Papers by George Aghajanian
The Journal of pharmacology and experimental therapeutics, 2000
In prefrontal cortex, 5-hydroxytryptamine(2A) (5-HT(2A)) receptors have been linked to the action... more In prefrontal cortex, 5-hydroxytryptamine(2A) (5-HT(2A)) receptors have been linked to the action of hallucinogens and atypical antidepressant/antipsychotic drugs. Previously, we have shown in cortical layer V pyramidal cells that a nonselective metabotropic glutamate (mGlu) receptor agonist suppresses the induction of excitatory postsynaptic potentials/currents (EPSPs/EPSCs) via activation of 5-HT(2A) receptors. In this study, we tested the ability of the selective mGlu2/3 agonist (1S,2S,5R, 6S)-2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylate monohydrate (LY354740) and the selective mGlu2/3 antagonist 2S-2-amino-2-(1S, 2S-2-carboxycycloprop-1-yl)-3(xanthy-9-yl)propanoic acid (LY341495) to modulate serotonin(5-HT)-induced EPSPs and electrically evoked EPSPs by using intracellular recording from layer V pyramidal cells in medial prefrontal cortex. The mGlu2/3 antagonist LY341495 increased the frequency and amplitude of 5-HT-induced EPSCs, suggesting a role for mGlu2/3 receptors in medi...
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European Journal of Pharmacology, 1994
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Science, 2006
Serotonin [5-hydroxytryptamine (5-HT)] neurotransmission in the central nervous system modulates ... more Serotonin [5-hydroxytryptamine (5-HT)] neurotransmission in the central nervous system modulates depression and anxiety-related behaviors in humans and rodents, but the responsible downstream receptors remain poorly understood. We demonstrate that global disruption of 5-HT2A receptor (5HT2AR) signaling in mice reduces inhibition in conflict anxiety paradigms without affecting fear-conditioned and depression-related behaviors. Selective restoration of 5HT2AR signaling to the cortex normalized conflict anxiety behaviors. These findings indicate a specific role for cortical 5HT2AR function in the modulation of conflict anxiety, consistent with models of cortical, “top-down” influences on risk assessment.
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The Journal of pharmacology and experimental therapeutics, 1967
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Science, 1966
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PsycEXTRA Dataset
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Neuropsychopharmacology, 2016
GLYX-13 is a putative NMDA receptor modulator with glycine-site partial agonist properties that p... more GLYX-13 is a putative NMDA receptor modulator with glycine-site partial agonist properties that produces rapid antidepressant effects, but without the psychotomimetic side effects of ketamine. Studies were conducted to examine the molecular, cellular, and behavioral actions of GLYX-13 to further characterize the mechanisms underlying the antidepressant actions of this agent. The results demonstrate that a single dose of GLYX-13 rapidly activates the mTORC1 pathway in the prefrontal cortex (PFC), and that infusion of the selective mTORC1 inhibitor rapamycin into the medial PFC (mPFC) blocks the antidepressant behavioral actions of GLYX-13, indicating a requirement for mTORC1 similar to ketamine. The results also demonstrate that GLYX-13 rapidly increases the number and function of spine synapses in the apical dendritic tuft of layer V pyramidal neurons in the mPFC. Notably, GLYX-13 significantly increased the synaptic responses to hypocretin, a measure of thalamocortical synapses, compared with its effects on 5-HT responses, a measure of cortical-cortical responses mediated by the 5-HT2A receptor. Behavioral studies further demonstrate that GLYX-13 does not influence 5-HT2 receptor induced head twitch response or impulsivity in a serial reaction time task (SRTT), whereas ketamine increased responses in both tests. In contrast, both GLYX-13 and ketamine increased attention in the SRTT task, which is linked to hypocretin-thalamocortical responses. The differences in the 5-HT2 receptor synaptic and behavioral responses may be related to the lack of psychotomimetic side effects of GLYX-13 compared with ketamine, whereas regulation of the hypocretin responses may contribute to the therapeutic benefits of both rapid acting antidepressants.Neuropsychopharmacology advance online publication, 19 October 2016; doi:10.1038/npp.2016.202.
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Life Sci, 1983
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Brain Res, 1980
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Brain Res, 1974
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Eur J Pharmacol, 1983
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European Journal of Pharmacology, 1986
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The Journal of Pharmacology and Experimental Therapeutics, Jun 1, 1973
('oniucticut iIental Health Genie,, _Vew Haven, Connecticut A('('('1)tt'... more ('oniucticut iIental Health Genie,, _Vew Haven, Connecticut A('('('1)tt'(1 for lJui)hication February 26, 1973 ... A B STRACT BUNNEY, BENJAMIN S., JUDITH R.. WALTERS, ROBERT H. ROTH AND GEORGE K. ... A(;HAJANIAN : Dopaminergic neurons : Effect of antipsycimotic ...
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Brain Research, Jul 2, 1984
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Experientia, 1968
ABSTRACT
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Brain Res, 1975
Following the intraventricular injection of a small amount of [3H]5-hydroxytryptamine ([3H]5-HT),... more Following the intraventricular injection of a small amount of [3H]5-hydroxytryptamine ([3H]5-HT), the amount of radioactivity in telencephalic structures on the injected side was 6--7 times larger than that in corresponding areas on the opposite side. Moreover, a multiphasic disappearance of [3H]5-HT from whole brain or midbrain was found after the intraventricular injection of the labeled amine. However, after the intraventricular injection of [3H]tryptophan, the levels of [3H]5-HT in midbrain declined in a monophasic manner. A significant portion of the labeled amine derived from intraventricularly administered [3H]5-HT was resistant to the depleting effect of Ro4-1284 or to that elicited by destruction of the midbrain raphe nuclei, both of which caused an almost complete loss of endogenous 5-HT and labeled 5-HT formed from tryptophan. It thus appears that the intraventricular injection of [3H]5-HT leads to the formation of artifactual pools which are not present if the amine is synthesized in vivo. Studies with 6-hydroxydopamine suggested, however, that uptake of [3H]5-HT into adrenergic neurons did not occur to any great extent.
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Eur J Pharmacol, 1996
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Nature Medicine, 2016
Depression is a common, devastating illness. Current pharmacotherapies help many patients, but hi... more Depression is a common, devastating illness. Current pharmacotherapies help many patients, but high rates of a partial response or no response, and the delayed onset of the effects of antidepressant therapies, leave many patients inadequately treated. However, new insights into the neurobiology of stress and human mood disorders have shed light on mechanisms underlying the vulnerability of individuals to depression and have pointed to novel antidepressants. Environmental events and other risk factors contribute to depression through converging molecular and cellular mechanisms that disrupt neuronal function and morphology, resulting in dysfunction of the circuitry that is essential for mood regulation and cognitive function. Although current antidepressants, such as serotonin-reuptake inhibitors, produce subtle changes that take effect in weeks or months, it has recently been shown that treatment with new agents results in an improvement in mood ratings within hours of dosing patients who are resistant to typical antidepressants. Within a similar time scale, these new agents have also been shown to reverse the synaptic deficits caused by stress.
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Progress in Neurobiology, Aug 31, 1997
The serotonergic system, because of very diffuse projections throughout the central nervous syste... more The serotonergic system, because of very diffuse projections throughout the central nervous system, has been implicated in numerous functions including nociception, analgesia, sleep-wakefulness and autonomic regulation. Despite an abundant literature indicating the presence of neurotensin-containing (neurotensinergic) neurons, fibres and terminals in most areas containing serotonergic neurons, little is known about the possible relationship between serotonergic and neurotensinergic systems. The purpose of this review is (i) to summarize current knowledge on the anatomical relation between neurotensinergic and serotonergic system, (ii) to summarize current knowledge on the action of neurotensin on serotonergic neurons and (iii) to discuss the possible physiological relevance of this action. Neurotensin-containing cell bodies can be found in the most rostral raphe nuclei. There are neurotensin-containing fibres and terminals in all raphe nuclei. Raphe nuclei have also been shown to contain neurotensin-receptor binding sites. In the dorsal raphe nucleus, neurotensin induces a concentration-dependent increase in the firing rate of a subpopulation of serotonergic neurons. The neurotensin-induced excitation, which is selectively blocked by the non-peptide neurotensin receptor antagonist SR 48692, is observed mainly in the ventral part of the nucleus. Most serotonergic neurons show marked desensitization to neurotensin, even at low concentrations. In intracellular experiments, neurotensin induces an inward current, associated in some cases with a decrease in apparent input conductance, which is occluded by supramaximal concentrations of the alpha 1-adrenoceptor agonist phenylephrine. In rare cases, neurotensin induces an excitation of GABAergic or glutamatergic neurons. Since the neurotensinergic system has also been implicated in nociception, analgesia, sleep-wakefulness, and autonomic regulation, the review discusses the possibility that part of this regulation could involve the activation of the serotonergic system.
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Papers by George Aghajanian