Interdepartmental Neuroscience Program, Section of Neurobiology, and Departments of Psychiatry and Pharmacology, Yale University School of Medicine, New Haven, CT, USA
![]() |
Abstract |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
![]() |
Introduction |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
A striking effect of 5-HT is to increase the frequency and amplitude of spontaneous (non-electrically evoked) excitatory post-synaptic currents (EPSCs) in neurons recorded in vitro in the mid-layers of the frontal cortex. The modulation of glutamate release is mediated by the activation of 5-HT2A receptors in the cerebral cortex and can be blocked by MDL 100907, an antagonist selective for the 5-HT2A receptor (Aghajanian and Marek, 1997). While the prefrontal neurons displaying 5-HT-evoked EPSCs were presumed to be layer V pyramidal cells (Aghajanian and Marek, 1997
), their morphology and laminar position have not been identified and confirmed with anatomical methods. The increase in EPSC amplitude may be due to a postsynaptic mechanism, whereas a presynaptic mechanism appears to underlie the 5-HT-induced increase in EPSC frequency. Although the 5-HT-induced EPSCs can be blocked by adding tetrodotoxin or by removing calcium from the bath, they do not appear to be impulse driven since neurons in the brain slice are rarely induced to fire by bath application of 5-HT (Marek and Aghajanian, 1998b
). Instead, the 5-HT-induced increase in EPSCs appears to result from a focal mechanism involving an increase in glutamate release from excitatory nerve terminals impinging upon the apical dendrite (Aghajanian and Marek, 1997
).
Thalamic afferents have been suggested as the possible source of these excitatory axon terminals which release glutamate onto the apical dendrites of layer V neurons (Marek and Aghajanian, 1998a). The µ-opiate receptor agonist DAMGO completely suppresses 5-HT2A-induced EPSCs in the medial prefrontal cortex. Since cortical glutamatergic cells do not appear to express µ-receptor mRNA (Mansour et al., 1994
), this suppression suggests that 5-HT induces glutamate release from subcortical afferents in the frontal cortex (Marek and Aghajanian, 1998a
). Among the glutamatergic efferents to the cerebral cortex, the neurons in the thalamus are notable in that they contain substantial levels of mRNA for the µ-opioid receptor (Mansour et al., 1994
). Moreover, there appears to be a coincidence in the laminar distribution of 5-HT2 receptors and a specific subset of thalamocortical projections in the cortex. An autoradiographic binding study by Blue et al. showed that layer I and superficial layer V have dense bands of 5-HT2 receptors (Blue et al., 1988
), and more recent studies have shown a high density of 5-HT2A receptor immunoreactivity on the apical dendrites of layer V neurons and, to a lesser extent, on nearby presynaptic terminals (Willins et al., 1997
; Hamada et al., 1998
; Jakab and Goldman-Rakic, 1998
). Similarly, the midline and intralaminar nuclei of the thalamus project mainly to layers I and superficial V of the frontal cortex (Berendse and Groenwegen, 1991).
To determine whether 5-HT-induced EPSCs in the neocortex are specific to layer V neurons, we measured the effect of a near-maximal concentration of 5-HT on EPSC frequency and amplitude in different layers of the rat frontal cortex using biocytin-filled electrodes to allow the recorded cells to be visualized and their laminar position to be determined by comparison with adjacent Nissl-stained sections.
![]() |
Materials and Methods |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Preparation of cortical slice
Male rats (50170 g) were deeply anesthetized with choral hydrate (400 mg/kg) and then decapitated. The brains were removed, placed in ice-cold, oxygenated artificial cerebrospinal fluid (ACSF) with equimolar sucrose substituted for NaCl (sucrose-ACSF) (Aghajanian and Rasmussen, 1989) and blocked perpendicular to the cortical surface to ensure that apical dendrites from cells in layer V remained intact. Coronal slices (500 µm thick) of the anterior frontal cortex were cut in sucrose-ACSF using a microslicer (DSK, Dosaka, Japan) and placed in an interface-type chamber. The standard ACSF (pH 7.35) used for slice perfusion was oxygenated with 95% O2/5% CO2 and contained the following: 128 mM NaCl, 3 mM KCl, 1.25 mM NaH2PO4, 10 mM D-glucose, 25 mM NaHCO3, 2 mM CaCl2 and 2 mM MgSO4. The slice was heated slowly from room temperature to ~33°C. There was a recovery period of 2 h prior to beginning the experiment.
Intracellular Recording
Sharp electrodes containing 1 M potassium acetate (3280 M) were used to record from cells in current or voltage clamp. This non-chloride-containing electrode solution was selected to ensure conditions preferential for the detection of EPSCs and contained 1% biocytin for the later visualization of the recorded neurons with avidin-biotin complex binding (ABC; Standard Elite kit, Vector, Burlingame, CA) followed by a diaminobenzidine (DAB) reaction. The holding potential was near the ECl and Vrest for the cells: 70 to 80 mV. Under these conditions, post-synaptic currents have been shown to be completely blocked by AMPA/kainate antagonists (Aghajanian and Marek, 1997
), indicating that they represent glutamatergic EPSCs. The baseline and 5-HT-induced EPSCs were recorded in the discontinuous single-electrode voltage clamp mode of the Axoclamp 2-A (Axon Instruments, Foster City, CA) at a switching frequency of ~6 kHz. Cells were recorded in medial prefrontal [Cg1, Cg2, Cg3 (Zilles, 1985
)] and frontoparietal [Fr1, Fr3, Par1 (Zilles, 1985
)] cortex.
Application of 5-HT
5-HT was bath-applied at 100 µM in ACSF. Previous work (Aghajanian and Marek, 1997) has shown that this concentration gives a near-maximal increase in EPSC frequency. Exposure to 5-HT was limited to 1 min and followed by at least a 5 min wash-out in order to avoid desensitization.
Data Collection and Analysis
P-Clamp software (Axon Instruments) via a Digidata 1200 interface was used for data collection. Cell and spike characteristics were measured using Clampfit software (Axon Instruments). EPSC frequency and amplitude were measured with the Mini Analysis Program software (Synaptosoft, Leonia, NJ). Statistical comparisons of changes in each cell's response to 5-HT with made using the non-parametric Kolmogorov-Smirnov two-tailed test for distributions (Goodman, 1954), with a significance criterion of P = 0.01. A one-factor analysis of variance (ANOVA) followed by post-hoc Scheffé F-tests were used to make statistical comparisons of the frequency changes from baseline for the three layers.
Histochemistry
As described above, the electrodes were filled with a 1 M potassium acetate solution containing 1% biocytin. After the cell characteristics and response to 5-HT were measured, the cells were held for an additional 1530 min to allow for diffusion of biocytin to the distal portions of the apical and basal dendrites. To allow visual confirmation of the laminar position of each cell, electrode penetrations were minimized and a maximum of three cells per slice were tested and filled. To establish that the slice was in good condition (based on preliminary evidence that hypoxia decreases the 5-HT response), each layer II/III or layer VI cell was obtained only after a layer V cell had been confirmed to have an increase in EPSC frequency after bath application of 100 µM 5-HT.
The agranular nature of the medial prefrontal cortex, which lacks a discernible layer IV, makes the distinction between layers II/III and V difficult to resolve. This distinction is much clearer in the lateral regions of frontal cortex. Since there is a sizeable response to 5-HT in the lateral as well as medial cortex (Aghajanian and Marek, 1997), cells were selected in both of these areas. The boundary between layers II and III is indistinguishable in both the medial and lateral frontal cortex of the rat.
Each slice was immediately post-fixed in 4% paraformaldehyde for 48 h at 4°C. Slices were cryoprotected in 20% sucrose solution and then resectioned to 80 µm on a freezing microtome. The sections were incubated for 3 h in serum solution with Triton X-100 to allow permeation and to block nonspecific binding. After several washes, the sections were incubated with ABC (Standard Elite kit) at 4°C overnight. A nickel-intensified DAB reaction was used to visualize the biocytin-filled cells. Sections were dehydrated in alcohol and cleared in xylene before being mounted on glass slides with cytoseal. Nissl staining of an adjacent section was used to confirm the laminar distribution of the filled cells.
![]() |
Results |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
|
|
|
|
|
|
![]() |
Discussion |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Receptor Localization
These findings are consistent with an earlier autoradiography study showing a dense band of 5-HT2A receptor binding in superficial layer V of both medial and lateral frontal cortex (Blue et al., 1988). Recent immunohistochemical studies in rat have demonstrated a particularly high density of 5-HT2A receptors in layer V cells, along their apical dendrites, and in the adjacent neuropil, although there is uncertainty about the degree of membrane insertion and the presence of 5-HT2A receptors in spines (Willins et al., 1997
; Hamada et al., 1998
; Cornea-Hébert et al., 1999
). The localization is consistent with an electrophysiological study showing hot spotsin the vicinity of the apical dendrite locations where the iontophoresis of 5-HT increases EPSC frequency at the soma (Aghajanian and Marek, 1997
). Immunohistochemical and autoradiographic analyses of 5-HT2A receptors in monkey and human neocortex also show an intense band of labeling in layer V, but with additional label in layer III (Burnet et al., 1995
; Pasqualetti et al., 1996
; Jakab and Goldman-Rakic, 1998
). This finding raises the question of how 5-HT would affect spontaneous EPSCs in layer III pyramidal cells of primate neocortex. However, a recent study by Newberry et al. (Newberry et al., 1999
) found that 5-HT did not increase the frequency or amplitude of EPSCs in layer III of human frontal cortex (Newberry et al., 1999
), suggesting that to this extent there is similarity in the laminar distribution of the 5-HT response across species. While most of the 5-HT2A receptor is located postsynaptically, there is also evidence for a presynaptic location (Jakab and Goldman-Rakic, 1998
; Leysen et al., 1982
). Differences between the immunohistochemical and physiological localization would be expected if increase in EPSCs results from the activation of a lesser population of presynaptic 5-HT2A receptors.
Projections to the Frontal Cortex
Previous work suggests that the activation of the 5-HT2A receptor modulates glutamate release from only a subset of glutamatergic projections to the apical dendrites of layer V pyramidal cells (Marek and Aghajanian, 1998a). The 5-HT-induced EPSCs appear to result from increased glutamate release from local terminals rather than an increase in impulse flow (Aghajanian and Marek, 1997
), since the relevant cell bodies are not in the slice. This conclusion is based partly on the fact that agonists of µ-opiate receptors can completely suppress the 5-HT-induced increases in EPSC frequency. Since cortical neurons do not appear to express µ-receptor mRNA (Mansour et al., 1994
), and since removal of all afferents to anterior cingulate cortex results in a dramatic decrease in µ-receptor binding (Vogt et al., 1995
), the relevant glutamatergic terminals are likely subcortical in origin (Marek and Aghajanian, 1998a
). The most likely sources are the midline and intralaminar nuclei which project to layers I and superficial layer V of the frontal cortex (Berendse and Groenwegen, 1991), layers which have dense bands of 5-HT2 receptor. While mRNA expression has been found for the 5-HT2A receptor in the midline thalamus (Pazos and Palacios, 1985
; Appel et al., 1990
) and 5-HT2A receptor protein has been found in transport along axonal tracts (Cornea-Hébert et al., 1999
), co-localization of 5-HT2A and µ-opioid receptors on thalamocortical axon terminals has not yet been examined. Ultrastructural analysis has revealed that the intralaminar thalamic projections form asymmetrical synapses on the spines of pyramidal cell dendrites (Marini et al., 1996
).
Larkman has shown that most pyramidal cells have the highest density of spines distal to the initial segment of the apical dendrite (Larkman, 1991). In layer V pyramidal cells, this region of highest spine density tends to fall in superficial layer V, the region of maximal 5-HT2A receptor density and maximal density of projections from the midline and intralaminar nuclei of the thalamus. This is the same region in which EPSC frequency is highly sensitive to the iontophoresis of 5-HT (Aghajanian and Marek, 1997
).
Layer V Projections
The laminar specificity of the 5-HT-induced increase in EPSC frequency is particularly interesting in view of the difference in projections from the different layers. Whereas layer II/III projections tend to be directed to other areas of cortex and layer VI projections mainly target the thalamus as well as some areas of the cortex (DeFelipe and Fariñas, 1992; Groenwegen et al., 1997), layer V pyramidal cells are output neurons with diverse projections to subcortical structures. These neurons have been shown to project to the basal ganglia (Gerfen, 1989
; Levesque et al., 1996
; Groenewegen et al., 1997
) and the thalamus (Giguere and Goldman-Rakic, 1988
; Schwartz et al., 1991
; Deschenes et al., 1994
), as well as many nuclei in the brainstem and midbrain (Neafsey et al., 1986
; Ferino et al., 1987
; Terreberry and Neafsey, 1987
; Zaborszky et al., 1997
; Hajós et al., 1998
; Peyron et al., 1998
) and spinal cord (Deschenes et al., 1994
; Levesque et al., 1996
). Layer V neurons in the medial frontal cortex appear to be involved in determining overall cortical tone and activation levels with projections to the periaquaductal gray matter (Neafsey et al., 1986
), as well as the monoamine-producing nuclei (Dalsass et al., 1981
; Arnsten and Goldman-Rakic, 1984
; Luppi et al., 1995
; Hajós et al., 1998
; Peyron et al., 1998
; Juckel et al., 1999
). The medial frontal cortex is the only source of cortical efferents to the raphe (Aghajanian and Wang, 1977
; Hajos et al., 1998
; Peyron et al., 1998
) and locus coeruleus (Cedarbaum and Aghajanian, 1978
; Luppi et al., 1995
), which respectively produce 5-HT and norepinephrine. Layer V neurons in the medial frontal cortex have also been demonstrated to play a major role in the affective modulation of the visceral or autonomic nervous system (Terreberry and Neafsey, 1987
).
Function
The induction of EPSCs by 5-HT in pyramidal cells of the frontal cortex has previously been shown to be mediated by 5-HT2A receptors (Aghajanian and Marek, 1997; Marek and Aghajanian, 1999
). Psychedelic hallucinogens are potent agonists at the 5-HT2A receptor in the cortex and produce a psychotic syndrome in healthy controls, which in some respects is comparable to that seen in acutely ill patients with schizophrenia (for further discussion of the controversial issues in this comparison, see Gouzoulis-Mayfrank et al. (Gouzoulis-Mayfrank et al., 1998
)]. The effects of hallucinogens, such as psilocybin, include disturbances of spatial and temporal perception, deficits in working and short-term memory, and cognitive dysfunction affecting judgement, planning and mental flexibility (Gouzoulis-Mayfrank et al., 1999
). A recent study by Vollenweider showed definitively that sensory and cognitive effects of the hallucinogen psilocybin can be blocked by pre-administration of 5-HT2 receptor antagonists (Vollenweider et al., 1998
). Both ketanserin and risperidone blocked, in a dose-dependent manner, psilocybin-induced psychosis, perceptual disturbances and spatial working memory deficits. Ketanserin is an antagonist for the 5-HT2 receptor that is 40 times more potent at blocking the 5-HT2A receptor than the 5-HT2C receptor (Roth et al., 1992
). Risperidone is an atypical neuroleptic which has demonstrated 5-HT2A antagonism in addition to a lesser degree of D2 antagonism. In contrast, the typical neuroleptic haloperidol, which is a strong D2 antagonist, did not block the effect of psilocybin in healthy subjects.
In conclusion, there are profound laminar differences in the serotonergic modulation of glutamate transmission. This result is consistent with studies showing laminar differences in the density of the 5-HT2A receptor, in the density of 5-HT axons and in the density of projections from the midline thalamus. Many layer V pyramidal cells send projections to the basal ganglia, brainstem and spinal cord. Imaging and lesion studies suggest that there are thalamocortical-subcortical circuits which are critical for attention, motivation and ability to concentrate (Kinomura et al., 1996; Van Der Werf et al., 1999
). Disrupting these circuits has been shown to have dramatic and deleterious effects on cognitive function. We have shown that 5-HT modulates neural transmission in one aspect of this circuit in vitro: the spontaneous release of glutamate onto layer V pyramidal cells. In vivo, animals placed in novel situations show increases in cortical 5-HT (Reuter and Jacobs, 1996
) and 5-HT- dependent increases in motor activity (Geyer, 1996
). Work from this laboratory suggests that these effects may be linked through the increase of asynchronous glutamatergic transmission (Aghajanian and Marek, 1999a
) preferentially to the output neurons of the cerebral cortex. The potential role of 5-HT2A receptor stimulation as a marker of novelty is further supported by the rapid desensitization of the receptor under normal conditions (Aghajanian and Marek, 1997
) and by the perturbations of cognition and behavior which result from the persistent activation of 5-HT2A receptors by psychedelic hallucinogens.
![]() |
Notes |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Address correspondence to Evelyn K. Lambe, Interdepartmental Neuroscience Program, Yale University School of Medicine, PO Box 208074, New Haven, CT 065208074, USA. Email: evelyn.lambe{at}yale.edu.
![]() |
References |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Aghajanian GK, Marek GJ (1999a) Serotonin, via 5-HT2A receptors, increase EPSCs in layer V pyramidal cells of prefrontal cortex by an asyn-chronous mode of glutamate release. Brain Res 825:161171.[ISI][Medline]
Aghajanian GK, Marek GJ (1999b) Serotonin-glutamate interactions: a new target for antipsychotic drugs. Neuropsychopharmacology 21: S122S133.[ISI]
Aghajanian GK, Rasmussen K (1989) Intracellular studies in the facial nucleus illustrating a simple new method for obtaining viable motoneurons in adult rat brain slices. Synapse 3:331338.[ISI][Medline]
Aghajanian GK, Wang RY (1977) Habenular and other midbrain raphe afferents demonstrated by a modified retrograde tracing technique. Brain Res 122:229242.[ISI][Medline]
Appel NM, Mitchell WM, Garlick RK, Glennon RA, Teitler M, DeSouza EB (1990) Autoradiographic characterization of DOI binding to 5-HT2 and 5-HT1C receptors in rat brain. J Pharmacol Exp Ther 255: 843857.[Abstract]
Arnsten AFT, Goldman-Rakic PS (1984) Selective prefrontal cortical projections to the region of the locus coeruleus and raphe in the rhesus monkey. Brain Res 306:93018.[Medline]
Berendse HW, Groenewegen HJ (1991) Restricted cortical termination fields of the midline and intralaminar thalamic nuclei in the rat. Neuroscience 42:73102.[ISI][Medline]
Blue ME, Yagaloff KA, Mamounas LA, Hartig PR, Molliver ME (1988) Correspondence between 5-HT2 receptors and serotonergic axons in rat neocortex. Brain Res 453:315328.[ISI][Medline]
Breier A (1995) Serotonin, schizophrenia and antipsychotic drug action. Schizophr Res 14:187202.[ISI][Medline]
Burnet PWJ, Eastwood SL, Lacey K, Harrison PJ (1995) The distribution of 5-HT1A and 5-HT2A receptor mRNA in human brain. Brain Res 676:157168.[ISI][Medline]
Cedarbaum JM, Aghajanian GK (1978) Afferent projections to the rat locus coeruleus as determined by a retrograde tracing technique. J Comp Neurol 178:116.[ISI][Medline]
Cornea-Hébert V, Riad M, Wu C, Singh SK, Descarries L (1999) Cellular and subcellular distribution of the serotonin 5-HT2A receptor in the central nervous system of adult rat. J Comp Neurol 409:187209.[ISI][Medline]
Dalsass M, Kiser S, Mendershausen M, German DC (1981) Medial pre-frontal cortical projections to the region of the dorsal periventricular catecholamine system. Neuroscience 6:657665.[ISI][Medline]
Deschenes M, Bourassa J, Pinault D (1994) Corticothalamic projections from layer V cells in rats are collaterals of long-range axons. Brain Res 664:215219.[ISI][Medline]
DeFelipe J, Fariñas I (1992) The pyramidal neuron of the cerebral cortex: morphological and chemical characteristics of the synaptic inputs. Prog Neurobiol 39:563607.[ISI][Medline]
Egan CT, Herrick-Davis K, Miller K, Glennon RA, Teitler M (1998) Agonist activity of LSD and lisuride at cloned 5-HT2A and 5-HT2C receptors. Psychopharmacology 136:409414.[ISI][Medline]
Ferino F, Thierry AM, Saffroy M, Glowinski J (1987) Interhemispheric and subcortical collaterals of medial prefrontal cortical neurons in the rat. Brain Res 417:257266.[ISI][Medline]
Gerfen CR (1989) The neostriatal mosaic: striatal patch-matrix organization is related to cortical lamination. Science 246:385388.[ISI][Medline]
Geyer MA (1996) Serotonergic functions in arousal and motor activity. Behav Brain Res 73:3135.[ISI][Medline]
Giguere M, Goldman-Rakic PS (1988) Mediodorsal nucleus: areal, laminar, and tangential distribution of afferents and efferents in the frontal lobe of rhesus monkeys. J Comp Neurol 277:195213.[ISI][Medline]
Glennon RA, Teitler M, McKenney JD (1984) Evidence for 5-HT2 involvement in the mechanism of action of hallucinogenic agents. Life Sci 35:25052511.[ISI][Medline]
Goodman LA (1954) Kolmogorov-Smirnov tests for psychological research. Psychol Bull 51:60168.
Gouzoulis-Mayfrank E, Habermeyer E, Hermle L, Steinmeyer AM, Kunert HJ, Sass H (1998) Hallucinogenic drug induced resemble acute endogenous psychoses. Eur Psychiat 13:399406.
Gouzoulis-Mayfrank E, Thelen B, Habermeyer E, Kunert HJ, Kovar KA, Lindenblatt H, Hermle L, Spitzer M, Sass H. (1999) Psychopathological, neuroendocrine and autonomic effects of 3,4-methylene-dioxyethyl-amphetamine (MDE), psilocybin and d-methamphetamine in healthy volunteers. Results of an experimental double-blind placebo-controlled study. Psychopharmacology 142:4150.[ISI][Medline]
Groenewegen HJ, Wright CI, Uylings HBM (1997) The anatomical relationships of the prefrontal cortex with limbic structures and the basal ganglia. J Psychopharmacol 11:99106.[ISI][Medline]
Hajós M, Richards CD, Székely AD, Sharp T (1998) An electro-physiological and neuroanatomical study of the medial prefrontal cortical projection to the midbrain raphe nuclei in the rat. Neurosci 87:95108.[ISI][Medline]
Hamada S, Senzaki K, Hamaguchi-Hamada K, Tabuchi K, Yamamoto H, Yamamoto T, Yoshikawa S, Okano H, Okado N (1998) Localization of 5-HT2A-receptor in rat cerebral cortex and olfactory system revealed by immunohistochemistry using two antibodies raised in rabbit and chicken. Mol Brain Res 54:199211.[ISI][Medline]
Jakab RL, Goldman-Rakic PS (1998) 5-Hydroxytryptamine2A serotonin receptors in the primate cerebral cortex: possible site of action of hallucinogenic and antipsychotic drugs in pyramidal cell apical dendrites. Proc Natl Acad Sci USA 95:735740.
Juckel G, Mendlin A, Jacobs BL (1999) Electrical stimulation of rat medial prefrontal cortex enhances forebrain serotonin output: implications for electroconvulsive therapy and transcranial magnetic stimulation in depression. Neuropsychopharmacology 21:393398.
Kinomura S, Larsson J, Gulyas B, Roland PE (1996) Activation by attention of the human reticular formation and thalamic intralaminar nuclei. Science 271:512515.[Abstract]
Larkman AU (1991) Dendritic morphology of pyramidal neurons of the visual cortex of the rat. III. Spine distributions. J Comp Neurol 306: 332343.[ISI][Medline]
Lee MA, Thompson PA, Meltzer HY (1994) Effects of clozapine on cognitive function in schizophrenia. J Clin Psychiatr 55(Suppl B): 8287.[ISI][Medline]
Levesque M, Charara A, Gagnon S, Parent A, Deschenes M (1996) Corticostriatal projections from layer V cells in rat are collaterals of long-range corticofugal axons. Brain Res 709:311315.[ISI][Medline]
Leysen JE, Geerts R, Gommeren W, Verwimp M, Van Gompel P (1982) Regional distribution of serotonin-2 receptor binding sites in the brain and effects of neuronal lesions. Arch Int Pharmacodyn 256:301305.[ISI]
Lieberman JA, Mailman RB, Duncan G, Sikich L, Chakos M, Nichols DE, Kraus JE (1998) Serotonergic basis of antipsychotic drug effects in schizophrenia. Biol Psychiat 44:10991117.[ISI][Medline]
Luppi P-H, Aston-Jones G, Akaoka H, Chouvet G, Jouvet M (1995) Afferent projections to the rat locus coeruleus demonstrated by retrograde and anterograde tracing with cholera-toxin B subunit and Phaseolus vulgaris leucoagglutinin. Neuroscience 65:119160.[ISI][Medline]
Mansour A, Fox CA, Thompson RC, Akil H, Watson SJ (1994) µ-Opioid receptor mRNA expression in the rat CNS: comparison to µ-receptor binding. Brain Res 643:245265.[ISI][Medline]
Marek GJ, Aghajanian GK (1998a) 5-Hydroxytryptamine-induced EPSCs in neocortical layer V pyramidal cell of prefrontal cortex: suppression by µ-opiate receptor activation. Neuroscience 86:485497.[ISI][Medline]
Marek GJ, Aghajanian GK (1998b) The electrophysiology of prefrontal serotonin systems: therapeutic implications for mood and psychosis. Biol Psychiat 44:11181127.[ISI][Medline]
Marek GJ, Aghajanian GK (1999) 5-HT2A receptor or 1-adrenoceptor activation induces excitatory postsynaptic currents in layer V pyramidal cells of the medial prefrontal cortex. Eur J Pharmacol 367:197206.[ISI][Medline]
Marini G, Pianca L, Tredici G (1996) Thalamocortical projection from the parafascicular nucleus to layer V pyramidal cells in frontal and cingulate areas of the rat. Neurosci Lett 203:8184.[ISI][Medline]
Meltzer HY, Nash JF (1991) Effects of antipsychotic drugs on serotonin receptors. Pharmacol Rev 43:587604.[ISI][Medline]
Neafsey EJ, Hurley-Guis KM, Arvantis D (1986) The topographical organization of neurons in the rat medial frontal, insular and olfactory cortex projecting to the solitary nucleus, olfactory bulb, periaqueductal gray and superior colliculus. Brain Res 377:261270.[ISI]
Newberry NR, Footitt DR, Papanastassiou V, Reynolds DJM (1999) Actions of 5-HT on human neocortical neurones in vitro. Brain Res 833:93100.[ISI][Medline]
Pasqualetti M, Nardi I, Ladinsky H, Marazziti D, Cassano GB (1996) Comparative anatomical distribution of serotonin 1A, 1Da and 2A receptor mRNAs in human brain postmortem. Mol Brain Res 39: 223233.[ISI][Medline]
Pazos A, Palacios JM (1985) Quantitative autoradiographic mapping of serotonin receptors in the rat brain. I. Serotonin-1 receptors. Brain Res 346:205230.[ISI][Medline]
Peyron C, Petit J-M, Rampon C, Jouvet M, Luppi P-H (1998) Forebrain afferents to the rat dorsal raphe nucleus demonstrated by retrograde and anterograde tracing methods. Neuroscience 82:443468.[ISI][Medline]
Rasmussen K, Aghajanian GK (1986) Effect of hallucinogens on spontaneous and sensory-evoked locus coeruleus unit activity in the rat: reversal by selective 5-HT2 antagonists. Brain Res 385:395400.[ISI][Medline]
Reuter LE, Jacobs BL (1996) A microdialysis examination of serotonin release in the rat forebrain induced by behavioral/experimental manipulations. Brain Res 739:5769.[ISI][Medline]
Roth BL, Ciaranello RD, Meltzer HY (1992) Binding of typical and atypical antipsychotic agents to transiently expressed 5-HT1C receptors. J Pharmacol Exp Ther 260:13611365.[Abstract]
Schwartz ML, Dekker JJ, Goldman-Rakic PS (1991) Dual mode of corticothalamic synaptic termination in the mediodorsal nucleus of the rhesus monkey. J Comp Neurol 309:289304.[ISI][Medline]
Terreberry RR, Neafsey EJ (1987) The rat medial frontal cortex projects directly to autonomic regions of the brainstem. Brain Res Bull 19: 639649.[ISI][Medline]
Van Der Werf YD, Weerts JGE, Jolles J, Witter MP, Lindeboom J, Scheltens P (1999) Neuropsychological correlates of a right unilateral lacunar thalamic infarction. J Neurol Neurosurg Psychiat 66:3642.
Vogt BA, Wiley RG, Jensen EL (1995) Localization of mu and delta opioid receptors to anterior cingulate afferents and projection neurons and input/output model of mu regulation. Exp Neurol 135:8392.[ISI][Medline]
Vollenweider FX, Vollenweider-Scherpenhuyzen MFI, Babler A, Vogel H, Hell D (1998) Psilocybin induces schizophrenia-like psychosis in humans via a serotonin-2 agonist action. NeuroReport 9:38973902.[ISI][Medline]
Willins DL, Deutch AY, Roth BL (1997) Serotonin 5-HT2A receptors are expressed on pyramidal cells and interneurons in the rat cortex. Synapse 27:7982.[ISI][Medline]
Zaborszky L, Gaykema RP, Swanson DJ, Cullinan WE (1997) Cortical input to the basal forebrain. Neuroscience 79:10511078.[ISI][Medline]
Zilles K (1985) The cortex of the rat: a stereotaxic atlas. Springer-Verlag, Berlin.