm which is not due to its psychostimulant properties.     

Desensitization of substance P-induced K+ release in rat parotid

The angiotensin converting enzyme inhibitor enalapril (0.5 mg/kg i.v.) potentiated significantly the inhibitor effect of the thromboxane A₂ antagonist L-640,035 (1 mg/kg i.v.) on electrically induced platelet accumulation in the rabbit in vivo. Enalapril had no effect upon platelet accumulation when given alone. The hypotensive effects of enalapril did not account for the potentiation because a combination of hexamethonium (5 mg/kg i.v.) and hydralazine (1 mg/kg i.v.), which decreased blood pressure similarly to enalapril, did not augment the effect of L-640,035. Determination by radioimmunoassay of plasma levels of immunoreactive 6-keto-PGF₁, suggested that increases in PGI₂ levels after combined administration of enalapril and L-640,035 could explain the observed potentiation.     

A comparison of the antinociceptive effects of voltage-activated Na+ channel blockers in two rat models of neuropathic pain

The pain-relieving effects of various voltage-activated Na(+) channel blockers have been evaluated in two rat models of neuropathic pain; the photochemically induced nerve injury model (Gazelius) and spared nerve injury model. Lidocaine (up to 40 mg/kg, i.p.) and lamotrigine (up to 60 mg/kg, i.p.) had no effect on mechanical or cold allodynia in either model. However, lamotrigine (10, 30 and 60 mg/kg) significantly attenuated mechanical hyperalgesia in the spared nerve injury model, while mexiletine (25 and 37.5 mg/kg, i.p.) attenuated mechanical allodynia in the Gazelius model. Tocainide (50, 75 and 100 mg/kg, i.p.) significantly reduced all types of pain behaviour measured. The present results show that these voltage-activated Na(+) channel blockers have broadly similar antinociceptive effects in these two models of neuropathic pain. They also show that these drugs can have markedly different effects on distinct neuropathic pain-related behaviours within models.     

Potentiation of the inhibitory effect of a thromboxane A2 antagonist (L-640,035) on arterial thrombosis formation in rabbit by the angiotensin converting enzyme inhibitor enalapril

The angiotensin converting enzyme inhibitor enalapril (0.5 mg/kg i.v.) potentiated significantly the inhibitor effect of the thromboxane A₂ antagonist L-640,035 (1 mg/kg i.v.) on electrically induced platelet accumulation in the rabbit in vivo. Enalapril had no effect upon platelet accumulation when given alone. The hypotensive effects of enalapril did not account for the potentiation because a combination of hexamethonium (5 mg/kg i.v.) and hydralazine (1 mg/kg i.v.), which decreased blood pressure similarly to enalapril, did not augment the effect of L-640,035. Determination by radioimmunoassay of plasma levels of immunoreactive 6-keto-PGF_1α, suggested that increases in PGI₂ levels after combined administration of enalapril and L-640,035 could explain the observed potentiation.     

Effects of calcium channel ligands on anaesthetic properties of ethanol in mice.

This study has examined the effect of two calcium channel antagonists--nifedipine, verapamil and a calcium channel agonist BAY K 8644 on duration of ethanol-induced anaesthetic activity measured as the loss of the righting reflex (LORR) in mice. Nifedipine (5 and 10 mg/kg, i.p.) and verapamil (10 and 20 mg/kg, i.p.) potentiated the acute general anaesthetic effect of ethanol (3.5 g/kg, i.p.). BAY K 8644 (2 mg/kg, i.p.) shortened the duration of ethanol-induced LORR. This action of BAY K 8644 was prevented by the pretreatment with nifedipine (2.5 mg/kg, i.p.) but not with verapamil (5 mg/kg, i.p.). Injections of both calcium channel blockers--nifedipine (2.5 mg/kg) and verapamil (5 mg/kg) did not influence the ethanol-induced hypnotic activity themselves. Our results suggest that the calcium ions are involved in the central depressant effects of acute ethanol administration at high doses. It can be supposed that the modification of the activity of voltage-dependent calcium channels plays an important role in the anaesthetic action of ethanol.     

The adenosine receptor antagonist theophylline induces a monoamine-dependent increase of the anticataleptic effects of NMDA receptor antagonists

Previous work revealed that adenosine antagonists as theophylline reversed neuroleptic-induced catalepsy and potentiated anticataleptic effects of dopamine agonists reflecting specific adenosine-dopamine receptor interactions in the central nervous system. We tested whether similar functional interactions exist between adenosine receptors and glutamate receptors of the N-methyl-D-asparte (NMDA) subtype. The present study demonstrates that the anticataleptic effects of the competitive NMDA receptor antagonist CGP37849 and the non-competitive NMDA receptor antagonist dizocilpine can be potentiated by coadministration of a threshold dose of the adenosine receptor antagonist theophylline (2.5 mg/kg, i.p.) in haloperidol (0.5 mg/kg, i.p.)-pretreated rats. This potentiation was elicited only with higher doses of CGP37849 (4 and 8 mg/kg, i.p.) or dizocilpine (0.16 mg/kg, i.p.) in haloperidol (0.5 mg/kg, i.p.), but not in reserpine (5 mg/kg, i.p.) plus -methyl-ptyrosine (100 mg/kg, i.p.)-pretreated animals. Therefore, these synergistic interactions seem to be brought about by indirect monoamine-dependent mechanisms rather than direct functional interrelationships between NMDA and adenosine A_2a receptors.     

Reversal of acute theophylline toxicity by calcium channel blockers in dogs and rats

Theophylline, widely used in the treatment of pulmonary diseases, has a narrow therapeutic index; the recommended plasma levels being 10–20 μg/ml in humans. The misuse or abuse of theophylline can cause life-threatening central nervous system and cardiovascular effects. Increased intracellular Ca²⁺ levels are thought to play an important role in theophylline toxicity and death. The objective of this study was to determine whether Ca²⁺ channel blockers, e.g. verapamil, nifedipine, or diltiazem, prevent sudden death caused by theophylline treatment in rats and dogs. Groups of Sprague-Dawley rats were treated with theophylline alone (150 mg/kg i.p.) or with theophylline pretreatment followed by administration of verapamil (0.25 to 0.5 mg/kg i.p.), nifedipine (0.25 to 1.0 mg/kg i.p.), or diltiazem (0.5 to 1.0 mg/kg i.p.), 2.5 to 15 min later. The rats were observed for toxic signs and survival over a period of 15 days. All three calcium channel blockers significantly reduced the theophylline-induced sudden death in rats. In a separate study, neither verapamil (0.5 mg/kg i.p.) nor nifedipine (1.0 mg/kg i.p.) prevented the theophylline-induced myocardial necrosis in the rat. In beagle dogs, verapamil (0.5 mg/kg i.v.) prevented theophylline (15 mg/kg/min i.v. for 10 min)-induced hypotension, arrhythmias, and sudden death. Our results support previously reported findings that calcium plays a major role in theophylline-induced toxicity and death.     

Alternative transcripts of the GABA(A) receptor epsilon subunit in human and rat

The effect of 1,4-dihydropyridine (DHP) calcium channel blockers (CCBs), nimodipine (NIM) and lercanidipine (LDP) on the analgesic response of selective kappa-opioid receptor agonists, U50,488H, PD117,302 and U69,593 was determined in male Sprague-Dawley rats using the tail-flick test. The effect of NIM on development of tolerance to U50,488H-induced analgesia and the status of brain DHP-sensitive Ca(2+) channel (L-type) binding sites in both U50,488H-naive and tolerant rats was determined using the highly selective DHP radioligand, [(3)H]PN200-110. Tolerance was induced by injecting U50,488H (25 mg/kg, i.p.) twice daily for 4 days. Intraperitoneal (i.p.) injection of kappa-opioid receptor agonists produced a dose-dependent acute analgesic response. NIM (1 mg/kg; i.p.) and LDP (0.3 mg/kg; i.p.) used in the study produced no tail-flick analgesia. Administration of NIM and LDP (15 min prior) significantly potentiated the analgesia produced by three kappa-opioid receptor agonists. Tolerance developed completely to the analgesic effect induced by U50,488H (25 mg/kg, i.p.) administered on the 5th day. NIM (1 mg/kg, i.p.) twice daily for 4 days not only completely inhibited the development of tolerance to analgesic response but also significantly potentiated it (supersensitivity). There was a significant up-regulation of DHP binding sites (B(max): +41%) in whole brain membranes of tolerant rats when compared to vehicle treated naive rats, implicating increased influx of Ca(2+) through L-type channels in kappa-opioid tolerance. U50,488H (25 mg/kg, i.p.) and NIM (1 mg/kg, i.p.) twice daily for 4 days also resulted in an equivalent up-regulation of DHP binding sites (+36%) as that of U50,488H alone. These results strongly suggest a functional role of L-type Ca(2+) channels in the regulation of pain sensitivity, mechanism of kappa-opioid analgesia and expression of tolerance.     

Reinstatement of nicotine-conditioned place preference by drug priming: effects of calcium channel antagonists

Reinstatement of drug-seeking behaviour in animals is relevant to drug relapse in humans. In the present study, we used the conditioned place preference paradigm to investigate the establishment, extinction, reinstatement and cross-reinstatement of nicotine-induced place conditioning in rats. Nicotine produced a place preference to the initially less-preferred compartment paired with its injections during conditioning (0.5 mg/kg, i.p., three drug sessions). Once established, nicotine place preference was extinguished by repeated training. Following this extinction phase, the reinstatement of place conditioning was investigated. For this purpose, nicotine-experienced rats were challenged with nicotine (0.5 mg/kg, i.p.) or morphine (10 mg/kg, i.p.). These priming injections of both drugs renewed a marked preference for the compartment previously paired with nicotine. In the second step, we examined the influence of the calcium channel antagonists, nimodipine (10 and 20 mg/kg, i.p.) and flunarizine (5 and 10 mg/kg, i.p.), on the reinstatement of nicotine-conditioned place preference induced by priming doses of nicotine and morphine. It was shown that the calcium channel blockers dose dependently attenuated the reinstatement of nicotine place preference induced by both drugs. These findings support the hypothesis that similar neural calcium-dependent mechanisms are involved in nicotine- and morphine-induced reinstatement. Finally, the conditioned place preference paradigm appears to be a useful tool for studies of the relapse of drug-seeking behaviour in laboratory animals.     

Influence of nimodipine and diltiazem, alone and in combination, on phencyclidine-induced effects in rats: an EEG and behavioural study

The influence of nimodipine and/or diltiazem on the EEG and behavioural effects induced by phencyclidine (PCP) was assessed in adult male Wistar rats. Nimodipine (2 and 10 mg/kg i.p.) and diltiazem (25-100 mg/kg i.p.) significantly potentiated both EEG (increase in background activity voltage, incidence of clustered slow waves) and behavioural (ataxia mean intensity) effects of PCP (5 mg/kg i.p.). A synergistic effect between low, ineffective doses of both nimodipine (0.5 mg/kg i.p.) and diltiazem (5 and 10 mg/kg i.p.) was also found. These data confirm the recent finding of a positive allosteric modulation existing between benzothiazepine (diltiazem) and dihydropyridine (nimodipine) binding sites. They also suggest that the modulation of calcium channels may play a pivotal role in the expression of PCP-induced effects.     

Comparison of the effect of levodopa and bromocriptine on naloxone-precipitated morphine withdrawal symptoms in mice

In this study, the effect of l-dopa and bromocriptine on morphine withdrawal syndrome was compared. Both l-dopa (125, 250 mg/kg, i.p.) and low doses of bromocriptine (0.04, 0.08 mg/kg, i.p.) potentiated naloxone-induced morphine withdrawal symptoms such as jumping, climbing and rearing in mice. Higher doses of bromocriptine (0.16, 0.32 mg/kg, i.p.) attenuated these naloxone-induced symptoms. SKF 83566, D(1) dopamine antagonist (0.4, 0.8 mg/kg, i.p.) and sulpiride, D(2) dopamine antagonist (5, 10 mg/kg, i.p.) when used alone, also produced inhibitory effects on naloxone-induced morphine withdrawal symptoms. Pretreatment with sulpiride (5, 10 mg/kg, i.p.) and SKF 83566 (0.4, 0.8 mg/kg, i.p.) attenuated the potentiating effects of l-dopa on withdrawal symptoms significantly. Pretreatment with sulpiride also decreased the potentiating effect of bromocriptine and reinforced the inhibitory action of it, but SKF 83566 pretreatment just reinforced the effect of higher doses of bromocriptine. Concurrent pretreatment of animals with sulpiride (10 mg/kg, i.p.) and SKF 83566 (0.8 mg/kg, i.p.) markedly decreased the potentiating effects of l-dopa and bromocriptine and reinforced the inhibitory action of bromocriptine on the naloxone-induced morphine withdrawal syndrome. Prazosin, alpha(1) antagonist (1, 2 mg/kg, i.p.) decreased the naloxone-induced morphine withdrawal syndrome significantly. Pretreatment with yohimbine, alpha(2)-antagonist (5 mg/kg, i.p.) reversed the inhibitory effects of bromocriptine (0.16, 0.32 mg/kg, i.p.) on naloxone-induced morphine withdrawal syndrome significantly. In conclusion, our results show that bromocriptine at lower doses (0.04, 0.08 mg/kg, i.p.) acts similar to l-dopa, but at higher doses (0.16, 0.32 mg/kg, i.p.) shows different effects on naloxone-induced morphine withdrawal syndrome which may be due to the interaction of bromocriptine with alpha-adrenoceptors. Copyright 2000 John Wiley & Sons, Ltd.     

Involvement of GABAA receptor sites in diazepam hypothermia

1. Intraperitoneal (i.p.) injection of diazepam (1.5-6 mg/kg) decreased the core body temperature (BT) of the rats. The effect was dose-dependent. 2. The hypothermia produced by diazepam (6 mg/kg, i.p.) was decreased in animals pretreated with high doses of bicuculline (BIC, 3 mg/kg, i.p.), while low doses of BIC (1.5 mg/kg, i.p.) potentiated the hypothermia. 3. Picrotoxin (PIC, 1 and 2 mg/kg, i.p.) pretreatment also decreased the hypothermic effect of diazepam. 4. Pretreatment of animals with atropine (AT, 10 mg/kg, i.p.) or propranolol (PRO, 10 mg/kg, i.p.) potentiated the hypothermic response of diazepam. Phenoxybenzamine (PHEN, 0.5 mg/kg, i.p.), methergoline (METH, 0.5 mg/kg, i.p.) or pimozide (PIM, 0.5 mg/kg, i.p.) did not change the diazepam hypothermia. 5. Single administration of BIC, PIC, PRO, PIM or METH also induced hypothermia. 6. One can postulate that diazepam hypothermia may be induced through GABAA receptor sites. However, further studies will clarify this hypothesis.     

Antagonistic activity of ascorbic acid (vitamin C) on dopaminergic modulation: apomorphine-induced stereotypic behavior in mice

Among the various neurotransmitter systems implicated in the mechanism of action of ascorbic acid (vitamin C), the relationship between the dopaminergic system and ascorbic acid is not particularly clear. Ascorbic acid is speculated to have an antagonistic effect on dopaminergic modulation. With this background in mind, in the present study we have seen the effect of ascorbic acid per se and in combination with typical and atypical antipsychotic agents against apomorphine-induced stereotypic behavior in mice. Male Laka mice weighing 20-25 g were used in the present study. Apomorphine-induced stereotypic behavior was used as an animal model. Various dopaminergic modulators were used. Ascorbic acid dose-dependently inhibited stereotypic behavior produced by apomorphine in mice. It potentiated the antipsychotic activity of haloperidol (0.1 mg/kg i.p.), a typical antipsychotic agent. When administered along with atypical antipsychotics, clozapine (1-2 mg/kg i.p.), sulpiride (10-20 mg/kg i.p.) and risperidone (0.0025 mg/kg i.p.), ascorbic acid also potentiated their activity. Also when given along with SCH-23390, a selective D(1) antagonist, an additive effect was observed. Ascorbic acid also inhibited the supersensitization response of apomorphine on reserpinization (2 mg/kg i.p.). Interestingly, at a lower dose (100 mg/kg i.p.), ascorbic acid potentiated the dopaminergic activity of apomorphine (0.5 mg/kg) and BHT-920 (0.25 mg/kg i.p.). However, when given concomitantly with SKF-38393, it failed to alter the response of SKF-38393. The data substantiate the hypothesis that ascorbic acid potentiated the activity of typical as well as atypical antipsychotics and that the effect of ascorbic acid on the dopaminergic system is markedly dose dependent; a low dose (100 mg/kg i.p.) potentiated the dopaminergic action while higher doses (400-1,600 mg/kg i.p.) blocked it.     

The role of bicuculline, aminooxyacetic acid and gabaculine in the modulation of ethanol-induced motor impairment

Ethanol's intoxicating effects may result from ethanol-induced changes in central gamma-aminobutyric acid (GABA) mechanisms. To further test this hypothesis, mice were pretreated with bicuculline (1 mg/kg s.c.), aminooxyacetic acid (15, 20, 25 or 30 mg/kg i.p.) or gabaculine (20 or 40 mg/kg i.p.). Following pretreatment, 20% ethanol (2.25 g/kg i.p.) was administered and rolling roller performance evaluated. All ethanol-treated control animals showed lack of rolling roller performance at 5 min post ethanol but regained rolling roller performance by 35 min. Only 42% of the bicuculline pretreated mice demonstrated lack of rolling roller performance at 5 min post ethanol and all regained rolling roller performance by 15 min. Impairment of rolling roller performance by ethanol was potentiated by aminooxyacetic acid in a dose-dependent manner. Aminooxyacetic acid (25 and 30 mg/kg doses) slowed blood ethanol disappearance although analysis of blood ethanol disappearance and motor impairment curves indicated that aminooxyacetic acid potentiation of ethanol-induced rolling roller performance impairment cannot be attributed solely to aminooxyacetic acid's effect on blood ethanol levels. Gabaculine also potentiated ethanol's impairment of rolling roller performance but was more effective than aminooxyacetic acid in slowing ethanol disappearance, suggesting that in comparison to aminooxyacetic acid, alteration of ethanol metabolism plays a greater role in gabaculine's potentiation of ethanol-induced motor impairment.     

Yawning induced by apomorphine,physostigmine or pilocarpine is potentiated by dihydropyridine calcium channel blockers

Previous studies have shown that dihydropyridine (DHP) calcium channel blockers can potentiate yawning induced by apomorphine in rats. The present study was undertaken to examine whether or not this interaction was seen with other compounds that induce yawning or if it represented a specific interaction with dopaminergic mechanisms. Yawning induced by apomorphine (40 µg/kg SC), physostigmine (50 µg/kg SC) or pilocarpine (1 mg/kg SC) was dose-dependently potentiated by the DHP calcium channel blocker nifedipine (1.25–10 mg/kg IP). Nimodipine (1.25–5 mg/kg IP) and nitrendipine (1.25–5 mg/kg IP) also significantly increased the yawning response. The DHP calcium channel blockers alone induced only a low incidence of yawning. The effects of nifedipine on physostigmine-induced yawning were reversed by the DHP calcium channel activator BAY K 8644 which also inhibited yawning induced by physostigmine (100 µg/kg SC) and pilocarpine (2 mg/kg SC). In contrast to the DHP compounds, diltiazem (2.5–10 mg/kg IP) and verapamil (2.5–10 mg/kg IP) failed to potentiate yawning. Sulpiride (10 mg/kg SC) antagonised the nifedipine potentiation of apomorphine-induced yawning but not that of physostigmine-induced yawning; atropine (2.5 mg/kg SC) antagonised both effects. These results support the hypothesis that this effect of dihydropyridine compounds is not dependent on, nor mediated through, dopaminergic mechanisms.     

Nitecapone and selegiline as effective adjuncts to L-DOPA in reserpine-induced catatonia in mice

Reserpine-induced catatonia is a widely accepted animal model of Parkinson's disease. In the present study, reserpine (5 mg/kg i.p.) and alpha-methylpara-tyrosine (AMPT) (200 mg/kg i.p.) induced catatonia in mice 20 h and 1 h before the experiment, respectively, as assessed using the rota-rod and bar tests after reserpine treatment. There was a significant decrease in fall-off time in the rota-rod test and a significant increase in time spent on the bar in the bar test as compared to the untreated control mice. Combination therapy with L-DOPA (100 mg/kg i.p.) and carbidopa (10 mg/kg i.p.) was less effective in reversing catatonia as compared to higher doses of L-DOPA (200 mg/kg i.p.) and carbidopa (20 mg/kg i.p.), which showed intense hyperactivity in reserpinized mice. Pretreatment with nitecapone (30 mg/kg i.p.), a COMT inhibitor, or selegiline (10 mg/kg i.p.), a MAO-B inhibitor potentiated the motor stimulant actions of subthreshold doses of the L-DOPA (100 mg/kg i.p.) and carbidopa (10 mg/kg i.p.) combination. Amantadine (40 mg/kg i.p.), but not bromocriptine, potentiated the effects of L-DOPA treatment. The NMDA antagonistic action of amantadine may have beneficial effects. It is concluded that COMT and MAO-B enzymes play an important role in the metabolism of dopamine and administration of a COMT or MAO-B inhibitor may prove to be a better adjunct to L-DOPA therapy than a dopamine receptor agonist in Parkinson's disease.     

Intensification of central catecholaminergic and serotonergic processes by the hypothalamic factors MIF and TRF and by angiotensin II

The present work deals with the action of MIF (melanocyte stimulating hormone release-inhibiting factor), TRF (thyrotropin releasing factor), and angiotensin II on the behavioral effects of L-DOPA and of D,L-5-hydroxytryptophan (5-HT) in mice. The influence of MIF and TRF on the antagonistic effect of L-DOPA of harmine tremors in rabbits was also studied. MIF and TRF, injected i.p., intensify the effects of L-DOPA in mice. The minimal dose of MIF required to induce a +3 response is 0.1 μg/kg; TRF is active at 500 μg/kg. When MIF or TRF are injected into the brain, potentiation of L-DOPA is obtained with exceedingly small quantities of MIF (0.1 pg); the effective dose of TRF is 1 μg. The behavioral effects of 5-HTP are potentiated by TRF only, at doses of 0.1 μg/kg, i.p. When TRF is administered intracerebrally, the active dose per mouse is 0.1 ng. Harmine (5 mg/kg i.v.) induces, in the rabbit, sustained whole body tremors; if L-DOPA (5 mg/kg) is administered i.v. at the peak of the harmine effect, the tremors subside. When the rabbit is pretreated with MIF, administered i.p. 1–2 hr before harmine, in doses devoid of an antitremor effect per se (10 μg/kg), the L-DOPA antagonism appears at lower doses. Also dopamine (5–10 mg/kg i.v.) proved effective in abating harmine tremors; previous treatment with MIF (50 μg/kg) potentiated the antagonistic effect of dopamine. According to the prevailing theories on the mechanism of neurotransmission, some hypothesis will be discussed to explain the observed potentiation: impaired uptake, impaired degradation, interference with the turnover of the bioamines, supersensitivity of the receptors.     

Analgesic effects of diltiazem and verapamil after central and peripheral administration in the hot-plate test

1. The analgesic effects of diltiazem and verapamil, both per se and together with morphine, were studied using subcutaneous (s.c.) and intracerebroventricular (i.c.v.) administrations, in the hot-plate test in mice. 2. The i.c.v. injection of verapamil (15-120 micrograms/mouse) and diltiazem (60-120 micrograms/mouse) induced dose-dependent analgesic effects. 3. The i.c.v. administration of verapamil (30-120 micrograms/mouse) and diltiazem (60-120 micrograms/mouse) significantly enhanced, in a dose-dependent way, the analgesic effects of morphine and produced a parallel displacement to the left of the morphine log dose-response line. 4. When these calcium channel blockers were administered subcutaneously at doses of 40 and 80 mg/kg, they exerted no analgesic actions, but dose-dependently potentiated the analgesic effects of morphine, producing a parallel shift to the left of the morphine log dose-response line. 5. These results suggest that inhibition of calcium entry through calcium channels induced by verapamil and diltiazem may play a role in analgesia development.