This document summarizes several research publications on neuroscience topics: 1. One study found that acetaminophen affects central monoaminergic neurotransmission in rats, increasing serotonin levels in various brain regions and decreasing dopamine metabolites, suggesting monoamines may be involved in its analgesic action. 2. Another study showed that the benzodiazepine triazolam suppresses the induction of long-term potentiation in hippocampal neurons, consistent with its positive modulation of GABA-A receptor function. 3. A third study found that chronic treatment with either a substance P receptor antagonist or conventional antidepressant increases burst firing of neurons in the locus coeruleus, similarly to how imipramine works.

1. Neurosciences publication
ETUDE DU MECANISME D'ACTION CENTRAL DU PARACETAMOL: RELATION AVEC LE SYSTEME
SEROTONINERGIQUE
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Publication Date: Jan 1, 1997
http://www.worldcat.org/oclc/490419896
EFFECTS OF ACETAMINOPHEN ON MONOAMINERGIC SYSTEMS IN THE RAT CENTRAL
NERVOUS SYSTEM.
Naunyn Schmiedebergs Arch Pharmacol. 2001 Dec;364(6):534-7.
Effects of acetaminophen on monoaminergic systems in the rat central nervous system.
Courade JP1, Caussade F, Martin K, Besse D, Delchambre C, Hanoun N, Hamon M, Eschalier A, Cloarec A.
Author information
1UPSA Laboratoires (Bristol-Myers Squibb group), Paris La Defense, France.
Abstract
Although acetaminophen is a well established analgesic, its mechanism of action is still unknown. We
investigated whether this drug could affect central monoaminergic neurotransmission in rats. Significant
increases in serotonin (5-HT) levels were found in the posterior cortex, hypothalamus, striatum,
hippocampus and brain stem, but not spinal cord, 45 min after per os administration of 200-400 mg/kg of
acetaminophen. However, this treatment altered neither the levels of 5-hydroxyindoleacetic acid nor the
accumulation of 5-hydroxytryptophan after blockade of aromatic L-amino acid decarboxylase. On the other
hand, a decrease in both the levels of the dopamine (DA) metabolite, dihydroxyphenylacetic acid, and the
accumulation of dihydroxyphenylalanine were noted in the striatum of acetaminophen-treated rats. Finally,
acetaminophen administration significantly increased noradrenaline (NA) levels in the posterior cortex. In
vitro studies showed that acetaminophen (1 mM) enhanced K+-evoked overflow of [3H]5-HT, but not
[3H]DA and [3H]NA, previously taken up in brain slices, and exerted no direct effect on monoamine oxidase
A, tyrosine hydroxylase and catechol-O-methyl-transferase activities. These results indicate that
acetaminophen affects central monoaminergic neurotransmission, thereby suggesting that monoamines
(especially 5-HT) might participate in its analgesic action.
PMID: 11770008 [PubMed - indexed for MEDLINE]
http://www.ncbi.nlm.nih.gov/pubmed/11770008
TRIAZOLAM SUPPRESSES THE INDUCTION OF HIPPOCAMPAL LONG-TERM POTENTIATION.
Neuroreport. 2004 May 19;15(7):1145-9.
Triazolam suppresses the induction of hippocampal long-term potentiation.
Maubach KA(1), Martin K, Choudhury HI, Seabrook GR.
Author information:
(1)Molecular and Cellular Neuroscience, Merck Sharp and Dohme Research
Laboratories, Terlings Park, Harlow, Essex, CM20 2QR, UK. karen_maubach@merck.com
Benzodiazepines are sedative hypnotics that produce marked anterogradeamnesia in
humans. These pharmacological properties are thought to result from the
potentiation of GABA-A receptor function and subsequent attenuation of long-term
potentiation (LTP), however many reports have suggested this is not the case for
triazolam. Using electrophysiological recordings in a cell line expressing
recombinant GABA-A receptors, we confirm that triazolamis an efficacious

2. positive allosteric modulator of GABA-A receptors. Triazolam also slowed the
decay of spontaneous inhibitory synaptic currents, reduced the amplitude of
fEPSPs elicited during a theta burst and reduced the magnitude of LTP in
hippocampal CA1 neurones in vitro. These data show that triazolam modifies LTP
induction consistent with an enhancement of GABA-A receptor function via
activation of the allosteric benzodiazepine-site.
Copyright 2004 Lippincott Williams and Wilkins
PMID: 15129163 [PubMed - indexed for MEDLINE]
CHRONIC SUBSTANCE P (NK1) RECEPTOR ANTAGONIST AND CONVENTIONAL ANTIDEPRESSANT
TREATMENT INCREASES BURST FIRING OF MONOAMINE NEURONES IN THE LOCUS COERULEUS.
Neuroscience. 2002;109(3):609-17.
Chronic substance P (NK1) receptor antagonist and conventional antidepressant
treatment increases burst firing of monoamine neurones in the locus coeruleus.
Maubach KA(1), Martin K, Chicchi G, Harrison T, Wheeldon A, Swain CJ, Cumberbatch
MJ, Rupniak NM, Seabrook GR.
Author information:
(1)Department of Pharmacology, Merck Sharp & Dohme Neuroscience Research Centre,
Essex CM20 2QR, UK. karen_maubach@merck.com
The mechanism of action of conventional antidepressants (e.g. imipramine) has
been linked to modulation of centralmonoamine systems. Substance P (NK1)
receptor antagonists may have antidepressant and anxiolytic effects in patients
with major depressive disorder and high anxiety but, unlike conventional
antidepressants, are independent of activity at monoamine reuptake sites,
transporters, receptors, or monoamine oxidase. To investigate the possibility
that substance P receptor antagonists influence central monoamine systems
indirectly, we have compared the effects of chronic administration of imipramine
with that of the substance P receptor antagonist L-760735 on the spontaneous
firing activity of locus coeruleus neurones. Electrophysiological recordings were
made from brain slices prepared from guinea-pigs that had been dosed orally every
day for 4 weeks with either L-760735 (3 mg/kg), imipramine (10 mg/kg), or vehicle
(water), or naive animals. Chronic, but not acute, treatment with the substance P
receptor antagonist L-760735, induced burst firing of neurones in the locus
coeruleus. This effect resembles that of the conventional antidepressant
imipramine. However, their effects are dissociable since, in contrast to chronic
imipramine treatment, chronic L-760735 treatment does not cause functional
desensitisation of somatic alpha2 adrenoceptors. The mechanism by which chronic
substance P receptor antagonist or conventional antidepressant treatment
influences the pattern of firing activity of norepinephrine neurones remains to
be elucidated. However, an indirect action in the periphery or distant brain
nuclei has been excluded by the use of the in vitro slice preparation, suggesting
a local site of action in the locus coeruleus.
PMID: 11823070 [PubMed - indexed for MEDLINE]
SUBSTANCE P STIMULATES INHIBITORYSYNAPTIC TRANSMISSION IN THE GUINEA PIG
BASOLATERAL AMYGDALA IN VITRO.

3. 3. Neuropharmacology. 2001 May;40(6):806-17.
Substance P stimulates inhibitory synaptic transmission in the guinea pig
basolateral amygdala in vitro.
Maubach KA(1), Martin K, Smith DW, Hewson L, Frankshun RA, Harrison T, Seabrook
GR.
Author information:
(1)Merck Sharp & Dohme Research Laboratories, Neuroscience Research Centre,
Terlings Park, Eastwick Road, Harlow, Essex CM20 2QR, UK. karen_maubach@merck.com
To determine the physiological role of tachykinin NK1 receptors in the
basolateral nucleus of the amygdala (BLN) we have studied the
electrophysiological effects of substance P (SP) in the absence and presence of
selective tachykinin receptor antagonists in guinea pig brain slices. Recordings
were made from two populations of neurones; spiny pyramidal and stellate
neurones, both thought to be projection neurones. Activation of NK1 receptors
with SP increased the frequency of spontaneous inhibitory postsynaptic potentials
in the majority of cells. This effect was blocked by bicuculline or tetrodotoxin,
but not ionotropic glutamatereceptor antagonists. The enhanced synaptic activity
induced by SP was antagonised by the NK1 receptor antagonist L-760,735 but not by
the less active enantiomer L-781,773 or the NK3 receptor antagonist L-769,927.
Thus in the basolateral nucleus of the guinea pig amygdala, NK1 receptor
activation preferentially stimulates inhibitory synaptic activity. Consistent
with this observation, immunohistochemistry revealed NK1 receptor
immunoreactivity to be largely restricted to a subset of GABA interneurones.
These studies support a physiological role for SP in the regulation of pathways
involved in the control of emotional behaviour.
PMID: 11369034 [PubMed - indexed for MEDLINE]
IDENTIFICATION OF AMINO ACID RESIDUES RESPONSIBLE FOR THE ALPHA5 SUBUNIT BINDING
SELECTIVITY OF L-655,708, A BENZODIAZEPINE BINDINGSITE LIGAND AT THE GABA(A) RECEPTOR.
4. J Neurochem. 2001 Apr;77(2):445-51.
Identification of amino acid residues responsible for the alpha5 subunit binding
selectivity of L-655,708, a benzodiazepine binding site ligand at the GABA(A)
receptor.
Casula MA(1), Bromidge FA, Pillai GV, Wingrove PB, Martin K, Maubach K, Seabrook
GR, Whiting PJ, Hadingham KL.
Author information:
(1)Neuroscience Research Centre, Merck Sharp and Dohme Research Laboratories,
Harlow, Essex, UK.
L-655,708 is a ligand for the benzodiazepine site of the gamma-aminobutyric acid
type A (GABA(A)) receptor that exhibits a 100-fold higher affinity for
alpha5-containing receptors compared with alpha1-containing receptors. Molecular
biology approaches have been used to determine which residues in the alpha5
subunit are responsible for this selectivity. Two amino acids have been

4. identified, alpha5Thr208 and alpha5Ile215, each of which individually confer
approximately 10-fold binding selectivity for the ligand and which together
account for the 100-fold higher affinity of this ligand at alpha5-containing
receptors. L-655,708 is a partial inverse agonist at the GABA(A) receptor which
exhibited no functional selectivity between alpha1- and alpha5-containing
receptors and showed no change in efficacy at receptors containing alpha1
subunits where amino acids at both of the sites had been altered to their alpha5
counterparts (alpha1Ser205-Thr,Val212-Ile). In addition to determining the
binding selectivity of L-655,708, these amino acid residues also influence the
binding affinities of a number of other benzodiazepine (BZ) site ligands. They
are thus important elements of the BZ site of the GABA(A) receptor, and further
delineate a region just N-terminal to the first transmembrane domain of the
receptor alpha subunit that contributes to this binding site.
PMID: 11299307 [PubMed - indexed for MEDLINE]
PHARMACOLOGY OF RECOMBINANT HUMAN GABA(A) RECEPTOR SUBTYPES MEASURED USINGA
NOVEL PH-BASED HIGH-THROUGHPUT FUNCTIONAL EFFICACY ASSAY.
5. J Neurosci Methods. 2000 Jun 30;99(1-2):91-100.
Pharmacology of recombinant human GABA(A) receptor subtypes measured using a
novel pH-based high-throughput functional efficacy assay.
Simpson PB(1), Woollacott AJ, Pillai GV, Maubach KA, Hadingham KL, Martin K,
Choudhury HI, Seabrook GR.
Author information:
(1)Neuroscience Research Centre, Merck Sharp & Dohme Research Laboratories,
Terlings Park, Essex CM20 2QR, Harlow, UK. peter_simpson@merck.com
To facilitate the discovery of novel compounds that modulate human GABA(A)
receptor function, we have developed a high throughput functional assay using a
fluorescence imaging system. L(tk-) cells expressing combinations of human
GABA(A) receptor subunits were incubated with the pH-sensitive dye
2',7'bis-(2-carboxyethyl)-5-(and 6)-carboxyfluorescein, then washed and placed in
a 96-well real-time fluorescence plate reader. In buffer adjusted to pH 6.9 there
was a robust and persisting acidification response to addition of GABA, which was
antagonised by the GABA(A) receptor antagonist bicuculline. The
concentration-response relationship for GABA was modulated by allosteric ligands,
including benzodiazepine (BZ) site agonists and inverse agonists. The effects of
BZ site ligands on the pH response to GABAfor receptors containing
alpha1beta3gamma2, alpha3beta3gamma2 or alpha5beta3gamma2 subunits were well
correlated with results from electrophysiological studies on the same receptor
subunit combinations expressed in Xenopus oocytes. Most modulatory compounds
tested were found to be relatively unselective across the three subunit
combinations tested; however, some showed subtype-dependent efficacy, such as
diazepam, which had highest agonist effects on the alpha3beta3gamma2 subtype,
substantial but lesser agonism on alpha1beta3gamma2 and still substantial but the
least agonism on alpha5beta3gamma2. This indicates that the alpha subunit within
the recombinant receptor expressed in L(tk-) cells can affect the efficacy of the
response to some BZ compounds. Inhibitors of Na(+)/Cl(-) cotransport, anion/anion
exchange and the gastric type of H(+)/K(+) ATPase potently inhibited GABA-evoked
acidification, indicating that multiple transporters areinvolved in the

5. GABA-evoked pH change. This novel fluorescence-based high throughput functional
assay allows the rapid characterizationof allosteric ligands acting on human
GABA(A) receptors.
PMID: 10936648 [PubMed - indexed for MEDLINE]