1 animal models of schizophrenia and depression: studies on the neurobiological basis for...
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Animal Models of Schizophrenia and Depression: Studies on the Neurobiological Basis for Comorbidity with
Drug and Alcohol Abuse
R. Andrew Chambers, M.D. Laboratory for Translational Neuroscience of
Dual Diagnosis Disorders
Institute of Psychiatric Research
Indiana University School of Medicine
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Impact of SUDs in Mental Illness
• Effects on patients:
-diagnostic confusion
-poor compliance/efficacy of standard medications,
-more severe mental illness, risk of violence/suicide, increased hospitalization
- increased medical morbidity/mortality
(Dickey et al 2002; RachBeisel et al 1999; Siegfried 1999)
• Social Effects:
-increased economic deprivation, homelessness, risk of incarceration (Rosen et al 2002)
• General Epidemiology of Dual Diagnosis: > 50% of patients presenting for SUDs treatments have current or past mental illness (Little 2001)
>50% of patients presenting for mental illness treatment, have current or past SUDs (RachBeisel et al 1999).
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Causal Model of Mental Disorders
Genes
Environment
CLINICAL SYNDROMES
CAUSAL ELEMENTS “BLACK BOX”
A
B
C
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Causal Model adapted to Dual Diagnosis
Genes
Environment
CLINICAL SYNDROMES
CAUSAL ELEMENTS “BLACK BOX”
SUBSTANCE USE DISORDERS
MENTAL ILLNESSES
Dual Diagnosis Cuts Across the Diagnostic Spectrum
Dual Diagnosis Cuts Across Drugs of Abuse
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Causal Model adapted to Dual Diagnosis
Genes
Environment
CLINICAL SYNDROMES
CAUSAL ELEMENTS “BLACK BOX”
SUBSTANCE USE DISORDERS
MENTAL ILLNESSESThe BRAIN:
Neurochemistry
& Neurocircuitry
Neuroimaging
Animal Models
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Neurobiological Effects of Addictive Drugs
Cocaine
Amphetamine
Nicotine
Cannabis
Opiates
Alcohol
DA, 5HT, NE transporters DA
prefrontal cortex, striatum Nucleus Accumbens
‘’ ‘’
Acetylcholine receptors DA
thalamus, striatum,frontal, parietal cortex Nucleus Accumbens
Cannabinoid receptors DA
Cingulate, palladum, hippocampus, cerebellum Nucleus Accumbens
Mu and Kappa receptors DA
Neocortex, thalamus, striatum, cerebellum, PAG Nucleus Accumbens
GABA and NMDA receptors DA
Everywhere! Nucleus Accumbens
Too many investigators to Credit: Thanks NIDA/NIAA
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Cocaine
Amphetamine
Nicotine
Cannabis
Opiates
Alcohol
DA, 5HT, NE transporters DA
prefrontal cortex, striatum Nucleus Accumbens
‘’ ‘’
Acetylcholine receptors DA
thalamus, striatum,frontal, parietal cortex Nucleus Accumbens
Cannabinoid receptors DA
Cingulate, palladum, hippocampus, cerebellum Nucleus Accumbens
Mu and Kappa receptors DA
Neocortex, thalamus, striatum, cerebellum, PAG Nucleus Accumbens
GABA and NMDA receptors DA
Everywhere! Nucleus Accumbens
Diverse Intoxicating/Withdrawal Motivational Effects/Addiction
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So how do we reconcile these two:
Temporal-Limbic Dysfunction involvement across the Spectrum of Mental Illness
Ventral Striatal/DA systems involvement in Addictive Drug Action
….Back to Neurocircuitry
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THALAMUS
AMYGDALA
HIPPOCAMPUS
PREFRONTAL CORTEX (PfC)
VENTRAL TEGMENTAL AREA (VTA)
SUBSTANIANIGRA
STRIATUM NUCLEUSACCUMBENS (NAc)
CAUDATE- PUTAMEN
HYPOTHALAMUS-SEPTUM
SENSORY-MOTOR ASSOCIATION CORTICES
PRIMARY MOTIVATION CIRCUITRY
SECONDARY MOTIVATION CIRCUITRY
GLUTAMATE
GABA
DOPAMINE
SEROTONIN
NEUROTRANSMISSION
CORTICO-STRIATAL-THALAMO-CORTICAL PATHWAY
Neurocircuitry of Motivation (adapted from Chambers et al, Am J Psychiatry, 2003)
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An Integrated Neurocircuitry Hypothesis of Dual Diagnosis
A testable hypothesis
Genes
Environment
MENTAL ILLNESSESThe BRAIN:
Neurochemistry
& Neurocircuitry
Probe with Neurocircuit-based Comprehensive Animal Models of Mental illness
SUBSTANCE USE DISORDERS
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NVHL model of schizophrenia
VTA
dorsal
ventral
1. POSITIVE-LIKE SYMPTOMS
hyperactivity to stress, novelty, dopaminergic drugs
post-adolescent onset
respond to typical/atypical neuroleptics (Lipska et al, 1993,1994)
2. NEGATIVE-LIKE SYMPTOMS
social deficits/grooming failure (Becker et al,1999)
3. COGNITIVE SYMPTOMS
deficits of working memory (Chambers et al, 1996)
PPI, LI (Lipska et al,1995; Grecksch et al, 1999)
mPfC
NAc
LESION
hippocampus
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NVHL neurobiology
VTA
dorsal
ventralLESION
Medial Prefrontal Cortex•Decreases in neuronal markers and estimated neuronal counts (Bernstein et et, 1999), dendritic length and spine density (Lipska et al,2001), decreased GAD 67 mRNA , altered AMPA receptor mRNA (Steine et al, 2001).
•Attenuated time course of c-Fos expression after amphetamine (Lillrank et al., 1996), and basal and stress induced BDNF expression (Lipska et al.2001, Ashe et al. 2002; Bhardwaj, 2003)
•Abnormal neuronal firing in response to VTA stimulation (O’Donnell et al, 2002)
Nucleus Accumbens•Attenuated DA release after stress and amphetamine (Lipska et al., 1999) and time course of c-Fos expression after amphetamine (Lillrank et al., 1996)
•Reduced dendritic length and spine density (Lipska et al., 2001)
•Abnormal firing responses to VTA stimulation (Goto at al, 2002)
mPfC
NAc
HIPPOCAMPUS
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So what do NVHL rats do in addiction-related paradigms?
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NVHL: Cocaine Self-AdministrationChambers and Self, Neuropsychopharmacololgy, 2002
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Incidence of reaching max infusions: % sessions rat reached 120 reinforcement maximum/ 2hrs. Incidence of perseverative inactive lever responding : #session that rat hit non-drug lever > 100 times while receiving 30+ reinforcements.
Cocaine Acquisition:Group Extremes in Responding
SHAM (N=13), NVHL (N=10)
Mann-Whitney U, z-2.27,p=0.02
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NVHL: Cocaine Self-Administration
After maintenance phase (15 sessions total of > 25 hits @ 0.4 mg dose), extinction in 2 hr sessions, extinction criteria <15 lever presses on right lever and < 30 lever presses on both levers combined (3 days post last cocaine)
Rats habituated without reward delivery for 2 hrs. Then received i.p. injections, and responding measured for another hour. Rats not habituating (<30 total lever presses in hour before injection were excluded from the analysis (two weeks post last cocaine)
DRUG SEEKING AFTER WITHDRAWAL
DRUG-INDUCED RELAPSE
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Locomotor sensitization• A direct test of the capacity of addictive drugs to produce incrementally increasing behavioral changes with repeated doses.
i.e. produces clean, easily reproducible curves
Reminiscent of learning curves!
And axomatic to neuroscience: neuroplasticity mediates learning!
• Indirectly models the addictive process:
Psychomotor sensitization ~ Motivational Sensitization
(Robinson and Berridge, 1993)
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Lesion status x drug *
15 mg/kg daily cocaine vs saline
[mean post-injection activity- mean pre-injection activity]
Lesion status **
Long-term sensitization in cocaine-only exposed rats
Phenotypic threshold of addiction/ psychotic phenomena?
?
NVHL rats in Locomotor Sensitization to Cocaine
Chambers and Taylor, Biol. Psychiatry, 2004
7 days of initial injections
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Impulsivity as a General Trait Marker of Addiction Vulnerability
•Impulsivity/ impulse control disorders may be a common trait feature shared among psychiatric disorders substance use disorders (Grant et al AM J Psychiatry, Nov. 2005)
•Impulsivity may emerge as a normative transient trait marker in adolescence that heightens vulnerability to acquiring addictions (Chambers et al, Am J Psychiatry, 2003).
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NVHL rats demonstrate Impulsivity in Natural Reward-Related Learning (Chambers et al, Psychopharmacology 2005) H2Olight
tone
No differences in 1) total time of head entry, 2)% of time of head entry during UCS , But….
% time head entry
CS interval INA interval
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Dual Diagnosis Cuts across the Diagnostic Spectrum…
Try An Alternative Lesion Model:
Olfactory Bulbectomy (OBX) lesion model of Affective Disorders
Adult age lesion
Indirect effects to Temporal Limbic Structures
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OBX
BSTN
MED N. AMY
ENTORHINAL CTX
CORTICAL N. AMYPYRIFORM CTX
RAPHAE
LOC CER
MSDB
BASIC OLFACTORY-LIMBIC CIRCUITRYOUTPUTSINPUTS
AOB
MOB
HYPOTHALAMUS
OLFACTORY TUBERCLE
1.NEUROVEGETATIVE (weight loss, sleep changes)
2 SOCIO-EMOTIONAL (increased aggression, infanticide, muricide; altered anxiety)
3. LOCOMOTOR-BEHAVIORAL (hyperactive, treated with chronic antidepressants)
4. COGNITIVE impairment
5. IMMUNOLOGICAL ALTERATIONS
(Jesberger et al,1988; van Riezen and Leonard, 1990; Kelly et al 1997).
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OBX neurobiology
AOB
MOB
PYRIFORM
PfC
AMYGDALA
HIPPOCAMPUSReduced excitotoxin induced CA3
pyramidal cell death (3 months) (Gary 2002)
Reduced spine density in CA1, CA3, DG, reversed by chronic Elavil (2 weeks (Norrholm, 2001)
AMYGDALAIncrease 2-deoxyglucose uptake 1,2,3
weeks post lesion (Shibata, 1994)
Hyperexcitable medial n. neurons (Watanabe, 1982; Nakanshi, 1990)
PREFRONTAL CTX Increased markers of 5-HT
hyperinnervation (3 months) (Grecksch, 1997; Zhou, 1998)
PIRIFORM CTXMolecular markers of apoptosis (24 hrs post
lesion) (TUNEL) labeling (Capurso, 1997)
VTA
HIPPOCAMPUS
NAc
LESION
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OBX rats in Locomotor Sensitization to CocaineChambers et al, Synapse, 2004
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Lesion Psychiatric syndrome-like Addiction Paradigm
self-administration sensitization
NVHL Schizophrenia elevated elevated
OBX Affective Disorders elevated* elevated
*Holmes et al (2002) with amphetamine
Dual Diagnosis Cuts Across the Diagnostic Spectrum
Dual Diagnosis Cuts across Differential Drugs of Abuse…
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Thus far Animal models of dual diagnosis are consistent with clinical epidemiological data that…
Dual Diagnosis cuts across the diagnostic spectrum
Dual Diagnosis cuts across differential drugs of abuse
Together, these findings support an integrated neurocircuit-theory of dual diagnosis in which frontal-temporal-limbic dysfunction in mental illnesses potentiates motivational and related responses to addictive drugs encoded by frontal-striatal circuits.
Summary
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Future DirectionsStudying the neurobiological correlates of drug-induced change in animal models of dual diagnosis will:
… enhance our understanding of mental illness and addiction as both stand alone and integrated disease processes.
… be critical in engineering more definitive, parsimonious and integrated treatments for the now main stream psychiatric patient who is dually diagnosed.
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Thanks
Ed Levin
David Self
NARSAD
NIDA