Behavioural

Pharmacology in the
Developing Brain
Emeritus Professor Charles Marsden
School of Biomedical Sciences
Nottingham University Medical School
Nottingham, NG7 2UH

charles.marsden@nottingham.ac.uk
Behavioural Pharmacology and
The Developing Brain

• Drug action and Neurotransmission –

present & future

• Neurotransmitters , Neuroplasticity &

Development

• Environmental Factors & Behaviour

 We need to understand both the
brain & environment
“In more than 30 years as a neuroscientist, my
most profound lesson has been that the brain
and behaviour are products of multiple
interacting influences, and that the most
powerful of these are located outside our
heads”

Judith Grisel. The Guardian 30/12/2019

 Adolescent Brain Development

• Linear increase in white matter. More complex changes in

grey, initial increases followed by synaptic pruning in which
pubertal hormones may play a role.

• Complex behavioural and cognitive changes (ie risk taking)

that might reflect earlier development of limbic versus
prefrontal functions.

• Not all neurotransmitters develop at the same pace –

Serotonin fully develops earlier than dopamine or
noradrenaline.

• These differences may in part explain adolescent vulnerability

to psychopathologies and response to drugs.
 Neurotransmission & Drugs
• Dopamine
Amphetamine, Ritalin, Antipsychotics, Abuse drugs
New interest in the role of dopamine in depression.

• Serotonin –tricyclics, SSRIs & new multimodal agents

• (Psylocibin, LSD)
• Noradrenaline - tricyclics
Atomoxetine and other NA re-uptake inhibitors
Clonidine/Guanfacine

• Glutamate – valproate etc, antidepressants

(Esketamine), cognition?
• GABA - benzodiazepines
• Neuropeptides (CRF,orexins & oxytocin)
• Neurosteroids
• Endocannabinoids
 Dopamine Pathways
Dorsal
Frontal Striatum
cortex

Nucleus
accumbens
(Ventral
striatum)

Olfactory
bulb

Pituitary
1. Nigrostriatal pathway
Parkinson’s disease
2. Mesocortical and mesolimbic pathways
Schizophrenia?
3. Tuberoinfundibular pathway
Prolactin release
 Dopamine
• Pathways
Nigrostriatal
Mesocortical/ Mesolimbic
Tuberoinfundibular
• Receptors
D1 & D5 - Excitatory – cognition/attention
D2,D3,D4 – Inhibitory, important in striatum &
limbic system including pre-frontal cortex.
Drugs
Amphetamine/ Ritalin: block reuptake &
increase release of DA & NA
Classic Antipsychotics: Block D2 receptors
“Atypicals” :dopamine plus other receptors (5HT,
histamine). Partial agonists.
Triple monoamine uptake inhibitors – depression
 Noradrenaline
Locus
Coeruleus

Limbic Areas Hypothalamus

Cortex
• Active when awake
• Maintains cortical activity rather than Behavioural Waking
• Vigilance and attention
• Chronic response to stress – anxiety
• Mood - depression
• Cognition – learning/memory
• CNS control of cardiovascular function
• Neuroendocrine control
 Noradrenergic Drugs
• Antidepressants
– Tricyclics – block NA membrane transporter plus 5HT
– Mirtazapine - α2 receptor antagonist plus 5HT2 and 5HT3
antagonism
– New triple monoamine uptake inhibitors

• ADHD
– Atomoxetine – blocks NA membrane transporter
• Increases PFC function – attention?
• No abuse potential
• Metabolised by hepatic CYP-2D6
– Guanfacine/Clonidine - α2 agonists
• Increase PFC function

• Role of Noradrenaline in the action of Amphetamine?

 Serotonin (5HT)
5-Hydroxytryptamine
Raphe Nuc. Raphe Nuc.
(Dorsal / Medial) (Magnus, Obscurus)

Striatum Cortex Hippocampus Spinal Cord

Aversion (Anxiety) 5HT1A 5HT2C

ROLES IN BEHAVIOUR Circadian Rhythms
Emotion (Depression) 5HT1A
Sexual Behaviour
Feeding 5HT2C
Motor Function (Spinal Cord)
Memory 5HT1A 5HT6
Central CVS
Emesis (Vomiting) 5HT3
Cerebral Blood Flow (Migraine)
 Serotonin
• Pathways
Raphe (dorsal & medial) to limbic regions

• Receptors- 14!
5HT1A - 5HT7
Important ones 5HT1A (resilience, mood) 5HT2A (sedation)
5HT2C (threat appraisal, appetite) 5HT6 (cognition) 5HT7

• Drugs
SSRIs/ Tricyclics -Inhibit reuptake (SERT), slow onset,
side effects
MAOI - Inhibit metabolism
Vortioxetine (Brintellix) – multimodal (SERT + receptors)
5HT3 antagonists - not psychiatry (emesis, IBS)
5HT1D - migraine
Future? – 5HT4, 5HT6 and cognition
 Serotonin Terminal

Tryptophan

Tryptophan
Parachlorophenylalanine

5-OH-Tryptophan
MAO inhibitors

5HT

5HIAA
Reserpine 5-HT MAO
Tetrabenazine SSRIs
5-HT Tricyclics
pre-synaptic auto-
receptor (5-HT1A/B/D) mCPP
(5HT2C)
Lysergic acid 5HT
diethlamide (LSD)
(5HT2A)

8-0HDPAT (5HT1A)
BUSPAR
Hypothalamic-pituitary-adrenal
Axis
NA 5HT ACh

CRF - HYPOTHALAMUS

ACTH - PITUITARY

CORTISOL - ADRENAL

CRF receptors
CRF1 & CRF2 - also in brain
Glucocorticoid receptors - also in brain, decreased in depression

Early cortisol response to stress. Major changes during adolescence

Interplay between amines & HPA & Depression
 Amines, Amino Acids & Growth
Factors
HIPPOCAMPAL
SEROTONIN/AMINO ACIDS

mTor CREB NGF1-B

BDNF Glucocorticoid
LTP/MEMORY
(synaptogenesis) Receptor

•mTor- transcription factor important in neuronal plasticity

•NGF1-B - Steroid hormone receptor regulator
•CREB - c-AMP response element binding protein – important link
between receptor activation and gene expression
•BDNF - Brain derived neurotrophic factor –role in action of AD?
FGF – Fibroblast growth factor – role in wiring and resilience
 Neurobiological effects of increased
amine transmission in depression
• Block 5HT/NE uptake - acute increase in amine release
resulting in activation of feedback inhibition thus reduced
amine release – cause of some acute side effects of SSRIs –
anxiety?
• Reduced inhibitory feedback with chronic treatment -
5HT1A receptor desensitization - subsequent increased
extracellular amine function.
• Combined with activation of BDNF - enhanced neuronal
plasticity & neurogenesis so improved circuitry.
• Positive emotional bias - more exposure to social cues and
reinforcement leading to re-learning of positive emotional
associations – possible role for FGF - potential target for new
drugs?
 Single Target to Rich
Pharmacology
• Behaviour is complex – no single target
explains a specific behavioural response
• Some drugs have many uses – complex
pharmacology and active metabolites

• Fluoxetine & Norfluoxetine

• Quetiapine and Norquetiapine.
 Quetiapine (and Norquetiapine)
• Quetiapine introduced as an “atypical”
antipsychotic, now also used in bipolar
disorder, depression & anxiety.
• Low affinity D2 antagonist, 5HT1A agonist
and 5HT2A & 5HT2C antagonist
• Norquetiapine is active metabolite – blocks
NE uptake plus 5HT1A agonist & 5HT2A &
5HT2C antagonist.
 Glutamate
• Increasing importance in our understanding of brain
development and potential drug development

• Role in plasticity, early wiring and aspects of

astrocyte development and survival

• Major interest in terms of depression- ketamine

(glutamate NMDA antagonist)

• Can “ketamine like drugs” (Esketamine) act as

rapid acting antidepressant working via
mechanisms to promote neural plasticity?
 How might ketamine act as a
rapid onset antidepressant ?
• Theory 1. Increase in amine release leading to rapid
changes in transcription of growth factors.

• Theory 2. Increase in both glutamate and GABA release

in human PFC. Glutamate increases both BDNF and
mTor with subsequent increase in synaptic proteins and
sprouting of new synaptic spines.

• Recent idea: Ketamine also acts on AMPA receptors.

Metabolite of Ketamine (HNK) acts on AMPA but not
NMDA receptors – is AMPA activation the key to
antidepressant action?
 Ketamine in adolescent
resistant depression.
• Journal ofChild & Adolescent
Psychophamacology (2018) Cullen K et al.
• Ketamine tested in adolescents with
resistant depression. Small study using iv
ketamine ( 6 doses over 6 weeks).
• Improvement in about 50% and less relapse.
• Esketamine reduces suicidal thoughts (Am.J
Psychiatry 2018)
 Inflammation and Immune
Responses
• Gut to brain communication can modulate
behaviour (gut microbiome).
• Role of microglia in brain inflammation &
glutamate function.
• Role of inflammation in depression and
schizophrenia?
• Influence of inflammation on tryptophan
and serotonin metabolism – Kynurenine
pathway.
 Inflammation and Depression

• Inflammation caused by HPA function, Metabolic

disorders & Personality Factors.
• Inflammation activates brain microglia and
Indoleamine 2,3 Deoxygenase (IDO) which shifts
tryptophan metabolism to kynurenine so
decreasing serotonin production.
• Kynurenine metabolised to Quinolinic acid which
enhances glutamate receptor function while
activated brain microglia increases glutamate
release…….. Depression?
Drug Treatment & The Young

• Rates of absorption, metabolism, distribution.

• Hepatic microsomal enzyme metabolism – sub-optimal

• Compare Young versus Adult versus Old

• Children are not simply ‘mini-adults’ (David Coghill)

• Brain Development and the young

• Major differences between childhood and

adolescence
 NEUROTRANSMITTERS

In Utero Brain Development

Post-natal Brain Development

Child/Adolescent Behaviour

Adult Behaviour
 Neurotransmitters & Brain
Development
• Amines functional at an early stage – DA 1st
trimester
– Ca++ dependent release
– Receptor coupling
• Role in brain development, maturation & plasticity
• Deplete 5HT - loss of hippocampal synapses
• 5HT2c knock-out mice - high susceptibility to
epileptic fits
• Other systems important too – dopamine.
Glutamate. Endocannabinoids.
Determinants of Behaviour
• Genetic Factors
• Environmental Factors – social,
physiological and pharmacological
Pre, Peri and Post-natal
Combination – genetic link (variants of
Fox 01, A2M, TGF-b1 genes) to
depression linked to early life trauma

Cattaneo A et al (2018) Molecular

Psychiatry DOI.10.1038/S41380-017-
0002-4
 Influence of Environmental
Factors
• Maternal drug use (Thompson et al 2000

Nature Reviews 10, 303)- nicotine, alcohol,

drugs of abuse (eg cocaine) and clinical drugs

• Maternal separation & social isolation

• Childhood/ adolescent drug use

• Early brain damage

 Maternal Cocaine
Direct effects on brain plus placental blood flow.

Reduced pre-synaptic dopamine function –altered

Development and neuronal plasticity leading to long-term

behavioural effects.

• Reduced exploration

• Reduced attention and learning

• Long-term changes in social behaviour

Frederick and Stanwood (2009) Dev. Neurosci 31

 Early Drug Use
• Cocaine- similar effects to maternal use
• Ecstasy – much debate
– Long-term loss of Social Behaviour?
– Cognitive deficits ?
– Model of Social Phobia ?

• Cannabis – debate about effects of early use

- High strength varieties - high THC and low CBD

 Cannabis
1. Plant
2. Endogenous
(Endocannabinoids)

3. Synthetic
11
7
9
8 10 OH 1
1 6 2
OH
7 10b
2
1’ 2’
10a
6a 5
13 3 3 3’
4
12 6 O 5
4 1' 3' 5' 8 6’ 4’
9 OH 5’ 1’' 3’' 5’'
(–)-∆9-THC
(–)-Cannabidiol

• major psychoactive cannabinoid THC • major non-psychoactive cannabinoid

•THC identified in 1964 (Mechoulam) • low affinity for CB1 and CB2 receptors
• high affinity for CB1 and CB2 receptors
 Hash versus Skunk and
Importance of CBD

• How protective is CBD?

• New synthetic cannabinoids?

M. Di Forta et al (2015) Proportion of patients in

south London with first-episode psychosis
attributable to use of high potency cannabis: a case
control study.
Lancet Psychiatry
 Early drug exposure -What are
the issues?
• Acute drug effects – acute deaths
• Dependence and social consequences
• Long-term effects – can some (methamphetamine,
ecstasy) cause specific neurodegeneration?
• Effects of maternal and childhood use on brain
development and maturation? (cocaine, cannabis
methylphenidate)
• Poly drug use –confounding factor in research
• Translational value of animal studies – ecstasy?
Methamphetamine? pharmacokinetics?
 Conclusions
• Drugs based on amine pharmacology remain the key drugs used
in psychiatry.

• Some drugs may have important long-term effects on neuronal

plasticity and neurogenesis. Is this the route for new drugs?

• Environmental factors (social, physiological and

pharmacological) influence neurodevelopment to cause
pervasive changes in behaviour and cognition.

• Animal models and human imaging studies indicate resulting

impaired cortical and hippocampal function.

• Are the effects of drugs of abuse and other environmental

insults in early life mediated by altered cortical and
hippocampal development and neuronal plasticty ?
Publications - Cannabis Debate
For:
McGrath J et al (2010) Association between
cannabis use and psychosis-related outcomes
using sibling pair analysis in a cohort of young
adults. Arch.Gen. Psychiatry 67, 440-447
Against:
MacLeod J and Hickman M (2010) How ideology
shapes the evidence and policy: what we know
about cannabis use and what we should do?
Addiction 105, 1326-1330
 Behavioural Pharmacology And The
Developing Brain - References
1. General Introduction to the basic science associated with paediatric
psychopharmacology:-
Introduction to Neuropsychopharmacology.
Iversen L,L, Iversen S.D, Bloom F.E, Roth R.H. (2009) Oxford Univ. Press

2. Fundamentals in Clinical Psychopharmacology 4th Edition 2015

Anderson and McAllister-Williams. Taylor & Francis

3. Special issue of Neuropharmacology (2009) 57 (Ed: C.A.Marsden)

devoted to ADHD which includes various reviews on neurobiology.

4. Mattson M. P et al (2004)
BDNF and 5HT: a dynamic duo in age related neuronal plasticity and
neurodegenerative disorders.
Trends in Neuroscience (TIPS) 27 589-594

5. Behavioural Neuroscience of ADHD and its treatment (eds Stanford C &

Tannock R) –Current Topics in Behavioural Neuroscience vol.9 Springer.
1.Wainright S.R & Galea L. (2013)The neural plasticity
theory of depression etc. in Neural Plasticity (online)

2 Thompson B L, Levitt P and Stanwood GD (2009)

Prenatal exposure to drugs: effects on brain
development and implications for policy and education
Nature Reviews/Neuroscience 10; 303-312

3. Marsden C A et al (2011) Influence of social isolation in

the rat on serotonergic function and memory –
relevance to models of schizophrenia and the role of 5-
HT6 receptors
Neuropharmacology 61, 400-407

4. Cousins L & Goodyear I.M (2015) Antidepressants and

the adolescent brain. J. Psychopharmacol. 29; 545-555
5. Lane R.M (2015) Antidepressant drug development:
Focus on triple monoamine reuptake. J.Psychopharm.
29, 526-544.
• Current Topics in Behavioural Neuroscience 16.
The Neurobiology of Childhood (2014)
Susan Andersen & David Pine (eds) Springer.

• M.Di.Forti et al (2015) Lancet Psychiatry online.

• Ortuno MJ et al (2016) Serotonin-reuptake inhibitors act

centrally to cause bone loss in mice by counteracting a
local anti-resorptive effect. Nature Medicine 22, 1170-
1179.
• Dantzer R and Capuron L (eds) (2017) Inflammation-
Associated Depression: Evidence, Mechanisms and
Implications. Current Topics in Behavioral Neuroscience
Volume 31. Springer
 Ketamine publications
• Malveychuck et al (2020) Ketamine as an antidepressant:
overview of its mechanisms of action and potential
predictive biomarkers. Ther.Adv.Psychopharmacol. 10.
doi:10.1177/2045125320916657
• Zanos P et al (2016) NMDAR inhibition-independent
antidepressant actions of ketamine metabolites. Nature
533, 481-486
• See also slides.