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 Professor
Depts. Psychiatry, Anatomy, Pharmacology, and Neuroscience
New England Medical Center
750 Washington Street
Boston, MA 02111
Phone: 617-636-8936
Email: Ron.Hammer@Tufts.edu
Research Interests:
My laboratory studies plasticity and neural adaptation in mesocorticolimbic
systems. We have focused on the nucleus accumbens (NAc) due to its
involvement in addiction and certain symptoms of schizophrenia (i.e.,
sensorimotor gating deficits), but we are currently developing strategies
for elucidating caudate dysfunction which may afford a more unified
model of etiology in schizophrenia. Furthermore, the lack of plasticity
and consequent behavioral rigidity which this model attributes to
caudate dysfunction are common features of other neuropsychiatric
disorders, such as autism, obsessive-compulsive disorder and Tourette
syndrome. This work is interdisciplinary, involving cellular and
molecular neurobiology and neuropsychopharmacology, and
translational by nature, permitting the extension of our basic research
findings into potential therapies for neuropsychiatric disorders.
Molecular and genetic substrates of neuropsychiatric disorders
Our recent studies examine mechanisms underlying sensorimotor gating
deficits which are altered by stress or drug treatment. Sensorimotor
gating deficits underlie thought disorder and sensory flooding in
patients with schizophrenia, and they can be rigorously quantified
in human and animal subjects by measuring prepulse inhibition of
acoustic startle responses. We discovered that repeated treatment
with selective dopamine D2-like receptor agonists completely reverses
sensorimotor gating deficits in rats. This recovery of sensorimotor
gating depends on stimulation of D3 receptors. Furthermore, functional
recovery lasts for weeks after termination of treatment, and blocks
deficits produced by phencyclidine and other non-competitive NMDA
receptor antagonists. The mechanism underlying recovery involves
heterologous sensitization of cAMP signaling in the NAc; we observed
up-regulation of cAMP-dependent protein kinase (PKA) and enhanced
phosphorylation of the transcription factor cAMP response element
binding protein (CREB). We are currently examining whether phosphoCREB
is required for recovery using adeno-associated viral gene transfer
of a dominant negative CREB mutant into NAc neurons. NAc CREB is
no longer activated during sustained recovery, however, suggesting
that transcriptional regulation by CREB during treatment induces
the expression of additional proteins underlying recovery.
Additional efforts are directed toward identification and characterization
of specific proteins critical to resolution of sensorimotor gating
symptoms. We recently identified differentially-expressed candidate
genes using comparative microarray gene expression profiling.
Using bioinformatics and pathway analyses, we observed that adenosine
A2A receptor gene expression is highly induced, and brain-derived
neurotrophic factor is altered in the NAc by repeated D2-like agonist
treatment. Either or both these proteins could underlie heterologous
sensitization of cAMP signaling associated with reversal of sensorimotor
gating symptoms.
Sensorimotor gating deficits also serve as an endophenotype amenable
to genetic analysis. We utilized prepulse inhibition to determine
putative sensorimotor gating genes in consomic (chromosome
substitution) mouse strains in collaboration with colleagues at
the MIT/Harvard Broad Institute. Thus far, we have identified chromosome
16 as a putative locus, along with two genes that are differentially
expressed and map to a suggestive sensorimotor gating QTL in consomic
mice. One of these is the D3 receptor gene, supporting our hypothesis
that D3 receptor-related neuroadaptation regulates recovery of sensorimotor
gating.
The intracellular adaptation associated with recovery of sensorimotor
gating, enhanced CREB activation, is clinically significant because
it is identical to that observed upon treatment with existing antipsychotic
drugs. Furthermore, the selectivity of this effect in NAc reduces
the possibility of extrapyramidal side effects. Although experimental
inactivation of Gi/Go proteins in the NAc is capable of attenuating
dopamine-induced sensorimotor gating deficits, we showed that coupling
of D2-like receptors to G proteins is not altered by the low doses
of agonist drugs that produce behavioral recovery. Thus, receptor
function remains intact even after chronic treatment. Together,
these data reveal that compensatory neuroadaptation in NAc neurons
has antipsychotic-like effects which may lead to a palliative “cure”
for these schizophrenia symptoms. Future studies will utilize a
different behavioral model, conditioned avoidance responding, to
confirm the antipsychotic efficacy of this approach.
Neuronal and neurochemical effects of stress and psychostimulant
drugs
Various reinforcing drugs as well as stress exposure are known to
induce dopamine release in the NAc. We have shown that repeated
exposure to a salient social stressor in rats leads to the development
of sensorimotor gating deficits, and is associated with induction
of FosB expression in NAc, amygdala and limbic frontal cortex. We
plan to investigate the causative influence of this persistent cortical
Fos expression on NAc dopamine by overexpression of δFosB or a dominant
negative inhibitor of δFosB under the control of a tetracycline-regulated
gene expression system. These and other persistent changes in specific
forebrain circuits may represent the substrate by which stress triggers
the onset or relapse of schizophrenia symptoms in humans.
Recent work explores the role of corticosterone and corticotropin
releasing factor (CRF) in stress-induced brain changes. Our results
reveal that corticosterone is not directly involved; rather, elevated
CRF disrupts sensorimotor gating. This effect is blocked by clozapine
and attenuated by the selective D2-like receptor antagonist, raclopride,
implicating dopamine in the mechanism of CRF-induced sensorimotor
gating disruption. Furthermore, pretreatment with raclopride alters
CRF-induced Fos expression in the NAc and amygdala, suggesting that
these regions mediate CRF-induced sensorimotor gating deficits.
Exposure to social defeat stress also causes behavioral cross-sensitization
to psychostimulants. We have shown that repeated cocaine self-administration
that induces behavioral sensitization selectively increases functional
activation of limbic frontal cortical neurons that innervate the
NAc in response to drug challenge, even in the absence of altered
expression of glutamate receptor subunits in the NAc. We showed
that chronic social stress exposure induces transient expression
of functional µ-opioid receptors in ventral tegmental area
which increases mesolimbic dopamine tone. However, a subsequent
induction of brain-derived neurotrophic factor may underlie the
eventual transition to long-lasting drug cross-sensitization. Thus,
mesocorticolimbic output can convey motivation and control behavior
by regulating various neural circuits utilizing different signaling
mechanisms.
A cognitive neuroscience approach to schizophrenia
Neuroimaging studies of schizophrenia have identified deficits in
various brain regions (e.g., prefrontal, temporal and occipital
cortex), hippocampus, thalamus, striatum, and others. The diversity
of these regions and the breadth of cognitive deficits in schizophrenia
suggests a pervasive disorder. Alternatively, a more parsimonious
explanation might be that deficits in critical striatal neurochemistry
could alter neural response to produce widespread symptoms.
We are developing a testable model of caudate involvement in positive
symptoms of schizophrenia. The basis of this model is that limbic,
motor and cognitive striatum are connected via parallel circuits
which originate and terminate in various cortical regions. Just
as putamen regulates the initiation of motor activity and the generation
of motor patterns, we propose that caudate regulates the initiation
of cognitive activity (i.e., thoughts) and generation of cognitive
patterns (i.e., beliefs). Thus, dysfunction caused by excessive
dopamine in caudate may lead to abnormal thoughts or beliefs related
to specific cortical regions, thereby producing hallucinations or
delusions, the hallmarks of psychosis. Furthermore, reduced glutamatergic
stimulation of caudate would enhance this effect, and deficient
glutamate-associated plasticity would promote behavioral rigidity
and “fixed” cognitive patterns observed in schizophrenia.
Ongoing experiments assess cortical response to intracranial manipulation
of relevant receptors in rat caudate to demonstrate the putative
substrate of these effects.
Recent Publications:
Swerdlow, N.R., A.S. Krupin, M,J. Bongiovanni, J.M. Shoemaker, J.C. Goins and R.P. Hammer: Heritable differences in the dopaminergic regulation of behavior in rats: Relationship to D2-like receptor G protein function, Neuropsychopharmacology, 31(4): 721-729, 2006 .
Petryshen, T.L., A. Kirby, R.P. Hammer, A. Hill, J. Singer, J. Nadeau, M.J. Daly and P. Sklar: Two QTLs for prepulse inhibition of startle on mouse chromosome 16 using chromosome substitution strains, Genetics, 171:1895-904, 2005 .
Culm, K.E., N. Lugo-Escobar, B.T. Hope and R.P. Hammer: Repeated quinpirole treatment reverses sensorimotor gating deficits by increasing cAMP-dependent protein kinase activity and CREB phosphorylation in nucleus accumbens, Neuropsychopharmacology, 29: 1823-1830, 2005.
Covington H.E., T. Kikusui, J. Goodhue, E.M. Nikulina ,R.P. Hammer and K.A. Miczek: Brief social-defeat stress: persistent changes in cocaine taking during binges and zif268 mRNA expression in the amygdala and prefrontal cortex, Neuropsychopharmacology, 30: 310-321, 2005.
Nikulina E.M., K.A. Miczek and R.P. Hammer: Prolonged effects of repeated social defeat stress on mRNA expression and function of µ-opioid receptors in the ventral tegmental area of rats, Neuropsychopharmacology, 30: 1096-1103, 2005.
Miczek K.A., H.E. Covington, Nikulina E.M., and R.P. Hammer: Aggression and defeat: Persistent effects on cocaine self-administration and gene expression in peptidergic and aminergic mesocorticolimbic circuits, Neuroscience and Biobehavioral Reviews, 27: 287-802, 2004.
Nikulina E.M., H.E. Covington, J. Goodhue, L. Ganschow, R.P. Hammer, and K.A. Miczek: Long-term behavioral and neuronal cross-sensitization to amphetamine induced by repeated brief social defeat stress: Fos in the ventral tegmental area and amygdala, Neuroscience, 123: 857-865, 2004.
Culm, K.E. and R.P. Hammer: Recovery of sensorimotor gating deficits without G protein adaptation after chronic dopamine D2-like receptor agonist treatment, Journal of Pharmacology and Experimental Therapeutics, 308:487-494, 2004.
Culm, K.E., A. Lim, J.A. Onton, and R.P. Hammer: Reduced Gi and Go protein function in the nucleus accumbens attenuates sensorimotor gating deficits, Brain Research, 982: 12-18, 2003.
Hammer, R.P.: Neural circuitry and signaling in addiction, pp. 99-124 in: G.B. Kaplan and R.P. Hammer (eds.), Brain Circuitry and Signaling in Psychiatry; Basic Science and Clinical Implications, American Psychiatric Publishing, Inc., 2002.
Hammer, R.P. The neural circuitry and signaling of addiction, in:
G.B. Kaplan and R. P. Hammer (eds.), Brain Signaling and Circuitry
in Psychiatry, American Psychiatric Press, in press, 2000.
Byrnes, JJ. and Hammer, R.P. The disruptive effect of cocaine on
prepulse inhibition is prevented by repeated administration in rats,
Neuropsychopharmacology, 22:551-554, 2000.
Gulledge, C.C., Mann P., Bridges, R.S., Bialos, M. and Hammer,
R.P. Expression of u-opioid receptor mRNA in the medial preoptic
area of juvenile rats, Developmental Brain Research, 119: 269-276,
2000.
Nikulina, E.M., Hammer, R.P., Miczek, K.A. and Kream R.M. Social
defeat stress increases expression of u-opioid receptor-encoding
mRNA in the rat ventral tegmental area, NeuroReport, 10: 3015-3019,
1999.
Search PubMed for a complete listing of Dr. Hammer's publications
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