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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

robchamb@iupui.edu

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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