The interaction between the locus coeruleus and dorsal raphe nucleus studied with dual-probe microdialysis

Pudovkina, Olga L.; Cremers, Thomas; Westerink, Ben H.C.

doi:10.1016/s0014-2999(02)01663-1

Cited by 58 publications

(40 citation statements)

References 30 publications

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“…It was demonstrated for the first time that stimulation of LC cholinergic or glutamatergic receptors disrupts PPI in an anatomically, behaviorally, and neurochemically specific manner, consistent with previous reports that such manipulations activate LC neuronal firing and elevate NE release in LC terminal regions (Berridge and Abercrombie, 1999;Berridge and Foote, 1991;Pudovkina et al, 2002;Van Gaalen et al, 1997). These disruptions likely result from specific actions within the LC, because infusions of BET even 250 mm away from the active drug zone had no effect, co-infusion of the a2 autoreceptor agonist clonidine (which reliably and markedly reduces activity of LC neurons and downstream NE release including in unanesthetized rats (Berridge et al, 1993;Pudovkina et al, 2002;Pudovkina et al, 2001;Van Gaalen et al, 1997)) prevented the BET-induced deficit, and systemic administration of the a1 NE antagonist prazosin completely reversed the PPI deficit following peri-LC BET.…”

Section: Discussionsupporting

confidence: 88%

“…Four Pulse-Alone trials were also presented at the beginning and the end of the session to ensure that startle magnitude was stable during the portion of the session when PPI was measured, as the most rapid habituation of the startle response occurs within the first several presentations (Geyer et al, 1990); these Pulse-Alone trials were excluded from the calculations of startle and %PPI. The duration of this test session was designed specifically to match the timeframe during which it has been reported that pharmacological stimulation of LC activates these neurons and causes NE release in terminal fields (Berridge and Abercrombie, 1999;Pudovkina et al, 2002;Van Gaalen et al, 1997). During the week before drug testing, all rats underwent one exposure/ day on three separate days to this session with sham infusions preceding the last test to familiarize rats with the testing and microinfusion procedures.…”

Section: Startle Chambers and Ppi Testingmentioning

confidence: 99%

“…Are LC-mediated PPI deficits specific to NE transmission? First, to confirm that the peri-LC BET effect was due to activation of LC neurons, we determined whether co-infusion of clonidine, an a2 NE (autoreceptor) agonist that significantly reduces activity of LC neurons and NE release in terminal regions after peri-LC delivery in anesthetized or awake rats (Berridge et al, 1993;Pudovkina et al, 2002;Pudovkina et al, 2001;Van Gaalen et al, 1997), prevented the peri-LC BET-induced PPI deficit. Thus, rats (N ¼ 7) received a 'cocktail' of clonidine (0 or 1500 ng) and BET (0 or 500 ng) into peri-LC immediately before startle/ PPI testing; each rat received all the four drug combinations in a counterbalanced order over four test days.…”

Section: Experimental Designmentioning

confidence: 99%

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Pharmacological Stimulation of Locus Coeruleus Reveals a New Antipsychotic-Responsive Pathway for Deficient Sensorimotor Gating

Alsene

Bakshi

2011

Neuropsychopharmacol

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Surprisingly little is known about the modulation of core endophenotypes of psychiatric disease by discrete noradrenergic (NE) circuits. Prepulse inhibition (PPI), the diminution of startle responses when weak prestimuli precede the startling event, is a widely validated translational paradigm for information-processing deficits observed in several mental disorders including schizophrenia, Tourette's syndrome, and post-traumatic stress disorder (PTSD). Despite putative NE disturbances in these illnesses, NE regulation of PPI remains poorly understood. In these studies, regulation of PPI by the locus coeruleus (LC), the primary source of NE to forebrain, was evaluated in rats using well-established protocols to pharmacologically activate/inactivate this nucleus. The ability of drugs that treat deficient PPI in these illnesses to reverse LC-mediated PPI deficits was also tested. Stimulation of LC receptors produced an anatomically and behaviorally specific deficit in PPI that was blocked by clonidine (Cataprese, an a2 receptor agonist that reduces LC neuronal firing after peri-LC delivery), a postsynaptic a1 NE receptor antagonist (prazosin), and second-generation antipsychotics (olanzapine, seroquel), but not by drugs that antagonized dopamine-1 (SCH23390), dopamine-2 (the first-generation antipsychotic Haloperidol), or serotonin-2 receptors (ritanserin). These results indicate a novel substrate in the regulation of PPI and reveal a novel functional role for the LC. Hence, a hyperactive LC-NE system might underlie a deficient sensorimotor gating endophenotype in a subset of patients suffering from psychiatric illnesses including schizophrenia, Tourette's syndrome, and PTSD, and the ability to normalize LC-NE transmission could contribute to the clinical efficacy of certain drugs (Cataprese, prazosin, and second-generation antipsychotics) in these conditions.

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Section: Discussionsupporting

confidence: 88%

Section: Startle Chambers and Ppi Testingmentioning

confidence: 99%

Section: Experimental Designmentioning

confidence: 99%

See 1 more Smart Citation

Pharmacological Stimulation of Locus Coeruleus Reveals a New Antipsychotic-Responsive Pathway for Deficient Sensorimotor Gating

Alsene

Bakshi

2011

Neuropsychopharmacol

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“…For instance, bilateral lesions of LC NA neurons with 6-OHDA in DA lesioned rats increased the firing activity of SN pars reticulata neurons (Wang et al, 2010a) and medial prefrontal cortex pyramidal neurons (Wang et al, 2010b). In addition, firing rate of serotonin neurons (Haddjeri et al, 1996;Vandermaelen and Aghajanian, 1983;Svensson et al, 1975) and serotonin synthesis and release (Adell and Artigas, 1999;Pudovkina et al, 2002Pudovkina et al, , 2003Amargos-Bosch et al, 2003;Mongeau et al, 1997;Yoshioka et al, 1992) has been shown to be modified by NA input. All of these types of neurons are known to be involved in the expression of both L-DOPA-induced dyskinesia and motor performance.…”

Section: Discussionmentioning

confidence: 99%

Noradrenaline neuron degeneration contributes to motor impairments and development of L-DOPA-induced dyskinesia in a rat model of Parkinson's disease

Shin

Rogers

Devoto

et al. 2014

Experimental Neurology

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Parkinson's disease (PD) is characterized by progressive loss of dopaminergic (DA) neurons in the substantia nigra. However, studies of post-mortem PD brains have shown that not only DA neurons but also the noradrenergic (NA) neurons in the locus coeruleus degenerate, and that the NA neurodegeneration may be as profound, and also precede degeneration of the midbrain DA neurons. Previous studies in animal models of PD have suggested that loss of forebrain NA will add to the development of motor symptoms in animals with lesions of the nigrostriatal DA neurons, but the results obtained in rodents have been inconclusive due to the shortcomings of the toxin, DSP-4, used to lesion the NA projections. Here, we have developed an alternative double-lesion paradigm using injections of 6-OHDA into striatum in combination with intraventricular injections of a powerful NA immunotoxin, anti-DBH-Saporin, to eliminate the NA neurons in the brain.Animals with combined DA and NA lesions were more prone to develop L-DOPAinduced dyskinesia, even at low L-DOPA doses, and they performed significantly worse in tests of reflexive and skilled paw use, the stepping and staircase tests, compared to DA-only lesioned rats. Post-mortem analysis revealed that NA depletion did not affect the degree of DA depletion, or the loss of tyrosine hydroxylase-positive innervation in the striatum. Cell loss in the substantia nigra was similar in both single and double lesioned animals, showing that the worsening effect was not due to increased loss of nigral DA neurons. The results show that damage to the NA neurons in the central nervous system contributes to the development of motor impairments and the appearance of L-DOPAinduced dyskinesia in 6-OHDA lesioned rats, and provide support for the view that the development of motor symptoms and dyskinetic side effects in PD patients reflects the combined loss of midbrain DA neurons and NA neurons.3

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“…TH is also present along NE fibres projecting towards target areas and regulation terminally is likely because the DR does not seem to exert a direct inhibitory influence on the release of NE in the LC [87]. While 5-HT and NE fibres with synaptic varicosities co-localize in forebrain regions, a feedback loop, involving alpha 2 -adrenergic receptors on 5-HT fibres and 5-HT 3 receptors on NE fibres, allows a reciprocal regulation of the release of both neurotransmitters by which 5-HT 3 receptors stimulate the synaptic release of NE [88].…”

Section: (C) Monoamine Transmitters and Neuronsmentioning

confidence: 99%

Targeting brain serotonin synthesis: insights into neurodevelopmental disorders with long-term outcomes related to negative emotionality, aggression and antisocial behaviour

Lesch

Araragi

Waider

et al. 2012

Phil. Trans. R. Soc. B

128

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Aggression, which comprises multi-faceted traits ranging from negative emotionality to antisocial behaviour, is influenced by an interaction of biological, psychological and social variables. Failure in social adjustment, aggressiveness and violence represent the most detrimental long-term outcome of neurodevelopmental disorders. With the exception of brain-specific tryptophan hydroxylase-2 (Tph2), which generates serotonin (5-HT) in raphe neurons, the contribution of gene variation to aggression-related behaviour in genetically modified mouse models has been previously appraised (Lesch 2005 Novartis Found Symp. 268, 111 -140; Lesch & Merschdorf 2000 Behav. Sci. Law 18, 581 -604). Genetic inactivation of Tph2 function in mice led to the identification of phenotypic changes, ranging from growth retardation and late-onset obesity, to enhanced conditioned fear response, increased aggression and depression-like behaviour. This spectrum of consequences, which are amplified by stress-related epigenetic interactions, are attributable to deficient brain 5-HT synthesis during development and adulthood. Human data relating altered TPH2 function to personality traits of negative emotionality and neurodevelopmental disorders characterized by deficits in cognitive control and emotion regulation are based on genetic association and are therefore not as robust as the experimental mouse results. Mouse models in conjunction with approaches focusing on TPH2 variants in humans provide unexpected views of 5-HT's role in brain development and in disorders related to negative emotionality, aggression and antisocial behaviour.Keywords: tryptophan hydroxylase (TPH2); cognition; emotion; impulsivity; aggression; violence INTRODUCTIONNegative emotionality, aggression and antisociality are complex temperamental traits and social behaviours that arise out of multiple causes involving biological and psychological dynamisms and social forces, and different forms of emotional behaviour may each result from different biopsychosocial pathways. The societal implications of aggressiveness, which results in numerous facets of aggressive behaviour and ranges from the establishment of hierarchies and dominance to antisocial behaviour and delinquency, have been examined with preclinical and clinical frameworks.Developmentally inappropriate conduct, aggressiveness and failure in social adjustment represent the most detrimental and harmful long-term outcome of a wide spectrum of neurodevelopmental disorders characterized by deficits in cognitive control and emotion regulation.In both humans and animals, the term aggression comprises a variety of behaviours that are heterogeneous for clinical phenomenology and neurobiological features. While the impact of complex cultural variables on behaviour impedes simple extrapolation of animal phenotypes to human traits, clinical observation, experimental paradigms in the laboratory and cluster/ factor-analytic statistics have been used in attempts to subdivide aggression. On the basis of different approaches, hu...

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The interaction between the locus coeruleus and dorsal raphe nucleus studied with dual-probe microdialysis

Cited by 58 publications

References 30 publications

Pharmacological Stimulation of Locus Coeruleus Reveals a New Antipsychotic-Responsive Pathway for Deficient Sensorimotor Gating

Pharmacological Stimulation of Locus Coeruleus Reveals a New Antipsychotic-Responsive Pathway for Deficient Sensorimotor Gating

Noradrenaline neuron degeneration contributes to motor impairments and development of L-DOPA-induced dyskinesia in a rat model of Parkinson's disease

Targeting brain serotonin synthesis: insights into neurodevelopmental disorders with long-term outcomes related to negative emotionality, aggression and antisocial behaviour

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