Biomedical subjects

F G Graeff

Publications and source records attributed to F G Graeff.

At least 73 records · Page 4Linked to original sources

PubMed1993

D-fenfluramine reduces anxiety induced by simulated public speaking.

To further explore the role of serotonin (5-HT) in anxiety, 28 healthy volunteers received in a double-blind study d-fenfluramine (30 mg, p.o.) or placebo, and were submitted to a simulated public speaking test (SPS), consisting of speaking in front of a video camera. The SPS induced significant increases in subjective anxiety evaluated by the visual analogue mood scale of Norris [MANCOVA, F(1.66,39.93) = 8.51, P < 0.001], as well as in systolic blood pressure [F(3,72) = 5.70, P = 0.001] and in heart rate [F(3,72) = 3.95, P = 0.012]. The drug decreased the anxiety factor [F(1,23) = 5.21, P = 0.032], without significantly affecting physical sedation, mental sedation or other feelings and attitudes. Also, the physiological measurements were not significantly changed by d-fenfluramine. Reported evidence shows that d-fenfluramine releases 5-HT from nerve endings and blocks 5-HT reuptake, indirectly stimulating postsynaptic 5-HT receptors. Therefore, the present results indicate that 5-HT inhibits the neural substrate of SPS-induced anxiety.

Adolescent↗

PubMed1993

The elevated T maze, a new experimental model of anxiety and memory: effect of diazepam.

In rats placed in a T maze consisting of an enclosed arm at right angles with two open arms elevated 50 cm above the ground, ip doses of 2 and 4 mg/kg diazepam (DZP) abolished the delay of withdrawal from the enclosed arm towards the open arms, measured by retesting in the presence of the drug soon after training, as well as by further retesting 72 h later, in the absence of the drug. Therefore, DZP had both anxiolytic and amnestic effects on this inhibitory avoidance task. In contrast, DZP did not affect the latency of withdrawal from one of the open arms towards the closed arm on the first day. Moreover, the latency of this escape response similarly decreased in all treatment groups in the retest performed 72 h later, indicating that memory of this task was resistant to DZP. These results support the view that the anxiolytic and amnestic effects of benzodiazepines are closely related, and suggest that this new elevated T maze model may be useful for simultaneous measurement of drug effects on anxiety and memory.

Animals↗

PubMed1993

Influence of stimulus preexposure and of context familiarity on conditioned freezing behavior.

1. This paper reports an experiment examining the influence of context on latent inhibition using conditioned freezing behavior as an index. 2. Two groups of 8 Wistar rats (290-320 g) were placed in one chamber (Context 2) and either exposed 7 times or not to a sound stimulus (68 dB, 90 s). Two additional groups of 8 rats received the same stimulation in a different environment (Context 1). Next, each rat was required to form a sound-shock (0.2 mA, 1.5 s) association (20 trials) in Context 2. Freezing behavior was measured both during sound (CS) presentation and during an equal period of time immediately preceding the CS. 3. When the test environment was familiar, the conditioning of fear was greater in the non-preexposed than in the CS-preexposed group. Acquisition of conditioned freezing was intermediate when the test environment was unfamiliar, irrespective of CS preexposure. 4. These results further support the context specificity of latent inhibition. In addition, they suggest that novelty interferes with sound-shock associations.

Analysis of Variance↗

PubMed1992

Anxiolytic effect of carbamazepine in the elevated plus-maze: possible role of adenosine.

In order to extend previously reported observations with other animal models of anxiety, the effect of carbamazepine (CBZ) was presently measured in rats placed on the elevated plus-maze. Intraperitoneal injection of CBZ (5-40 mg/kg) increased the percentage of open arm entries as well as the percentage of time spent on the open arms of the maze, without affecting the total number of arm entries. This effect is characteristic of anxiolytic drugs. The inhibitor of adenosine neuronal uptake papaverine (5-40 mg/kg) caused a similar anxiolytic effect, whereas the adenosine receptor antagonist aminophylline (1-4 mg/kg) selectively decreased the percentage of open arm entries, indicative of an anxiogenic effect. Furthermore, the combination of an anxiogenic dose (4 mg/kg) of aminophylline with an anxiolytic dose (40 mg/kg) of CBZ resulted in cancellation of each other effects. Since reported neurochemical evidence shows that CBZ interacts with adenosine receptors, the present results provide preliminary support for a participation of this neurotransmitter in the anxiolytic action of CBZ.

Adenosine↗

PubMed1992

Effects of early postnatal malnutrition and chlordiazepoxide on experimental aversive situations.

In order to study the lasting 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. At 49 and 70 days of age, independent groups of animals were tested in the locomotor activity, step-down inhibitory avoidance, and flinch-jump nociceptive tests. Also, at 49 days of age, malnourished and control rats were sacrificed in order to evaluate the weight of brain regions. Malnourished rats had lower body and brain weights (telencephalon and brain stem) than control rats. Malnourished rats also showed less locomotor activity at the beginning of the test session, lower flinch and jump thresholds, and longer step-down latencies than control animals. Chlordiazepoxide (5 mg/kg, IP) shortened step-down latency of well-nourished rats, but was ineffective in malnourished rats. These and previously reported results indicate that early protein malnutrition causes long-lasting impairment of neuronal systems underlying emotional behavior.

Animals↗

PubMed1992

Opioid mediation of the antiaversive and hyperalgesic actions of bradykinin injected into the dorsal periaqueductal gray of the rat.

Reported evidence indicates that the dorsal region of the periaqueductal gray matter (PAG) is involved in the modulation of both pain and aversion, and that opioid mechanisms, among others, participate in their modulation. Since many central actions of bradykinin (BK) have been shown to be similar to those of morphine, the present was undertaken to measure the effects of microinjection of BK into the PAG on the thresholds of aversive electrical stimulation of the same brain area and of dental pulp electrical stimulation. Bradykinin, injected into the dorsal PAG, induced a dose-dependent increase in the aversive threshold, an effect similar to that reported by others for morphine. Also, as reported for morphine, the antiaversive effect of BK was antagonized by naloxone injected intraperitoneally. Whereas subcutaneously administered morphine induced marked analgesia, intra-PAG administration of BK caused a small but significant hyperalgesia. Similarly, morphine injected into the dorsal PAG tended to cause hyperalgesia instead of analgesia. Furthermore, the hyperalgesic effect of BK also appears to involve opioid mechanisms since it was blocked by naloxone. As in previously reported studies, intracerebroventricularly injected BK raised the pain threshold. These results indicate that BK mobilizes opioid mechanisms in the dorsal PAG that inhibit aversion but not pain.

Animals↗

PubMed1992

Defense reaction elicited by microinjection of kainic acid into the medial hypothalamus of the rat: antagonism by a GABAA receptor agonist.

Electrical stimulation of either the midbrain central gray or the medial hypothalamus induces a defense reaction in the rat, characterized mainly by increased locomotion, rearing, and leaping. However, microinjection of the excitatory amino acid glutamate was effective only in the former region. Because excitatory amino acids do not depolarize axons of passage, it was suggested that the hypothalamus is devoid of soma/dendrites of neurons commanding the defense reaction. In the present study, we show that a subtoxic dose (60 pmol) of another excitatory amino acid, kainic acid, injected into the medial hypothalamus significantly enhanced locomotion and rearing of Wistar rats systematically observed in an open field. Similar behavioral changes have been reported following microinjection of drugs impairing GABAergic neurotransmission. Local pretreatment with the GABAA receptor agonist THIP (2 nmol) blocked the effect of kainic acid. Therefore, the medial hypothalamus of the rat seems to contain a population of neuronal cell bodies commanding the defense reaction, which is activated by excitatory amino acids and tonically inhibited by GABAergic fibers.

Agonistic Behavior↗

PubMed1991

Electrophysiological evidence for excitatory 5-HT2 and depressant 5-HT1A receptors on neurones of the rat midbrain tectum.

It has been claimed that the aversive behaviour induced by electrical stimulation of the midbrain tectum (MT) has validity as an animal model of panic attack. A great deal of evidence obtained from behavioural studies suggests that 5-HT2 mechanisms phasically inhibit the substrates of aversion in the MT. In order to test this hypothesis we employed the technique of microiontophoresis of drugs onto neurons of the MT to assess the identity of the receptors mediating the effects of 5-hydroxytryptamine (5-HT). The results obtained show that the majority of 5-HT responsive cells in MT are cells excited by 5-HT (72%). These cells were silent or showed very low spontaneous firing activity, whereas cells depressed by 5-HT showed high spontaneous firing activity at baseline. The 5-HT1A receptor agonists, 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT), buspirone and gepirone caused consistent reduction in the firing rate of cells depressed by 5-HT while they did not change the firing activity of cells excited by 5-HT. The excitatory effects induced by 5-HT on MT neurones were clearly attenuated by concomitant application of ketanserin, a highly specific 5-HT2 antagonist. Excitatory responses to DL-homocysteic acid were not affected by ketanserin. Previous administration of zimelidine, a selective 5-HT uptake inhibitor, caused a significant enhancement of the excitatory effects of 5-HT while similar application of gepirone did not affect the size of the excitatory responses to 5-HT.(ABSTRACT TRUNCATED AT 250 WORDS)

8-Hydroxy-2-(di-n-propylamino)tetralin↗

PubMed1991

Anxiolytic effect in the elevated plus-maze of the NMDA receptor antagonist AP7 microinjected into the dorsal periaqueductal grey.

In order to localise the often reported anxiolytic action of N-methyl-D-aspartate (NMDA) receptor antagonists, 2-amino-7-phosphonoheptanoic acid (AP7) was injected into the dorsal periaqueductal grey (DPAG) of rats exposed to the elevated plus-maze model of anxiety. Doses of 0.2, 2 and 20 nmol AP7 caused a dose-dependent increase in the percentage of open arm entries, the effect of the last two doses being significantly different from control. A non-significant tendency to increase the percentage of time spent on the open arms of the maze was also noticed. In contrast, the total number of entries into either the open or enclosed arms was not affected. Injections of AP7 localized outside the DPAG were ineffective. Therefore, microinjection of AP7 into the DPAG caused a selective anxiolytic effect in the elevated plus-maze. It may be suggested that the DPAG is a site of the anxiolytic action of NMDA antagonists reported following systemic administration.

2-Amino-5-phosphonovalerate↗

PubMed1991

Early life protein malnutrition changes exploration of the elevated plus-maze and reactivity to anxiolytics.

In order to investigate whether protein malnutrition in early life causes lasting changes in reactivity to anxiolytic drugs, exploration of the elevated plus-maze was used. Rat dams during lactation (21 days) and pups after weaning until day 49 of life were fed on 8% casein diet (M rats), while their well-nourished controls received 25% casein (W rats). From day 50 on all animals ate the same balanced diet. Experiments started on day 70. Under the non-drug condition, M rats tended to explore the open arms of the maze relatively more than W rats. Diazepam (0.5-5 mg/kg, IP) dose-dependently increased the percentage of open/total arm entries without significantly affecting the total number of arm entries in W rats. This selective anxiolytic effect of diazepam was considerably smaller in M rats. Ipsapirone (0.5-5 mg/kg) caused a similar though less pronounced anxiolytic effect in W rats, whereas the drug decreased both the % open/total and total arm entries in M rats. In contrast, ritanserin (0.05-1 mg/kg) significantly increased the % open/total arm entries in M rats only, though not in a dose-dependent way. Isamoltane (2.5-20 mg/kg) was ineffective on both M and W rats. These results indicate that early protein malnutrition causes long-lasting alterations in brain systems regulating emotional behaviour.

Animals↗

PubMed1991

Microinjection of propranolol into the dorsal periaqueductal gray causes an anxiolytic effect in the elevated plus-maze antagonized by ritanserin.

The 5-HT1A/1B receptor antagonist propranolol was injected into the dorsal periaqueductal gray (DPAG) of rats exposed to the elevated plus-maze in order to investigate the participation in anxiety of 5-HT mechanisms operating in this brain region. Microinjection of D,L- or L-propranolol into the DPAG increased the percentage of total arm entries without affecting the total number of entries into either open or enclosed arms of the maze, an effect characteristic of anxiolytic drugs injected systemically. The doses of 5 nmol L-propranolol and 10 nmol D,L-propranolol caused anxiolytic effects of comparable magnitude, while the doses of 2.5 nmol of the former and 5 nmol of the latter were ineffective. Therefore, the L-isomer is likely to be the main one responsible for the pharmacological activity observed. In addition, the anxiolytic effect of 10 nmol D,L-propranolol was antagonized by 10 nmol of the 5-HT2/1C receptor antagonist ritanserin, previously injected into the DPAG. The present as well as previously reported results suggest that the anxiolytic effect of propranolol injected into the DPAG is due to increased release of 5-HT acting on post-synaptic 5-HT2 receptors, resultant from blockade of 5-HT1B autoreceptors that inhibit amine release from serotonergic nerve endings.

Analysis of Variance↗

PubMed1991

Strain-dependent effects of morphine injected into the periaqueductal gray area of mice.

1. Microinjection of morphine (0.31, 1.25 and 5.0 micrograms) into the periaqueductal grey area (PAG) of C57BL/6 (C57) and DBA/2 (DBA) mice increased the pain threshold in the tail-flick test. The highest dose also caused a behavioral reaction in both strains characterized by periods of immobility alternating with explosive motor behavior. 2. In the DBA strain, the analgesic effect was demonstrated with all doses of morphine, while in the C57 strain only the highest dose induced analgesia. 3. DBA mice presented a decrease in activity with the lowest dose of morphine, whereas in the C57 strain, this effect was obtained only with the highest dose of morphine. 4. These data corroborate at the PAG level the results of other studies which have shown that central and peripheral injections of morphine produce analgesia and alter motor activity in C57 and DBA strains. They also confirm that these two strains of mice present genotype-dependent differences in sensitivity to opioids as determined after injections of morphine into the PAG.

Animals↗

PubMed1991

Anxiolytic effect of midazolam microinjected into the dorsal periaqueductal grey area of rats.

In order to investigate the role of the dorsal periaqueductal grey (DPAG) area in the anxiolytic effect of benzodiazepines male Wistar rats (N = 10), weighing 200-250 g at the time of surgery, were microinjected into this structure with midazolam (80 nmol) and submitted to the elevated plus-maze, an ethologically based model of anxiety. Midazolam significantly increased the percentage of open arm entries from 32.4 +/- 4.6 (control) to 49.5 +/- 3.0 and of time spent in the open arms from 21.0 +/- 4.5 (control) to 35.6 +/- 4.8 without affecting the total number of entries into either open or enclosed arms. This effect typifies an anxiolytic effect in the test and was antagonized by the benzodiazepine receptor antagonist flumazenil (80 nmol) microinjected into the same site 10 min before the midazolam (80 nmol) microinjection. Microinjection of flumazenil alone had no effect. These results provide additional evidence for the participation of the DPAG in the physiopathology of anxiety and suggest that it may be a site for the anxiolytic effect of systemically injected benzodiazepines.

Analysis of Variance↗

PubMed1990

Antianxiety effect of cannabidiol in the elevated plus-maze.

In order to assess the presence of anxiolytic properties in cannabidiol (CBD) the drug was tested in an elevated plus-maze model of anxiety, in rats. Doses of 2.5, 5.0 and 10.0 mg/kg significantly increased the entry ratio (open/total number of entries), an anxiolytic-like effect. CBD at a dose of 20.0 mg/kg was no longer effective. None of the doses of CBD used changed total number of entries, a measure of total exploratory activity. Diazepam (2.0 mg/kg) also caused an anxiolytic-like effect in this model. These results indicate that CBD causes a selective anxiolytic effect in the elevated plus-maze, within a limited range of doses.

Animals↗

PubMed1990

Decreased reactivity to anxiolytics caused by early protein malnutrition in rats.

In order to investigate whether early malnutrition causes lasting changes in the reactivity to anxiolytic drugs, rat dams during lactation (21 days) and pups after weaning until the 49th day of life were fed on 8% casein diet (M rats), while their well-nourished controls received 25% casein (W rats). From day 50 on all animals ate the same balanced diet. Experiments started on the 91st day. Rats deprived for 22 hours drank water containing either 1.8% or 2.7% sodium chloride for 30 min in a test chamber, total intake being measured. Dose-effect curves for diazepam (0.5-5.0 mg/kg, IP), as well as for the nonbenzodiazepine anxiolytics ipsapirone (0.5-5.0 mg/kg), ritanserin (0.05-1.0 mg/kg) and isamoltane (2.5-20.0 mg/kg) were determined in M as well as in W rats. Diazepam and ipsapirone dose-dependently released drinking suppressed by either salt concentration in W rats, but caused little or no effect in M rats. Ritanserin and isamoltane were ineffective in both groups. These and previously reported results show that early protein malnutrition markedly reduces anticonflict effects of anxiolytics, indicating long-lasting impairment of neuronal systems underlying emotional behavior.

Animals↗

PubMed1990

Behavioral effects of 5-HT receptor ligands in the aversive brain stimulation, elevated plus-maze and learned helplessness tests.

In order to illustrate the use of animal models in the study of the anxiolytic and antidepressant properties of drugs acting on 5-HT receptors, a series of experiments is described. With electrical stimulation of the midbrain central gray (CG), an aversive area of the brain, the 5-HT-1 receptor antagonist propranolol raised the aversive threshold in a dose-dependent way, following its microinjection into the CG. This antiaversive effect of propranolol, which is similar to that of benzodiazepine anxiolytics, was prevented by microinjection into the same brain site of the 5-HT-2 receptor blocker ritanserin. Ritanserin itself and the 5-HT-1A receptor ligand ipsapirone caused either little or no effect. In another animal model of anxiety, the elevated plus-maze, intra-CG propranolol also caused an anxiolytic-like effect, antagonized by ritanserin, indicating a 5-HT mediation. However, systemically injected isamoltane, a congener of propranolol, was ineffective in the elevated plus-maze, whereas ipsapirone caused an anxiolytic effect. Ritanserin was again inactive. Finally, both ipsapirone as well as another 5-HT-1A receptor ligand BAY R 1531, given IP, reversed the learning deficit resulting from exposure to uncontrollable foot-shocks, an effect characteristic of antidepressant drugs.

Animals↗

PubMed1990

Stereoselectivity of the anxiolytic effect of propranolol microinjected into the dorsal midbrain central gray.

In a previous study we have shown that microinjection of d,1-propranolol into the dorsal midbrain central gray of the rat causes an anxiolytic effect in the elevated plus-maze model which is likely to be mediated by endogenous 5-hydroxytryptamine. In the present experiment, the effects of 1- and d,1-propranolol were compared under the same experimental conditions. Both the 1-isomer and the racemic mixture increased the percentage of open arm entries without affecting the total number of entries into either open or enclosed arms of the maze, thus reproducing the selective anxiolytic effect previously described. The doses of 5 nmol 1-propranolol and 10 nmol d,1-propranolol caused anxiolytic effects of comparable magnitude, while the doses of 2.5 nmol of the former and 5 nmol of the latter were ineffective. Therefore, the 1-isomer was nearly twice as potent as the racemic mixture, thus being responsible for the pharmacological activity observed. These results are compatible with the proposal that propranol blocks stereospecific autoreceptors in serotonergic nerve endings that inhibit neurotransmitter release.

Animals↗

PubMed1990

Anxiolytic effect of kynurenic acid microinjected into the dorsal periaqueductal gray matter of rats placed in the elevated plus-maze test.

The effect of kynurenic acid (20 to 160 nmol) microinjected into the dorsal periaqueductal gray matter was measured in rats placed in an elevated plus-maze. Microinjection of 160 nmol of kynurenic acid increased the percentages of open arm entries and of time spent in the open arms. Both of these measures may be considered indexes of anxiolysis. Although kynurenic acid also increased the total number of entries, analysis of covariance shows that the increase in open arm entries is independent of the effect on closed arm entries. Thus, the anxiolytic effect of kynurenic acid detected in the elevated plus-maze strengthens the proposal that glutamatergic neurons of the dorsal periaqueductal gray matter play an important role in anxiety.

Analysis of Variance↗