Adrenergic nonspecific potentiation of yohimbine toxicity in mice by antidepressants and related drugs and antiyohimbine action of antiadrenergic and serotonergic drugs

Thirteen imipramine-like antidepressants and three anticholinergics potentiated yohimbine toxicity in mice. The strongest potentiation was observed after the nonantidepressant adrenergic compound AW 151129. Monomethyl derivatives were significantly stronger than their parent dimethyl compounds. Quaternary imipramine and amitriptyline, amphetamine, and inhibitors of monoamine oxidase were inactive. Pretreatment with an inhibitor of tyrosine hydroxylase (-methyl-p-tyrosine) or the -adrenergic-blocking drug pindolol diminished lethality in mice treated with a combination of desmethylimipramine (AW 151129) and yohimbine. The inhibitor of brain serotonin synthesis p-chlorophenylalanine and a depletor of serotonin and catecholamine synthesis, reserpine, enhanced yohimbine toxicity whereas serotonin and its precursors tryptophan and 5-hydroxytryptophan pro-longed survival time. Thus, a test of yohimbine potentiation toxicity in mice reveals an adrenergic component of pharmacological activity of antidepressants. The predictive value of this test is limited similarly to antihypothermic tests of antagonism to reserpine and the related drugs apomorphine and 5-hydroxytryptophan.     

Adrenergic and serotonergic mechanisms in morphine-induced respiratory depression

The influence of drugs which modify brain amine concentration was studied on morphine-induced respiratory depression in decerebrate cats. Resting and CO₂-stimulated respiration were evaluated. The respiratory depression was partially antagonized by pretreatment with reserpine and p-chlorophenylalanine; enhanced by two monoamine oxidase inhibitors, pargyline and tranylcypromine, and, to some extent, by -methyl-tyrosine. It was not changed by intracerebral 6-hydroxydopamine. The results show that, as with the other central actions of morphine, the presence of 5-HT is necessary for morphine activity to be complete.The change in the level of brain amines also modified the respiratory activity in a way that suggests that the respiratory center is stimulated by adrenergic and damped by serotonergic tone.     

Nicotine antagonizes the effects of reserpine on the striatal metabolism of dopamine, 5-hydroxytryptamine and noradrenaline in hypothermic but not in normothermic mice

Summary Our previous studies indicate that repeated nicotine administration inhibits the release of striatal dopamine in hypothermic mice. To study if similar inhibition occurs in noradrenergic and serotoninergic neurons mice were given (–)-nicotine (3 mg/kg, s.c.) repeatedly at 110, 80, 50, and 20 min before sacrifice. The interactions of nicotine with reserpine were also investigated. Reserpine (5 mg/kg, i.p.) was administered after the second nicotine dose at 60 min before sacrifice. To prevent the effects of nicotine on autonomic ganglia all mice were given hexamethonium (10 mg/kg, i.p.). Experiments were carried out at 20–22°C at which ambient temperature nicotine induced deep hypothermia or at 32–34°C to prevent the drug-induced hypothermia. The changes in striatal metabolism of dopamine, noradrenaline and 5-hydroxytryptamine (5-HT) weNicotine had temperature dependent effects on the dopamine metabolism which indicates a block of dopaminergic neurons as suggested in our earlier studies. Reserpine per se increased the homovanillic acid (HVA) and 3,4-dihydroxyphenylacetic acid (DOPAC) contents and decreased the 3-methoxytyramine (3-MT) and dopamine contents at both ambient temperatures. In hypothermic but not in normothermic, nicotine-treated mice reserpine's effect on dopamine metabolism was almost totally vanished. Nicotine and reserpine per se increased the 3-methoxy-4-hydroxyphenylethylglycol (MOPEG) content and decreased the noradrenaline content at both ambient temperatures. In hypothermic but not in normothermic mice nicotine antagonized the reserpine-induced decrease of noradrenaline content. Nicotine tended to decrease the 5-hydroxy-indoleacetic acid (5-HIAA) content in hypothermic mice but increased it in normothermic ones. Reserpine decreased the 5-HT content and increased the 5-HIAA content at both ambient temperatures. In hypothermic but not in normothermic, nicotine-treated mice the reserpine-induced effects on 5-HT metabolism were clearly reduced. These results indicate that in hypothermic mice repeatedly administered nicotine blocks the release of striatal dopamine and 5-HT and perhaps also noradrenaline. The nicotine-induced antagonism of the effects of reserpine is temperature-dependent as the nicotine-induced blockade of the neurons and thus the main mechanism behind both of these phenomena could be the sustained depolarization of the monoaminergic neurons. Send offprint requests to H. Haikala at the above address     

兔耳动脉的交感性血管收缩对α肾上腺素能受体拮抗剂的部分阻抗(英文)

本文利用离体组织灌流技术,对刺激家兔颈上神经节内壁交感神经引起兔耳中央动脉收缩的本质进行探讨,α受体拮抗剂仅部分阻断跨壁神经刺激(TNS)引起的收缩,若预先使用利血平耗竭离体血管内源性儿茶酚胺,由TNS引起的此种家兔耳中央动脉收缩则明显减弱,与此同时,α受体拮抗剂却增强了后期(residual)收缩反应,这种增强作用可能是因突触前膜α受体同时被阻断而引起,由此可见,交感神经冲动引起的家兔耳中央动脉收缩绝大部分是由去甲肾上腺素(NE)介导的,但后期收缩反应则可能是由另一种不明递质所介导,而这种属于外周循环系统的耳动脉交感神经与血管之间冲动传递方式又有别于大脑动脉的传递方式。     

Effects of nitrous oxide on decision-strategy and sustained attention

The significance of central noradrenergic, dopaminergic and serotonergic neural systems for the locomotor stimulant effects of methylphenidate was investigated in the rat. In order to study the role of brain catecholamines, rats were pretreated with reserpine (2.5 mg/kg) followed 24 hrs later by treatment with -methyltyrosine (25 mg/kg) or U-14,624 (75 mg/kg), a dopamine--hydroxylase inhibitor. In these experiments, methylphenidate stimulated motor activity was antagonized by -methyltyrosine and enhanced after treatment with U-14,624, suggesting that release of newly synthesized dopamine is important to a locomotor stimulant action of methylphenidate. Evidence implicating brain serotonin in the actions of methylphenidate was obtained in rats pretreated with pargyline or p-chlorophenylalanine (PCPA). Administration of pargyline 1 hr prior to methylphenidate was found to reduce the locomotor activity induced by methylphenidate and this was antagonized by pretreatment with low doses of PCPA. Higher doses of PCPA caused a significant elevation of methylphenidate induced activity which could be reduced by 5-hydroxytryptophan. Destruction of serotonergic neurons with 5,7-dihydroxytryptamine also potentiated methylphenidate induced locomotion. These latter findings suggest that serotonergic fibers have an inhibitory function in brain. These results are discussed in relation to the possible mechanism by which methylphenidate may act in hyperkinesis.     

Responding for conditioned reinforcement in C57BL/6 and CD-1 mice,and Sprague-Dawley rats: Effects of methylphenidate and amphetamine

Rationale

Characterization of responding for conditioned reinforcement in mice is important to implement genetic tools in examining the neurobiological mechanisms underlying reward-related learning and incentive motivation.

Methods

Inbred C57BL/6 mice, outbred CD-1 mice, and outbred Sprague–Dawley rats underwent Pavlovian conditioning in which a conditioned stimulus (CS) was paired with saccharin. Subsequently, subjects were allowed to respond for that CS in tests of responding for conditioned reinforcement. Experiments measured the effects of methylphenidate (MPH) and amphetamine (AMPH) on lever pressing for conditioned reinforcement in mice and rats. We further examined the stability of responding for conditioned reinforcement in mice after repeated testing and the extinction of this behaviour following omission of the reinforcer. We also determined whether the CS exhibited reinforcing properties if it was not paired with saccharin.

Results

C57BL/6 and CD-1 mice learned to respond for a conditioned reinforcer similarly to rats, and the behaviour was stable over time. MPH increased responding in CD-1 mice and rats, but not in C57BL/6 mice. AMPH only increased responding in rats. Responding was reduced following omission of the conditioned reinforcer, and responding was only established when the CS was paired with saccharin.

Conclusions

These experiments characterize a conditioned reinforcement test which produces stable responding in two different mouse backgrounds. These findings also show that dopaminergic psychomotor stimulants can differently affect rats and mice in tests of responding for conditioned reinforcement.     

Developmental alterations in anxiety and cognitive behavior in serotonin transporter mutant mice

Rationale

A promoter variant of the serotonin transporter (SERT) gene is known to affect emotional and cognitive regulation. In particular, the “short” allelic variant is implicated in the etiology of multiple neuropsychiatric disorders. Heterozygous (SERT^+/?) and homozygous (SERT^?/?) SERT mutant mice are valuable tools for understanding the mechanisms of altered SERT levels. Although these genetic effects are well investigated in adulthood, the developmental trajectory of altered SERT levels for behavior has not been investigated.

Objectives

We assessed anxiety-like and cognitive behaviors in SERT mutant mice in early adolescence and adulthood to examine the developmental consequences of reduced SERT levels. Spine density of pyramidal neurons was also measured in corticolimbic brain regions.

Results

Adult SERT^?/? mice exhibited increased anxiety-like behavior, but these differences were not observed in early adolescent SERT^?/? mice. Conversely, SERT^+/? and SERT^?/? mice did display higher spontaneous alternation during early adolescence and adulthood. SERT^+/? and SERT^?/? also exhibited greater neuronal spine densities in the orbitofrontal but not the medial prefrontal cortices. Adult SERT^?/? mice also showed an increased spine density in the basolateral amygdala.

Conclusions

Developmental alterations of the serotonergic system caused by genetic inactivation of SERT can have different influences on anxiety-like and cognitive behaviors through early adolescence into adulthood, which may be associated with changes of spine density in the prefrontal cortex and amygdala. The altered maturation of serotonergic systems may lead to specific age-related vulnerabilities to psychopathologies that develop during adolescence.     

Role of superior colliculus serotonin in the grooming behaviour of cats.

The present study provides evidence that a serotonergic system in the superior colliculus is involved in the regulation of grooming behaviour. Significant decreases in tryptophan hydroxylase activity and serotonin content were found in the superior colliculi of cats with pontile lesions and frontal neocortical lesions, which display a dissociation of appetitive and consummatory grooming behaviours. Neither tryptophan hydroxylase activity nor serotonin content were significantly changed in thyroidectomized cats, which display the same abnormal grooming behaviour. 5-Hydroxytryptophan administration or monoamine oxidase inhibition plus tryptophan administration abolished the abnormal grooming behaviour in each of the three groups of cats, suggesting that the change in a serotonergic system is a critical aspect of the abnormal behaviour in cats with pontile lesions and frontal neocortical lesions, and that a serotonergic system may also be involved in the genesis of the abnormal grooming behaviour in thyroidectomized cats. Functional inactivation of the serotonergic system by lysergic acid diethylamide administration or by serotonin receptor blockade did not induce the abnormal grooming behaviour in normal cats, indicating that other factors are involved in the genesis of the abnormal behaviour. Previous studies indicated that glucocorticoids are the other critical factor. Thus, a serotonergic system in the superior colliculi, operating at some level of glucocorticoid function, is involved in the integration of appetitive and consummatory grooming behaviours. These data provide the first demonstration of the biological mechanisms underlying the integration of the appetitive (learned) and consummatory (unlearned) components of instinctive behaviour.     

Nicotine-induced hypothermia through an indirect dopaminergic mechanism

The effect of nicotine on core body temperature was studied in mice. Intraperitoneal (i.p.) injection of nicotine (0.5, 1 and 2 mg/kg) induced a dose-dependent hypothermia. The response was inhibited by reserpine (5 mg/kg), the centrally active nicotinic receptor antagonist mecamylamine (0.1-1 mg/kg) and the D-2 dopamine receptor antagonist sulpiride (25-100 mg/kg). The β-adrenoceptor antagonist propranolol (5 and 10 mg/kg) and the serotonergic blocker methysergide (5 and 10 mg/kg) did not inhibit but increased the nicotine response. The α-adrenoceptor antagonist phenoxybenzamine, the antimuscarinic agent atropine, the D-1 dopamine receptor antagonist SCH 23390, the peripheral dopamine antagonist domperidone and the peripheral nicotinic antagonist hexamethonium did not alter the nicotine-induced hypothermia. It is concluded that nicotine may cause a fall in core body temperature through a central dopaminergic mechanism.     

On the role of central noradrenaline in the regulation of motor activity and body temperature in the mouse

Summary Inhibition of dopamine--hydroxylase by FLA-63 [bis-(4-methyl-1-homopiperazinylthiocarbonyl)-disulfide], 40 mg/kg, in the mouse caused decrease in motor activity, depletion of brain noradrenaline (NA) and reduction in body temperature. Injection ofd,l-threo-3,4-dihydroxyphenylserine (DOPS), 1000mg/kg, restored behaviour, central NA and temperature. In the experiments nialamide, 50 mg/kg, was given 10 min after FLA-63 in order to prevent at least part of the catabolism of the NA formed from DOPS. This injection of nialamide, which by itself caused elevation of central monoamine levels, increase in motor activity but no change in temperature, did not antagonize the effects of FLA-63. The effects of DOPS were likely to be mediated via the central nervous system since injection of NA, causing sympathomimetic and biochemical effects in the periphery similar to those elicited by DOPS, did not antagonize the FLA-63-induced effects. The data support the view that central NA neurons are involved in the control of motor activity and body temperature in the mouse.This work was supported by the Swedish Medical Research Council (grant No. B71-14X-155-07C), the Medical Faculty, University of Göteborg and Gustav och Majen Lindgrens donationsfond. The skilful technical assistance of Miss Barbro Jörblad is gratefully acknowledged. For generous supply of drugs I am indebted to Hässle Ltd., Mölndal (DOPS, FLA-63) and the Swedish Pfizer Ltd., Täby (nialamide).     

On the mechanism of the synergistic effect of perazine and hexobarbital

Summary The synergistic effect of perazine and hexobarbital was studied by interference with drugs which alter the adrenergic, serotonergic and cholinergic systems. The determination of hexobarbital level in blood and brain was used as an indication of the rate of its biotransformation.According to the findings perazine, dihydroergotamine (DHE), and phentolamine (in low doses) as well as an elevation of dopamine level prolong the anaesthesia by way of a central mechanism. Phentolamine (in higher doses) and the anticholinergic drug biperidin slow down the metabolism of hexobarbital, probably by inhibiting the hepatic microsomal enzymes.An alteration of the overall level of catecholamines, serotonin and acetylcholine had no effect on the hexobarbital-induced anaesthesia.The mild hyperthermia caused by all drugs tested, did not influence the duration of hexobarbital sleeping time.The possibility that perazine, like other -receptor blocking agents, causes a preponderance of inhibitory dopaminergic neurons by obstructing the excitatory norepinephrine receptors in the central nervous system is discussed. This effect might also occur if the dopamin level in the brain is increased.     

Mechanism of the protective effect of reserpine on aggregated mice treated with (+)-amphetamine

Experiments were made to see if the effect of reserpine in protecting aggregated mice from the toxic effect of (+)-amphetamine depended on the hypothermia or on the depletion of brain noradrenaline it induces. In aggregated mice, a 7 mg/kg dose of amphetamine elevated body temperature, lowered the level of brain noradrenaline and caused 100% mortality. In reserpinized aggregated mice, amphetamine did not cause hyperthermia or any further depletion of brain noradrenaline. Prevention of the hypothermic effect of reserpine by keeping amphetamine-treated reserpinized animals at a higher environmental temperature markedly lowered the protective effect of reserpine. When also the depletion of noradrenaline by reserpine was antagonized by dopa, reserpine no longer protected aggregated mice from the toxic effect of amphetamine. The lowering of 5-hydroxytryptamine content brought about by reserpine remained unaltered during these procedures. Complete protection against amphetamine toxicity was also offered by α-methyl-1-tyrosine in doses which lowered brain noradrenaline to almost the same extent as reserpine, but which did not lower temperature or brain 5-hydroxytryptamine. When the body temperature of aggregated mice with brain noradrenaline lowered by α-methyl-1-tyrosine was elevated by subjecting the animals to heat stress, the protective effect was reduced. Hypothermia induced by reserpine could thus be related to its noradrenaline-depleting action. The results show that both properties contribute to reserpine's protective action. However, the abolition by dopa of this protective effect of reserpine and the complete protection offered by α-methyl-1-tyrosine without hypothermia suggest that depletion of brain noradrenaline plays the more important role in the protective effect of reserpine.     

Low doses of the putative serotonin agonist 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT) elicit feeding in the rat

The effects of the putative serotonin agonist 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT) on food intake in non-deprived male rats were investigated. Low doses of 8-OH-DPAT (15–60 g/kg) significantly increased food intake, without affecting drinking, grooming, rearing or locomotion. Microstructural analysis of the elicited feeding behaviour revealed that the rate of eating after 8-OH-DPAT treatment was very similar to that previously reported following 16 h food deprivation. Higher drug doses (250–4,000 g/kg) also elicited feeding and caused locomotor stimulation and serotonin-related stereotyped behaviour (i.e. forepaw padding, headweaving, wet dog shakes, flat body posture). When feeding and stereotypy were observed concurrently, response competition was evident and feeding behaviour was fragmented into numerous short eating bouts. As drug-induced stereotypy declined with time, this fragmented pattern of eating was succeeded by long bouts of eating which were similar to those observed at doses of 15–60 g/kg 8-OH-DPAT. The induction of feeding by a serotonin agonist appears paradoxical, since drugs which enhance brain serotonergic activity usually inhibit feeding.     

Head-twitch response induced by tyramine

The intracerebroventricular (IC) administration of tyramine (TyA) induced a characteristic head-twitch response in mice pretreated with safrazine, a monoamine oxidase inhibitor. Safrazine-pretreated mice exhibited similar head-twitches following the IC treatment of serotonin (5-HT). The maximum dose of 5-HT which did not elicit head-twitches significantly potentiated TyA-induced head-twitches. Antiserotonergic drugs such as morphine and dimethothiazine antagonized TyA-induced head-twitches. A serotonergic denervator, 5,6-dihydroxytryptamine, potentiated head-twitch induced by TyA or 5-HT. Both TyA-induced and 5-HT-induced head-twitches were inhibited by dopamine and noradrenaline, while catecholaminergic denervators such as reserpine and 6-hydroxydopamine, and diethyldithiocarbamic acid, a dopamine--hydroxylase inhibitor, increased the TyA response. These results indicate that head-twitches induced by TyA may be mediated via the serotonergic system and may inhibit the catecholaminergic system.     

Effects of cannabinoids on neurotransmission

The CB1 cannabinoid receptor is widely distributed in the central and peripheral nervous system. Within the neuron, the CB1 receptor is often localised in axon terminals, and its activation leads to inhibition of transmitter release. The consequence is inhibition of neurotransmission via a presynaptic mechanism. Inhibition of glutamatergic, GABAergic, glycinergic, cholinergic, noradrenergic and serotonergic neurotransmission has been observed in many regions of the central nervous system. In the peripheral nervous system, CB1 receptor-mediated inhibition of adrenergic, cholinergic and sensory neuroeffector transmission has been frequently observed. It is characteristic for the ubiquitous operation of CB1 receptor-mediated presynaptic inhibition that antagonistic components of functional systems (for example, the excitatory and inhibitory inputs of the same neuron) are simultaneously inhibited by cannabinoids. Inhibition of voltage-dependent calcium channels, activation of potassium channels and direct interference with the synaptic vesicle release mechanism are all implicated in the cannabinoid-evoked inhibition of transmitter release. Many presynaptic CB1 receptors are subject to an endogenous tone, i.e. they are constitutively active and/or are continuously activated by endocannabinoids. Compared with the abundant data on presynaptic inhibition by cannabinoids, there are only a few examples for cannabinoid action on the somadendritic parts of neurons in situ.     

The effect of taurine on motor behaviour,body temperature and monoamine metabolism in rat brain

Summary Taurine, a putative inhibitory neurotransmitter, was injected in various doses intracerebroventricularly to conscious rats via pre-implanted polythene cannulas. The formation of DOPA and 5-hydroxytryptophan (5-HTP) in various brain regions was investigated by measuring the accumulation of these monoamine precursors induced within 30 min by the intraperitoneal injection of 3-hydroxybenzyl hydrazine HCl (NSD 1015, 100 mg/kg), an inhibitor of the aromatic L-amino acid decarboxylase readily penetrating into the brain. DIPA formation, but not 5-HTP formation was significantly enhanced by taurine in dose-related manner in all brain regions studied, indicating an increased synthesis of both dopamine and noradrenaline. Dopamine depletion induced by -methyltyrosine was significantly retarded by taurine, whereas noradrenaline depletion tended to be enhanced. Endogenous levels of dopamine were increased, whereas the following brain constituents were unchanged: tyrosine, tryptophan, noradrenaline, 5-HT and 5-hydroxyindoleacetic acid. In the exoeriments with NSD 1015, a dose-related decrease in rectal temperature and in motility was observed after taurine treatment, as compared to treatment with the decarboxylase inhibotor alone. Systemic parenteral administration of taurine caused no significant changes in brain monoamines, body temperature or behaviour but decreased the heart noradrenaline levels. The data indicate that taurine, which apparently has to be given intracerebroventricularly in order to reach the brain in sufficient amounts, causes inhibition of firing in central dopamine neurons but has the opposite effect on noradrenaline neurons, perhaps also peripherally, whereas 5-HT neurons appear to be unaffected. In addition, taurine appears to interfere with motor behaviour and temperature regulation, possibly via effects on catecholaminergic systems.     

Quantification of ten neuroactive steroids in plasma in Withdrawal Seizure-Prone and -Resistant mice during chronic ethanol withdrawal

Rationale

The rapid membrane actions of neuroactive steroids, particularly via an enhancement of γ-aminobutyric acid_A receptors (GABA_ARs), participate in the regulation of central nervous system excitability. Prior evidence suggests an inverse relationship between endogenous GABAergic neuroactive steroid levels and behavioral changes in excitability during ethanol withdrawal.

Objectives

Previously, we found that ethanol withdrawal significantly decreased plasma allopregnanolone (ALLO) levels, a potent GABAergic neuroactive steroid, and decreased GABA_AR sensitivity to ALLO in Withdrawal Seizure-Prone (WSP) but not in Withdrawal Seizure-Resistant (WSR) mice. However, the effect of ethanol withdrawal on levels of other endogenous GABA_AR-active steroids is not known.

Methods

After validation of a gas chromatography-mass spectrometry method for the simultaneous quantification of ten neuroactive steroids, we analyzed plasma from control male WSP-1 and WSR-1 mice and during ethanol withdrawal.

Results

We quantified levels of nine neuroactive steroids in WSP-1 and WSR-1 plasma; levels of pregnanolone were not detectable. Basal levels of five neuroactive steroids were higher in WSR-1 versus WSP-1 mice. Ethanol withdrawal significantly suppressed five neuroactive steroids in WSP-1 and WSR-1 mice, including ALLO.

Conclusions

Due to lower basal levels of some GABA_AR-active steroids in WSP-1 mice, a withdrawal-induced decrease in WSP-1 mice may have a greater physiological consequence than a similar decrease in WSR-1 mice. Because WSP-1 mice also exhibit a reduction in GABA_AR sensitivity to neuroactive steroids during withdrawal, it is possible that the combined decrease in neuroactive steroids and GABA_AR sensitivity during ethanol withdrawal in WSP-1 mice represents a neurochemical substrate for severe ethanol withdrawal.     

Amphetamine induced release of endogenous dopamine in vitro is not reduced following pretreatment with reserpine

Summary The release of endogenous dopamine evoked by electrical stimulation or by exposure to (+)-amphetamine (10 M) was determined in superfused striatal slices of the rat.The spontaneous and the electrically-evoked release of dopamine were significantly increased in the presence of nomifensine (10 M). After reserpine pretreatment (5 mg/kg, s.c., 24 h), the striatal dopamine content was reduced by about 90%. Exposure to 10 M (+)-amphetamine during 2 min released similar amounts of dopamine from striatal slices of untreated or reserpine pretreated rats. Similar results were obtained when monoamine oxidase activity was inhibited in vivo with pargyline.Pretreatment with reserpine does not modify the (+)-amphetamine-induced release of dopamine, in spite of the marked reduction of the striatal dopamine content. These results provide direct evidence for the view that (+)-amphetamine releases dopamine from a special, reserpine-resistant pool of newly synthetized transmitter.Some of the results described in this publication have been presented at the British Pharmacological Society Meeting (Arbilla et al. 1984a)     

Cardiovascular effects of 6-hydroxydopamine injected into a lateral brain ventricle of the rat

Summary 6-Hydroxydopamine (6-OH-DA) was injected into the left lateral brain ventricle of normotensive, DOCA/NaCl or spontaneously hypertensive rats, and its effect on heart rate and blood pressure was studied. A single injection of 250 g 6-OH-DA or 3 successive administrations of the same dose caused a reduction of noradrenaline content and tyrosine hydroxylase activity in several parts of the brain to 10–50% of the control values, indicating a considerable destruction of central adrenergic neurons. Heart rate and blood pressure decreased within 10 to 20 min after a single intraventricular injection of 6-OH-DA and both parameters returned to normal after 7 h. This effect was equally observed in normotensive and both types of hypertensive rats and regardless of whether the animals were conscious or anaesthetized. It was prevented by a prior intraventricular injection of phentolamine; this suggests that it is mediated by central alpha-adrenoceptors. The 6-OH-DA-induced bradycardia and hypotension were not influenced by a blockade of peripheral muscarinic receptors with scopolamine methylbromide; however, they were accompanied by a decrease of spontaneous discharges in the splanchnic nerve and, therefore, seem to be due to a reduction in peripheral sympathetic tone.The early cardiovascular effects of 6-OH-DA were sometimes followed by a second phase of bradycardia and hypotension. It occurred in normotensive rats 1–2 days after the second or third intraventricular injection of 6-OH-DA, and in spontaneously hypertensive rats already after a single injection. The hypotension of the second phase lasted 5–6 days, the bradycardia showed no recovery during the observation period which was limited to 3 weeks. Such long term cardiovascular effects of intraventricular 6-OH-DA were never observed in DOCA/NaCl hypertensive rats even after repeated administrations of the compound. The results provide evidence for the existence of a central adrenergic regulation of blood pressure and heart rate which seems to differ in normotensive and hypertensive rats.Preliminary results have been presented at the 11 th Spring Meeting of the German Pharmacological Society in Mainz (Haeusler, Gerold and Thoenen, 1970).     

Rasgrf2 controls noradrenergic involvement in the acute and subchronic effects of alcohol in the brain

Rationale

Alcohol addiction is a major psychiatric disease, and yet, the underlying molecular adaptations in the brain remain unclear. Recent evidence suggests a functional role for the ras-specific guanine-nucleotide releasing factor 2 (Rasgrf2) in alcoholism. Rasgrf2^?/? mice consume less alcohol and show entirely absent dopamine responses to an alcohol challenge compared to wild types (WT).

Objective

In order to further investigate how Rasgrf2 modifies the acute and subchronic effects of alcohol in the brain, we investigated its effects on the noradrenergic and serotonergic systems.

Methods

We measured noradrenaline and serotonin activity in the brain by in vivo microdialysis and RNA expression by chip analysis and RT-PCR after acute and sub-chronic alcohol exposure in Rasgrf2^?/? and WT mice.

Results

In vivo microdialysis showed a significantly reduced noradrenergic response and an absent serotonergic response in the nucleus accumbens (NAcc) and caudate putamen (CPu) after an alcohol challenge in Rasgrf2^?/? mice. A co-expression analysis showed that there is a high correlation between Rasgrf2 and α2 adrenoceptor RNA expression in the ventral striatum in naïve animals. Accordingly, we further assessed the role of Rasgrf2 in the response of the noradrenergic system to subchronic alcohol exposure. A decrease in β1 adrenoceptor gene expression was seen in Rasgrf2^+/+, but not Rasgrf2^?/? mice following alcohol exposure. Conversely, alcohol resulted in a decrease in both β2 and α2 adrenoceptor gene expression in knockout but not WT Rasgrf2 mice.

Conclusions

These findings suggest that adaptations in the noradrenergic system contribute to the Rasgrf2 enhanced risk of alcoholism.