Biomedical subjects

F G Graeff

Publications and source records attributed to F G Graeff.

At least 91 records · Page 5Linked to original sources

PubMed1989

Serotonergic mediation of the anxiolytic effect of intracerebrally injected propranolol measured in the elevated plus-maze.

The effect of intracerebrally injected propranolol was measured in the elevated plus-maze, an animal model of anxiety. Microinjection of 10 nmol of propranolol into the dorsal midbrain central gray of the rat increased the percentage of open arm entries, without affecting the total number of arm entries. This selective anxiolytic effect of propranolol was antagonized by 10 nmol of ritanserin, also injected into the dorsal midbrain. The same dose of ritanserin, given alone, did not affect the percentage of open arm entries, though it tended to decrease the total number of entries, an indication of unspecific behavioral depression. Since propranolol is a stereospecific antagonist of presynaptic serotonin (5-HT) autoreceptors and ritanserin is a selective blocker of type 2 5-HT receptors, the present results suggest that the anxiolytic action of propranolol in the midbrain central gray is due to release of endogenous 5-HT acting upon 5-HT2 receptors.

Animal Testing Alternatives↗

PubMed1989

Anxiolytic effect of carbamazepine measured in the elevated plus-maze.

The anxiolytic effect of carbamazepine was measured in rats placed in an elevated plus-maze. Doses from 5 to 40 mg/kg, ip, of carbamazepine increased the percentage of open arm entries as well as the percentage of time spent in the two open arms of the maze. Both of these measures are interpreted as indexes of anxiety. The total number of entries in either the open or the two enclosed arms, considered as an index of general activity, was not changed by the drug. Therefore, carbamazepine caused a selective anxiolytic effect as measured in the elevated plus-maze, which is predictive of clinical efficacy.

Animal Testing Alternatives↗

PubMed1989

Effects of ipsapirone and BAY R 1531 on learned helplessness.

The effects of the 5-hydroxytryptamine-1A (5-HT1A) receptor agonists on the learned helplessness test were investigated. Rats were submitted to a single session of 60 uncontrollable shocks (10-s duration, 1.0 mA, every 60 +/- 40 s) and then treated twice daily with ip injections of either ipsapirone (13 mg/kg daily) or BAY R 1531 (0.375 mg/kg daily) for four consecutive days. On the last day, the animals were submitted to an escape test. The results showed that both drug treatments blocked the deficit in the escape learning (helplessness effect). These data suggest that drugs which stimulate 5-HT1A receptors have an antidepressant-like activity in this animal model of depression.

Animals↗

PubMed1988

Early malnutrition alters the effect of chlordiazepoxide on inhibitory avoidance.

In order to study the functional consequences of brain changes caused by early malnutrition, rats were fed a protein-deficient diet from birth until 49 days of age and a balanced diet from day 50 to day 70. The animals were submitted to a step-down inhibitory avoidance task and to the flinch-jump nociceptive test at 49 and 70 days of age. Malnourished rats showed longer step-down latencies and lower flinch and jump thresholds than eutrophic animals. Chlordiazepoxide (5 mg/kg, ip) shortened step-down latency of well-nourished rats, whereas it failed to do so in malnourished rats. Since well-nourished animals also became resistant to chlordiazepoxide when tested with a higher shock intensity, generating avoidance latencies comparable to those of malnourished animals, we conclude that the drug resistance induced by malnutrition may be secondary to enhanced pain sensitivity and/or reactivity.

Animals↗

PubMed1988

Defense reaction elicited by microinjection of kainic acid in the medial hypothalamus of the rat.

In order to localize groups of neurons commanding the defense reaction, a subtoxic dose (66 pmol) of kainic acid was microinjected into the medial hypothalamus of the rat. After drug treatment, the animals were placed inside a shuttle-box for 15 min and the number of midline crossings, rearings and forward leaps were recorded. Autonomic changes such as occurrence of micturition and defecation were also measured. Injection of kainic acid significantly increased locomotion, rearing and micturition, indicating that the medial hypothalamus of the rat contains perikarya/dendrites of neurons integrating the defense reaction.

Animals↗

PubMed1987

GABAA receptors in the midbrain central grey mediate the antiaversive action of GABA.

Intracerebral injection of the GABAA agonists muscimol (1 nmol), isoguvacine (1 nmol) or THIP (1, 2 and 4 nmol) in rats with chemitrodes implanted in the dorsal midbrain central grey raised the threshold electrical current for inducing escape behaviour. The effect of THIP was dose-dependent. In contrast, the GABAB agonist baclofen (10 and 100 nmol) did not affect the aversive threshold. Furthermore, pretreatment with baclofen (10 nmol and 100 nmol) did not significantly change the effect of THIP (2 nmol). These results indicate that the antiaversive action of GABA in the midbrain central grey is mediated by GABAA but not by GABAB receptors.

Animals↗

PubMed1987

GABA-benzodiazepine modulation of aversion in the medial hypothalamus of the rat.

Earlier results indicate that the neurons of the midbrain central gray (CG) responsible for the elaboration and/or expression of aversive states are tonically inhibited by the GABA-benzodiazepine system. In the present study, chemitrodes were implanted in the medial hypothalamus (MH) of the rat, another aversive area of the brain deeply interrelated with the dorsal CG. Microinjection of the benzodiazepine receptor agonist midazolam raised the aversive threshold of electrical stimulation of the MH in a dose-dependent way, though in only about half of the animals tested. In the remaining rats, midazolam was ineffective. Similar antiaversive effects were caused by the GABA-A receptor agonist THIP. In contrast, microinjection of the GABA-A receptor blocker bicuculline induced aversive-like behavioral and autonomic changes. The effects of bicuculline were antagonized by pretreatment with either THIP or midazolam, the latter being counteracted by the competitive benzodiazepine receptor blocker Ro 15-1788. These results extend to the MH, the hypothesis of GABA-benzodiazepine modulation of neurons integrating aversive motivational states.

Animals↗

PubMed1986

Modulation of the brain aversive system by GABAergic and serotonergic mechanisms.

Experiments performed in our laboratory, using electrical stimulation combined with microinjection of drugs in the dorsal midbrain central grey (CG) of the rat, evidenced that direct stimulation of GABA receptors with locally administered gamma-aminobutyric acid (GABA) or the GABAA receptor agonists 4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol, isoguvacine and muscimol raised the aversive threshold, defined as the lowest electrical current intensity inducing flight or escape behaviour when applied to the dorsal CG. The GABAB receptor agonist baclofen was ineffective. Also, enhancement of endogenous GABA action through local injection of the benzodiazepines chlordiazepoxide and midazolam or of pentobarbital resulted in anti-aversive effects. Ro 15-1788 antagonized both chlordiazepoxide and midazolam, suggesting benzodiazepine receptor mediation. In contrast to pro-GABAergic drugs, microinjection of the GABA antagonists bicuculline and picrotoxin into the CG elicited flight behaviour, like the electrical stimulation. Similar experiments with drugs influencing serotonergic neurotransmission evidenced that intra-CG microinjection of serotonin (5-HT) or of the direct 5-HT receptor agonist 5-methoxy-N,N-dimethyltryptamine increased the aversive threshold. The anti-aversive effect of 5-HT was potentiated by the selective inhibitor of 5-HT neuronal uptake, zimelidine. Also, the latter drug increased the aversive threshold when given alone. The anti-aversive effect of 5-HT was antagonized by local pretreatment with either metergoline or ketanserin, the latter being a selective blocker of 5-HT2 receptors. In contrast to the GABA antagonists mentioned above, the 5-HT receptor blockers did not evoke aversive behaviour per se. Therefore, both GABAergic and serotonergic mechanisms are likely to play an inhibitory role in the dorsal CG integrating aversive behaviour. The former seem to act tonically, whereas 5-HT would act in a phasic way. The implications of these results for the pathophysiology and drug treatment of chronic anxiety, panic states and pain disorders are briefly discussed.

Animals↗

PubMed1986

Modulation of the brain aversive system by GABAergic and serotonergic mechanisms.

Animals↗

PubMed1986

Role of GABA in the anti-aversive action of anxiolytics.

The above results with intracerebral drug injection and electrical brain stimulation in rats indicate that enhancement of GABAergic activity in the dorsal CG or in the MH raises the threshold of electrical stimulation inducing aversive behavior when applied to these brain areas. Conversely, drug-induced reduction of GABA action in the dorsal CG or in the MH leads to aversive-like behavioral changes. Therefore, GABAergic fibers seem to exert tonic inhibition on neuronal groups in the CG and MH integrating aversive behavioral states. Anxiolytics may cause anti-aversive effects by enhancing this GABAergic modulation. As discussed elsewhere, serotonergic and opioid mechanisms are also likely to operate in periventricular brain areas. In conjunction with GABAergic mechanisms, they may be involved in the pathophysiology of anxiety, panic attacks and pain, as well as in the therapeutic action of anxiolytics, anti-panic drugs and centrally-acting analgesics.

Animals↗

PubMed1985

Anti-aversive role of serotonin in the dorsal periaqueductal grey matter.

Microinjection of 5, 10, and 20 nmol serotonin (5-HT) and of 0.5, 1, and 2 nmol 5-methoxy-N, N-dimethyltryptamine (5-MeODMT) into the dorsal midbrain of rats bearing chronically implanted chemitrodes raised the electrical threshold for inducing escape behaviour following stimulation of the dorsal periaqueductal grey matter (DPAG). Linear regressions of log dose against drug-induced increase in aversive threshold were obtained for 5-HT and 5-MeODMT. The 5-MeODMT dose-effect curve was steeper and lay to the left of the 5-HT dose-effect curve. Local pre-treatment with 10 nmol metergoline or ketanserin blocked the anti-aversive effect of 10 nmol 5-HT, whereas pre-treatment with 100 nmol zimelidine potentiated this effect of 5-HT. The same dose of zimelidine raised the aversive threshold when given alone. These results suggest that 5-HT plays an inhibitory role in the DPAG controlling aversion, probably mediated by 5-HT2 receptors.

Animals↗

PubMed1985

Effect of metergoline on human anxiety.

In order to assess the role played by serotonin (5-HT) in subjective anxiety, three groups of 12 healthy volunteers were given 12 mg metergoline (MET), 10 mg diazepam (DZ) or placebo (PB), under double-blind conditions, and submitted to a simulated public speaking (SPS) test. MET increased state-anxiety scores, measured by Spielberg's State-Trait Anxiety Inventory. The effect of MET was significantly different from both the PB and DZ groups immediately before the SPS test (prestress) as well as 24 h after medication, and from the DZ group only, 2.5 h after the test (poststress). In contrast, DZ did not significantly affect subjective anxiety. The SPS test significantly increased anxiety in DZ- or PB-treated subjects as compared to prestress scores, whereas the increases in the MET group were not significant, probably because pretest levels were already high. No drug effect on heart rate, skin electrical conductance and quality of sleep during the night following medication was found. In addition, the drugs did not cause bodily symptoms that could secondarily affect mood. Since MET is a 5-HT receptor antagonist, active on the central nervous system, an inhibitory role of 5-HT on subjective anxiety might be suggested.

Adult↗

PubMed1985

Defensive behavior and hypertension induced by glutamate in the midbrain central gray of the rat.

In order to localize groups of neurons commanding the defense reaction, microinjections of L-glutamate (GLU, 5 nmol in 0.2 microliter, during 20 s) were made inside the dorsal midbrain of unanesthetized rats provided with an intra-arterial cannula for blood pressure (BP) recording. In 9 rats, GLU microinjection induced freezing behavior or flight, accompanied by a 30.1 +/- 4.8 mmHg increase in BP. The latency of the GLU effect was 16 +/- 2 s and its duration 89 +/- 8 s, as measured from the BP recordings. In 9 other rats, GLU microinjection did not evoke defensive behavior and the BP increase was 6.0 +/- 0.9 mmHg, significantly lower (P less than 0.001) than in the former group. Control injections of artificial cerebrospinal fluid (CSF) did not cause behavioral changes and increased BP by less than 3 mmHg. Histology revealed that in all rats in which GLU induced a defense reaction the injection sites were inside the dorsal periaqueductal gray (PAG). Sites in which GLU injection was ineffective were localized in the midbrain tegmentum, outside the borders of the PAG (8 rats), or inside the ventral PAG (1 rat). Since GLU stimulates neuron cell bodies and their dendritic processes but not passing axons, these results strongly suggest that the dorsal PAG of the rat contains a group of neurons that controls behavioral and autonomic manifestations of the defense reaction.

Animals↗

PubMed1984

Benzodiazepine receptors in the periaqueductal grey mediate anti-aversive drug action.

The microinjection of 80, 160 and 320 nmol chlordiazepoxide (CDP) as well as of 20, 40 and 80 nmol midazolam (MDZ) into the dorsal midbrain of rats bearing chronically implanted chemitrodes raised the threshold electrical current inducing escape behaviour by stimulating the dorsal periaqueductal grey matter (DPAG). Parallel linear regressions were obtained by plotting the log dose against drug-induced increases in escape threshold, MDZ being 3.55 times more potent than CDP (95% confidence limits 1.21 and 8.57). Local pretreatment with 80 nmol of the benzodiazepine antagonist Ro 15-1788 blocked the anti-aversive effect of either 160 nmol CDP or 40 nmol MDZ. The same dose of Ro 15-1788 was ineffective when given alone. These results suggest that the anti-aversive action of CDP and MDZ is due to their combination with benzodiazepine receptors in the DPAG.

Animals↗

PubMed1983

Role of 5-hydroxytryptamine in amphetamine effects on punished and unpunished behaviour.

In order to assess the contribution of serotonergic (5-HT) mechanisms in the suppressant effect of amphetamine on punished responding, dose-effect curves of amphetamine on key-pecking behaviour of pigeons maintained by food presentation and punished by electric-shock were determined before and after pretreatment with methergoline, a potent and specific 5-HT receptor blocker in the central nervous system. A multiple fixed-interval 5 min, fixed-interval 5 min schedule of reinforcement in which every response, except the reinforced one, was punished in one of the two components (mult FI5 FI5-shock) was used. Effective doses of amphetamine decreased unpunished as well as punished FI response rates. However, the decreases in punished behaviour were more evident and dose-dependent. Methergoline markedly increased FI responding in the punished FI component but only slightly increased or decreased unpunished FI response rates. The most effective dose of methergoline for increasing punished responding was 0.56 mg/kg. Pretreatment with this dose of methergoline unmasked the facilitatory effects of amphetamine on unpunished responding, but did not antagonize its suppressant effect on punished responding. Therefore, although 5-HT seems to mediate punishment-induced response suppression and to inhibit the facilitatory effects of amphetamine on unpunished responding, it is not apparently involved in the suppressant effect of amphetamine on punished behaviour.

Amphetamine↗

PubMed1983

GABA modulation of the defense reaction induced by brain electrical stimulation.

Earlier behavioral results led to the suggestion that GABA exerts a tonic inhibitory influence in the dorsal periaqueductal gray (DPAG) matter of the rat integrating defensive behavior. In the present experiments, the role of GABAergic mechanisms in the modulation of the autonomic component of the defense reaction was studied. Thus, the effects of intravenous (IV) injections of chlordiazepoxide as well as of intracerebral (IC) injections of midazolam in the dorsal midbrain, on the blood pressure (BP), heart rate (HR) and respiratory increases induced by electrical stimulation of the DPAG were measured in rats anesthetized with urethane. Chlordiazepoxide (10 mg/kg, IV) as well as midazolam (40 and 160 nmol, IC) attenuated the centrally-induced hypertension, without affecting basal BP. The tachycardia induced by aversive brain stimulation was similarly decreased by the benzodiazepines. In addition, the HR baseline was significantly raised by chlordiazepoxide and by the highest dose of midazolam. The tachypnea induced by brain electrical stimulation was also reduced by both benzodiazepines. Basal respiratory rate was slightly, but significantly decreased by chlordiazepoxide as well as by the two doses of midazolam used and to a lesser extent by the vehicle alone. Chlordiazepoxide attenuated the increase in respiratory depth caused by brain stimulation, while basal respiratory amplitude was not affected. The effects of midazolam on this parameter were unclear. Microinjection of bicuculline (5 and 10 nmol) or picrotoxin (0.3 and 1 nmol) into the DPAG increased the BP, HR and respiration, like the electrical stimulation. The latency and duration of bucuculline effects were shorter than those of picrotoxin.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1983

Neuroeffector mechanisms of the defense reaction in the rat.

Electrical stimulation of the dorsal periaqueductal gray matter (DPAG) eliciting flight behavior in awake rats caused an increase in arterial blood pressure (BP), heart rate (HR) and respiration in rats anesthetized with urethane. The hypertension was markedly reduced by 5 mg/kg of intravenously injected hexamethonium or bretylium, virtually abolished by 5 mg/kg of phentolamine and partially antagonized by 0.1 mg/kg of the alpha 1-adrenoceptor blocker, prazosin. The tachycardia induced by DPAG stimulation was partially antagonized by hexamethonium or bretylium and abolished by propranolol (5 mg/kg, IV) or practolol (5 mg/kg, IV), but not affected by N-butylscopolamine (10 mg/kg, IV). Phentolamine increased basal HR and abolished the tachycardic response caused by either brain stimulation or intravenous noradrenaline. Prazosin moderately decreased the response to noradrenaline, but did not affect basal HR or the tachycardia induced by brain stimulation. The increase in respiratory amplitude occurring during brain stimulation was abolished by phentolamine as well as by prazosin, while the increase in respiratory rate was moderately reduced by phentolamine and propranolol. These results demonstrate that the cardiovascular component of the defense reaction of the rat is almost entirely due to a sharp increase in sympathetic tone. They also suggest that the hyperventilation induced by aversive brain stimulation is modulated by central and peripheral adrenergic mechanisms.

Animals↗

PubMed1982

GABA mediation of the anti-aversive action of minor tranquilizers.

Earlier observations have shown that systematically injected minor tranquilizers decrease the aversive consequences of electrical stimulation of the dorsal periaqueductal gray (DPAG) matter of the rat brain. In order to verify if these drugs can act directly on the DPAG, chlordiazepoxide (CDP) and pentobarbital (PB) were locally injected into the dorsal midbrain of rats chronically implanted with chemitrodes, allowing electrical stimulation of the same brain area. Microinjection of doses of 0.16 and 0.32 mumol of CDP and 0.16 mumol of PB significantly increased the threshold electrical current including flight behavior by stimulating the dorsal midbrain. Flight behavior was measured by the number of times rats crossed dividing line while running from one compartment of a shuttle-box to the other. The same effect was caused by the intracerebral injection of 0.32 and 0.64 mumol of the inhibitory neurotransmitter, gamma-aminobutyric acid (GABA). Conversely, local injection of the GABA antagonists. bicuculline (5-20) nmol) or picrotoxin (0.3 and 0.6 nmol), into the dorsal midbrain induced flight behavior, like the electrical stimulation. On the other hand, the glycine antagonist, strychnine (40 nmol) caused convulsive behavior only, while the intracerebral injection of the cholinergic agonist, carbachol (10-40 nmol), increased locomotion, sniffing and turning behavior, but did not induce flight. Pretreatment with locally injected GABA (0.64 mumol) antagonized the aversive effect of either bicuculline (10 nmol) or picrotoxin (0.3 nmol), whereas CDP (0.32 mumol) antagonised bicuculline only and PB (0.16 mumol) was ineffective against either bicuculline or picrotoxin. These results suggest that minor tranquilizers act directly upon the DPAG by enhancing the tonic inhibitory influence of endogenous GABA. This action may underly the antiaversive affects of these drugs.

Animals↗