Neuromodulatory Systems in the Brainstem A Focus on

Neuromodulatory Systems in the Brainstem: A Focus on Monoamines in Brain and Behavior Steven T. Szabo, M. D. , Ph. D. Department of Psychiatry and Behavioral Sciences Duke University Durham, NC

Learning Objectives 1. Brainstem location of monoamine neurons Serotonin (5 -HT); Norepinephrine (NE); Dopamine (DA) 2. Regulation of monoamine neurons in the brain 3. Monoamine neuron associated behaviors

Serotonin System (5 -HT) • 5 -HT neurons originate from raphe nuclei in the pons and project to areas throughout the brain • 5 -HT neurons have a primarily inhibitory function, acting in opposition to cholinergic, norepinephrine & dopaminergic systems Szabo, Gould, Manji, 2009 APA Textbook of Psychopharmacology

Serotonin System (5 -HT) • Increased 5 -HT activity is associated with reduced levels of behavioral activation and arousal • 5 -HT exerts a major role in sleep, mood, appetite, temperature regulation and pain perception • Acute tryptophan depletion cause a temporary recurrence of depressive symptoms in subjects (~50%) who have a hx of depression Szabo, Gould, Manji, 2009 APA Textbook of Psychopharmacology

Dopamine System (DA) • Brainstem DA neurons originate from the VTA and substantia nigra (midbrain of brainstem). • VTA neurons are involved in addiction, cognition, & motivation related to the mesocortical pathway and nucleus accumbens. • Substantia nigra neurons control fine motor movements through inputs to the striatum. Szabo, Gould, Manji, 2009 APA Textbook of Psychopharmacology

Dopamine System • DOPA is a precursor to DA production used to treat Parkinson’s Disease. Antipsychotics block D 2 receptors and can produce Parkinson’s symptoms and antipsychotic effects through mesolimbic modulation. • Increasing DA levels in the brain result in hyperactivity and goal-directed behavior. • Commonly associated drugs are cocaine, amphetamine, and haloperidol Szabo, Gould, Manji, 2009 APA Textbook of Psychopharmacology

Norepinephrine System • NE neurons that originate from locus coeruleus, a blue colored nucleus, is responsible for 90% of the NE in the brain (pons) • NE neuron ascend to the limbic system and forebrain and is believed to be involved in arousal, fear, and sleep-wake changes. • Descending projections control blood pressure (i. e. , clonidine) Szabo, Gould, Manji, 2009 APA Textbook of Psychopharmacology

Norepinephrine System • Similar to DA, tyrosine is the amino acid precursor • Dopamine beta hydroxylase (DBH) converts DA to NE • Reserpine (monoamine vesicle depleter) and propranolol (beta blocker) impacts the cardiovascular system (decreases BP), but also reduces psychotic symptoms and situational anxiety, respectively. • Yohimbine can induce panic Szabo, Gould, Manji, 2009 APA Textbook of Psychopharmacology

Most Psychotropics Target Monoamine Neurons Serotonin Norepinephrine Dopamine

Serotonin, Dopamine, Norepinephrine Szabo and Nemeroff, 2014 Rosenberg’s Molecular and Genetic Basis of Neurological and Psychiatric Disease, Fifth Edition

Outside Nerve Inside Nerve Serotonin Glutamate Initial Effects of psychotropics (occurs in hrs) Turns on a switch in the Information superhighway Gradual changes in important circuits Days--> weeks

Phosphodiesterase System Szabo, Gould, Manji, 2009 APA Textbook of Psychopharmacology

Neuromodulation Mechanisms 1 NE 5 -HT Glu 2 5 Glia Rs Gs AC Gi/o RI/o AMPA 3 NMDA 4 Ca 2+ -dependent or MAP kinase cascades c. AMP PKA CREB 6 BDNF/trk. B Bcl-2 Enhancement of synaptic plasticity and cellular resilience Restoration, enhancement & maintenance of neural connectivity mechanisms essential for healthy affective functioning and buffering against deterioration of neural functioning

Szabo and Nemeroff, 2014 Rosenberg’s Molecular and Genetic Basis of Neurological & Psychiatric Disease, 5 th Ed

Glutamate Regulates Brainstem and Forebrain Szabo and Nemeroff, 2014 Rosenberg’s Molecular and Genetic Basis of Neurological and Psychiatric Disease, Fifth Edition

Stress Impacts Brain and Behavior • Stress increases synaptic glutamate and can lead to neuronal-circuit damage and modifications. • Brainstem Calmodulin monoamine neurons are thought important in this process, as well as targeted treatments potentially reverse stress effects and provide resilience to stress. Calmodulin Du, Szabo, Gray, Manji, 2004 Int J Neuropsychopharm

REFERENCES SZABO, S. T. , GOULD, T. D. , and MANJI, H. K. : Chapter 1 - Introduction to Neurotransmitters, Receptors, Signal Transduction, and Second Messengers in Psychiatric Disorders. The American Psychiatric Publishing Textbook of Psychopharmacology, Fourth Edition, 2009, 3 -51 (AVAILABLE ON-LINE THROUGH DUKE LIBRARY). SZABO S. T. , NEMEROFF C. B. "Depression": Rosenberg’s Molecular and Genetic Basis of Neurological and Psychiatric Disease, Fifth Edition, 2014. DU, J; SZABO, S. T. ; GRAY, N. A. , MANJI, H. K. : Stress Related Effects on Ca. MKII: Relevance in Psychiatric Disorders. International Journal of Neuropsychopharmacology Calmodulin(2004) 7: 243 -248. Calmodulin