Differential mechanisms involved in the anticonflict action of benzodiazepines injected into the central amygdala and mammillary body

doi:10.1016/0006-8993(87)90903-6

Brain Research

Volume 416, Issue 2, 28 July 1987, Pages 243-247

https://doi.org/10.1016/0006-8993(87)90903-6 Get rights and content

Abstract

The present study was designed to clarify the mechanism of action of benzodiazepines (BDZ) injected into the central amygdala (ACE) and mammillary body (MB). When γ-aminobutyric acid (GABA) at doses of 30 and 70 μg, muscimol (0.01 and 0.03 μg), valproate (200 μg), atropine (20 μg) and cyproheptadine (3 μg were bilaterally injected into ACE, a significant and marked increase in the punished responses of conflict schedule was observed. These drugs injected into MB failed to increase the punished responses. In MB, only noradrenaline (NA, 20 μg) showed the anticonflict action. NA 20 μg also produced the anticonflict action in ACE. These results suggest that the mechanism of anticonflict action of BDZ is different in brain areas. The GABA-ergic, cholinergic, serotonergic and NA-ergic system sseem to be involved in the mechanism of anticonflict action of BDZ in ACE. While the NA-ergic system appears to be operative in MB.

References (26)

EmsonP.C. et al.
Contributions of different afferent pathways to the catecholamine and 5-hydroxytryptamine-innervation of the amygdala: a neurochemical and histochemical study
Neuroscience
(1979)
FibigerH.C.
The organization and some projections of cholinergic neurons of the mammalian forebrain
Brain Res. Rev.
(1982)
KataokaY. et al.
Mammillary body is a potential site of antiaxiety action of benzodiazepines
Brain Research
(1982)
KlepnerC.A. et al.
Resolution of two biochemically and pharmacologically distinct benzodiazepine receptors
Pharmacol. Biochem. Behav.
(1979)
Legal La SalleG. et al.
Neurochemical mapping of GABAergic systems in the amygdaloid complex and bed nucleus of the stria terminalis
Brain Research
(1976)
LippaA.S. et al.
A synthetic non-benzodiazepines ligand for benzodiazepine receptors: a probe for investigating neuronal substrates of anxiety
Pharmacol. Biochem. Behav.
(1979)
LippaA.S. et al.
Benzodiazepine receptors: cellular and behavioral characteristics
Pharmacol. Biochem. Behav.
(1979)
MargulesD.L.
Localization of antipunishment actions of norepinephrien and atropine in amygdala and entopenduncular nucleus rats
Brain Research
(1971)
MargulesD.L.
Alpha and beta adrenergic receptors in amygdala: reciprocal inhibitors and facilitators of punished operant behavior
Eur. J. Pharmacol.
(1971)
ShibataK. et al.
Localization of the site of the anticonflict action of benzodiazepines in the amygdaloid nucleus of rats
Brain Research
(1982)

ShibataK. et al.

An important role of the central amygdaloid nucleus and mammillary body in the mediation of conflict behavior in rats

Brain Research

(1986)

TappazM.L. et al.

Glutamate decarboxylase (GAD) and γ-aminobutyric acid (GABA) in discrete nuclei of hypothalamus and substantia nigra

Brain Research

(1977)

FallonJ.H. et al.

Catecholamine innervation of the basal forebrain

J. Comp. Neurol.

(1978)

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Although the mammillary bodies were among the first brain regions to be implicated in amnesia, the functional importance of this structure for memory has been questioned over the intervening years. Recent patient studies have, however, re-established the mammillary bodies, and their projections to the anterior thalamus via the mammillothalamic tract, as being crucial for recollective memory. Complementary animal research has also made substantial advances in recent years by determining the electrophysiological, neurochemical, anatomical and functional properties of the mammillary bodies. Mammillary body and mammillothalamic tract lesions in rats impair performance on a number of spatial memory tasks and these deficits are consistent with impoverished spatial encoding. The mammillary bodies have traditionally been considered a hippocampal relay which is consistent with the equivalent deficits seen following lesions of the mammillary bodies or their major efferents, the mammillothalamic tract. However, recent findings suggest that the mammillary bodies may have a role in memory that is independent of their hippocampal formation afferents; instead, the ventral tegmental nucleus of Gudden could be providing critical mammillary body inputs needed to support mnemonic processes. Finally, it is now apparent that the medial and lateral mammillary nuclei should be considered separately and initial research indicates that the medial mammillary nucleus is predominantly responsible for the spatial memory deficits following mammillary body lesions in rats.
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We investigated the mechanism underlying the anxiolytic actions of the neuropeptide nociceptin/orphanin FQ (N/OFQ) with an elevated plus-maze test. In mice, intracerebroventricular (i.c.v.) infusions of N/OFQ (0.1 and 0.32 nmol) led to an increase in time spent in the open arms (anxiolytic-like effects). A non-peptidyl N/OFQ receptor (NOP) antagonist, J-113397(1-{(3R,4R)-1-cyclooctylmethyl-3-hydroxymethyl-4-piperidyl}-3-ethyl-1,3-dihydro-2H-benzimidazol-2-one), (1.0 and 3.2 mg/kg, s.c.) blocked the increase induced by N/OFQ. On the other hand, a benzodiazepine receptor antagonist, flumazenil, (10 mg/kg, i.p.) and a GABAA receptor antagonist, (+)-bicuculline, (5.6 mg/kg, i.p.) also inhibited the increase induced by N/OFQ. In rats, microinfusions of N/OFQ (10 and 32 pmol) into the amygdala led to an increase in time spent in the open arms. However, intracranial infusions of N/OFQ (10–100 pmol) into the dorsal hippocampus did not affect the time spent in the open arms. These findings suggest that the anxiolytic-like effects of N/OFQ may be related to the GABA/benzodiazepine system in the amygdala.
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Citation Excerpt :
The present results show that inactivation of the rat CeA with unilateral injections of muscimol reduced avoidance of open arms in the plus-maze, expressed in terms of the conventional and novel measures of the EPM. The “anxiolytic-like” effects of muscimol in the EPM are in line with the reported anxiolytic effects of BZD receptor agonists in the social interaction and conflict paradigms following intra-CeA infusions [29,33,60,61]. Together, these data support the suggestion that the CeA mediats the exploratory behaviour in the EPM.
The amygdala has a crucial role in detecting motivationally significant inputs and in communicating relevant information to other limbic structures. Behavioural studies have shown that the central (CeA) and basolateral (BLA) nuclei of amygdala differentially regulate conditioned and unconditioned fear. Indeed, much evidence has accumulated suggesting that regulatory mechanisms in the BLA serve as a filter for unconditioned and conditioned aversive information that ascends to higher structures from the brainstem, whereas the CeA is the main output for the autonomic and somatic components of fear reaction through major projections to other limbic regions. It is still unclear, however, how amygdaloid nuclei function in high and open spaces so as to determine the characteristic exploratory behaviour of rats submitted to the elevated plus-maze test (EPM). In the present study, we carried out an ethopharmacological analysis of the behaviour of rats submitted to the elevated plus-maze test together with analysis of the tissue content of monoamine dopamine (DA) and serotonin (5-HT) and their metabolites in the dorsal hippocampus (DH), nucleus accumbens (NAC) and dorsal striatum (DS) of animals injected with saline or muscimol (1.0 nmol/0.2 μL) into the BLA or CeA. The data obtained show that injections of muscimol into the CeA, but not into the BLA, caused anxiolytic-like effects in the EPM. Such effects of muscimol into the CeA were accompanied by increases in 5-HT content of the DH, whereas corresponding injections into the BLA caused a reduction in the DA content of the NAC. There was no change in the turnover rates of these monoamines. These data suggest that the BLA and CeA have distinct roles in the exploratory behaviour of rodents in the EPM. While BLA appears to be related to the detection and validation of threatening stimuli, the CeA appears to be involved in the expression of fear behaviours in the EPM.
The interaction of morphine and γ-aminobutyric acid (GABA)ergic systems in anxiolytic behavior: Using μ-opioid receptor knockout mice
2002, Brain Research Bulletin
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In contrast, morphine did not affect [3H]muscimol binding in any brain area examined in MOR-knockout mice. The enhanced binding in the amygadala is particularly of interest because it has been shown to be the main site of action for the anxiolitic effect of benzodiazepine in conflict-based behavioral assays, such as elevated plus-maze [7]. These data suggest a pathological pathway, initiated by MOR deficit, leading to alteration in the GABAA receptor, which in turn results in changes in benzodiazepine-sensitivity and anxiety.
We investigated the interaction of morphine and γ-aminobutyric acid (GABA)ergic systems in anxiolytic action using μ-opioid receptor knockout and wild-type female mice. An elevated plus-maze test was used to assess anxiolytic behavior. The anxiolytic activities were monitored after experimental animals were pretreated with morphine [15 mg/kg, subcutaneous (s.c.)] and 3 h later received a single dose of muscimol (0.5 mg/kg, s.c.). In another experiment, mice received a single dose of opioid antagonist, naloxone [1.0 mg/kg, intraperitoneal (i.p.)], or GABA_A receptor antagonist, (+)bicucullin (2.0 mg/kg, i.p.), 2.5 h after the morphine and 30 min before the muscimol injection. Control mice received vehicle only. The results show that morphine enhanced muscimol-induced staying time in open arms by 160% in wild-type mice. Moreover, the effect of morphine in the wild type was inhibited by the pretreatment of either naloxone or (+)bicucullin. Autoradiographic analysis indicated that morphine-administration raised [³H]muscimol binding by around 25% of the basal level in posterior thalamic, mediodorsal thalamic, and amygdaloid areas, but not in the hippocampal area in wild-type mice. In contrast, morphine administration did not alter the [³H]muscimol binding in μ-opioid receptor knockout mice. The present results reveal that μ-opioid receptor may play a role in the modification of anxiolytic behavior regulated by GABAergic neurotransmission.
Regulation of benzodiazepine receptor binding and GABA<inf>A</inf> subunit mRNA expression by punishment and acute alprazolam administration
2000, Brain Research
Citation Excerpt :
Increases in punished responding can also be obtained in humans [1], allowing for follow-up studies when appropriate methods are developed. A number of studies in animals have shown that direct injections of BZs or GABAA receptor agonists into limbic sites can increase punished responding [17,30,33]. In addition, intra-amygdala injections of the BZ antagonist Ro 15-1788 can block BZ-induced increases in punished responding [34].
Quantitative autoradiography of benzodiazepine (BZ) receptors and competitive reverse transcription–polymerase chain reaction were used to characterize changes in BZ binding and GABA_A receptor subunit transcription levels associated with the anxiolytic effects of alprazolam. Effects were assessed on punished and non-suppressed water consumption using a lick suppression (Vogel) paradigm. Alprazolam had no effect on non-suppressed licking, [³H]Ro 15-1788 binding or receptor subunit transcript levels, compared to non-drug controls. When each fifth lick produced a shock (0–0.5 mA), responding was suppressed in an intensity-related manner. The highest intensity significantly decreased licking (85%), [³H]Ro 15-1788 binding (12%) and α1 transcript levels (63%) in the basolateral nucleus of the amygdala, and [³H]Ro 15-1788 binding in the mediodorsal thalamic nucleus (15%), compared to non-punished controls. Punishment increased the ratio of γ2L/S transcripts in the basolateral nucleus of the amygdala. Alprazolam blocked or reversed each of these effects. These results show that punishment has similar effects on BZ binding and GABA_A receptor subunit expression and that alprazolam can block or reverse those effects. Such changes may be related to the anxiolytic effects of alprazolam.
Differential expression of EGR-1 mRNA in the amygdala following diazepam in contextual fear conditioning
2000, Brain Research
Citation Excerpt :
Most studies have also demonstrated that the central nucleus of the amygdala (CeA) is not a site of anxiolytic or amnesic action of benzodiazepines [9, 58, 62, 67]. However, several studies have found benzodiazepines to act anxiolytically in the CeA [26, 61]. Anatomically, GABA is found in non-pyramidal neurons in the lateral, basolateral, and central nuclei of the amygdala [37, 64, 65], with higher levels in the central nucleus [36, 37].
The amygdaloid complex is thought to be a major site of action of anxiolytic benzodiazepine agonists. To investigate whether activity in the amygdaloid complex is altered with anxiolytic effects of diazepam, mRNA expression of the immediate-early gene EGR-1 was examined in the amygdala following blockade of fear conditioning by diazepam. It was previously shown that mRNA expression of EGR-1 (also called, NGFI-A, Zif 268, Krox 24) increases in the lateral nucleus of the amygdala (LA) shortly following contextual fear conditioning. It was therefore hypothesized that diazepam would block both contextual fear and the concomitant increase in EGR-1 mRNA expression in the LA induced by fear conditioning. Rats administered systemic diazepam before fear conditioning displayed both anxiolytic effects during the post-shock period and amnesic effects during a retention test 24 h later. Diazepam blocked the fear-conditioning-induced increase in EGR-1 expression in the LA. In addition, diazepam significantly increased EGR-1 mRNA expression in the central nucleus of the amygdala (CeA) in a dose-dependent manner. The results reveal differential regulation of EGR-1 by diazepam in the central and lateral nuclei of the amygdala suggesting that these two amygdala nuclei act in a reciprocal manner during the anxiolytic and amnesic action of the benzodiazepine agonist.

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^*: Present address: Department of Biodynamics, School of Medicine, Fukuoka University, Fukuoka 814-01, Japan.

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Differential mechanisms involved in the anticonflict action of benzodiazepines injected into the central amygdala and mammillary body

Abstract

Neuroscience

Brain Res. Rev.

Brain Research

Pharmacol. Biochem. Behav.

Brain Research

Pharmacol. Biochem. Behav.

Pharmacol. Biochem. Behav.

Brain Research

Eur. J. Pharmacol.

Brain Research

Brain Research

Brain Research

Catecholamine innervation of the basal forebrain

J. Comp. Neurol.