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ADHD Animal Model Presentation

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Amelia NI

on 19 April 2013

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Transcript of ADHD Animal Model Presentation

Defining ADHD in Animals A Steep Slope: Overview Behavioural paradigms modelling ADHD & measuring drug actions in "normal" rats •Causative mechanisms unknown

•No biomedical laboratory diagnostic test

•Diagnosis based on behavior observations over time – inattention, impulsivity and hyperactivity

•‘relative’ symptoms, compared to control

•Basic science definitions vary from clinical definitions Stop Signal Reaction Time Task measures impulsivity
human test (Alderson 2007)
ability to withhold or inhibit an already initiated or pre-potent motor response
go signal triggers response, then stop signal is sometimes presented to indicate trials requiring inhibition Delay Discounting Paradigm 5-Choice Serial Reaction Time Test measures 'impulsive choice' - greater tendency to choose an earlier, smaller reinforcer in preference to a larger, later reinforcer
can vary amount and delay of reinforcer
organisms sharply discount future rewards as a function of the delay from the time of choice
even if it results in fewer total reinforcers (Evenden 1996) Spontaneously Hyperactive Rat (SHR) model Originated from CPT in humans (Robbins 2002)
Animals nose poke into 1/5 apertures after visual stimulus to apparatus to obtain food reward
Short duration of stimulus requires rat to attend closely
Tests vigilance and impulsivity
Elevation of frequency of premature responses reflect higher levels of impulsivity
identifies rats w/deficit in selective attention
accompanied by impulsivity within 'normal' population
selected rats also have high levels of impulsive decision making on delay task
THUS proposed as rodent model of ADHD Strain developed by selecting for hypertensive phenotype (high blood pressure) in outbred Wistar rats
Inbreeding of SHR fixed certain behaviors in genome like hyperactivity (unintentional development) Okamoto and Aoki 1963 New Zealand Hypertensive Rats High Voluntary Wheel Running Mice selectively bred (23-24 generations) for increaseed running-wheel activity
useful genetic model
BUT doses of methylphenidate
100x clinically relevant dose
note-simple increases in activity are not a good marker of ADHD! Wistar-Kyoto: Controls for the SHR Symptoms of ADHD defined relativistically; thus SHR needs its own relative control WISTAR STRAIN Spontaneoulsy Hyperactive Rat Wistar-Kyoto Rat Select for hypertension Select for normal blood pressure Problems with Wistar-Kyoto Low genetic similartiy with SHRs
Genetic differences noted between US and Japanase SHRs
Also gentic differences between different distributors Genetic differences Abnormally inactive? "...we are unable to conclude that SHRs or CDs show excessive impulsivity, rather that WKY rats show a uniformly low resopnse rate." (Bull et al. 2000) SHR summary SHR has face validity
Drug studies have produced inconsistent results
Additionally: Behavioral Characteristics of SHR Abnormal Reponse to Reward SHRs have much greater FI scallop than controls (Sagvolden et al. 1992)
Interpreted as impulsivity (Wickens et al. 2011) Same behavior observed in ADHD children (Sagvolden et al. 1998) Delay of Reinforcement Curve Sagvolden et al. 1998 Observed in children (Sagvolden et al. 1998)
SHRs also sensitive to delay of reinforcement (Sutherland et al. 2009) Effects of Stimulants on SHR Open Field Behavior Not a reliable indicator of therapeautic effectiveness of stimulants
Lack of sensitivity to context? Multiple FI-EXT Schedule Drug treatment produces subtle differences in SHR but still distinguishable from controls Kantak et al. 2008 Tested SHRs in three tasks (memory, habit learning, and attention/behavioral flexibility)
Performance after methyphenidate treatment indistinguishable from controls
Relevance of behaviors to ADHD? Sustained Attention in SHR "...there is no guarantee that the differences between the SHR and reference strains are the same as the differences between children with and without ADHD at the physiological/biological level." Wickens et al. 2011 Aetiology of ADHD NATURE strong familial genetic contribution
high heritability found in twin studies
gene associations:
dopamine D4 receptor
dopamine D5 recepotr
dopamine transporter (DAT1)
serotonin transporter
dopamine beta hydroxylase (DBH)
serotoning receptor 1B (HTR1B)
SNAP-25 (t-SNARE) NURTURE childhood exposure to lead or polychlorinated biphenyls?
not specifc to ADHD nor sufficient BOTH prenatal smoking exposure + DAT1 = increased ADHD symtpoms (non-significant)
prenatal alcohol exposure + DAT1 = increased risk for ADHD Dopamine-depleted animals Development Lesion dopaminergic neurons in neonatal rat through injection of 6-hydroxydopamine (6-OHDA)
Phenotype = higher hyperactivity into adulthood Stimulant studies 6-OHDA animals show increased hyperactivity and reduced activity in reponse to stimulants Avale et al. 2004 Avale et al. 2004 DA-depleted animals: Clincally relevant? Doses of methylphenidate which produce similar blood levels as those in human ADHD patients also reduced locomoter activity in 6-OHDA animals But such low doses preferentially increase NE levels in the prefrontal cortex (PFC) as opposed to DA, implying effects on NOREPINEPHRINE transporter (NET)as well as DAT Berrdige et al. 2006 Impulsivity of 6-OHDA animals not yet validated.

6-OHDA rats may have learning deficits. Summary of DA-depleted animals Have informed us of biological basis of ADHD but have not yet enlightened treatment response in a manner which translates to humans Dopamine Transporter Knockout Mouse DAT associated with risk for ADHD DAT1 + prenatal effect = ADHD
Over- and underegulation of DAT reported in human ADHD
Genetic engineering to reduce or eliminate DAT proposed as model of ADHD Behavioral characteristics of DAT-knockouts more spontaneous locomotion than w.t. controls
easily aroused by novelty
preference for active, repetitive behaviors Drug effects on DAT-knockouts Hyperactivity reduced by administration of haloperidol Haloperidol = dopamine antagonist
Role of DA in hyperactivity? Hyperactivity also reduced by administration of methylphenidate Methylphenidate = DAT antagonist
But effect mediated by increases in SEROTONIN levels! Limitations of transgenic approach Role of DAT in ADHD unclear Construct validity? Altered DAT expression could be the result of another pathological change, like altered DA innervation Face validity? Behavior of knockouts in open field doesn't match that of humans Lost in translation? "...animal researchers need to appreciate that they are dealing with a disorder that has no known pathology and no specific combination of features that can be considered necessary and sufficient to define ADHD." No in vivo ADHD animal models of proven effectiveness exist for studying effects of drugs
SHRs and 6-OHDAs exhibit the symptoms of ADHD, but SHR validity is questionable and 6-OHDAs have not been extensively studied
Human ADHD is context dependent - therefore animal ADHD should be too (but the models aren't!) Wickens et al. 2011 THE BAD: THE GOOD: operant behavior paradigms which examine delay of reinforcement show promise for studying drug effects "Future progress requires close interaction of clinical and basic science perspectives to prevent the core behavioural characteristics of ADHD from being lost in translation to animal models." Wickens et al. 2011 Do SHRs have excellent sustained attention, or are WKYs simply hypoactive by comparison? Nicholas et al., 2013 Rhodes 2001
sensitive to DAT (DA reuptake) inhibitors-cocaine & GBR, decreasing running when administered
higher basal activity when deprived of wheels
association b/w genetically determined hyperactive wheel-running behavior and dysfunction in DA neuromodulatory system
Rhodes 2003
DA receptors have reduced function in high-running mice
Ritalin decreased wheel running
good model! Developed by Wistar (WI) rats for hypertension
no evidence of hyperactivity within an open field
higher terminal response rates and response bursts
greater level of continued responding during testing Wickens 2004
tested using FI-EXT task with the NZ and SHR model (more on that later!)
FI-EXT-fixed interval schedule of lever pressing
higher terminal response rates and response bursts
greater level of continued responding
dissociation b/w hyperactivity and hyptertension, not related per se
convergence across strains suggests relevant genes may be physically close but not identical FI(fixed)-EXT(extinction)-A two component fixed interval schedule of 120 s with a 5 min extinction
First lever press after 2 min was rewarded with water from the liquid dipper and then the interval was reset
Water was available for 3 s after the animal opened the door in front of the water dipper
Cubicle was illuminated when the water was available
During FI, the house light was on and both left and right levers were extended but only responding on the left lever was rewarde
Each 2-min interval was repeated seven times before the EXT period of 5 min was initiated, during which the house light was switched off and no reward was available
Entire sequence was then repeated a second time
Feedback light above the left lever was illuminated during each left lever press throughout FI and EXT periods. Eagle 2008
sensitive to noradrenaline, but not 5-HT, which is strongly implicated in inhibitory control of similar test (go/no go)
Robinson 2008
stimulants and atomoxetine decrease impulsivity
another useful paradigm! Clinical Features Differential reinforcement of low rates of responding (DRL) another measure of impulsivity
reinforcement only available at certain inter-response intervals, and interval b/w responses is reset if there is premature movement
failure to inhibit premature responding is considered increased impulsivity

HOWEVER methylphenidate doesn't greatly affect boys w/ADHD
D-amphetamine impairs performance on DRL schedules - increasing response rate & decreasing reinforcement rate (Bizot, 1998)
not considered useful marker for therapeutic efficacy Puumala 1996
methylphenidate at doses of 100 & 1000 μg slightly improved the attentional performance of poorly performing animals
At dose 100μg slightly decreased the probability of premature responses (impulsivity) in poor, but 1000 μg methylphenidate increased the impulsivity of both normal and poor
methylphenidate didn't affect choice accuracy of normal animals tested at baseline conditions or with reduced stimulus duration which impaired their performance
good model! Psychostimulants Inattention •ADHD does not necessarily mean lack of focus ; focus can present with high rate of immediate reward; ADHD can be distinguished as the reinforcement is decreased (Barkley, 1990)

•behavior regulation and consequence may be underlying mechanisms, as opposed to direct attention deficit primarily

•No valid/direct test – but subjective evaluations based on parents/teachers;

Continuous performance task – detects sustained attention deficits; stimulants improve performance, but this test has not been consistent in distinguishing adhd groups – Hyperactivity •DSM IV definition: lack of control over activity in a particular situation
•Methods in lab: acceleration sensitive devices - ADHD children more active overall than normal (Porrino et al, 1983b) – but sensitive to context
•Hyperactivity seen in familiar settings only – particularly relevant to animal models, which focus on high levels of activity in all conditions
•Evidence from clinics points to behavior regulation by effects/consequences and not primary motor deficits Impulsivity •Again, a reflection of preference for immediate reinforcement (‘difficulty waiting’) and difficulty withholding responses (‘blurts out’), expression to an abnormally persistent/developmentally inappropriate
•Another aspect - lack of inhibitory control over behavior •Not all symptoms have to be present for the diagnosis to be made – therefore heterogeneous population Bizot 2011
trained rats in T-maze to choose between small immediate reward and larger, 30s delayed reward
methylphnidate, atomoxetine, D-amphetamine, and desipramine increases number of large rewards •Findings indicate a reduction in total brain size persisting into adolescence and reduced dimensions of several brain regions
•Differences in activation of specific regions during task performance; specifically in regions associated with reward mechanisms, suggesting altered reinforcement mechanisms/rewired reward circuitry Pathophysiology •Animal models are assessed on the basis of face, construct and predictive validation
•3 major classes are used to treat ADHD
oAmphetamine enantiomers 3:1::D:L mix; Adderall {psychostimulants, dopaminergic}
oThreo-methylphenidate enantiomers; Ritalin/Concerta {psychostimulants, dopaminergic}
oAtomexitine – selective norepinephrine reuptake inhibitor; Strattera, {indirectly dopaminergic}
oPsychostimulants shown to be very effective in reducing symptoms , but no therapeutic effects that outlast drug exposure Pharmacological Treatment References Alderson RM, Rapport MD, Kofler MJ (2007). Attention-deficit/hyperactivity disorder and behavioral inhibition: a meta-analytic review of the stop-signal paradigm. J Abnorm Child Psychol 35:745–758.
Avale ME, Falzone TI, Gelman DM, Low MJ, Grandy DK, Rubinstein M (2004a). The dopamine D4 receptor is essential for hyperactivity and imparied behavioral inhibition in a mouse model of attention deficit/hyperactivity disorder. Mol Psychiatry 9: 718-726.
Berridge CW, Devilbiss DM, Andizejewski ME, Arnsten AF, Kelley AE, Schmeichel B et al. (2006). Methylphenidate preferentially increases catecholamine neurotransmission within the prefrontal cortex at low doeses that enhance cognitive function. Biol Psychiatry 60: 1111-1120.
Bizot JC, David S, Trovero F (2011). Effects of atomoxetine, desipramine, d-amphetamine and methylphenidate on impulsivity in juvenile rats, measured in a T-maze procedure. Neurosci Lett 489:20–24.
Bradley C (1937). The behavior of children receiving Benzedrine. Am J Psychiatry 94: 577–585.
Barkley RA (1990). A critique of current diagnostic criteria for attention deficit hyperactivity disorder: clinical and research implications. J Dev Behav Pediatr 11: 343–352.
Porrino LJ, Rapoport JL, Behar D, Sceery W, Ismond DR, Bunney WE Jr (1983b). A naturalistic assessment of the motor activity of hyperactive boys. I. Comparison with normal controls. Arch Gen Psychiatry 40: 681–687.
Bull E, Reavill C, Hagan JJ, Overrend P, Jones DN (2000). Evaluation of the spontaneously hypertensive rat as a model of attention deficit hyperactivity disorder: acquisition and performance of the DRL-60s test.
Eagle DM, Bari A, Robbins TW (2008a). The neuropsychopharmacology of action inhibition: cross-species translation of the stop-signal and go/no-go tasks. Psychopharmacology (Berl) 199: 439–456.
Eagle DM, Baunez C, Hutcheson DM, Lehmann O, Shah AP, Robbins TW (2008b). Stop-signal reaction-time task performance: role of prefrontal cortex and subthalamic nucleus. Cereb Cortex 18:178–188.
Evenden J (1999a). Impulsivity: a discussion of clinical and experimental findings. J Psychopharmacol 13: 180–192.
Navarra R, Graf R, Huang Y, Logue S, Comery T, Hughes Z et al. (2008). Effects of atomoxetine and methylphenidate on attention and impulsivity in the 5-choice serial reaction time test. Prog Neuropsychopharmacol Biol Psychiatry 32: 34–41.
Puumala T, Ruotsalainen S, Jakala P, Koivisto E, Riekkinen P Jr, Sirvio J (1996). Behavioral and pharmacological studies on the validation of a new animal model for attention deficit hyperactivity disorder. Neurobiol Learn Mem 66: 198–211.
Robbins TW (2002). The 5-choice serial reaction time task: behavioural pharmacology and functional neurochemistry. Psychopharmacology (Berl) 163: 362–380.
Wickens JR, Macfarlane J, Booker C, McNaughton N (2004). Dissociation of hypertension and fixed interval responding in two separate strains of genetically hypertensive rat. Behav Brain Res152: 393–401. Psychostimulants- Theory of Action •Original discovery when drug that was tested to treat headaches improved school-life (Bradley 1937)
o Paradoxical effect – stimulant can lead to calm/focused behaviour
o Upon further research – as amphetamine compounds result in focusing action
•precise mechanism unknown, but understood to act as an indirect dopamine & norepinephrine reuptake inhibitor
•dopamine linked to motivation •stimulants reduce inattention, motor activity and impulsivity in children with/out ADHD

•animal models may not have to simulate abnormality to predict drug effects Psychostimulant Pharmacology & implications • Possibility of multiple types of ADHD must be incorporated by animal models

• Relative symptoms must be isolated, compared to control group

• Actometer records demonstrate good predictive power; other tests do exist, but are not very powerful

• Sensitivity to delay in reinforcement, under further investigation Clinical features implication for animal models Experiments Navarra 2008
methylphenidate
modest increase in attention
increased number of premature responses, or increased impulsivity
decrease in time to retreive food from magazine Experiments Experiments Actual Animal Models High voluntary wheel running
New Zealand
Spontaenously hyperactive
DA-depleted
DA transporter knockout Amelia, Ben, & Sai
BBB 482
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