Animal Models of Schizophrenia and Depression: Neurobiological Basis for Comorbidity with Substance Use Disorders

1. 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

2. Impact of SUDs in Mental Illness 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). • 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)

3. Causal Model of Mental Disorders CAUSAL ELEMENTS CLINICAL SYNDROMES “BLACK BOX” A Genes B Environment C

4. Causal Model adapted to Dual Diagnosis CAUSAL ELEMENTS CLINICAL SYNDROMES “BLACK BOX” MENTAL ILLNESSES Genes SUBSTANCE USE DISORDERS Environment Dual Diagnosis Cuts Across the Diagnostic Spectrum Dual Diagnosis Cuts Across Drugs of Abuse

5. Causal Model adapted to Dual Diagnosis CAUSAL ELEMENTS CLINICAL SYNDROMES “BLACK BOX” MENTAL ILLNESSES Genes The BRAIN: Neurochemistry & Neurocircuitry SUBSTANCE USE DISORDERS Environment Neuroimaging Animal Models

6. 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 receptorsDA Cingulate, palladum, hippocampus, cerebellum Nucleus Accumbens Mu and Kappa receptorsDA Neocortex, thalamus, striatum, cerebellum, PAG Nucleus Accumbens GABA and NMDA receptors DA Everywhere! Nucleus Accumbens Too many investigators to Credit: Thanks NIDA/NIAA

7. Motivational Effects/Addiction Diverse Intoxicating/Withdrawal 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 receptorsDA Cingulate, palladum, hippocampus, cerebellum Nucleus Accumbens Mu and Kappa receptorsDA Neocortex, thalamus, striatum, cerebellum, PAG Nucleus Accumbens GABA and NMDA receptors DA Everywhere! Nucleus Accumbens

8. 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

9. Neurocircuitry of Motivation (adapted from Chambers et al, Am J Psychiatry, 2003) PRIMARY MOTIVATION CIRCUITRY PREFRONTAL CORTEX (PfC) SENSORY-MOTOR ASSOCIATION CORTICES THALAMUS HYPOTHALAMUS- SEPTUM CAUDATE- PUTAMEN STRIATUM NUCLEUS ACCUMBENS (NAc) VENTRAL TEGMENTAL AREA (VTA) HIPPOCAMPUS SUBSTANIA NIGRA AMYGDALA SECONDARY MOTIVATION CIRCUITRY GLUTAMATE GABA DOPAMINE SEROTONIN NEUROTRANSMISSION CORTICO-STRIATAL-THALAMO-CORTICAL PATHWAY

10. An Integrated Neurocircuitry Hypothesis of Dual DiagnosisA testable hypothesis MENTAL ILLNESSES Genes The BRAIN: Neurochemistry & Neurocircuitry SUBSTANCE USE DISORDERS Environment Probe with Neurocircuit-based Comprehensive Animal Models of Mental illness

11. NVHL model of schizophrenia mPfC dorsal hippocampus LESION ventral NAc VTA • POSITIVE-LIKE SYMPTOMS • hyperactivity to stress, novelty, dopaminergic drugs • post-adolescent onset • respond to typical/atypical neuroleptics (Lipska et al, 1993,1994) • NEGATIVE-LIKE SYMPTOMS • social deficits/grooming failure (Becker et al,1999) • COGNITIVE SYMPTOMS • deficits of working memory (Chambers et al, 1996) • PPI, LI (Lipska et al,1995; Grecksch et al, 1999)

12. NVHL neurobiology mPfC dorsal HIPPOCAMPUS LESION ventral NAc VTA • 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)

13. So what do NVHL rats do in addiction-related paradigms?

14. NVHL: Cocaine Self-AdministrationChambers and Self, Neuropsychopharmacololgy, 2002

15. Cocaine Acquisition:Group Extremes in Responding SHAM (N=13), NVHL (N=10) 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. Mann-Whitney U, z-2.27,p=0.02

16. NVHL: Cocaine Self-Administration DRUG SEEKING AFTER WITHDRAWAL 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) DRUG-INDUCED RELAPSE 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)

17. 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)

18. NVHL rats in Locomotor Sensitization to Cocaine Chambers and Taylor, Biol. Psychiatry, 2004 7 days of initial injections 15 mg/kg daily cocaine vs saline [mean post-injection activity- mean pre-injection activity] Lesion status x drug * Long-term sensitization in cocaine-only exposed rats Phenotypic threshold of addiction/ psychotic phenomena? Lesion status ** ?

19. 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).

20. NVHL rats demonstrate Impulsivity in Natural Reward-Related Learning (Chambers et al, Psychopharmacology 2005) light H2O 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

21. 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

22. OBX BASIC OLFACTORY-LIMBIC CIRCUITRY OUTPUTS INPUTS HYPOTHALAMUS LOC CER AOB BSTN MED N. AMY OLFACTORY TUBERCLE RAPHAE MSDB MOB ENTORHINAL CTX PYRIFORM CTX CORTICAL N. AMY 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).

23. OBX neurobiology PfC HIPPOCAMPUS HIPPOCAMPUS Reduced 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) LESION NAc AOB MOB VTA PYRIFORM AMYGDALA AMYGDALA Increase 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 CTX Molecular markers of apoptosis (24 hrs post lesion) (TUNEL) labeling (Capurso, 1997)

24. OBX rats in Locomotor Sensitization to CocaineChambers et al, Synapse, 2004

25. Dual Diagnosis Cuts Across the Diagnostic Spectrum LesionPsychiatric syndrome-like Addiction Paradigm self-administrationsensitization NVHL Schizophrenia elevated elevated OBX Affective Disorders elevated* elevated *Holmes et al (2002) with amphetamine Dual Diagnosis Cuts across Differential Drugs of Abuse…

26. Summary 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.

27. Future Directions Studying 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.

28. Thanks Ed Levin David Self NARSAD NIDA