Influence of positive allosteric modulation of the mglu2-receptor on the behavioral responses in animal models of depression

Transcription

1 Influence of positive allosteric modulation of the mglu2-receptor on the behavioral responses in animal models of depression Neuroscience Discovery Janssen Research and Development, a Division of Janssen Pharmaceutica NV, Luc Ver Donck, J Adriaan Bouwknecht, Hilde Lavreysen ADAA Chicago, March 28,

2 Disclosure: Luc Ver Donck Employment: Janssen Pharmaceutica NV, a Johnson&Johnson company Stock shareholder: Johnson&Johnson 2

3 Glutamate Primary excitatory neurotransmitter in CNS (Riaza Bermudo-Soriano et al, 2012) Activates glutamate receptors (Kew & Kemp, 2005): Ionotropic: NMDA, AMPA Metabotropic GPCRs (mglu) mglu receptors (Niswender & Conn, 2010): 8 subtypes, 3 main groups modulate glutamate tone and phasic release in a subtle manner 3

4 The metabotropic glutamate 2 receptor (mglu2) Pre-synaptic group II receptor, Gi-coupled (Cartmell & Schoepp, 2000) Expression in prefrontal cortex, thalamus, striatum, hippocampus, amygdala (Wright et al, 2001, 2013; Lavreysen et al, 2013) (Ferragutti & Shigemoto, 2006) mglu2-activation reduces EPSPs: glutamatergic neurotransmission (Kew et al, 2001) 4

5 Excessive glutamatergic transmission Dysfunctional glutamatergic neurotransmission may be implicated in the pathophysiology of psychiatric illness. (Weinberger, 2007; Olney et al, 1999) Hypothesis: therapeutic efficacy by activation of group II mglu receptors to normalise glutamatergic hyperexcitability. (Fell et al, 2011; Coyle, 2006; Johnson et al, 2005) 5

6 mglu2 receptor activation Tateyama et al, 2004 Havlackova et al, 2005 Rondard et al, 2006 Brock et al,

7 mglu2 receptor activation Tateyama et al, 2004 Havlackova et al, 2005 Rondard et al, 2006 Brock et al,

8 mglu2 receptor activation Tateyama et al, 2004 Havlackova et al, 2005 Rondard et al, 2006 Brock et al,

9 mglu2 receptor modulation via allosteric site Orthosteric agonist No subtype-selectivity Possibility of overactivation, desensitisation (tolerance) PAM JNJ Structurally diverse and subtype-selective, wider chemical space Potentially better drug-like properties PAMs enhance transmission by endogenous transmitters and preserve temporal pattern of signaling (effective and safer approach?) Tateyama et al, 2004 Havlackova et al, 2005 Rondard et al, 2006 Brock et al,

10 c p m cpm % max Glu response % o f m a x im a l G lu re s p o n s e JNJ , an mglu2 Positive Allosteric Modulator (PAM) JNJ (M) control c o n tro l M J N J M J N J M J N J M J N J M J N J M J N J M J N J in p re s e n c e o f E C 2 0 G lu (P A M ) w ith o u t G lu (A G O ) EC 50 :147 nm +Glu [EC20 ] (PAM) no Glu (AG) [Glutamate], Log (M) g lu ta m a te, L o g (M ) Positive efficacy cooperativity Minor intrinsic agonism hmglu2_chok1_glutamate_gtpγs; Mean ± SEM, n= [JNJ ], Log (M) [J N J ], L o g (M ) Lavreysen et al,

11 JNJ , a PAM at native mglu2 receptors glutamate (µm) JNJ (µm) 1 10 No effect in mglu2 KO-mice Acts as PAM at native mglu2 receptors Brain Slices-[ 35 S]GTPγS autoradiography Lavreysen et al,

12 % mglu2 occupancy JNJ : target engagement at mglu2 [ 3 H]JNJ ex vivo occupancy WT mglu2 KO observed predicted rat EC 50 :1032 ng/ml mouse [JNJ ] plasma (ng/ml) 5HT 2A occupancy due to rat-specific metabolite Lavreysen et al,

13 Rodent tests of despair Acute tests: Forced swim test Tail suspension test (sub)-chronic test: Dominant/submissive test 13

14 Forced swim test in mice -30 min Test 0-6 min Key measures: Time Immobile Distance Moved 14

15 mglu2-pam does not reduce immobility time in forced swim test in mice (%) 60 Immobility (cm) 300 * Distance * imipramine AAA Dose (mg/kg s.c.) imipramine AAA Dose (mg/kg s.c.) NMRI mice, n=10/group. 1w-ANOVA: * p<0.05 vs. vehicle Treatment: 30 min pre-test FSTM_100430_

16 Tail suspension test in mice -30 min Test 0-6 min Key measures: Time Immobile Distance Moved 16

17 mglu2-pam does not reduce immobility time in tail suspension test in mice (sec) 200 Immobility * (cm) 1000 * Distance * 100 * Imipramine AAA Dose (mg/kg s.c.) Imipramine AAA Dose (mg/kg s.c.) NMRI mice, n=15/group. 1w-ANOVA: * p<0.05 vs. vehicle Treatment: 30 min pre-test TST_100504_ AAA 17

18 D/S : dominant/submissive test in rat Principle: competition for food between dominantsubmissive pair of food deprived rats Malatynska et al, J Neurosci Meth 165 : ,

19 D/S : dominant/submissive test in rat Model of human depression Hypothesis: submissive behavior in social animals is related to human depression (Price, 1967) Like depressed humans, subordinate rats show: (Malatynska & Knapp, 2005) Increased defensive behavior, weight loss Major alterations in sleep, eating and active behaviors 19

20 D/S : dominant/submissive test in rat Reduction of Submissive Behavior Model: Rodent model for depression depressed state is represented by the behavior of the submissive animal Clinically effective antidepressants attenuate submissive behaviour: (des)imipramine, fluoxetine No effect: neuroleptics, anxiolytics Malatynska et al, 2002, 2007; Malatynska & Knapp,

21 D/S : dominant/submissive test in rat Principle: competition for food between dominantsubmissive pair of food deprived rats Malatynska et al, J Neurosci Meth 165 : ,

22 Dominant/submissive: study design Week: Selection of D/S pairs (Δ>25%) (n=220) Baseline drinking times (n=80) QD Submissive: vehicle/drug Dominant: vehicle (n=10 pairs/group) + Daily D/S-test 23h food deprivation 5-min D/S test 1h food Treatments: 1h prior to test (*) D/S: Dominant/Submissive Male Sprague Dawley rats, age 8-10 w (*) : imipramine after test Key measures: Feeding score per rat Dominance level 22

23 Imipramine reverses submissive behaviour in rat Feeding score (s) vehicle Feeding score (s) imipramine Dominant Dominant *** ** ** Submissive vehicle ** *** *** Submissive imipramine Time (week) Time (week) Mean ± SEM, n= 9 pairs; vehicle = 20% β-oh-cyclodextrin, imipramine: 10 mg/kg IP, QD week 3 through 5 **, *** P<0.01, vs. dominance feeding score (student-t test) IVP

24 JNJ reverses submissive behaviour Feeding score (s) Dominant Feeding score (s) Dominant *** ** Submissive 10 mg/kg *** * *** Submissive 20 mg/kg Time (week) Time (week) Mean ± SEM, n= 9 pairs; JNJ : SC, QD week 3 through 5 *, **,*** P<0.05, 0.01, vs. dominance feeding score (student-t test) IVP

25 Imipramine and JNJ reduce dominance levels in rat % CD imipramine 10 mg/kg Dominance Level (s) JNJ mg/kg * ** *** JNJ mg/kg * ** (week) Mean ± SEM, n= 9 pairs; vehicle (β-oh-cyclodextrin) or drugs, QD week 3 through 5 *,**,*** P<0.05, 0.01, vs.dominance level of second week (2w-ANOVA followed by Bonferroni post tests) IVP

26 Summary No effect of mglu2-pam in acute stress-related paradigms mglu2-pam reduces dominance level Suggestive for antidepressant effect 26

27 Interpretation of drug effect in D/S test: potential caveats No mglu2-pam effect observed in (acute) depression paradigms forced swim and tail suspension tests Different state of mind in sub-chronic D/S-test? Increased aggression in submissive animals? mglu2-pam reduces aggressive behaviour in mice. Anxiolytic effects? mglu2-pam had no effect in elevated plus maze, stress-induced hyperthermia, hole board. Change in food intake or appetite mglu2-pam reduces food intake. 27

28 Conclusions The dominant-submissive model differentiates itself from the classical acute models of depression. Animals are continuously exposed to psychosocial stressor (aggressor stress by the dominant partner) Subchronic stress conditions to submissive rat may affect: Neurochemical signaling Associated behaviour Continued treatment with an mglu2-pam under this subchronic stress condition: Elicited antidepressant-like effects Reflected by normalization of the behavioral responses 28

29 Acknowledgements Janssen Neuroscience Discovery and Early Development Teams Addex Therapeutics 29

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