Involvement of NMDA receptors in alcohol-mediated behavior: mice with reduced affinity of the NMDA R1 glycine binding site display an attenuated sensitivity to ethanol.

Background: Ethanol antagonizes central effects of glutamate by inhibition of the N-methyl-D-aspartate (NMDA) receptor function. The co-agonist glycine has been shown to reverse alcohol-mediated effects. The aim of this study was to evaluate the influence of the glycine binding site of the NMDA receptor on the behavioral effects of alcohol by investigating mice with an 80% reduced affinity of the NMDA R1 subunit for glycine (Grin1(D481N)).

Alpha-helical-corticotropin-releasing hormone reverses anxiogenic effects of C-type natriuretic peptide in rats.

Previously we have shown that atrial natriuretic peptide (ANP) has anxiolytic-like properties after intraperitoneal, intracerebroventricular and intraamygdala infusion in rats. Since C-type natriuretic peptide (CNP) exerts endocrine and behavioral effects opposing those of ANP, we characterized the behavioral properties of CNP after icv infusion in rats by their performance in the elevated plus maze with and without the corticotropin-releasing hormone (CRH) antagonist alpha-helical-CRH (alpha-CRH). Low CNP doses of 0.

Functional consequences of reduction in NMDA receptor glycine affinity in mice carrying targeted point mutations in the glycine binding site.

We have used site-directed mutagenesis in conjunction with homologous recombination to generate two mouse lines carrying point mutations in the glycine binding site of the NMDAR1 subunit (Grin1). Glycine concentration-response curves from acutely dissociated hippocampal neurons revealed a 5- and 86-fold reduction in receptor glycine affinity in mice carrying Grin1(D481N) and Grin1(K483Q) mutations, respectively, whereas receptor glutamate affinity remained unaffected. Homozygous mutant Grin1(D481N) animals are viable and fertile and appear to develop normally.

Targeted disruption of the orphanin FQ/nociceptin gene increases stress susceptibility and impairs stress adaptation in mice.

The neuropeptide orphanin FQ (also known as nociceptin; OFQ/N) has been implicated in modulating stress-related behavior. OFQ/N was demonstrated to reverse stress-induced analgesia and possess anxiolytic-like activity after central administration. To further study physiological functions of OFQ/N, we have generated OFQ/N-deficient mice by targeted disruption of the OFQ/N gene.

Assessment of neuroleptic-like properties of progesterone.

There is considerable evidence from epidemiological studies that the onset of psychiatric disorders may be related to changes in the secretion of gonadal hormones. For example, the postpartum period appears to be a vulnerable phase for the occurrence of psychiatric disturbances such as dysphoric mood and even severe psychotic disturbances. It has been suggested that a sudden drop in progesterone concentrations may contribute to the development of such disorders.

Long-term potentiation in the hippocampal CA1 region of mice lacking cGMP-dependent kinases is normal and susceptible to inhibition of nitric oxide synthase.

Long-term potentiation (LTP) is a potential cellular mechanism for learning and memory. The retrograde messenger nitric oxide (NO) is thought to induce LTP in the CA1 region of the hippocampus via activation of soluble guanylyl cyclase (sGC) and, ultimately, cGMP-dependent protein kinase (cGK). Two genes code for the isozymes cGKI and cGKII in vertebrates.

Behavioural profiles of two Wistar rat lines selectively bred for high or low anxiety-related behaviour.

Over the past years, two breeding lines, derived originally from outbred Wistar rats, have been established that differ markedly and consistently in their anxiety-related behaviour in the elevated plus-maze. At the age of ten weeks, rats were tested once on the elevated plus-maze and the males and females displaying the most anxious and the least anxious behaviour were sib-mated to start a new generation of the high anxiety-related behaviour (HAB) and the low anxiety-related behaviour (LAB) lines, respectively. The resulting difference in emotionality between these two lines was also evident in an open field test and correlated with differences in the forced swim test.

Age- and stimulus-dependent changes in anxiety-related behaviour of transgenic mice with GR dysfunction.

Transgenic mice expressing antisense directed against glucocorticoid receptor (GR) mRNA were used for a longitudinal study on the effects of hypothalamic-pituitary-adrenocortical dysfunction on anxiety-related behaviour and locomotor activity. Compared with age-matched controls and 5-week-old transgenic animals, 13- and 36-week-old transgenic mice made significantly more entries into and spent significantly more time on the open arms of the elevated plus-maze thereby indicating reduced basal anxiety. In contrast, time spent in the central area of the open field was significantly reduced in transgenic animals indicating an enhanced anxiety under conditions of increased stress.

C-type natriuretic peptide exerts effects opposing those of atrial natriuretic peptide on anxiety-related behaviour in rats.

As evidence exists that C-type natriuretic peptide (CNP) exerts effects opposing those of atrial natriuretic peptide (ANP), we studied the behavioural properties of CNP after central infusion in rats by their performance in the elevated plus maze. Doses of 0.5 microg and 5 microg i.

Enhanced morphine-induced behavioural effects and dopamine release in the nucleus accumbens in a transgenic mouse model of impaired glucocorticoid (type II) receptor function: influence of long-term treatment with the antidepressant moclobemide.

In vivo microdialysis experiments were conducted in transgenic mice with impaired glucocorticoid receptor function resulting from expression of antisense directed against glucocorticoid receptor messenger RNA. Basal corticosterone and serotonin levels in the nucleus accumbens of untreated transgenic mice were enhanced compared to control mice (B6C3F1). Following a systemic morphine injection (15 mg/kg) mesolimbic dopamine and serotonin release was markedly increased in transgenic mice compared to control mice and in parallel enhanced behavioural stimulation was observed in these animals.

Endocrine profile and neuroendocrine challenge tests in transgenic mice expressing antisense RNA against the glucocorticoid receptor.

A transgene expressing antisense RNA complementary to a fragment of the glucocorticoid receptor cDNA was incorporated into the mouse genome and resulted in a transgenic animal that has decreased glucocorticoid receptor function. The transgenic mice showed basal plasma ACTH and corticosterone levels similar to those of the normal control animals. We have further investigated changes in HPA axis regulation by use of different neuroendocrine challenge tests including a dexamethasone suppression test (DST).

Central administration of IL-1 reduces anxiety and induces sickness behaviour in rats.

In the present study, we examined the effects of various doses of recombinant human interleukin-1beta on anxiety-like behaviour, on body temperature, and on behavioural changes typical of sick animals. First, we assessed the behaviour of rats in the elevated plus-maze before and 20 min after intracerebroventricular injection of IL-1 at six doses ranging from 0.001 to 100 ng.

Behavioural performance in three substrains of mouse strain 129.

Recently, the possibility has been raised that the behavioural abnormalities seen in null-mutant mice might be determined by their genetic background rather than by loss of gene function, especially when the 129 mouse strain is used as supplier for embryonic stem (ES) cells. To examine this issue we tested three 129 mouse substrains (129/J, 129/Ola, 129/Sv-ter/+) and C57BL/6 (B6) in the Morris water maze, the open field, the plus maze and two tests assessing motor co-ordination. We identified only for the 129/J substrain substantial behavioural deficits.

Central and peripheral administration of atriopeptin is anxiolytic in rats.

The effects of the central and peripheral administration of atriopeptin II, a 23-amino acid residue peptide of atrial natriuretic peptide (Ser103-Arg125) on anxiety-related behavior and on locomotor activity, was studied in male Wistar rats. Their behavior on the elevated plus-maze after social defeat stress indicated that intracerebroventricular (2.5 and 5 micrograms) and intraperitoneal (50 micrograms) administration of atriopeptin II produced anxiolysis.

Increased stress-induced adrenocorticotropin response after long-term intracerebroventricular treatment of rats with antisense mineralocorticoid receptor oligodeoxynucleotides.

Brain corticosteroid receptors, the type 1 mineralocorticoid receptor (MR) and the type 2 glucocorticoid receptor (GR), are involved in the regulation of neuroendocrine and behavioral responses during ongoing and stressful conditions. To further investigate the role of MR in these responses, we treated male Wistar rats intracerebroventricularly (icv) for 1 week with an 18-base end-capped phosphorothioate-protected antisense oligodeoxynucleotide (ODN) directed against MR mRNA (MR-AS). A mixed bases sequence (MR-MB) and vehicle (0.

Neonatal treatment of rats with the neuroactive steroid tetrahydrodeoxycorticosterone (THDOC) abolishes the behavioral and neuroendocrine consequences of adverse early life events.

Stressful experience during early brain development has been shown to produce profound alterations in several mechanisms of adaptation, while several signs of behavioral and neuroendocrine impairment resulting from neonatal exposure to stress resemble symptoms of dysregulation associated with major depression. This study demonstrates that when applied concomitantly with the stressful challenge, the steroid GABA(A) receptor agonist 3,21-dihydropregnan-20-one (tetrahydrodeoxycorticosterone, THDOC) can attenuate the behavioral and neuroendocrine consequences of repeated maternal separation during early life, e.g.

Intact spatial learning and memory in transgenic mice with reduced BDNF.

Long-term potentiation (LTP) in hippocampal CA1 pyramidal cells is considered to be a cellular analogue of learning and may be useful in studying the molecular foundations of learning and memory. Because brain-derived neurotrophic factor (BDNF) had been shown to have a role in activity-dependent neuroplasticity in the hippocampus we studied spatial learning in mice with BDNF deficiency produced by gene-targeted mutation. Heterozygous BDNF knockout mice reportedly underexpress BDNF and have reduced LTP, but their spatial memory and search strategy assessed with Morris water maze (distally cued version) as well as their performance on the elevated plus maze were indistinguishable from that of controls.

Release of vasopressin within the rat paraventricular nucleus in response to emotional stress: a novel mechanism of regulating adrenocorticotropic hormone secretion?

The effects of emotional stressors on the release of arginine vasopressin (AVP) and oxytocin (OXT) within the rat hypothalamus and the origin and physiological significance of AVP released within the hypothalamic paraventricular nucleus (PVN) were investigated. First, adult male Wistar rats with a microdialysis probe aimed at the PVN or the supraoptic nucleus were exposed to either a dominant male rat (social defeat) or a novel cage. Release of AVP within the PVN was significantly increased in response to social defeat but not to novelty.

Endocrine and behavioral effects of airpuff-startle in rats.

Adult male rats chronically implanted with cannulae in the jugular vein were used to characterize the endocrine and behavioral consequences of airpuff-startle. In the first series of experiments, resting animals subjected to three blocks of airpuff (blocks of three airpuffs each with each block separated by 1 min) showed a 10-fold increase in plasma adrenocorticotropin (ACTH) and corticosterone levels, indicating a significant but moderate activation of the hypothalamo-pituitary-adrenal (HPA) axis when compared with the untreated controls (n = 5 each). In the second series of experiments, monitoring of anxiety-related behavior in the defensive withdrawal paradigm revealed a significant increase in anxiety induced by airpuff-startle application compared with the untreated controls (n = 10 each).

Anxiety: a potential predictor of vulnerability to the initiation of ethanol self-administration in rats.

Anxiolytic effects of ethanol have been proposed to be important factors in the initiation of ethanol consumption. To examine this hypothesis, drug-naive Wistar rats were tested in the elevated plus-maze to determine their initial level of anxiety. Based on their response, we separated the animals into anxious and non-anxious groups.

Long-term antidepressant treatment reduces behavioural deficits in transgenic mice with impaired glucocorticoid receptor function.

Impaired cognitive function and enhanced activity of the hypothalamic-pituitary-adrenocortical system are among the cardinal symptoms of major depression in humans that resolve after successful antidepressant treatment. We used a transgenic mouse model expressing antisense RNA complementary to that of glucocorticoid receptor (GR) mRNA to test the hypothesis that reduced GR function can cause these clinical disturbances. The transgenic mice show profound behavioural changes in a number of animal tests that are indicative of cognitive impairment.

Chronic infusion of a CRH1 receptor antisense oligodeoxynucleotide into the central nucleus of the amygdala reduced anxiety-related behavior in socially defeated rats.

We studied the role of central amygdala CRH receptors in behavioral responses to an anxiogenic stimulus. An antisense oligodeoxynucleotide corresponding to the rat CRH1 receptor mRNA was infused chronically into the central amygdaloid nucleus of male rats via osmotic minipumps (0.25 micrograms/0.

V1 vasopressin receptor antisense oligodeoxynucleotide into septum reduces vasopressin binding, social discrimination abilities, and anxiety-related behavior in rats.

To develop and validate a vasopressin (AVP) receptor knockdown strategy, we infused an antisense oligodeoxynucleotide to the V1 subtype mRNA into the septum of male rats with osmotic minipumps and measured behavioral, cellular and molecular parameters. Compared to vehicle and scrambled-sequence oligo controls, chronic antisense administration for up to 4 d diminished the ability of the animals to distinguish a previously exposed juvenile from a novel one and to respond to exogenous AVP (1 ng/5 microliters, intracerebroventricular) with an improved social memory. Furthermore, anxiety-related behavior was reduced.

Corticotropin-releasing hormone (CRH) antisense oligodeoxynucleotide treatment attenuates social defeat-induced anxiety in rats.

1. The neuropeptide corticotropin-releasing hormone (CRH) is the main mediator of the neuroendocrine and behavioral response to stress. End-capped phosphorothioate antisense and sense oligodeoxynucleotides (ODN) corresponding to the start coding region of rat CRH mRNA were infused intracerebroventricularly (30 micrograms/3 microliters per injection) three times at 12 hr intervals.