Aghajanian GK. Modeling ‘psychosis’ in vitro by inducing disordered neuronal network activity in cortical brain slices. Psychopharmacology (Berl) 206: 575-585

Yale School of Medicine and the Connecticut Mental Health Center, New Haven, CT 06508, USA.
Psychopharmacology (Impact Factor: 3.88). 03/2009; 206(4):575-85. DOI: 10.1007/s00213-009-1484-9
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Dysregulation of neuronal networks has been suggested to underlie the cognitive and perceptual abnormalities observed schizophrenia.

An in vitro model of psychosis is proposed based on the two different approaches to cause aberrant network activity in layer V pyramidal cells of prefrontal brain slices: (1) psychedelic hallucinogens such as lysergic acid diethylamide and (2) minimal GABAA receptor antagonism, modeling the GABA interneuron deficit in schizophrenia. A test of this model would be to determine if drugs that normalize aberrant networks in brain slices have efficacy in the treatment of schizophrenia. Selective agonists of glutamate mGlu2/3 metabotropic receptors, which are highly effective in suppressing aberrant network activity in slices, are the most advanced toward reaching that clinical endpoint. In accord with the model, a recent phase II clinical trial shows that an mGlu2/3 receptor agonist is equivalent in efficacy to a standard antipsychotic drug for both negative and positive symptoms in schizophrenic patients, but without the usual side effects. D1/5 dopamine receptor agonists are also effective in normalizing aberrant network activity induced by both hallucinogens and minimal GABAA antagonism; clinical efficacy remains to be determined. A general model of network regulation is presented, involving astrocytes, GABA interneurons, and glutamatergic pyramidal cells, revealing a wide range of potential sites hitherto not considered as therapeutic targets.

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Available from: George K Aghajanian, Dec 20, 2013
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    • "Further, as this effect is widespread over the cortex, such gamma oscillations are likely to spread more freely across the thalamocortical system, recruiting areas of the cortex without the tight restraint normally held by serotonin. One can envisage, for example, how information could be spread from one sensory modality to another, generating synaesthesia effects (Aghajanian 2009). Illusions, or misinterpretations of sensory information, can be explained as underconstrained novel reinterpretations of such information. "
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    ABSTRACT: Arguably the most remarkable property of the human brain is its ability to construct the world that appears to consciousness. The brain is capable of building worlds during waking life, but also in the complete absence of extrinsic sensory data, entirely from intrinsic thalamocortical activity , as during dreaming. DMT, an extraordinary psychedelic, perturbs brain activity such that indescribably bizarre and apparently alien worlds are built. This property of DMT continues to defy explanation. However, by regarding this unique molecule as equivalent to serotonin, an endogenous neuro-modulator with a long-standing relationship with the brain, DMT's eff ects may be explained. Serotonin has evolved to hold the brain's thalamocortical system in a state in which the consensus world is built. When serotonin is replaced by DMT, the thalamocortical system shifts into an equivalent state, but one in which an apparently alien world is built. This suggests that DMT may be an ancestral neuromodulator, at one time secreted endogenously in psychedelic concentrations—a function apparently now lost. However, DMT maintains a number of unique pharmacological characteristics and a peculiar affi nity with the human brain that supports this model. Thus, the modern practice of ingesting exogenous DMT may be the reconstitution of an ancestral function. Friends, right here and now, one quantum away, there is raging a universe of active intelligence that is transhuman, hyperdimensional, and extremely alien. —Terence McKenna
    Journal of Scientific Exploration 01/2013; 27(3):455-503.
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    • "Glutamatergic and GABAergic neurons were thought to release their transmitters exclusively at synapses, where they mediate the classical “fast synaptic transmission” (Vizi et al., 2010). However, it has been shown that ambient GABA and glutamate can also tonically activate high-affinity, extrasynaptic receptors, suggesting their spill-over from synaptic boutons, mediating a slower synaptic transmission (Semyanov et al., 2004; Farrant and Nusser, 2005; Aghajanian, 2009). Extrasynaptic GABAA inhibition can modulate the generation of hippocampal fast rhythms (Scanziani, 2000; Towers et al., 2004; Mann and Mody, 2010; Papatheodoropoulos and Koniaris, 2011), and it is likely that such modulation also occurs in the preBötC, where increasing the extracellular concentration of GABA, by inhibiting its uptake with nipecotic acid, decreases the respiratory frequency (Ren and Greer, 2006). "
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    ABSTRACT: The generation of neural network dynamics relies on the interactions between the intrinsic and synaptic properties of their neural components. Moreover, neuromodulators allow networks to change these properties and adjust their activity to specific challenges. Endogenous continuous ("tonic") neuromodulation can regulate and sometimes be indispensible for networks to produce basal activity. This seems to be the case for the inspiratory rhythm generator located in the pre-Bötzinger complex (preBötC). This neural network is necessary and sufficient for generating inspiratory rhythms. The preBötC produces normal respiratory activity (eupnea) as well as sighs under normoxic conditions, and it generates gasping under hypoxic conditions after a reconfiguration process. The reconfiguration leading to gasping generation involves changes of synaptic and intrinsic properties that can be mediated by several neuromodulators. Over the past years, it has been shown that endogenous continuous neuromodulation of the preBötC may involve the continuous action of amines and peptides on extrasynaptic receptors. I will summarize the findings supporting the role of endogenous continuous neuromodulation in the generation and regulation of different inspiratory rhythms, exploring the possibility that these neuromodulatory actions involve extrasynaptic receptors along with evidence of glial modulation of preBötC activity.
    Frontiers in Physiology 07/2012; 3:253. DOI:10.3389/fphys.2012.00253 · 3.53 Impact Factor
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    • "Similarly, NVHL rats show cellular and physiological markers of cortical GABAergic hypofunctionality (Endo et al., 2007; Francois et al., 2009; Tseng et al., 2008), and dysfunctional glutamatergic transmission associated with stimulus-dependent discoordination and/or hyper-active firing of cortical neurons (Chambers et al., 2010; O'Donnell et al., 2002; Tseng et al., 2007). These themes mirror histopathological and physiological evidence suggesting that GABAergic hypofunction and disorganization of excitatory transmission are themes characteristic of the schizophrenic cortex (Aghajanian, 2009; Coyle, 2004; Lewis and Moghaddam, 2006). Notably, we also observed a robust effect of ketamine on ASSR power, which was not observed as an independent NVHL effect. "
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    ABSTRACT: Alterations in neural synchrony and oscillations may contribute to the pathophysiology of schizophrenia and reflect aberrations in cortical glutamatergic and GABAergic neurotransmission. We tested the effects of a GABA agonist and an NMDA antagonist on auditory steady state responses (ASSRs) in awake rats with neonatal ventral hippocampal lesions (NVHLs) as a neurodevelopmental model of schizophrenia. NVHL vs. SHAM lesioned rats were injected with saline then either ketamine (NMDA antagonist) or muscimol (GABA(A) agonist). Time-frequency analyses examined alterations in phase locking (consistency) across trials and changes in total power (magnitude). ASSRs were compared at five stimulation frequencies (10, 20, 30, 40, and 50Hz). In SHAM rats, phase locking and power generally increased with stimulation frequency. Both ketamine and muscimol also increased phase locking and power in SHAM rats, but mostly in the 20 to 40Hz range. NVHL and ketamine altered the frequency dependence of phase locking, while only ketamine changed power frequency dependence. Muscimol affected power, but not phase locking, in the NVHL rats. NVHL and ketamine models of schizophrenia produce similar independent effects on ASSR, potentially representing similar forms of cortical network/glutamatergic dysfunction, albeit the effects of ketamine were more robust. Muscimol produced NVHL-dependent reductions in ASSR measures, suggesting that cortical networks in this model are intolerant to post-synaptic GABAergic stimulation. These findings suggest the utility of combining lesion, pharmacological, and ASSR approaches in understanding neural mechanisms underlying disturbed synchrony in schizophrenia.
    International journal of psychophysiology: official journal of the International Organization of Psychophysiology 04/2012; 86(2). DOI:10.1016/j.ijpsycho.2012.04.002 · 2.88 Impact Factor
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