Monoamine Systems Susan R. Sesack

Professor, Neuroscience

Nolte

Nolte

histidine decarboxylase

Cooper, Bloom and Roth

Nolte

“An underlying assumption in behavioral neurochemistry is that certain substances, neuroregulators, play a key role in communication among nerve cells. These compounds may be subdivided into those which convey information between adjacent nerve cells (neurotransmitters) and those which amplify or dampen neuronal activity (neuromodulators).” J Barchas et al. 1978 Science

“Neuromodulation...is taken to mean the enhancement, reduction, prolongation or curtailment of information processing by activity within these [monoamine] systems, often with only their minor participation in the computations of the neural networks they innervate.” TW Robbins

“Each neuron has characteristic intrinsic response properties that result from the ensemble of ion channels found in its membrane. Modulatory substances can modify the type, number, and/or kinetic properties of these ion channels and thus change the excitability of the cell... Consequently, a single neuron can display a variety of intrinsic activity patterns and can switch between them, depending on the modulatory environment.” E Marder

Purves

Nicoll et al., 1987

Wang et al., 2006 Neuron

Monoamine axons are thin and unmyelinated, placing them at the low end of the conduction velocity range (0.5 m/sec), consistent with their modulatory function.

Netter, Ciba Series

Monoamine axon varicosities sometimes form recognizable synapses and sometimes do not, consistent with their use of both classical wiring transmission and volume transmission.

Descarries; Sesack

Bezard and Gross, 1998

Fuxe and Agnati, 1991

Sanford Palay:

"Topographic proximity of the pre- and postsynaptic elements is dispensed with in systems for which speed, efficiency, and precise focal interaction are not important." Non-synaptic transmission provides "an efficient way to produce generalized effects without directly and repetitiously contacting every single cell in a target area…comparable to sounding a fire alarm instead of ringing the doorbell of every home in an area threatened by fire."

Limitations on volume transmission: • amount of transmitter released • tortuosity factors/glia • receptor localization and affinity • reuptake

Sesack

Postsynaptic receptors for monoamines, such as these D1 receptors in a striatal dendrite, have been amply demonstrated at extrasynaptic sites and further shown to be functional (e.g. they internalize in response to agonist exposure).

Dumartin et al., 1998, J Neurosci

Postsynaptic receptors for monoamines, such as these D1 receptors in a striatal dendrite, have been amply demonstrated at extrasynaptic sites and further shown to be functional (e.g. they internalize in response to agonist exposure).

Dumartin et al., 1998, J Neurosci

Sesack

Plasma membrane transporters (e.g. DAT) are typically localized to the immediate perisynaptic area and at extrasynaptic sites all along monoamine axons.

This is at least consistent with the possibility of extrasynaptic release.

Hersch et al., 1997, J Comp Neurol

The essential role played by monoamine transporters is evidenced by transgenic mice, such as the DAT knock-out mouse, which exhibits a hyperactive state associated with excessive extracellular DA levels, despite the system’s many attempts at homeostasis.

wild type heterozygote knockout

Giros et al., 1996, Nature

Monoamine transmission is also typically regulated by autoreceptors located on axonal and somatodendritic membranes.

The latter are consistent with dendritic release events.

Saper, 2000

Dopamine System

Saper, 2000

Dopamine System

In target areas, DA terminals frequently synapse onto spines and distal dendrites where they converge with glutamate inputs onto the same structures.

Corticostriatalglutamate

Nigrostriataldopamine

Medium SpinyStriatal Neuron

adapted from Smith et al., 1990, TINS; and Sesack

Dopamine System

DA modulates glutamate transmission by either attenuating or facilitating drive depending on receptor subtype and other factors.

Mogenson

Dopamine System

DA cells fire spontaneously due to pacemaker potentials. These slow depolarizing currents are voltage-dependent, carried by both Na+ and Ca2+ and are initiated upon the decay of the afterhyperpolarization.

Grace, 1985/7 and 1995

Dopamine System

Many DA cells maintain a mean firing rate of 3-5 Hz (some populations are faster). DA neurons exhibit little variation in activity across different sleep-wake stages and are the only monoamine cells demonstrating such stability despite changes in behavioral state.

Trulson, 1985

Dopamine System

Strong excitatory drive leads to NMDAR-dependent bursts of action potentials that have a characteristic decreasing amplitude and increasing interspike interval within the burst. DA release from terminals during a burst is reportedly greater than during the same number of evenly spaced spikes. DA cells also show brief pauses after bursts or in response to strong synaptic inhibition.

In vivo, DA neurons fire in an irregular tonic mode that reflects excitatory and inhibitory synaptic inputs superimposed on the pacemaker activity.

Grace, 1987 and 1995

Dopamine System

Schultz, 1998, J Neurophysiol

In awake animals, the activity patterns of DA cells involve:

• activation to unpredicted rewards

• activation to conditioned stimuli that predict reward (but no longer to predictable rewards)

• inhibition when expected rewards are not delivered

Hence, DA neurons appear to signal their targets with information regarding future expectancy.

Dopamine System

Historically, activation of forebrain DA systems has been associated with natural and drug rewards:

• food (presentation, not consumption)

• sex (preparation, not consummation)

• introduction of conspecifics to isolated animals

• cocaine

• amphetamine

• heroin

• nicotine

• alcohol

Web images

Dopamine System

DA cell firing is altered by:

Natural and drug rewards (usually excitation)

Conditioned stimuli predicting reward (usually excitation)

Prediction of no reward (usually inhibition)

Absence of predicted reward (usually inhibition)

Stress and aversive/noxious stimuli (usually inhibition)

Uncertainty (altered rate of tonic firing)

Novel stimuli with fast rise times and high intensity (usually excitation): light flash, click, whistle, clap, hiss, strong odor, whisker stimulation, novel environment, etc.

Dopamine System

DA cells are reticular! They are activated by conditions that cause the animal to:

• respond to the environment

• maintain a representation of the triggering event

• prepare for action

Horvitz, 2000

• DA cells are inhibited by conditions that call for halting action.

Dopamine System

Saper, 2000

Norepinephrine & Epinephrine

Saper, 2000

Norepinephrine System

Jedema et al (1999) Brain Res

NE cells are reticular! • are activated by multisensory stimuli

• are activated by acute stressors

• function in attention and arousal

Aston-Jones et al (1994) J Neurosci

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Tail shock

Norepinephrine System

NE cells in the LC decrease activity progressively from waking to slow-wave sleep and then shut off during REM sleep (i.e., REM-off cells).

Aston-Jones & Bloom, 1991

Norepinephrine System

LC neurons increase their activity during stressful events and in response to arousing stimuli. The LC operates like a central sympathetic system, cognitively preparing an animal by increasing attention and vigilance. In target areas, NE selectively enhances cell firing in response to sensory events that have high affective valence.

Norepinephrine System

Activation of the LC NE system facilitates memory for emotionally disturbing events, which is better than for emotionally neutral events.

Norepinephrine System

Alterations in the NE system also underlie certain anxiety disorders, including PTSD, that are characterized by hyper-vigilance and hyper-responsiveness.

Norepinephrine System

NE dysfunction might also contribute to attention deficits seen in attention deficit hyperactivity disorder (ADHD).

Norepinephrine System

Saper, 2000

Serotonin System

5HT neurons show a progressive decline in activity through various stages of slow-wave sleep, and they shut off during REM sleep (i.e., REM-off cells).

Serotonin System

5HT raphe cells fire around 3 Hz during active and quiet waking. They can fire up to 6 Hz by phasic stimuli (e.g. auditory clicks) linked to arousal. But they typically cannot be driven to fire faster, even by extreme stress.

5HT - “cardiovascular and respiratory activity, sleep, aggression and sexual behavior, nutrient intake, anxiety, mood, motor control, neuroendocrine secretion, and nociception and analgesia.”

Drugs that act on the serotonin system can be used to treat a range of disorders from migraines to obsessive compulsive disorder to depression, and they can cause side effects ranging from hallucinations to sexual dysfunction.

BL Jacobs and CA Fornal: “Serotonin is an enigma. It is at once implicated in virtually everything, but responsible for nothing.”

Serotonin System

DA – reward, approach/avoidance, response initiation NE – vigilance

Serotonin System

Heninger, 1995

Serotonin System

Saper, 2000

Histamine System

Sleep-Wake Cycles Histamine projections to the thalamus and cortex regulate arousal and consciousness. GABA neurons in the VLPO of the hypothalamus initiate non-REM sleep in part by shutting off the histamine neurons, mimicking the action of antihistamines.

Web image

Histamine System

Reticular formation ACh neurons play a major role in sleep-wake cycles. Their extensive projections to thalamus provide diffuse activation signals that maintain thalamocortical activity in an awake state. These cells turn off during slow-wave sleep, then turn ON again in REM sleep (REM ON cells). This reactivation of thalamus and cortex maintains the awake EEG pattern characteristic of REM.

Cooper, Bloom and Roth

Acetylcholine System

Saper, 2000

Acetylcholine System

Muscarinic acetylcholine receptors are associated with learning, memory and attention. Drugs that are anti-muscarinics can produce amnesia (e.g. the “twighlight sleep” of scopolamine). Basal forebrain cholinergic neurons degenerate in Alzheimer’s disease.

Acetylcholine “mediates increases in neuronal activity associated with enhanced demands for attentional processing.” M Sarter Acetylcholine “mediates the detection, selection, and processing of stimuli and associations, and the allocation of processing resources for these attentional functions” J Bruno

Acetylcholine System

Nicotine is the single most addictive substance known, almost certainly via its direct stimulant action on the midbrain DA system.

Nicotinic receptors are associated with vigilance and concentration.

Web images

Acetylcholine System