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Central Neuronal Communication, Neuropeptides, Abused Drugs, and Neuropathology
G.R. Siggins, P. Schweitzer, S. Madamba, T. Krucker, Z. Nie, M. Roberto, R. Vlkolinsky, M. Bajo, A. Mosley, T. Lamp, K. Lindsley,
T. Acosta, I.L. Campbell, L.H. Parsons, L. de Lecea,* J.G. Sutcliffe,* S. Moore,** G. Martin,***
M. Tallent****
* Department of Molecular Biology, Scripps Research
** Duke University, Raleigh-Durham, North Carolina
*** University
of Massachusetts Medical School, Worcester, Massachusetts
**** Drexel University, Philadelphia,
Pennsylvania
For the past 21 years, we have studied mechanisms of neuronal function and synaptic transmission and
the effects thereon of neuropeptides, abused drugs, and neuropathologic insults. We use extracellular,
intracellular, and patch recording of neurons in vitro, and we administer transmitters, drugs,
cytokines, and neurotoxins by micropipettes and by bath superfusion. We activate synaptic transmission
via stimulating electrodes.
We study somatostatin-related neuropeptides that inhibit hippocampal pyramidal neurons and dentate neurons by opening postsynaptic potassium
channels and presynaptically depressing excitatory glutamatergic neurotransmission. We found
that the somatostatin analog cortistatin also increases a hyperpolarization-activated cationic
current. As previously reported, both cortistatin and somatostatin provide an antiepileptic
function and could be treatment targets for seizures, and both depress long-term potentiation,
a cellular model of learning, in the CA1 hippocampus and dentate gyrus. With L. de Lecea, Department
of Molecular Biology, we found that long-term potentiation in the dentate gyrus was blocked in
transgenic mice overexpressing cortistatin and enhanced in mice that lack the gene for cortistatin,
indicating that endogenous cortistatin dampens synaptic plasticity.
We also study drug effects in the hippocampus, nucleus accumbens, and central amygdala, brain regions prominently involved in drug abuse. As
described previously, we found that the opioid-like peptide nociceptin had an inhibitory role
in the hippocampus and that it depressed epileptiform events there, suggesting that endogenous
nociceptin also could dampen seizures. Our new studies of the central amygdala suggest that nociceptin
also decreases presynaptic release of the inhibitory transmitter γ-aminobutyric
acid (GABA) and reverses the effect of ethanol in enhancing GABA release.
Some evidence suggests that receptors for N-methyl-D-aspartate (NMDA) play a role in opiate and ethanol dependence; thus, glutamatergic
synapses could be involved in opiate and alcohol abuse. We previously found that chronic morphine
treatment altered several pharmacologic and biophysical properties of NMDA receptor–mediated
excitatory postsynaptic potentials (EPSPs) in neurons of slices of the nucleus accumbens, in
ways suggestive of changes in the composition or function of the subunits of NMDA receptors. Therefore,
we used patch-clamp recording, pharmacologic studies, and, in collaboration with L. de Lecea,
reverse transcriptase–polymerized chain reaction of freshly isolated nucleus accumbens
neurons and real-time polymerized chain reaction and Western blots of NMDA receptor subunit mRNA
and protein in nucleus accumbens tissue. The combined results suggest that chronic morphine treatment
reduces the number of neurons with multiple types of NR2 subunits (heteromultimeric) and increases
the levels of NR1 and NR2B subunit proteins.
We previously showed that ethanol has complex effects in the hippocampus and nucleus accumbens. It augments GABAA receptor–mediated
inhibitory postsynaptic potentials (IPSPs), but only if presynaptic GABAB receptors
are blocked. In some neurons from the nucleus accumbens (but not in neurons from the hippocampus),
ethanol postsynaptically enhanced responses to exogenous GABA, without GABAB antagonism,
but via activation of metabotropic glutamate receptors. In slices of the central amygdala from
both naive and chronic ethanol-treated rats, ethanol consistently increased the amplitude of
GABAergic IPSPs (without GABAB blockade) and decreased glutamatergic EPSPs, indicating
that ethanol reciprocally alters GABAergic and glutamatergic systems in the central amygdala,
with no tolerance after chronic ethanol treatment. Several tests, including microdialysis studies
with L.H. Parsons, Department of Neuropharmacology, indicate that the effect of ethanol on IPSPs
is largely presynaptic, enhancing GABA release.
Corticotropin-releasing factor (CRF), reportedly involved in alcohol dependence, also presynaptically enhanced IPSPs in mouse and
rat central amygdala. Interestingly, antagonists of CRF receptor 1 or a mutation that deleted
the receptor abolished the effects of both CRF and ethanol, suggesting that the effects of ethanol
are mediated by endogenous CRF. Our recent studies indicate that ethanol increases GABA release
in neurons from the central amygdala in mice with a δ opioid
receptor null mutation more than in neurons of control mice, suggesting that an endogenous opioid
peptide may reduce the effects of ethanol on the GABAergic system.
Acute ethanol treatment also reduced glutamatergic transmission, including NMDA-EPSPs, in the central amygdala. However, the depressant effect
of acute ethanol treatment on NMDA-EPSPs was enhanced, and glutamate release was increased (as
determined by microdialysis in vivo) after chronic ethanol treatment and withdrawal, suggesting
that presynaptic and postsynaptic mechanisms may underlie behavioral sensitization to ethanol.
The postsynaptic effect of chronic ethanol treatment appears to involve a change in the composition
of NMDA receptors to a preponderance of NR2B subunits. These synaptic actions of ethanol and interactions
with neuropeptides may represent novel cellular neuroadaptations that underlie ethanol dependence.
We also use animal models to study dementias due to viral infections, cytokines, and chemokines, as described in the report from T. Krucker,
Department of Neuropharmacology. In collaboration with I.L. Campbell, Department of Neuropharmacology,
we found that exogenous CXC chemokine ligand 10, but not its chronic production in transgenic mice
expressing this chemokine, reduced long-term potentiation by acting on a CXCR3 receptor. Thus,
chemokines, like cytokines, can disrupt aspects of brain function. Our other studies indicated
that the psychostimulant methamphetamine may exacerbate the increased glutamate release and
reduction of long-term potentiation that occurs in transgenic mice expressing the HIV coat protein
gp120.
Publications
Martin, G., Guandano-Ferraz, A.,
Morte, B., Ahmed, S., Koob, G.F., de Lecea, L., Siggins, G.R.
Chronic morphine treatment alters NMDA receptors in neurons freshly isolated from nucleus accumbens.
J. Pharmacol. Exp. Ther., in press.
Nie, Z., Schweitzer, P., Roberts, A.J., Madamba, S.G., Moore, S.D., Siggins, G.R.
Ethanol augments GABAergic transmission in the central amygdala via CRF1 receptors.
Science 303:1512, 2004.
Roberto, M., Schweitzer, P., Madamba, S.G., Stouffer, D.G., Parsons, L.H., Siggins, G.R. Acute
and chronic ethanol alter glutamatergic transmission in rat central amygdala: an in vitro and
in vivo analysis. J. Neurosci. 24:1594, 2004.
Schweitzer. P., Madamba, S.G., Siggins, G.R. The sleep-modulating peptide cortistatin
augments the H-current in hippocampal neurons. J. Neurosci. 23:10884, 2003.
Schweitzer, P., Roberto, M., Madamba, S.G., Siggins, G.R. γ-Hydroxybutyrate
increases a potassium conductance and decreases the H-current in hippocampal neurons via GABAB
receptors J. Pharmacol. Exp. Ther., in press.
Siggins, G.R., Martin, G., Roberto, R., Nie, Z., Madamba, S., de Lecea, L. Glutamatergic transmission
in opiate and alcohol dependence, Ann. N. Y. Acad. Sci. 1003:196, 2003.
Vlkolinsky, R., Siggins, G.R., Campbell, I.L., Krucker, T. Acute exposure to CXC chemokine
ligand 10, but not its chronic astroglial production, alters synaptic plasticity in mouse hippocampal
slices. J. Neuroimmunol. 150:37, 2004.
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