Search PubMed⌕ Search

Biomedical subjects

F G Graeff

Publications and source records attributed to F G Graeff.

At least 55 records · Page 3Linked to original sources
PubMed1996

Effects of anxiety and memory of systemic and intra-amygdala injection of 5-HT3 receptor antagonist BRL 46470A.

This study deals with the effects of the 5-HT3 receptor antagonist, BRL 46470A, on memory and anxiety, using the elevated T-maze. This method is useful for investigating the effects of anxiolytic drugs on memory, and the relationships between neural subsystems involved in emotionally related behaviors and in processes underlying learning. After the drug was either injected peripherally or microinjected into the amygdala, the animals were tested on the elevated T-maze (30 or 15 min later, respectively). Two kinds of aversively motivated behaviors, inhibitory avoidance and one-way escape, were recorded. These behaviors may reflect different types of fear/anxiety, namely, anticipatory anxiety and innate fear. Three days later, memory for these tasks was assessed by reexposing the subjects to the maze. The compound had an anxiolytic effect on the inhibitory avoidance response when given systemically, but an anxiogenic effect when injected into the amygdala. It had an anxiolytic action on the escape response when given either systemically or into the amygdala. The compound had no adverse effects on memory for either task. These results suggest that this new 5-HT3 antagonist may be useful in the treatment of certain types of anxiety disorders, especially those related to unconditioned fear, e.g. phobic or panic disorders, with the likelihood of having no side effects on memory processes. The contrasting results obtained with different measures of anxiety may also account for the inconsistencies found in the experimental literature dealing with compounds of this nature.

Amygdala↗
PubMed1996

Effect of d-fenfluramine on human experimental anxiety.

To investigate the role of 5-HT in human anxiety, the 5-HT releaser and uptake blocker d-fenfluramine (FEN) was administered to healthy volunteers under two models of experimental anxiety. The first was a simulated public speaking (SPS) test consisting of talking in front of a video camera, anxiety being evaluated mainly by self-rating scales. The second was a conditioned fear test, in which the changes in skin electrical conductance caused by a tone associated once with an aversive white noise were measured. The doses of 15 and 30 mg FEN, PO, decreased anxiety induced by SPS in a dose-dependent way, as indicated by the anxiety factor of Norris Visual Analogue Mood Scale. In the conditioned fear test, however, the amplitude and level of skin conductance responses to the conditioned aversive stimulus were not significantly changed by FEN. The differential effects of FEN in these human experimental models of anxiety, together with similar results reported in rats, support the view that 5-HT exerts a dual action on brain mechanisms regulating anxiety, facilitating conditioned while inhibiting unconditioned fear. The presumed reduction in unconditioned fear caused by FEN may have implications for the treatment of panic disorder.

Adolescent↗
PubMed1996

D-fenfluramine selectively releases 5-HT from dorsal raphe terminals.

The aim of this study was to investigate whether D-fenfluramine (FEN) releases 5-hydroxytryptamine (5-HT) selectively from dorsal raphe (DR) terminals. Male Wistar rats, 180-200 g, were implanted with microdialysis probes ir the amygdala (Am; N = 5) and dorsal hippocampus (DH; N = 6) and 5-HT levels were measured by electrochemical detection. Under basal conditions, 5-HT levels were approximately 50 and 230 fmol per 30 min sample, in the Am and DH, respectively. FEN (10 mg/kg. ip) produced a 3-4-fold increase in 5-HT release in the Am, but not in the DH. Since the Am is mainly innervated by DR fibers while the DH receives 5-HT input chiefly from the median raphe (MR), the present results support the view that FEN selectively releases 5-HT from DR terminals.

Amygdala↗
PubMed1995

c-fos immunoreactivity in the brain following electrical or chemical stimulation of the medial hypothalamus of freely moving rats.

c-fos immunoreactivity was used to map brain areas in which neurons reacted either to electrical stimulation or to microinjection of the excitatory amino acid kainate and of the GABAA antagonist, SR-95531, applied to the medial hypothalamus of freely moving rats. All these stimulations induced flight behavior of moderate intensity. Immunoreactive cells were found within a radius of 0.5 mm around the stimulated area. Distally, clusters of labeled cells were found ipsilaterally in the piriform and entorhinal cortices, in several amygdaloid nuclei, in the bed nucleus of the stria terminalis, in the septo-hypothalamic nucleus, in the paraventricular, anterior and dorsomedial hypothalamic nuclei, the the paraventricular thalamic nucleus, in the dorsal periaqueductal gray extending to the cuneiform nucleus, and bilaterally in the supramammillary decussation and the locus coeruleus. The specificity of the brain areas thus labeled was indicated by the unilateral pattern of activation as well as by the different pattern obtained after control microinjection of saline. Therefore, these results are likely to provide sound information about the brain structures involved in defensive-aversive behavior evoked from the medial hypothalamus.

Animals↗
PubMed1995

Role of 5-HT receptor subtypes in the modulation of dorsal periaqueductal gray generated aversion.

To explore the role of 5-HT receptor subtypes in controlling aversion, we measured the effect of 5-HT1A and 5-HT2A/2C receptor agonists microinjected into the dorsal periaqueductal gray (DPAG) of rats on aversive behavior induced by electrical stimulation of the same brain area. The 5-HT1A agonists 8-OH-DPAT (4-16 nmol) and BAY-R-1531 (4-16 nmol) raised the threshold of aversive electrical stimulation in a dose-dependent way. Similarly, microinjection of the 5-HT2A/2C agonist DOI (4-16 nmol) increased the aversive mCPP (16 and 32 nmol) was ineffective. Previous intra-DPAG administration of the 5-HT1A receptor blocker NAN-190 (40 nmol) antagonized the antiaversive effect of 8-OH-DPAT (8 nmol), whereas pretreatment with the 5-HT2A receptor blocker spiperone (10 nmol) antagonized the effect of DOI (16 nmol). Spiperone also counteracted the effect of 8-OH-DPAT and NAN-190 counteracted the effect of DOI. These results indicate that activation of 5-HT1A and 5-HT2A receptors inhibits aversion in the DPAG and that both receptors have to be functional for the expression of each one's activation to occur.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1994

Anxiolytic effect of glycine antagonists microinjected into the dorsal periaqueductal grey.

To investigate if blockade of the modulatory glycine site of NMDA receptors in the dorsal periaqueductal grey (DPAG) would produce anxiolytic effects, groups of 9-14 rats received microinjections into this structure of 7-chloro-kynurenic acid (7-Cl-KY, 4 and 8 nmol) or 3-amino-1-hydroxypyrrolid-2-one (HA-966, 30 or 100 nmol), two selective antagonists at the strychnine-insensitive glycine modulatory site, and were submitted to the elevated plus-maze, an ethologically based animal model of anxiety. Both drugs increased the percentage of entries and of time spent in open arms as compared to rats receiving isotonic saline. Injections of the active compounds outside the DPAG were not effective. In another experiment microinjections of 7-Cl-KY (8 nmol) and HA-966 (100 nmol) into the DPAG raised the threshold of aversive electrical stimulation of the rat DPAG. These results indicate that microinjections of 7-Cl-KY and HA-966 into the DPAG cause anxiolytic effects in two different models of anxiety and support the proposal that NMDA-mediated neurotransmission in the DPAG may be related to anxiety and panic.

Animals↗
PubMed1994

The elevated T-maze: a new animal model of anxiety and memory.

In an attempt to analyze different types of anxiety, and at the same time assess memory, a new experimental model was developed. The apparatus, named the elevated T-maze, consisted of three arms of equal dimensions (50 x 10 cm) elevated 50 cm from the ground. One arm, enclosed by 40-cm high walls, was perpendicular to two open arms. The first experimental session was conducted 25 min after IP injection of either drug or saline. To assess inhibitory (passive) avoidance, the rat was placed at the end of the enclosed arm and the time taken to withdraw from this arm was recorded three times in succession. Soon afterwards, the rat was placed at the end of one of the open arms and the time taken to withdraw from this arm was measured, thus estimating one-way escape. To assess memory, inhibitory avoidance and escape were measured again 3 days later, without drug. Dose-response curves were determined for the benzodiazepine anxiolytic and amnestic agent diazepam (DZP, 0.5-4 mg/kg), as well as for ipsapirone (IPS, 0.25-2 mg/kg), an azapirone anxiolytic that is devoid of clinically significant amnestic effects. The doses of 1, 2, and 4 mg/kg DZP and of 1 and 2 mg/kg IPS impaired inhibitory avoidance, an effect that may be viewed as anxiolytic. Inhibitory avoidance remained impaired 3 days later in the rats treated with 1-4 mg/kg DZP, indicating anterograde amnesia. This effect was not due to state-dependent learning, because rats injected both at pretraining and pretesting with 2 mg/kg DZP still showed complete amnesia.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

Ethopharmacological analysis of rat behavior on the elevated plus-maze.

Behavioral categories were measured in rats left on an elevated plus-maze for 5 min, in addition to the traditional measures. Four independent factors emerged from a factor analysis. The variables that loaded highly and positively on Factor 1, seemingly related with anxiety, were: number of entries onto open arms, time spent on open arms, percentage of open/total arm entries, percentage of time on open arms, scanning over the edge of an open arm, and open arm end-exploring. The time spent on enclosed arms loaded highly, but negatively on the same factor. Risk-assessment from an enclosed arm also loaded negatively on Factor 1. Number of enclosed arm entries, total number of arm entries and rearing loaded highly on Factor 2, probably related to motor activity. However, the total number of entries also loaded on Factor 1, being thus a mixed index. Similarly, the number of open arm entries loaded on both Factors 1 and 2. As expected, the variables having high loads on Factor 1 were changed to one direction by administration of two anxiolytics (nitrazepam and midazolam) and to the opposite direction by two anxiogenic drugs (pentylenetetrazol and FG 7142). Such pattern of drug effects was not observed with the remaining variables.

Animals↗
PubMed1994

Behavioral effects of intra-amygdala injections of GABA and 5-HT acting drugs in the elevated plus-maze.

The effect of drugs bilaterally injected into the basolateral/medial nuclei of the amygdala on the behavior of male Wistar rats (300-330 g) in the elevated plus-maze was measured. The benzodiazepine agonist midazolam (MDZ, 20 and 40 nmol, 0.2 microliters; N = 8-14) significantly increased open-arm exploration (% open-arm entries: control = 20.27 +/- 3.71; 40 nmol MDZ = 42.63 +/- 7.16), having thus an anxiolytic effect. On the contrary, the non-selective 5-HT2 antagonist ketanserin (KET, 1 and 10 nmol, 0.2 microliters; N = 8-11) had an anxiogenic effect (% open-arm entries: control = 35.61 +/- 6.41; 10 nmol KET = 18.65 +/- 3.89). The 5-HT1A full agonist 8-OH-DPAT (2, 4, and 8 nmol, 0.2 microliters; N = 9-12) did not significantly change rat behavior in the plus-maze. While the present anxiolytic effect of midazolam agrees with results reported by others using punished behavior, the effect of the serotonergic drugs does not. Therefore, the effect of 5-HT acting drugs injected into the amygdala may be determined by the type of experimental model of anxiety used.

Amygdala↗
PubMed1994

Neuroanatomy and neurotransmitter regulation of defensive behaviors and related emotions in mammals.

1. There is suggestive evidence that the septo-hippocampal system and the amygdala are involved in risk assessment behavior, a response to potential threat possibly related to anxiety. In addition, experimental results have been reported implicating the medial hypothalamus in coordinated escape, while the periaqueductal gray matter (PAG) and the median raphe nucleus serotonergic projection to the hippocampus seem to mediate freezing. The latter defensive behaviors are evoked by distal danger stimuli and may be viewed as manifestations of fear. Finally, there is a sound body of evidence indicating that the PAG commands primitive fight or flight reactions elicited by proximal threat, acute pain or asphyxia. These defense reactions may be related to rage and panic, respectively. In contrast, the lateral septal area and the bed nucleus of the stria terminalis have been shown to exert tonic inhibitory influence on defense. 2. Experimental evidence indicates that gamma-aminobutyric acid (GABA) tonically inhibits defensive behavior in the amygdala, hypothalamus and the PAG, an effect opposed by excitatory amino acids. Among monoamines, serotonin (5-HT) has been suggested to facilitate anxiety in the amygdala while inhibiting panic in the PAG. The role of noradrenaline in defense is less clear, although hypotheses implicating the locus coeruleus in anxiety and panic have been suggested. Among peptides, corticotropin-releasing factor (CRF) acting as a central neurotransmitter is thought to mediate behavioral and physiological effects of acute stress, while opioid peptides have been shown to inhibit defense in the amygdala and in the dorsal PAG. Finally, acetylcholine seems to facilitate defensive behavior in the hypothalamus and the PAG.

Acetylcholine↗
PubMed1994

Regional distribution of Fos-like immunoreactivity in the rat brain after exposure to fear-inducing stimuli.

Fos protein immunohistochemistry was used to identify the neural substrate of fear/anxiety. The structures activated by exposure of Long Evans male rats (280-300 g) to the elevated plus-maze, a widely used animal model of anxiety, were compared with those activated by chemical stimulation of two aversive areas of the brain, the dorsal periaqueductal gray matter and the medial hypothalamus. Three different patterns of activation were obtained: Pattern 1 resulted from microinjection of the excitatory amino acid kainate (60 pmol; N = 5) or of the GABA(A) receptor antagonist SR-95531 (16 pmol; N = 3) into the dorsal periaqueductal gray matter and consisted mainly of caudal structures; Pattern 2 was observed after kainate injection (60 pmol; N = 4) into the medial hypothalamus and had a predominantly prosencephalic distribution; Pattern 3 extended from rostral to caudal brain regions and was induced by microinjection of either SR-95531 (16 pmol; N = 1) or kainate (120 pmol; N = 3) into the medial hypothalamus, as well as by 15-min exposure to the plus-maze (N = 3). Control animals were either injected with saline into the MH (N = 3) or the PAG (N = 3) or were exposed for 15 s to the elevated plus maze (N = 3) and exhibited no significant labeling. These results further support the participation of periventricular structures in the regulation of fear and aversion.

Animals↗
PubMed1993

Absence of amnestic effect of an anxiolytic 5-HT3 antagonist (BRL 46470A) injected into basolateral amygdala, as opposed to diazepam.

This experiment compares the effects of microinjections into the basolateral amygdala nucleus of diazepam (DZP) and a new 5-HT3 receptor antagonist, BRL 46470A, on acquisition and retention of an inhibitory avoidance tasks by rats. The animals were microinjected with DZP or BRL 46470A between 10 and 15 min before the learning trial. Retention testing 48 h later showed impaired retention in animals injected with DZP but not with BRL 46470A. These results show that BRL 46470A, a compound suggested to have anxiolytic effects does not induce amnesia. This evidence for a possible dissociation between anxiety-reducing and memory-disrupting effects of a drug has implications, for one, for the understanding of the neuronal substrates mediating these effects, and secondly, for the search for anxiolytic agents devoid of undesirable side effects on memory processes.

Amnesia↗
PubMed1993

Localization in the amygdala of the amnestic action of diazepam on emotional memory.

It is well known that systemically administered benzodiazepines (BZDs) induce anterograde amnesia in a variety of learning tasks. BZs effects are mediated through the GABAA complex by enhancing GABA-induced synaptic inhibition. As the GABAergic system in the amygdaloid complex (AC) is a site of action for the anxiolytic effects of BZs, such findings suggest that BZs may also influence memory through the amygdala. The present report summarizes a recent series of experiments designed to examine this implication. In a first experiment rats received either sham or bilateral AC lesion using N-methyl-D-aspartic acid (NMDA). One week later, animals were trained on an inhibitory avoidance task and tested 48 h later. Diazepam (DZP; 1.0 and 2.0 mg/kg, i.p.) or vehicle was injected 30 min prior to acquisition. The results demonstrate that DZP-induced retention deficits was blocked in rats with AC lesions. In a second experiment, in an attempt to localize the site of BZDs amnestic action in the AC, we tested the effects of DZP in rats with bilateral ibotenic acid-induced lesions of central (CE), lateral (LAT) or basolateral (BL) amygdala nuclei. The results shown that retention was impaired in animals with CE and LAT lesions but not in animals with BL lesions. In a third experiment we tested the effects of DZP microinjections in different nuclei of the AC on retention performance of rats trained in an avoidance task. The results demonstrate that DZP microinjection prior training in the BL/LAT, but not CE nuclei produce anterograde amnesia.(ABSTRACT TRUNCATED AT 250 WORDS)

Amnesia↗
PubMed1993

Role of the amygdala and periaqueductal gray in anxiety and panic.

The amygdala (AM) and the periaqueductal gray (PAG) represent the rostral and the caudal pole, respectively, of a longitudinally organized neural system, that is responsible for the integration of behavioral and physiological manifestations of defensive reactions against innate and learned threats. Microinjection of benzodiazepine (BZD) anxiolytics, GABAA receptor agonists or 5-HT receptor antagonists into the AM has anxiolytic effects in conflict tests and other models of conditioned fear, while similar administration of 5-HT or of a 5-HT1A receptor agonist has anxiogenic effects. On the other hand, in the test of electrical stimulation of the PAG, microinjection of 5-HT, 5-HT mimetics, or of drugs that enhance the action of endogenous 5-HT into the same brain area has an antiaversive effect, like BZD and GABAA agonists. Furthermore, microinjection of midazolam, of the NMDA receptor antagonist AP-7, or of the 5-HT1A/1B receptor blocker propranolol increased the exploration of the open arms of the elevated plus-maze, having therefore an anxiolytic effect. These results point to an inhibitory role of the GABA-BZD system in both the AM and the PAG. In contrast, 5-HT seemingly enhances conditioned fear in the AM, while inhibiting unconditioned fear in the PAG. Thus, 5-HT2/1C antagonists reportedly release punished behavior when injected into the AM, whereas they antagonized the antiaversive effect of 5-HT, zimelidine and 5-HT1A/1B receptor blockers in the PAG. Since reported clinical studies revealed that one of such compounds, ritanserin, relieves generalized anxiety but tends to aggravate panic disorder, a relationship may be established between the AM and anxiety and the PAG and panic.

Amygdala↗
PubMed1993

Induction of Fos immunoreactivity in the brain by exposure to the elevated plus-maze.

The Fos protein immunohistochemistry technique was used to map the brain areas activated by a 15-min exposure of rats to the elevated plus maze, an ethologically based animal model of anxiety. Two hours after the test, labeling was found mainly in the piriform and entorhinal cortices, amygdala, midline thalamic nuclei, several medial hypothalamic nuclei, periaqueductal gray matter, superior and inferior colliculus, cuneiform nucleus, dorsal raphe nucleus and locus coeruleus. These results support a participation of these structures in anxiety.

Animals↗
PubMed1993

Role of benzodiazepine receptors located in the dorsal periaqueductal grey of rats in anxiety.

Studies with electrical brain stimulation suggest that the dorsal periaqueductal grey matter (DPAG) is related to anxiety and to the anti-aversive effects of benzodiazepines (BZD) compounds. However, direct stimulation of the brain may prevent conclusions about the role of specific regions in the control of normal behaviour. In the present study we employed the elevated plus-maze, an ethologically based model of anxiety, to investigate the role of BZD receptors located in the DPAG in anxiety and in the anxiolytic effect of systemically injected BZD. The results showed that midazolam (20-80 nmol), a BZD agonist, dose-dependently increased the percentage of entries and time spent in open arms when microinjected into the DPAG. The effect of midazolam (80 nmol) was antagonized by flumazenil (80 nmol), a BZD antagonist, microinjected into the DPAG 10 min before the agonist. FG 7142 (20-80 nmol), a BZD partial inverse agonist, decreased time spent in open arms at the dose of 40 nmol and the number of open arms entries at all doses when microinjected into the DPAG. The microinjection of flumazenil (80 nmol) into the DPAG failed to antagonize the anxiolytic effect of systemically injected diazepam (2.5 mg/kg). These results strengthen the idea of an involvement of BZD receptors located in the DPAG with anxiety. They also suggest that the DPAG is not the only structure responsible for the anxiolytic effects of systemically injected BZD.

2-Amino-5-phosphonovalerate↗
PubMed1993

Trial 2 in the elevated plus-maze: a different form of fear?

A factor analysis of the scores from rats given two trials in the elevated plus-maze showed that four independent factors emerged. Measures of anxiolytic activity on trial 1 (number of open arm entries and time spent on open arms) loaded on factor 1, measures of anxiolytic activity on trial 2 loaded on factor 2, the measure of general activity (number of closed arm entries) on both trials loaded on factor 3, and a measure of decision time (time spent in central square) for both trials loaded on factor 4. The independence of trials 1 and 2 anxiety measures raises the possibility that the state of anxiety/fear on the second trial in the plus-maze is qualitatively different from that on trial 1. This difference is reflected in the loss of anxiolytic action of diazepam (2 mg/kg) on trial 2. However, this occurs only when the trials are short (5 min); when they are longer (10 min) diazepam retains anxiolytic efficacy. It is concluded that during a brief (5 min) trial in the plus-maze rats acquire a specific phobic anxiety, which is relatively resistant to benzodiazepines. With a longer exposure to the plus-maze this form of fear extinguishes.

Animals↗