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Interactions of Hallucinogens with the Glutamatergic System: Permissive Network Effects Mediated Through Cortical Layer V Pyramidal Neurons

  • Chapter
Behavioral Neurobiology of Psychedelic Drugs

Part of the book series: Current Topics in Behavioral Neurosciences ((CTBN,volume 36))

Abstract

Recordings made from layer V (L5) pyramidal cells of the prefrontal cortex (PFC) and neocortex in rodent slice preparations have shown that serotonin (5-hydroxytryptamine, 5-HT) and serotonergic hallucinogens induce an increase in the frequency of spontaneous excitatory postsynaptic currents (EPSCs) in the apical dendritic field by activating 5-HT2A receptors. Serotonergic hallucinogens induce late EPSCs and increase recurrent network activity when subcortical or mid-cortical regions are stimulated at low frequencies (e.g., 0.1 Hz). A range of agonists or positive allosteric modulators (PAMs) for mostly Gi/o-coupled receptors, including metabotropic glutamate2 (mGlu2), adenosine A1, or μ-opioid receptors, suppress these effects of 5-HT2A receptor stimulation. Furthermore, a range of mostly Gq/11-coupled receptors (including orexin2 [OX2]; α1-adrenergic, and mGlu5 receptors) similarly induce glutamate (Glu) release onto L5 pyramidal cells. Evidence implicates a number of brain regions in mediating these effects of serotonergic hallucinogens and Gq/11-coupled receptors including the midline and intralaminar thalamic nuclei, claustrum, and neurons in deep PFC. These effects on 5-HT2A receptors and related GPCRs appear to play a major role in the behavioral effects of serotonergic hallucinogens, such as head twitches in rodents and higher order behaviors such as rodent lever pressing on the differential-reinforcement-of-low rate 72-s (DRL 72-s) schedule. This implies that the effects of 5-HT2A receptor activation on the activity of L5 pyramidal cells may be responsible for mediating a range of behaviors linked to limbic circuitry with connectivity between the PFC, striatum, thalamus, claustrum, striatum, amygdala, and the hippocampal formation.

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References

  • Aghajanian GK (2009) Modeling “psychosis” in vitro by inducing disordered neuronal network activity in cortical brain slices. Psychopharmacology 206:575–585

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Aghajanian GK, Marek GJ (1997) Serotonin induces excitatory postsynaptic potentials in apical dendrites of neocortical pyramidal cells. Neuropharmacology 36(3/4):589–599

    Article  CAS  PubMed  Google Scholar 

  • Ardayfio PA et al (2008) The 5-hydroxytryptamine2A receptor antagonist R-(+)-a-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl-4-piperidinemethanol (M100907) attenuates impulsivity after both drug-induced disruption (dizocilpine) and enhancement (antidepressant drugs) of differential-reinforcement-of-low-rate 72-s behavior in the rat. J Pharmacol Exp Ther 327:891–897

    Article  CAS  PubMed  Google Scholar 

  • Avesar D, Gulledge AT (2012) Selective serotonergic excitation of callosal projection neurons. Front Neural circuits 6

    Google Scholar 

  • Ballanger B et al (2010) Serotonin 2A receptors and visual hallucinations in Parkinson disease. Arch Neurol 67:416–421

    Article  PubMed  Google Scholar 

  • Barre A et al (2012) Presynaptic serotonin 2A receptors modulate thalamocortical plasticity and associative learning. Proc Natl Acad Sci USA 113:E1382–E1391

    Article  CAS  Google Scholar 

  • Beique J-C et al (2007) Mechanism of the 5-hydroxytryptamine2A receptor-mediated facilitation of synaptic activity in prefrontal cortex. Proc Natl Acad Sci USA 104:9870–9875

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Benneyworth MA et al (2007) A selective positive allosteric modulator of metabotropic glutamate receptor subtype 2 blocks a hallucinogenic drug model of psychosis. Mol Pharmacol 72:477–484

    CAS  PubMed  Google Scholar 

  • Benvenga MJ et al (2006) Attenuation of DOI-induced head twitches in mGluR2 KO mice. FASEB J 20:A246

    Google Scholar 

  • Berman RM et al (2000) Antidepressant effects of ketamine in depressed patients. Biol Psychiatry 47:351–354

    Article  CAS  PubMed  Google Scholar 

  • Blin J et al (1993) Loss of brain 5-HT2 receptors in Alzheimer’s disease. Brain 116:497–510

    Article  PubMed  Google Scholar 

  • Bodkin JA et al (1995) Buprenorphine treatment of refractory depression. J Clin Psychopharmacol 15:49–57

    Article  CAS  PubMed  Google Scholar 

  • Bohnen NI, Albin RL (2011) The cholinergic system and Parkinson disease. Behav Brain Res 221:564–573

    Article  CAS  PubMed  Google Scholar 

  • Burgess S et al (2001) Lithium for maintenance treatment of mood disorders. Cochrane Database Syst. Rev., (2):CD003013

    Google Scholar 

  • Canal CE, Morgan D (2012) Head-twitch response in rodents induced by the hallucinogen 2,5-dimethoxy-4-iodoamphetamine: a comprehensive history, a re-evaluation of mechanisms, and its utility as a model. Drug Test Anal 4:556–576

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Carli M et al (2006) Dissociable contribution of 5-HT1AA and 5-HT2A receptors in the medial prefrontal cortex to different aspects of executive control such as impulsivity and compulsive perseveration in rats. Neuropsychopharmacology 31:757–767

    Article  CAS  PubMed  Google Scholar 

  • Carlson ET, Simpson MM (1963) Opium as a tranquilizor. Am J Psychiatry 120:112–117

    Article  CAS  PubMed  Google Scholar 

  • Carpenter LL, Yasmin S, Price LH (2002) A double-blind placebo-controlled study of antidepressant augmentation with mirtazapine. Biol Psychiatry 51:183–188

    Article  CAS  PubMed  Google Scholar 

  • Chen, CPL-H et al (1998) Post-synaptic 5-HT1A and 5-HT2A receptors are increased in Parkinson’s disease neocortex. Ann NY Acad Sci 861: 288–289

    Google Scholar 

  • Ciliax BJ et al (2000) Dopamine D5 receptor immunolocalization in rat and monkey brain. Synapse 37:125–145

    Article  CAS  PubMed  Google Scholar 

  • Cross AJ et al (1984) Serotonin receptor changes in dementia of the Alzheimer type. J Neurochem 43:1574–1581

    Article  CAS  PubMed  Google Scholar 

  • Cross AJ et al (1986) The selectivity of the reduction of serotonin S2 receptors in Alzheimer-type dementia. Neurobiol Aging 7:3–7

    Article  CAS  PubMed  Google Scholar 

  • Cummings J et al (2014) Pimavanserin for patients with Parkinson’s disease psychosis: a randomized, placebo-controlled phase 3 trial. Lancet 383:533–540

    Article  CAS  PubMed  Google Scholar 

  • Czyrak A et al (1993) Pharmacological effects of zotipine and other antipsychotics on the central 5-HT2 receptors. Pharmacopsychiatry 26:53–58

    Article  CAS  PubMed  Google Scholar 

  • Delille HK et al (2012) Heterocomplex formation of 5-HT(2A)-mGlu(2) and its relevance for cellular signaling cascades. Neuropharmacology 62:2183–2190

    Article  CAS  Google Scholar 

  • Delille HK, Mezler M, Marek GJ (2013) The two faces of the pharmacological interaction of mGlu2 and 5-HT2A—relevance of receptor heterocomplexes and interaction through functional brain pathways. Neuropharmacology 70:296–305

    Article  CAS  PubMed  Google Scholar 

  • Ding YQ et al (1996) Localization of the neuromedin K receptor (NK3) in the central nervous system of the rat. J Comp Neurol 364:290–310

    Article  CAS  PubMed  Google Scholar 

  • Doumazane E et al (2011) A new approach to analyze cell surface protein complexes reveals specific heterodimeric metabotropic glutamate receptors. FASEB J. 25:66–77

    Article  CAS  PubMed  Google Scholar 

  • Drevets WC, Furey ML (2010) Replication of scopolamine’s antidepressant efficacy in major depressive disorder: a randomized, placebo-controlled clinical trial. Biol Psychiatry 67:432–438

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Dunn RT, Richards JB, Seiden LS (1993) Effects of salbutamol upon performance on an operant screen for antidepressant drugs. Psychopharmacology 113:1–10

    Article  CAS  PubMed  Google Scholar 

  • Dursun SM, Handley SL (1996) Similarities in the pharmacology of spontaneous and DOI-induced head-shakes suggest 5-HT2A receptors are active under physiological conditions. Psychopharmacology 128:198–205

    Article  CAS  PubMed  Google Scholar 

  • Egashira N et al (2011) Role of endocannabinoid and glutamatergic systems in DOI-induced head-twitch response in mice. Pharmacol Biochem Behav 99:52–58

    Article  CAS  PubMed  Google Scholar 

  • Eison AS et al (1990) Nefazodone: preclinical pharmacology of a new antidepressant. Psychopharmacol Bull 26:311–315

    CAS  PubMed  Google Scholar 

  • Ellis JS et al (2014) Antidepressant treatment history as a predictor of response to scopolamine: clinical implications. J Affect Disord 162:39–42

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Emrich HM, Voght P, Herz (1982) Possible antidepressive effects of opioids: action of buprenorphine. Ann NY Acad Sci 398:108–112

    Article  CAS  PubMed  Google Scholar 

  • Fell MJ et al (2011) N-(4-((2-trifluoromethyl)-3-hydroxy-4-(isobutyryl)phenoxy)methyl)benzyl)-1-methyl-1H-imidazole-4-carboxamide (THIIC), a novel metabotropic glutamate 2 potentiator with potential anxiolytic/antidepressant properties: in vivo profiling suggests a link between behavioral and central nervous system neurochemical changes. J Pharmacol Exp Ther 336:165–177

    Article  CAS  PubMed  Google Scholar 

  • Ferreri M et al (2001) Benefits from mianserin augmentation of fluoxetine in patients with major depression non-responders to fluoxetine alone. Acta Psychiatr Scand 103:66–72

    Article  CAS  PubMed  Google Scholar 

  • Fitch TE, Benvenga MJ, Jesudason CD, Zink C, Vandergriff AB, Menezes MM, Schober DA, Rorick-Kehn LM, (2014) LSN2424100: a novel, potent orexin-2 receptor antagonist with selectivity over orexin-1 receptors and activity in an animal model predictive of antidepressant-like efficacy. Front Neurosci 8(Article 5): 1–11

    Google Scholar 

  • French Clozapine Parkinson Study Group (1999) Clozapine in drug-induced psychosis in Parkinson’s disease. Lancet 353: 2041–2042

    Google Scholar 

  • Fribourg M et al (2011) Decoding the signaling of a GPCR heteromeric complex reveals a unifying mechanism of action of antipsychotic drugs. Cell 147:1011–1023

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Friedman E, Cooper TB, Dallob A (1983) Effects of chronic antidepressant treatment on serotonin receptor activity in mice. Eur J Pharmacol 89:69–76

    Article  CAS  PubMed  Google Scholar 

  • Furey ML, Drevets WC (2006) Antidepressant efficacy of the antimuscarinic drug scopolamine. Arch Gen Psychiatry 63:1121–1129

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gao W-J, Krimer LS, Goldman-Rakic PS (2001) Presynaptic regulation of reccurent excitation by D1 receptors in prefrontal circuits. Proc Natl Acad Sci U S A 98:295–300

    Article  CAS  PubMed  Google Scholar 

  • Gaynor CM, Handley SL (2001) Effects of nicotine on head-shakes and tryptophan metabolites. Psychopharmacology 153:327–333

    Article  CAS  PubMed  Google Scholar 

  • Gewirtz JC, Marek GJ (2000) Behavioral evidence for interactions between a hallucinogenic drug and group II metabotropic glutamate receptors. Neuropsychopharmacology 23:569–576

    Article  CAS  PubMed  Google Scholar 

  • Gonzalez-Maeso J et al (2008) Identification of a serotonin/glutamate receptor complex implicated in psychosis. Nature 452:93–99

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Goodwin GM, Green AR, Johnson P (1984) 5-HT2 receptor characteristics in frontal cortex and 5-HT2 receptor-mediated head-twitch behavior following antidepressant treatment to mice. Br J Pharmacol 83:235–242

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gouzoulis-Mayfrank E et al (2005) Psychological effects of (S)-ketamine and N, N-dimethyltryptamine: a double-blind, cross-over study in healthy volunteers. Pharmacopsychiatry 38:301–311

    Article  CAS  PubMed  Google Scholar 

  • Granon S et al (2000) Enhanced and impaired attentional performance after infusion of D1 dopaminergic receptor agents into rat prefrontal cortex. J Neurosci 20:1208–1215

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hacksell U et al (2014) On the discovery and development of pimavanserin: a novel drug candidate for Parkinson’s psychosis. Neurochem Res 39:2008–2017

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Halliday G, Lees A, Stern M (2011) Milestones in Parkinson’s disease—Clinical and pathologic features. Mov Disord 26:1015–1021

    Article  PubMed  Google Scholar 

  • Handley SL, Singh L (1986) Neurotransmitters and shaking behaviour—more than a ‘gut-bath’ for the brain. Trends Pharmacol Sci 7: 324–328

    Article  CAS  Google Scholar 

  • Hasselbalch SG et al (2008) Reduced 5-HT2A receptor binding in patients with mild cognitive impairment. Neurobiol Aging 29:1380–1388

    Article  CAS  Google Scholar 

  • Hayslett RL, Tizabi Y (2005) Effects of donepezil, nicotine and haloperidol on the central serotonergic system in mice: Implications for Tourette’s syndrome. Pharmacol Biochem Behav 81:879–886

    Article  CAS  PubMed  Google Scholar 

  • Higgins GA et al (2003) The 5-HT2A receptor antagonist M100,907 attenuates motor and ‘impulsive-type’ behaviors produced by NMDA receptor antagonism. Psychopharmacology 170:309–319

    Article  CAS  PubMed  Google Scholar 

  • Hillhouse TM, Porter JH (2014) Ketamine, but not MK-801, produces antidepressant-like effects in rats responding on a differential-reinforcement-of-low-rate operant schedule. Behav Pharmacol 25:80–91

    Article  CAS  PubMed  Google Scholar 

  • Huang Q et al (1992) Immunohistochemical localization of the D1 dopamine receptor in rat brain reveals its axonal transport, pre- and postsynaptic localization, and prevalence in the basal ganglia, limbic system, and thalamic reticular nucleus. Proc Natl Acad Sci U S A 89:11988–11992

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Huot P et al (2010) Increased 5-HT2A receptors in the temporal cortex of parkinsonian patients with visual hallucinations. Mov Disord 25:1399–1408

    Article  PubMed  Google Scholar 

  • Jakab RL, Goldman-Rakic PS (1998) 5-HT2A serotonin receptors in the primate cerebral cortex: possible site of action of hallucinogens in pyramidal cell apical dendrites. Proc Natl Acad Sci USA 95:735–740

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Karp JF et al (2014) Safety, tolerability, and clinical effect of low-dose buprenorphine for treatment-resistant depression in midlife and older adults. J Clin Psychiatry 75:e785–e793

    Article  PubMed  PubMed Central  Google Scholar 

  • Kent JM et al (2016) Efficacy and safety of an adjunctive mGlu2 receptor positive allosteric modulator to a SSRI/SNRI in anxious depression. Prog Neuro-Psychopharmacol Biol Psychiatry 67:66–73

    Article  CAS  Google Scholar 

  • Khajavi D et al (2012) Oral scopolamine augmentation in moderate to severe major depressive disorder: A randomized, double-blind, placebo-controlled study. J Clin Psychiatry 73:1428–1433

    Article  CAS  PubMed  Google Scholar 

  • Klodzinska A, et al (2002) Group II mGlu receptor agonists inhibit behavioral and electrophysiological effects of DOI in mice. Pharmacol. Biochem. Behav 73: 327–332

    Article  PubMed  Google Scholar 

  • Kolaj M et al (2014) Intrinsic properties and neuropharmacology of midline paraventricular thalamic nucleus neurons. Front Behav Neurosci 8:132

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Koskinen T, Sirvio J (2001) Studies on the involvement of the dopaminergic system in the 5-HT2 agonist (DOI)-induced premature responding in a five-choice serial reaction time task. Br Res Bull 54:65–75

    Article  CAS  Google Scholar 

  • Koskinen T, Haapalinna A, Sirvio J (2003) Alpha-adrenoceptor-mediated modulation of 5-HT2 receptor agonist induced impulsive responding in a 5-choice serial reaction time task. Pharmacol Toxicol 92:214–225

    Article  CAS  PubMed  Google Scholar 

  • Kosten TR, Morgan C, Kosten TA (1990) Depressive symptoms during buprenorphine treatment of opioid abusers. J Substance Abuse Treatment 7:51–54

    Article  CAS  Google Scholar 

  • Lai MK et al (2005) Loss of serotonin 5-HT2A receptors in the postmortem temporal cortex correlates with rate of cognitive decline in Alzheimer’s disease. Psychopharmacology 179:673–677

    Article  CAS  PubMed  Google Scholar 

  • Lambe EK, Aghajanian GK (2001) The role of Kv1.2-containing potassium channels in serotonin-induced glutamate release from thalamocortical terminals in rat frontal cortex. J Neurosci 21: 9955–9963

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lambe EK, Aghajanian GK (2003) Hypocretin (orexin) induces calcium transients in single spines postsynaptic to identified thalamocortical boutons in prefrontal slice. Neuron 40:139–150

    Article  CAS  PubMed  Google Scholar 

  • Lambe EK, Aghajanian GK (2007) Prefrontal cortical network activity: opposite effects of psychedelic hallucinogens and D1/D5 dopamine receptor activation. Neuroscience 145:900–910

    Article  CAS  PubMed  Google Scholar 

  • Lambe EK, Picciotto MR, Aghajanian GK (2003) Nicotine induces glutamate release from thalamocortical terminals in prefrontal cortex. Neuropsychopharmacology 28:216–225

    Article  CAS  PubMed  Google Scholar 

  • Lambe EK, Olausson P, Horst NK, Taylor JR, Aghajanian GK (2005) Hypocretin and nicotine excite the same thalamocortical synapses in prefrontal cortex: correlation with improved attention in rat. J Neurosci 25:5225–5229

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lambe EK, Liu RJ, Aghajanian GK (2007) Schizophrenia, hypocretin (orexin), and the thalamocortical activating system. Schizophr Bull 33:1284–1290

    Article  PubMed  PubMed Central  Google Scholar 

  • Langlois X et al (2001) Detailed distribution of neurokinin 3 receptors in the rat, guinea pig and gerbil brain: a comparative autoradiographic study. Neuropharmacology 40:242–253

    Article  CAS  PubMed  Google Scholar 

  • Lebrand C et al (1996) Transient uptake and storage of serotonin in developing thalamic neurons. Neuron 17:991–1003

    Article  Google Scholar 

  • Lecrubier Y et al (1980) A beta adrenergic stimulant (salbutamol) versus clomipramine in depression: a controlled study. Br J Psychiatry 136:354–358

    Article  CAS  PubMed  Google Scholar 

  • Li N et al (2010) mTOR-dependent synapse formation underlies the rapid antidepressant effects of NMDA antagonists. Science 329:959–964

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Li N et al (2011) Glutamate N-methyl-D-aspartate receptor antagonists rapidly reverse behavioral and synaptic deficits caused by chronic stress exposure. Biol Psychiatry 69:754–761

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Liu RJ, Fuchikami M, Dwyer JM, Lepack AE, Duman RS, Aghajanian GK (2013) GSK-3 inhibition potentiates the synaptogenic and antidepressant-like effects of subthreshold doses of ketamine. Neuropsychopharmacology 38:2268–2277

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lorke DE et al (2006) Serotonin 5-HT2A and 5-HT6 receptors in the prefrontal cortex of Alzheimer and normal aging patients. BMC Neurosci 7:36

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Maes M et al (1999) Pindolol and mianserin augment the antidepressant activity of fluoxetine in hospitalized major depressed patients, including those with treatment resistance. J Clin Psychopharmacol 19:177–182

    Article  CAS  PubMed  Google Scholar 

  • Mansour A et al (1992) A comparison of D1 receptor binding and mRNA in rat brain using receptor autoradiographic and in situ hybridization techniques. Neuroscience 46:959–971

    Article  CAS  PubMed  Google Scholar 

  • Marder SR (1999) Limitations of dopamine-D2 antagonists and the search for novel antipsychotic strategies. Neuropsychopharmacology 21(S6):S117–S121

    Article  CAS  Google Scholar 

  • Marek GJ (2003) Behavioral evidence for μ-opioid and 5-HT2A receptor interactions. Eur J Pharmacol 474:77–83

    Article  CAS  PubMed  Google Scholar 

  • Marek GJ (2009) Activation of adenosine1 (A1) receptors suppresses head shakes induced by a serotonergic hallucinogen in rats. Neuropharmacology 56:1082–1087

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Marek GJ (2012) Activation of adenosine1 receptors induces antidepressant-like, anti-impulsive effects on differential reinforcement of low-rate 72-s behavior in rats. J Pharmacol Exp Ther 341:564–570

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Marek GJ, Aghajanian GK (1998a) 5-HT-induced EPSCs in neocortical layer V pyramidal cells: suppression by µ-opiate receptor activation. Neuroscience 86:485–497

    Article  CAS  PubMed  Google Scholar 

  • Marek GJ, Aghajanian GK (1998b) The electrophysiology of prefrontal 5-HT systems: therapeutic implications for mood and psychosis. Biol Psychiat 44:1118–1127

    Article  CAS  PubMed  Google Scholar 

  • Marek GJ, Aghajanian GK (1999) 5-HT2A or α1-adrenoceptor activation induces excitatory postsynaptic currents in layer V pyramidal cells of the medial prefrontal cortex. Eur J Pharmacol 367:197–206

    Article  CAS  PubMed  Google Scholar 

  • Marek GJ, Seiden LS (1988) Effects of selective 5-hydroxytryptamine-2 and nonselective 5-hydroxytryptamine antagonists on the differential-reinforcement-of-low-rate 72-second schedule. J Pharmacol Exp Ther 244(2):650–658

    CAS  PubMed  Google Scholar 

  • Marek GJ, Zhang C (2008) Activation of metabotropic glutamate 5 (mGlu5) receptors induces spontaneous excitatory synaptic currents in layer V pyramidal cells of the rat prefrontal cortex. Neurosci Lett 442(3):239–243

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Marek GJ, Li AA, Seiden LS (1989) Selective 5-hydroxytryptamine2 antagonists have antidepressant-like effects on differential-reinforcement-of-low-rate 72-second schedule. J Pharmacol Exp Ther 250(1):52–59

    CAS  PubMed  Google Scholar 

  • Marek GJ et al (2000) Physiological antagonism between 5-hydroxytryptamine2A and group II metabotropic glutamate receptors in prefrontal cortex. J Pharmacol Exp Ther 292:76–87

    CAS  PubMed  Google Scholar 

  • Marek GJ et al (2001) A major role for thalamocortical afferents in serotonergic hallucinogen receptor function in the rat neocortex. Neuroscience 105:379–392

    Article  CAS  PubMed  Google Scholar 

  • Marek GJ et al (2003) Synergistic action of 5-HT2A antagonists and selective serotonin reuptake inhibitors in neuropsychiatric disorders. Neuropsychopharmacology 28:402–412

    Article  CAS  PubMed  Google Scholar 

  • Marek GJ et al (2005) The selective 5-HT2A receptor antagonist M100907 enhances antidepressant-like behavioral effects of the SSRI fluoxetine. Neuropsychopharmacology 30:2205–2215

    Article  CAS  PubMed  Google Scholar 

  • Marek GJ, Day M, Hudzik TJ (2016) The utility of impulsive bias and altered decision making as predictors of drug efficacy and target selection: rethinking behavioral screening for antidepressant drugs. J Pharmacol Exp Ther 356:534–548

    Article  CAS  PubMed  Google Scholar 

  • Marner L et al (2011) The reduction of baseline serotonin 2A receptors in mild cognitive impairment is stable at two-year follow-up. J Alzheimers Dis 23:453–459

    Article  PubMed  Google Scholar 

  • Meltzer CC et al (1999) PET imaging of serotonin type 2A receptors in late-life neuropsychiatric disorders. Am J Psychiatry 156:1871–1878

    CAS  PubMed  Google Scholar 

  • Meltzer HY et al (2004) Placebo-controlled evaluation of four novel compounds for the treatment of schizophrenia and schizoaffective disorders. Am J Psychiatry 161:975–984

    Article  PubMed  Google Scholar 

  • Meltzer HY et al (2010) Pimavanserin, a serotonin(2A) receptor inverse agonist, for the treatment of parkinson’s disease psychosis. Neuropsychopharmacology 35:881–892

    Article  CAS  PubMed  Google Scholar 

  • Meltzer HY et al (2012) Pimavanserin, a selective serotonin (5-HT)2A-inverse agonist, enhances the efficacy and safety of risperidone, 2 mg/day, but does not enhance efficacy of haloperidol, 2 mg/day: comparison with reference dose risperidone, 6 mg/day. Schizophr Res 141:144–152

    Article  PubMed  Google Scholar 

  • Miner LAH et al (2003) Ultrastructural localization of serotonin2A receptors in the middle layers of the rat prelimbic prefrontal cortex. Neuroscience 116:107–117

    Article  CAS  PubMed  Google Scholar 

  • Mitrano DA et al (2012) Alpha-1 adrenergic receptors are localized on presynaptic elements in the nucleus accumbens and regulate mesolimbic dopamine transmission. Neuropsychopharmacology 37:2161–2172

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Moore NA et al (1992) The pharmacology of olanzapine, a novel “atypical” antipsychotic agent. J Pharmacol Exp Ther 262:545–551

    CAS  PubMed  Google Scholar 

  • Moreno JL et al (2011) Metabotropic glutamate mGlu2 receptor is necessary for the pharmacological and behavioral effects induced by hallucinogenic 5-HT2A receptor agonists. Neurosci Lett 493:76–79

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Moreno JL et al (2012) Identification of three residues essential for 5-hydroxtryptamine 2A-metabotropic glutamate 2 (5-HT2A-mGlu2) receptor heteromerizaiton and its psychoactive behavioral function. J Biol Chem 287:44301–44319

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Muguruza C et al (2014) Evaluation of 5-HT2A and mGlu2/3 receptors in postmortem prefrontal cortex of subjects with major depressive disorder: effect of antidepressant treatment. Neuropharmacology 86:311–318

    Article  CAS  PubMed  Google Scholar 

  • Nacca A et al (1998) Brain-to-blood partition and in vivo inhibition of 5-hydroxytryptamine reuptake and quipazine-mediated behaviour of nefazodone and its main active metabolites in rodents. Br J Pharmacol 1998:1617–1623

    Article  Google Scholar 

  • Narboux-Neme N et al (2008) Serotonin transporter transgenic (SERTcre) mouse line reveals developmental targets of serotonin specific reuptake inhbitors (SSRIs). Neuropharmacology 55:994–1005

    Article  CAS  PubMed  Google Scholar 

  • Nelson JC, Papakostas GI (2009) Atypical antipsychotic augmentation in major depressive disorders: A meta-analysis of placebo-controlled randomized trials. Am J Psychiatry 166:980–991

    Article  PubMed  Google Scholar 

  • Neto FL et al (2000) Differential distribution of metabotropic glutamate receptor subtype mRNAs in the thalamus of the rat. Brain Res 854:93–105

    Article  Google Scholar 

  • Nicholas AP, Pieribone VA, Hokfelt T (1993) Cellular localization of messenger RNA for beta-1 and beta-2 adrenergic receptors in rat brain: an in situ hybridization study. Neuroscience 56:1023–1039

    Article  CAS  PubMed  Google Scholar 

  • Nikiforuk A, Popik P, Drescher KU, van Gaalen M, Relo A-L, Mezler M, Marek G, Schoemaker H, Gross G, Bespalov A (2010) Effects of a positive allosteric modulatory of group II metabotropic glutamate receptors, LY487379, on cognitive flexibility and impulsive-like responding in rats. J Pharmacol Exp Ther 335:665–673

    Article  CAS  PubMed  Google Scholar 

  • O’Donnell JM (1990) Behavioral effects of beta adrenergic agonists and antidepressant drugs after down-regulation of beta-2 adrenergic receptors by clenbuterol. J Pharmacol Exp Ther 254(1):147–157

    PubMed  Google Scholar 

  • O’Donnell JM (1993) Effects of the beta-2 adrenergic agonist zinterol on DRL behavior and locomotor activity. Psychopharmacology 113:89–94

    Article  PubMed  Google Scholar 

  • O’Donnell JM (1987) Effects of clenbuterol and prenalterol on performance during differential reinforcement of low response rate in the rat. J Pharmacol Exp Ther 241:68–75

    PubMed  Google Scholar 

  • O’Donnell JM (1988) Behavioral consequences of activation of beta adrenergic receptors by clenbuterol: evidence for mediation by the central nervous system. Br Res 21(3):491–497

    Google Scholar 

  • O’Donnell JM, Frith S, Wilkens J (1994) Involvement of beta-1 and beta-2 adrenergic receptors in the antidepressant-like effects of centrally administered isoproterenol. J Pharmacol Exp Ther 271:246–254

    PubMed  Google Scholar 

  • O’Donnell JM, Marek GJ, Seiden LS (2005) Antidepressant effects assessed using behavior maintained under a differential-reinforcement-of-low-rate (DRL) operant schedule. Neurosci Biobehav Rev 29:785–798

    Article  PubMed  CAS  Google Scholar 

  • Palucha-Poniewierg A et al (2008) Peripheral administration of group III mGlu receptor agonist ACPT-I exerts potential antipsychotic effects in rodents. Neuropharmacology 55:517–524

    Article  CAS  Google Scholar 

  • Parkinson Study Group (1999) Low-dose clozapine for the treatment of drug-induced psychosis in Parkinson’s disease. N Eng J Med 340:757–763

    Article  Google Scholar 

  • Passetti F, Dalley JW, Robbins TW (2003) Double dissociation of serotonergic and dopaminergic mechanisms on attentional performance using rodenet five-choice reaction time test. Psychopharmacology 2003:136–145

    Article  CAS  Google Scholar 

  • Peroutka SJ, Lebovitz RM, Snyder SH (1981) Two distinct central serotonin receptors with different physiological function. Science 212:827–829

    Article  CAS  PubMed  Google Scholar 

  • Perry EK et al (1984) Cortical serotonin-S2 receptor binding abnormalities in patients with Alzheimer’s disease: comparisons with Parkinson’s disease. Neurosci Lett 51:353–357

    Article  CAS  PubMed  Google Scholar 

  • Petrou M, Kotagel V, Bohnen NI (2012) An update on brain imaging in Parkinson’s dementia. Imaging Med 4:201–213

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Preskorn SH et al (2008) An innovative design to establish proof of concept of the antidepressant effects of the NR2B subunit selective N-methyl-D-aspartate antagonist, CP-101,606, in patients with treatment-refractory major depressive disorder. J Clin Psychopharmacol 28:631–637

    Article  CAS  PubMed  Google Scholar 

  • Rainbow TC, Parsons B, Wolfe BB (1984) Quantitative autoradiography of β1- and β2-adrenergic receptors in rat brain. Proc Natl Acad Sci USA 81:1585–1589

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ramanathan S, Glatt SJ (2009) Serotonergic genes in psychosis of Alzheimer dementia: meta-analysis. Am J Geriatr Psychiatry 17:839–846

    Article  PubMed  Google Scholar 

  • Rasmussen NB et al (2016) 5-HT2A receptor binding in the frontal cortex of Parkinson’s disease patients and alpha-synuclein overexpressing mice: a post-mortem study. Parkinson’s Disease 2016

    Article  CAS  Google Scholar 

  • Rekling JC (2004) NK-3 receptor activation depolarizes and induces an after-depolarization in pyramidal neurons in gerbil cingulate cortex. Br Res Bull 63:85–90

    Article  CAS  Google Scholar 

  • Reynolds GP et al (1984) Reduced binding of [3H]ketanserin to cortical 5-HT2 receptors in senile dementia of the Alzheimer type. Neurosci Lett 44:47–51

    Article  CAS  PubMed  Google Scholar 

  • Rigby M, O’Donnell R, Rupniak NM (2005) Species differences in tachykinin receptor distribution: further evidence that the substance P (NK1) receptor predominates in human brain. J Comp Neurol 490:335–353

    Article  CAS  PubMed  Google Scholar 

  • Rojas-Corrales, MO, Gilbert-Rahola J, Mico JA (2007) Role of atypical opiates in OCD. Experimental approach through the study of 5-HT(2A/C) receptor-mediated behavior. Psychopharmacology 190: 221–231

    Article  PubMed  CAS  Google Scholar 

  • Rojoz Z (2012) Effect of co-treatment with mirtazapine and risperidone in animal models of the positive symptoms of schizophrrenia in mice. Pharmacol Rep 64:1567–1572

    Article  Google Scholar 

  • Romano C et al (1995) Distribution of metabotropic glutamate receptor mGluR5 immunoreactivity in rat brain. J. Comp. Neurol. 355:455–469

    Article  CAS  PubMed  Google Scholar 

  • Rorick-Kehn LM et al (2007) Pharmacological and pharmacokinetic properties of a structurally novel, potent, and selective metabotropic glutamate 2/3 receptor agonist: In vitro characterization of agonist (-)-(1R,4S,5S,6S)-4-Amino-2-sulfonylbicyclo[3.1.0]-hexane-4,6-dicarboxylic acid (LY404039). J Pharmacol Exp Ther 321:308–317

    Article  CAS  PubMed  Google Scholar 

  • Rotaru DC, Lewis DA, Gonzalez-Burgos G (2007) Dopamine D1 receptor activation regulates sodium-dependent EPSP amplication in rat prefrontal cortex pyramidal neurons. J Physiol 581(3):981–1000

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Saffroy M et al (2003) Autoradiographic distribution of tachykinin NK2 binding sites in the rat brain: comparison with NK1 and NK3 binding sites. Neuroscience 116:761–773

    Article  CAS  PubMed  Google Scholar 

  • Sanchez C, Arnt J (2000) In-vivo assessment of 5-HT2A and 5-HT2C antagonistic properties of newer antipsychotics. Behav Pharmacol 11:291–298

    Article  CAS  PubMed  Google Scholar 

  • Santana N, Mengod G, Artigas F (2012) Expression of α1-adrenergic receptors in rat prefrontal cortex: cellular co-localization with 5-HT2A receptors. Int J Neuropsychopharmacol 16:1139–1151

    Article  PubMed  CAS  Google Scholar 

  • Santhosh L et al (2009) Regional distribution and behavioral correlates of 5-HT(2A) receptors in Alzheimer’s disease with [(18)F]deuteroaltanserin and PET. Psychiatry Res 173:212–217

    Article  CAS  PubMed  Google Scholar 

  • Schreiber R et al (1995) (1-(2,5-Dimethoxy-4 iodophenyl)-2-aminopropane)-induced head-twitches in the rat are mediated by 5-hydroxytryptamine(5-HT)2A receptors: Modulation by novel 5-HT2A/2C antagonists, D1 antagonists and 5-HT1A agonists. J Pharmacol Exp Ther 273:101–112

    CAS  PubMed  Google Scholar 

  • Shaw E, Woolley DW (1956) Some serotoninlike activities of lysergic acid diethylamide. Science 124:121–122

    Article  CAS  PubMed  Google Scholar 

  • Shughrue PJ, Lane MV, Merchenthaler I (1996) In situ hybridization analysis of the distribution of neurokinin-3 mRNA in the rat central nervous system. J Comp Neurol 372:395–414

    Article  CAS  PubMed  Google Scholar 

  • Simon P et al (1984) Beta-Receptor Stimulation in the Treatment of Depression. In: Usdin E (ed) Frontiers in Biochemical and Pharmacological Research in Depression, Raven PRess, New York, p 293

    Google Scholar 

  • Simonyi A et al (2005) Expression of groups I and II metabotropic glutamate receptors in the rat brain during aging. Brain Res 1043(1–2):95–106

    Article  CAS  PubMed  Google Scholar 

  • Slawinska A et al (2013) The antipsychotic-like effects of positive allosteric modulators of metabotropic glutamate mGlu4 receptors in rodents. Br J Pharmacol 169:1824–1839

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Stutzman GE, Marek GJ, Aghajanian GK (2001) Adenosine preferentially suppresses serotonin2A receptor-enhanced excitatory postsynaptic currents in layer V neurons of the rat medial prefrontal cortex. Neuroscience 105:55–69

    Article  Google Scholar 

  • Talpos JC, Wilkinson LS, Robbins TW (2006) A comparison of multiple 5-HT receptors in two tasks measuring impulsivity. J. Psychopharmacol. 20:47–58

    Article  CAS  PubMed  Google Scholar 

  • Tizabi Y et al (2001) Nicotine attenuates DOI-induced head-twitch response in mice: Implications for Tourette Syndrome. Prog. Neuro-Psychopharmacol. & Biol. Psychiat. 25:1445–1457

    Article  CAS  Google Scholar 

  • Trillo L et al (2013) Ascending monoaminergic systems alterations in Alzheimer’s disease. Translating basic science into clinical care. Neurosci Biobehav Rev 37:1363–1379

    Article  CAS  PubMed  Google Scholar 

  • Vinals X et al (2015) Cognitive impairment induced by delta9-tetrahydrocannabinol occurs through heteromers between cannobinoid CB1 and serotonin 5-HT2A receptors. PLoS Biol 13:e1002194

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Voleti B, Navarria A, Liu RJ, Banasr M, Li M, Terwilliger R, Sanacora G, Eid T, Aghajanian G, Duman RS (2013) Scopolamine rapidly increases mammalian target of rapamycin complex 1 signaling, synaptogenesis, and antidepressant behavioral responses. Biol Psychiatry 74:742–749

    Article  CAS  PubMed  Google Scholar 

  • Vollenweider FX et al (1998) Psilocybin induces schizophrenia-like psychosis in humans via a serotonin-2 agonist action. NeuroReport 9:3897–3902

    Article  CAS  PubMed  Google Scholar 

  • Weisstaub NV et al (2006) Cortical 5-HT2A receptor signalling modulates anxiety-like behaviors in mice. Science 313:536–540

    Article  CAS  PubMed  Google Scholar 

  • Wettstein JG, Host M, Hitchcock JM (1999) Selectivity of action of typical and atypical anti-psychotic drugs as antagonists of the behavioral effects of 1-[2,5-dimethoxy-4-iodophenyl]-2-aminopropane (DOI). Prog Neuropsychopharmacol Biol Psychiatry 23:533–544

    Article  CAS  PubMed  Google Scholar 

  • Wieronska JM et al (2012) Opposing efficacy of group III mGlu receptor activators, LSP1-2111 and AMN082, in animal models of positive symptoms of schizophrenia. Psychopharmacology 220:481–494

    Article  CAS  PubMed  Google Scholar 

  • Wieronska JM et al (2013) The reversal of cognitive, but not negative or positive symptoms of schizophrenia by the mGlu2/3 receptor agonist, LY379268, is 5-HT1A dependent. Behav Brain Res 256:298–304

    Article  CAS  PubMed  Google Scholar 

  • Willins DL, Meltzer HY (1997) Direct injection of 5-HT2Areceptor agonists into the medial prefrontal cortex produces a head-twitch response in rats. J Pharmacol Exp Ther 282:699–706

    CAS  PubMed  Google Scholar 

  • Wischhof L, Koch M (2012) Pretreatment with the mGlu2/3 receptor agonist LY379268 attenuates DOI-induced impulsive responding and regional c-Fos protein expression. Psychopharmacology 219:387–400

    Article  CAS  PubMed  Google Scholar 

  • Wischhof, L., K.J. Hollensteiner, and M. Koch, Impulsive behavior in rats induced by intracortical DOI infusions is antagonized by co-administration of an mGlu2/3 receptor agonist. Behav. Pharmacol., 2011. 22: p. 805–813

    Article  CAS  PubMed  Google Scholar 

  • Wright RA, Schoepp DD (2003) Effect of chronic exposure to mGlu2/3 receptor ligands (LY354740, LY379268 or LY341495) or antipsychotic agents clozapine or haloperidol on binding to mGlu2/3 and 5-HT2A receptors in rat prelimbic cortex. Neuroscience Meeting Planner, Society for Neuroscience

    Google Scholar 

  • Wright RA et al (2013) CNS distribution of metabotropic glutamate 2 and 3 receptors: transgenic mice and [3H]LY459477 autoradiography. Neuropharmacology 66:89–98

    Article  CAS  PubMed  Google Scholar 

  • Zarate CA et al (2006) A randomized trial of an N-methyl-D-aspartate antagonist in treatment-resistant major depression. Arch Gen Psychiatry 63:856–864

    Article  CAS  PubMed  Google Scholar 

  • Zhang C, Marek GJ (2007) Group III metabotropic glutamate receptor agonists selectively suppress excitatory synaptic currents in the rat prefrontal cortex induced by 5-hydroxytryptamine2A receptor stimulation. J Pharmacol Exp Ther 320:437–447

    Article  CAS  PubMed  Google Scholar 

  • Zhang C, Marek GJ (2008a) AMPA receptor involvement in 5-hydroxytryptamine2A receptor-mediated pre-frontal cortical excitatory synaptic currents and DOI-induced head shakes. Prog Neuro-Psychopharmacol Biol Psychiatry 32:62–71

    Article  CAS  Google Scholar 

  • Zhang C, Marek GJ (2008b) AMPA receptors involvement in 5-hydroxytryptamine2A receptor-mediated prefrontal cortical excitatory synaptic currents and DOI-induced head shakes. Prog. Neuropsychopharmacol. & Biol. Psychiatry 32:62–71

    Article  CAS  Google Scholar 

  • Zhang L, Renaud LP, Kolaj M (2009) Properties of T-Type Ca2+ channel-activated slow afterhyperpolarization in thalamic paraventricular nucleus and other thalamic midline neurons. J Neurophysiol 101:2741–2750

    Article  CAS  PubMed  Google Scholar 

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  1. Global Medical Science, CNS and Pain, Astellas Pharma Global Development, 1 Astellas Way, Northbrook, IL, 60062, USA

    Gerard J. Marek

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  1. Department of Psychiatry, University of California San Diego, La Jolla, CA, USA

    Adam L. Halberstadt

  2. Psychiatric University Hospital, Heffter Research Center Zurich, University of Zurich, Zurich, Switzerland

    Franz X. Vollenweider

  3. Division of Chemical Biology and Medicinal Chemistry, University of North Carolina, Chapel Hill, NC, USA

    David E. Nichols

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Marek, G.J. (2017). Interactions of Hallucinogens with the Glutamatergic System: Permissive Network Effects Mediated Through Cortical Layer V Pyramidal Neurons. In: Halberstadt, A.L., Vollenweider, F.X., Nichols, D.E. (eds) Behavioral Neurobiology of Psychedelic Drugs. Current Topics in Behavioral Neurosciences, vol 36. Springer, Berlin, Heidelberg. https://doi.org/10.1007/7854_2017_480

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