Objective To provide an update on the “catecholamine hypothesis” of attention-deficit hyperactivity disorder (ADHD). Method Recent work examining the measurement of the norepinephrine, epinephrine, and dopamine systems in ADHD and normal subjects is reviewed and discussed in the context of recent neuroimaging and animal studies. Results While data clearly indicate a role for all three of the above neurotransmitters in ADHD, a hypothesis suggesting “too much” or “too little” of a single neurotransmitter will no longer suffice. The central norepinephrine system may be dysregulated in ADHD, such that this system does not efficiently “prime” the cortical posterior attention system to external stimuli. Effective mental processing of information involves an anterior “executive” attention system which may depend on dopamlnergic input. The peripheral epinephrine system may be a critical factor in the response of individuals with ADHD to stimulant medication. Conclusion A multistage hypothesis is presented which emphasizes the interaction of norepinephrine, epinephrine, and dopamine in modulation of attention and impulse control. J. Am. Acad. Child Adolesc. Psychiatry , 1996, 35(3):264–272

Catecholamines in attention-deficit hyperactivity disorder: Current perspectives

Postnatal olfactory learning produces both a conditioned behavioral response and a modified olfactory bulb neural response to the learned odor. The present report describes the role of norepinephrine (NE) on both of these learned responses in neonatal rat pups. Pups received olfactory classical conditioning training from postnatal days (PN) 1– 18. Training consisted of 18 trials with an intertrial interval of 24 hr. For the experimental group, a trial consisted of a pairing of unconditioned stimulus (UCS, stroking/tactile stimulation) and the conditioned stimulus (CS, odor). Control groups received either only the CS (Odor only) or only the UCS (Stroke only). Within each training condition, pups were injected with either the NE beta-receptor agonist isoproterenol (1, 20, or 4 mg/kg), the NE beta-receptor antagonist propranolol (10, 20, 40 mg/kg), or saline 30 min prior to training. On day 20, pups received one of the following tests: (1) behavioral conditioned responding, (2) injection with 14C-2-deoxyglucose (2-DG) and exposed to the CS odor, or (3) tested for olfactory bulb mitral/tufted cell single-unit responses to the CS odor. The results indicated that training with either: (1) Odor-Stroke-Saline, (2) Odor- Stroke-Isoproterenol-Propranolol, or (3) Odor only-Isoproterenol (2 mg/kg) was sufficient to produce a learned behavioral odor preference, enhanced uptake of 14C-2-DG in the odor-specific foci within the bulb, and a modified output signal from the bulb as measured by single-cell recordings of mitral/tufted cells. Moreover, propranolol injected prior to Odor-Stroke training blocked the acquisition of both the learned behavior and olfactory bulb responses. Thus, NE is sufficient and may be necessary for the acquisition of both learned olfactory behavior and olfactory bulb responses.

https://www.jneurosci.org/content/jneuro/9/11/3998.full.pdf

Norepinephrine and Learning-Induced Plasticity in Infant Rat Olfactory System

The locus coeruleus (LC), or 'blue spot', is a small nucleus located deep in the brainstem that provides the far-reaching noradrenergic neurotransmitter system of the brain. This phylogenetically conserved nucleus has proved relatively intractable to full characterization, despite more than 60 years of concerted efforts by investigators. Recently, an array of powerful new neuroscience tools have provided unprecedented access to this elusive nucleus, revealing new levels of organization and function. We are currently at the threshold of major discoveries regarding how this tiny brainstem structure exerts such varied and significant influences over brain function and behaviour. All LC neurons receive inputs related to autonomic arousal, but distinct subpopulations of those neurons can encode specific cognitive processes, presumably through more specific inputs from the forebrain areas. This ability, combined with specific patterns of innervation of target areas and heterogeneity in receptor distributions, suggests that activation of the LC has more specific influences on target networks than had initially been imagined.

Locus coeruleus: a new look at the blue spot.

Pontine regulation of REM sleep components in cats: integrity of the pedunculopontine tegmentum (PPT) is important for phasic events but unnecessary for atonia during REM sleep.

Neurobiology of associative learning in the neonate: early olfactory learning.

1. A method for adapting a standard stereotaxic frame for use with neonatal rats as young as postnatal day 1 (PD 1) was devised, and single-unit extracellular recordings were obtained from neurons in the locus ceruleus (LC) in urethan-anesthetized rats during different stages in development from PD 1 to PD 34. 2. The spontaneous firing pattern of neonatal LC neurons was characterized by long silent periods punctuated by brief epochs of sporadic firing. At PD 7-14, LC neurons exhibited periodic occurrences of irregular firing that lasted for 20-30 s. By PD 20, the pattern and rate of spontaneous activity were virtually indistinguishable from that of adults. 3. Conditioning stimulation of the dorsal noradrenergic bundle (DNB), given 10-200 ms prior to a test stimulus to the DNB, markedly reduced the amplitude of the antidromic action potentials to the test stimulus and sometimes resulted in spike decomposition. This refractoriness of the soma-dendritic membrane of LC cells was significantly attenuated with development and approached adult levels after PD 18. 4. Antidromic responses elicited by DNB stimulation were followed by a phase of inhibition or inhibition-excitation. Postactivation excitation was most prominent in cells that were not spontaneously active, and decreased steadily throughout development, probably because of the steady increase in spontaneous firing rate seen during maturation. 5. Although the conduction velocity of LC axons increased steadily from birth through PD 26, conduction time remained unchanged. 6. Neonatal LC neurons were equally sensitive to noxious and nonnoxious somatosensory stimuli. As development proceeded, LC neurons became less sensitive to innocuous somatosensory stimuli such as air puffs and tactile stimuli while simultaneously becoming more sensitive to noxious stimuli. Auditory and visual stimuli became effective for the first time at PD 14 and PD 12, respectively. 7. These results indicate that the electrical activity of LC neurons in the developing brain is intimately related to input from peripheral sensory sources. Therefore, the influence of the LC on the developing brain may occur predominantly through sensory input.

T. Sakaguchi

Papers

Postnatal development of electrical activity in the locus ceruleus.

Development and plasticity of the locus coeruleus: a review of recent physiological and pharmacological experimentation.

The role of alpha1-adrenoceptor-mediated collateral excitation in the regulation of the electrical activity of locus coeruleus neurons