Biomedical subjects

John F Cryan

Publications and source records attributed to John F Cryan.

At least 19 recordsLinked to original sources

PubMed2007

GABAB receptor-positive modulation-induced blockade of the rewarding properties of nicotine is associated with a reduction in nucleus accumbens DeltaFosB accumulation.

There is an increasing demand for a novel non-nicotinic, nondopaminergic therapeutic approach to nicotine addiction. GABAergic mechanisms have been implicated in drug dependence. Recently, a novel GABAB receptor allosteric-positive modulator, GS39783, was characterized. There are no investigations to date on the effects of GABAB receptor-positive modulators in animal models of nicotine reinforcement. Conditioned place preference (CPP) paradigms are based on the principle that animals, like humans, would learn to seek environmental stimuli that have been previously associated with rewarding events. Here we show that nicotine (0.06 mg/kg s.c.) induced a robust CPP response. Furthermore, GS39783 (30-100 mg/kg p.o.) during the conditioning phase blocked the rewarding effects of nicotine in the CPP paradigm in rats. However, GS39783 did not significantly alter the CPP effects of nicotine when given only immediately before the CPP test. A growing body of evidence suggests that repeated administration of drugs of abuse induced long-term molecular changes in brain plasticity, most notably an accumulation of DeltaFosB, in the striatal complex that contribute to the manifestation of dependence. There was a significant accumulation of DeltaFosB in the nucleus accumbens, but not in the dorsal striatum, of rats treated daily for 5 days with nicotine (0.06 mg/kg i.p.). GS39783 completely (30-100 mg/kg p.o.) counteracted these nicotine-induced molecular adaptations when given before the CPP acquisition phase but not when administered immediately before the test phase. Taken together, the behavioral and molecular changes induced by nicotine occur in concert and are concomitantly amenable to reversal by GABAB receptor-positive modulators.

Animals↗

PubMed2007

Animal models of mood disorders: Recent developments.

PURPOSE OF REVIEW: The wide spectrum of disruptions that characterizes depression and bipolar illness highlights the difficulties researchers are posed with as they try to mimic these disorders in the laboratory. Nonetheless, numerous attempts have been made to create rodent models of mood disorders, or at least models of the symptoms of depression and bipolar illness. Despite many advances, however, there are no satisfactory animal models available. The need for improved animal models for identifying new antidepressants and providing insights into the neuropathology underlying the disease is critical. This review focuses on the attempts to improve current paradigms and also illustrates examples where current paradigms are used to uncover novel molecular targets of antidepressants. RECENT FINDINGS: Currently, there is a shift away from traditional animal models to a more focused research dealing with an endophenotype-style approach, genetic models and incorporation of new findings from human neuroimaging and genetic studies. SUMMARY: Endophenotype-based modelling of depression and bipolar illness is opening up more tractable avenues for understanding the neurobiological and genetic bases of these disorders. Further, advances in the clinical dissection of the psychiatric illnesses using molecular genetics, coupled with functional neuroimaging techniques, promises to yield better translational animal models and hence more fruitful therapeutic targets.

Animals↗

PubMed2006

Evaluation of reward processes in an animal model of depression.

RATIONALE: Anhedonia is a core symptom of major depression. Deficits in reward function, which underlie anhedonia, can be readily assessed in animals. Therefore, anhedonia may serve as an endophenotype for understanding the neural circuitry and molecular pathways underlying depression. OBJECTIVE: Surprisingly, there is scant knowledge regarding alterations in brain reward function after olfactory bulbectomy (OB), an animal model which results in a behavioural syndrome responsive to chronic antidepressant treatment. Therefore, the present studies aimed to assess reward function after bulbectomy. MATERIALS AND METHODS: The present study utilized sucrose preference, cocaine-induced hyperlocomotion and intra-cranial self-stimulation (ICSS) responding to examine reward processes in the OB model. RESULTS: Bulbectomized animals showed a marked preference (>90%) for 0.8% sucrose solution compared with water; similar to the preference exhibited by sham controls. Importantly, there were pronounced deficits in brain reward function, as assessed using ICSS, which lasted 8 days before returning to baseline levels. Furthermore, bulbectomized animals were hyper-responsive to the locomotor stimulating properties of an acute and a repeated cocaine regimen. However, no difference in ICSS facilitation was observed in response to an acute cocaine injection. CONCLUSIONS: Taken together, these results suggest that bulbectomized rats display alterations in brain reward function, but these changes are not long-lasting and thus, not amenable to investigating the effects of pharmacological interventions. However, given that OB animals are hypersensitive to drugs of abuse, bulbectomy may be an appropriate inducing factor for the development of animal models of co-morbid depression and drug dependence.

Animals↗

PubMed2006

Behavioral evaluation of mice deficient in GABA(B(1)) receptor isoforms in tests of unconditioned anxiety.

RATIONALE: Emerging data support a role for GABA(B) receptors in anxiety. GABA(B) receptors are comprised of a heterodimeric complex of GABA(B1) and GABA(B2) receptor subunits. The predominant neuronal GABA(B1) receptor isoforms are GABA(B(1a)) and GABA(B(1b)). Recent findings indicate specific roles for these isoforms in conditioned fear responses, although their influence on behavior in tests of unconditioned anxiety is unknown. OBJECTIVE: The aim of this study was to examine the role of the GABA(B(1)) isoforms in unconditioned anxiety. MATERIALS AND METHODS: Mice deficient in the GABA(B(1a)) or GABA(B(1b)) receptor isoforms were examined in a battery of anxiety tests. RESULTS: In most tests, genotype did not significantly affect anxious behavior, including the elevated plus maze, marble burying, and stress-induced hypothermia tests. Corticosterone and adrenocorticotropic hormone levels were similarly unaffected by genotype. Female, but not male, GABA(-/-)B(1a) and GABA(-/-)B(1b) mice showed increased anxiety relative to wild-type controls in the elevated zero maze. In the staircase test, male GABA(-/-)B(1b) mice defecated more than male GABA(-/-)B(1a) mice, although no other test parameter was influenced by genotype. In the light-dark box, female GABA(-/-)B(1a) mice spent less time in the light compartment compared to the GABA(-/-)B(1b) females, whereas male GABA(-/-)B(1b) mice made fewer light-dark transitions than GABA(-/-)B(1a) males. CONCLUSIONS: Specific roles for either GABA(B(1)) isoform in unconditioned anxiety were not explicit. This differs from their contribution in conditioned anxiety and from the anxious phenotype of GABA(B1) and GABA(B2) subunit knockout mice. The findings suggest that the GABA(B(1)) isoforms have specific relevance for anxiety with a cognitive component, rather than for innate anxiety per se.

Adrenocorticotropic Hormone↗

PubMed2006

The rostral anterior cingulate cortex modulates depression but not anxiety-related behaviour in the rat.

A growing body of functional imaging studies suggests that human depression and anxiety symptoms are associated with functional abnormalities in the circuitry formed by the rostral anterior cingulate cortex (rACC) and its direct limbic and paralimbic connections. In rodents however, the role of the rACC (rCG1/rCG2) remains unknown in depression-related behaviours and elusive in acute anxiety. In order to address this, we specifically lesioned the rat rCG1/rCG2, and assessed the behavioural outcome using a modified forced swim test (FST) and the elevated plus maze (EPM), tests for depression and anxiety related behaviours respectively. Lesions of the rostral anterior cingulate cortex significantly increased the time spent immobile in the FST without affecting climbing or swimming performances, suggesting a pro-depressant effect. On the contrary, none of the parameters measured in the EPM was affected by the lesion. These data point to an involvement of the rCG1/rCG2 in depression-related coping behaviours.

Animals↗

PubMed2006

GABAB1 receptor subunit isoforms exert a differential influence on baseline but not GABAB receptor agonist-induced changes in mice.

GABA(B) receptor agonists produce hypothermia and motor incoordination. Two GABA(B(1)) receptor subunit isoforms exist, but because of lack of specific molecular or pharmacological tools, the relevance of these isoforms in controlling basal body temperature, locomotor activity, or in vivo responses to GABA(B) receptor agonists has been unknown. Here, we used mice deficient in the GABA(B(1a)) and GABA(B(1b)) subunit isoforms to examine the influence of these isoforms on both baseline motor behavior and body temperature and on the motor-incoordinating and hypothermic responses to the GABA(B) receptor agonists l-baclofen and gamma-hydroxybutyrate (GHB). GABA(B(1b))(-/-) mice were hyperactive in a novel environment and showed slower habituation than either GABA(B(1a))(-/-) or wild-type mice. GABA(B(1b))(-/-) mice were hyperactive throughout the circadian dark phase. Hypothermia in response to l-baclofen (6 and 12 mg/kg) or GHB (1 g/kg), baclofen-induced ataxia as determined on the fixed-speed Rotarod, and GHB-induced hypolocomotion were significantly, but for the most part similarly, attenuated in both GABA(B(1a))(-/-) and GABA(B(1b))(-/-) mice. We conclude that l-baclofen and GHB are nonselective for either GABA(B(1)) receptor isoform in terms of in vivo responses. However, GABA(B(1)) receptor isoforms have distinct and different roles in mediating locomotor behavioral responses to a novel environment. Therefore, GABA(B(1a)) and GABA(B(1b)) isoforms are functionally relevant molecular variants of the GABA(B(1)) receptor subunit, which are differentially involved in specific neurophysiological processes and behaviors.

Animals↗

PubMed2006

GABA(B(1)) receptor isoforms differentially mediate the acquisition and extinction of aversive taste memories.

Conditioned taste aversion (CTA) is a form of aversive memory in which an association is made between a consumed substance and a subsequent malaise. CTA is a critical mechanism for the successful survival, and hence evolution, of most animal species. The role of excitatory neurotransmitters in the neurochemical mechanisms of CTA is well recognized; however, less is known about the involvement of inhibitory receptor systems. In particular, the potential functions of metabotropic GABA(B) receptors in CTA have not yet been fully explored. GABA(B) receptors are metabotropic GABA receptors that are comprised of two subunits, GABA(B(1)) and GABA(B(2)), which form heterodimers. The Gabbr1 gene is transcribed into two predominant isoforms, GABA(B(1a)) and GABA(B(1b)), which differ in sequence primarily by the inclusion of a pair of sushi domains (also known as short consensus repeats) in the GABA(B(1a)) N terminus. The behavioral function of mammalian GABA(B(1)) receptor isoforms is currently unknown. Here, using a point mutation strategy in mice, we demonstrate that these two GABA(B(1)) receptor isoforms are differentially involved in critical components of CTA. In contrast to GABA(B(1b))-/- and wild-type mice, GABA(B(1a))-/- mice failed to acquire CTA. In contrast, GABA(B(1b))-/- mice robustly acquired CTA but failed to show any extinction of this aversion. The data demonstrate that GABA(B) receptors are involved in both the acquisition and extinction of CTA; however, receptors containing the GABA(B(1a)) or the GABA(B(1b)) isoform differentially contribute to the mechanisms used to learn and remember the salience of aversive stimuli.

Animals↗

PubMed2006

Concomitant deficits in working memory and fear extinction are functionally dissociated from reduced anxiety in metabotropic glutamate receptor 7-deficient mice.

Metabotropic glutamate receptor 7 (mGluR7), a receptor with a distinct brain distribution and a putative role in anxiety, emotional responding, and spatial working memory, could be an interesting therapeutic target for fear and anxiety disorders. mGluR7-deficient (mGluR7-/-) mice showed essentially normal performance in tests for neuromotor and exploratory activity and passive avoidance learning but prominent anxiolytic behavior in two anxiety tests. They showed a delayed learning curve during the acquisition of the hidden-platform water maze, and three interspersed probe trials indicated that mGluR7-/- mice were slower to acquire spatial information. Working memory in the water maze task and the radial arm maze was impaired in mGluR7-/- mice compared with mGluR7+/+. mGluR7-/- mice also displayed a higher resistance to extinction of fear-elicited response suppression in a conditioned emotional response protocol. In a non-fear-based water maze protocol, mGluR7-/- mice displayed similar delayed extinction. These observed behavioral changes are probably not attributable to changes in AMPA or NMDA receptor function because expression levels of AMPA and NMDA receptors were unaltered. Extinction of conditioned fear is an active and context-dependent form of inhibitory learning and an experimental model for therapeutic fear reduction. It appears to depend on glutamatergic and higher-level brain functions similar to those involved in spatial working memory but functionally dissociated from those that mediate constitutional responses in anxiety tests.

Analysis of Variance↗

PubMed2006

Differential compartmentalization and distinct functions of GABAB receptor variants.

GABAB receptors are the G protein-coupled receptors for the main inhibitory neurotransmitter in the brain, gamma-aminobutyric acid (GABA). Molecular diversity in the GABAB system arises from the GABAB1a and GABAB1b subunit isoforms that solely differ in their ectodomains by a pair of sushi repeats that is unique to GABAB1a. Using a combined genetic, physiological, and morphological approach, we now demonstrate that GABAB1 isoforms localize to distinct synaptic sites and convey separate functions in vivo. At hippocampal CA3-to-CA1 synapses, GABAB1a assembles heteroreceptors inhibiting glutamate release, while predominantly GABAB1b mediates postsynaptic inhibition. Electron microscopy reveals a synaptic distribution of GABAB1 isoforms that agrees with the observed functional differences. Transfected CA3 neurons selectively express GABAB1a in distal axons, suggesting that the sushi repeats, a conserved protein interaction motif, specify heteroreceptor localization. The constitutive absence of GABAB1a but not GABAB1b results in impaired synaptic plasticity and hippocampus-dependent memory, emphasizing molecular differences in synaptic GABAB functions.

Animals↗

PubMed2006

GABA(B) receptor-positive modulation decreases selective molecular and behavioral effects of cocaine.

Exposure to cocaine induces selective behavioral and molecular adaptations. In rodents, acute cocaine induces increased locomotor activity, whereas prolonged drug exposure results in behavioral locomotor sensitization, which is thought to be a consequence of drug-induced neuroadaptive changes. Recent attention has been given to compounds activating GABA(B) receptors as potential antiaddictive therapies. In particular, the principle of allosteric positive GABA(B) receptor modulators is very promising in this respect, as positive modulators lack the sedative and muscle relaxant properties of full GABA(B) receptor agonists such as baclofen. Here, we investigated the effects of systemic application of the GABA(B) receptor-positive modulator GS39783 (N,N'-dicyclopentyl-2-methylsulfanyl-5-nitro-pyrimidine-4, 6-diamine) in animals treated with acute and chronic cocaine administration. Both GS39783 and baclofen dose dependently attenuated acute cocaine-induced hyperlocomotion. Furthermore, both compounds also efficiently blocked cocaine-induced Fos induction in the striatal complex. In chronic studies, GS39783 induced a modest attenuation of cocaine-induced locomotor sensitization. Chronic cocaine induces the accumulation of the transcription factor deltaFosB and upregulates cAMP-response-element-binding protein (CREB) and dopamine- and cAMP-regulated phosphoprotein of 32 kDa (DARPP-32). GS39783 blocked the induction/activation of DARPP-32 and CREB in the nucleus accumbens and dorsal striatum and partially inhibited deltaFosB accumulation in the dorsal striatum. In summary, our data provide evidence that GS39783 attenuates the acute behavioral effects of cocaine exposure in rodents and in addition prevents the induction of selective long-term adaptive changes in dopaminergic signaling pathways. Further investigation of GABA(B) receptor-positive modulation as a novel therapeutic strategy for the treatment of cocaine dependence and possibly other drugs of abuse is therefore warranted.

Animals↗

PubMed2006

Metabotropic glutamate receptor subtype 7 ablation causes dysregulation of the HPA axis and increases hippocampal BDNF protein levels: implications for stress-related psychiatric disorders.

Regulation of neurotransmission via group-III metabotropic glutamate receptors (mGluR4, -6, -7, and -8) has recently been implicated in the pathophysiology of affective disorders, such as major depression and anxiety. For instance, mice with a targeted deletion of the gene for mGluR7 (mGluR7-/-) showed antidepressant and anxiolytic-like effects in a variety of stress-related paradigms, including the forced swim stress and the stress-induced hyperthermia tests. Deletion of mGluR7 reduces also amygdala- and hippocampus-dependent conditioned fear and aversion responses. Since the hypothalamic-pituitary-adrenal (HPA) axis regulates the stress response we investigate whether parameters of the HPA axis at the levels of selected mRNA transcripts and endocrine hormones are altered in mGluR7-deficient mice. Over all, mGluR7-/- mice showed only moderately lower serum levels of corticosterone and ACTH compared with mGluR7+/+ mice. More strikingly however, we found strong evidence for upregulated glucocorticoid receptor (GR)-dependent feedback suppression of the HPA axis in mice with mGluR7 deficiency: (i) mRNA transcripts of GR were significantly upregulated in the hippocampus of mGluR7-/- animals, (ii) similar increases were seen with 5-HT1A receptor transcripts, which are thought to be directly controlled by the transcription factor GR and finally (iii) mGluR7-/- mice showed elevated sensitivity to dexamethasone-induced suppression of serum corticosterone when compared with mGluR7+/+ animals. These results indicate that mGluR7 deficiency causes dysregulation of HPA axis parameters, which may account, at least in part, for the phenotype of mGluR7-/- mice in animal models for anxiety and depression. In addition, we present evidence that protein levels of brain-derived neurotrophic factor are also elevated in the hippocampus of mGluR7-/- mice, which we discuss in the context of the antidepressant-like phenotype found in those animals. We conclude that genetic ablation of mGluR7 in mice interferes at multiple sites in the neuronal circuitry and molecular pathways implicated in affective disorders.

Adrenocorticotropic Hormone↗

PubMed2006

Global down-regulation of gene expression in the brain using RNA interference, with emphasis on monoamine transporters and GPCRs: implications for target characterization in psychiatric and neurological disorders.

RNA interference (RNAi) is a natural mechanism for regulating gene expression, which exists in plants, invertebrates, and mammals. We investigated whether non-viral infusion of short interfering RNA (siRNA) by the intracerebroventricular route would enable a sequence-specific gene knockdown in the mouse brain and whether the knockdown translates into disease-relevant behavioral changes. Initially, we targeted enhanced green fluorescent protein (EGFP) in mice overexpressing EGFP. A selective knockdown of both EGFP protein and mRNA was observed throughout the brain, with lesser down-regulation in regions distal to the infusion site. We then targeted endogenous genes, encoding the dopamine (DAT) and serotonin transporters (SERT). DAT-siRNA infusion in adult mice produced a significant down-regulation of DAT mRNA and protein and elicited hyperlocomotion similar, but delayed, to that produced on infusion of GBR-12909, a potent and selective DAT inhibitor. Similarly, SERT-siRNA infusion resulted in significant knockdown of SERT mRNA and protein and elicited reduced immobility in the forced swim test similar to that obtained on infusion of citalopram, a very selective and potent SSRI. Application of this non-viral RNAi approach may accelerate target validation for neuropsychiatric disorders that involve a complex interplay of gene(s) from various brain regions.

Animals↗

PubMed2005

A selective metabotropic glutamate receptor 7 agonist: activation of receptor signaling via an allosteric site modulates stress parameters in vivo.

Metabotropic glutamate receptor (mGluR) subtypes (mGluR1 to mGluR8) act as important pre- and postsynaptic regulators of neurotransmission in the CNS. These receptors consist of two domains, an extracellular region containing the orthosteric agonist site and a transmembrane heptahelical domain involved in G protein activation and recognition of several recently synthesized pharmacological modulators. The presynaptic receptor mGluR7 shows the highest evolutionary conservation within the family, but no selective pharmacological tool was known. Here we characterize an mGluR7-selective agonist, N,N'-dibenzhydrylethane-1,2-diamine dihydrochloride (AMN082), which directly activates receptor signaling via an allosteric site in the transmembrane domain. At transfected mammalian cells expressing mGluR7, AMN082 potently inhibits cAMP accumulation and stimulates GTPgammaS binding (EC50-values, 64-290 nM) with agonist efficacies comparable with those of L-2-amino-4-phosphonobutyrate (L-AP4) and superior to those of L-glutamate. AMN082 (< or = 10 microM) failed to show appreciable activating or inhibitory effects at other mGluR subtypes and selected ionotropic GluRs. Chimeric receptor studies position the binding site of AMN082 in the transmembrane region of mGluR7, and we demonstrate that this allosteric agonist has little, if any, effect on the potency of orthosteric ligands. Here we provide evidence for full agonist activity mediated by the heptahelical domain of family 3 G protein-coupled receptors (which have mGluR-like structure) that may lead to drug development opportunities. Further, AMN082 is orally active, penetrates the blood-brain barrier, and elevates the plasma stress hormones corticosterone and corticotropin in an mGluR7-dependent fashion. Therefore, AMN082 is a valuable tool for unraveling the role of mGluR7 in stress-related CNS disorders.

Allosteric Regulation↗

PubMed2005

Differential behavioral effects of the antidepressants reboxetine, fluoxetine, and moclobemide in a modified forced swim test following chronic treatment.

RATIONALE: The forced swim test (FST) is the most widely used model for assessing potential antidepressant activity in rodents following acute or short-term treatment. However, few studies have compared the effects of short- and long-term antidepressant treatment on behaviors in the test, despite the need to treat patients chronically to produce clinical effects. OBJECTIVES: The current studies examined whether antidepressants from different classes produce different behavioral effects following short-term treatment and whether such effects change following administration for a longer duration. METHODS: The effects of administering short-term (3 days) and long-term (14 days) treatments of antidepressants from three different chemical classes with distinct mechanisms of action via osmotic minipump were examined: the selective norepinephrine reuptake inhibitor reboxetine (10 and 60 mg kg(-1) day(-1)), the selective serotonin reuptake inhibitor fluoxetine (2.5 and 15 mg kg(-1) day(-1)), and the reversible inhibitor of monoamine oxidase moclobemide (2.5 and 15 mg kg(-1) day(-1)). All testing was carried out in a 15-min test with no preswim session in order to negate any confounding aspect of an induction procedure. RESULTS: The majority of antidepressant-sensitive behavioral changes were observed in the first 5 min of the test. The low dose of reboxetine failed to alter behavior in the test after 3 days but significantly decreased immobility and increased climbing behavior following administration for 14 days, whereas the high dose of reboxetine was equally effective following 3 and 14 days of treatment. In a similar fashion, the low dose of fluoxetine failed to alter behavior in the test following 3 days, but showed an augmented response on immobility and increased swimming following administration for 14 days. The high dose of fluoxetine was slightly more effective at reducing immobility following administration for 14 days than 3 days. The low dose of moclobemide decreased immobility and increased climbing behavior following treatment for 3 days, but increases in both swimming and climbing behaviors were measured following treatment for 14 days. Treatment with the high dose of moclobemide for 3 days decreased immobility and increased swimming, whereas treatment for 14 days significantly increased both active behaviors (swimming and climbing). CONCLUSIONS: Antidepressants from three different classes produce different effects on active behaviors in the FST. The effects of antidepressants were augmented following chronic administration for 14 days, especially when given at low doses. This suggests that modifications of the FST can be used to examine the onset of action of antidepressant agents produced by long-term administration.

Animals↗

PubMed2005

Interfering with the brain: use of RNA interference for understanding the pathophysiology of psychiatric and neurological disorders.

Psychiatric and neurological disorders are among the most complex, poorly understood, and debilitating diseases in medicine. The burgeoning advances in functional genomic technologies have led to the identification of a vast number of novel genes that are potentially implicated in the pathophysiology of such disorders. However, many of these candidate genes have not yet been functionalized and require validation in vivo. Traditionally, abrogating gene function is one of the primary means of examining the physiological significance of a given gene product. Several methods have been developed for gene ablation or knockdown, however, with limited levels of success. The recent discovery of RNA interference (RNAi), as a highly efficient method for gene knockdown, has been one of the major breakthroughs in molecular medicine. In vivo application of RNAi is further demonstrating the promise of this technology. Recent efforts have focused on applying RNAi-based knockdown to understand the genes implicated in neuropsychiatric disorders. However, the greatest challenge with this approach is translating the success of RNAi from mammalian cell cultures to the brain in animal models of disease and, subsequently, in patients. In this review, we describe the various methods that are being developed to deliver RNAi into the brain for down-regulating gene expression and subsequent phenotyping of genes in vivo. We illustrate the utility of various approaches with a few successful examples and also discuss the potential benefits and pitfalls associated with the use of each delivery approach. Appropriate tailoring of tools that deliver RNAi in the brain may not only aid our understanding of the complex pathophysiology of neuropsychiatric disorders, but may also serve as a valuable therapy for disorders, where there is an immense unmet medical need.

Animals↗

PubMed2005

Altered anxiety and depression-related behaviour in mice lacking GABAB(2) receptor subunits.

Metabotropic GABAB receptors predominantly function as heterodimers of GABAB(1) and GABAB(2) subunits, but GABAB(1) can also form functional receptors in the absence of GABAB(2). Mice lacking the GABAB(1) subunit have altered behavioural responses in tests for anxiety and depression. In these studies, we investigated anxiety and depression in GABAB(2)-deficient mice. We compared the effects directly with that of genetic deletion of the GABAB(1) receptor subunit. Both GABAB(1) and GABAB(2)-deficient mice were found to be more anxious than wild type in the light-dark box paradigm. In contrast, these mice exhibited an antidepressant-like behaviour in the forced swim test. Taken together, these data suggest that heterodimeric GABAB(1,2) receptors are required for the normal regulation of emotional behaviour.

Animals↗

PubMed2005

Blockade of the mGlu5 receptor decreases basal and stress-induced cortical norepinephrine in rodents.

RATIONALE: Glutamate, the major excitatory neurotransmitter in the brain mediates its effects by both ionotropic and metabotropic receptor subtypes. Recently, the search for selective ligands for glutamate receptor subtypes has led to the discovery of 2-methyl-6-(phenylethynyl)pyridine (MPEP), an antagonist specific for metabotropic glutamate receptor 5 (mGlu5). This receptor is highly expressed in limbic forebrain regions and is thought to modulate anxiety-related processes. The noradrenergic nucleus locus coeruleus (LC) is an important mediator of stress responses and dysfunction of this system is implicated in affective disorders such as anxiety and depression. OBJECTIVES: We sought to assess the effects of mGlu5 receptor antagonists, MPEP and 3-[(2-methyl-1,3-thiazol-4-yl)ethynyl]pyridine (MTEP) on cortical norepinephrine (NE) levels. METHODS: In vivo microdialysis and high-pressure liquid chromatography with electrochemical detection (HPLC-ED) were used to assess the effects of mGlu5 antagonism on extracellular NE in the frontal cortex, a major terminal field of the LC. RESULTS: Blockade of the mGlu5 receptor elicited significant reductions in extracellular NE in the frontal cortex. The benzodiazepine diazepam also reduced cortical NE. Furthermore, MPEP administration attenuated stress-induced increases in extracellular NE. CONCLUSIONS: Taken together, these data show that MPEP and MTEP, through their blockade of the mGlu5, reduce extracellular norepinephrine, the impact of which may contribute to their anxiolytic actions.

Animals↗

PubMed2005

Differential sensitivity to the motor and hypothermic effects of the GABA B receptor agonist baclofen in various mouse strains.

RATIONALE: Comparison of different mouse strains can provide valuable information about the genetic control of behavioural and molecular phenotypes. Recent evidence has demonstrated the importance of GABA B receptors in anxiety and depression. Investigation of the phamacogenetics of GABA B receptor activation may aid in the understanding of mechanisms underlying the role of GABA B in affect. OBJECTIVES: The aim of current study was to determine the relative sensitivity of different mouse strains to GABA B receptor agonism in two models of GABA B receptor function, namely hypothermia and motor incoordination. METHODS: Mice each from 11 strains (BALB/cByJIco, DBA/2JIco, OF1, FVB/NIco, CD1, C3H/HeOuJIco, 129/SvPasIco, NMRI, C57BL/6JIco, A/JOlaHsd and Swiss) were trained to walk on a rotarod for 300 s. On the following day, mice received 0, 3, 6 or 12 mg/kg of L: -baclofen PO. Rectal temperature and rotarod performance were measured at 0, 1, 2 and 4 h after drug application. RESULTS: L: -Baclofen produced a significant dose-dependent hypothermia and ataxia in most, but not all, mouse strains examined. The magnitude and duration of response was influenced by strain, with mice of the 129/SvPasIco strain showing largest hypothermic response to 12 mg/kg l-baclofen and C3H/HeOuJIco the lowest, whereas the BALB/cByJIco strain demonstrated greatest ataxic response on the rotarod, and NMRI the least. Interestingly, some strains (notably C3H/HeOuJIco) had marked differential hypothermic and ataxic responses, with minimal body temperature responses to L: -baclofen but significant ataxia on the rotarod observed. CONCLUSION: There is differential genetic control on specific GABA B receptor populations that mediate hypothermia and ataxia. Further, these studies demonstrate that background strain is an important determinant of GABA B receptor mediated responses, and that hypothermic and ataxic responses may be influenced by independent genetic loci.

Animals↗