Lecture 59 Part 2 - Stimulants and ADHD Flashcards
The Reticular Activation System
Very complex, contains dopamine, adrenergic, serotonergic, and cholinergic neurons.
Regulates arousal, sleep-wake transitions and synchronization of EEG.
Pathophysiology of ADHD
genetic vs non-genetic factors
Implicated systems:
– Dopamine transporter, COMT, cholinergic receptors, cholesterol metabolism, CNS development, glutamate receptors
Environmental factors
Imaging studies reveal reduced total brain volume and activity in key areas
Clinical Presentation of ADHD
Symptoms at ages 5-9 yo (generally before 12 for diagnosis)
Six or more symptoms must be present
Significant impairment in two or more settings (e.g., home vs. school)
Symptoms documented by parent, teacher, and clinician
Interferes with functioning and development
Symptoms
– Inattention examples: difficulty organizing tasks/activities, does not seem to listen, easily distracted, loses things for activities
– Hyperactivity examples: fidgets or squirms
– Impulsivity examples: leaves seat, runs/climbs excessively (e.g., in the mouse model) interrupts – possible circuity mechanism: medial prefrontal
cortex functional (mPFC) control might not be fully functional
Pharmacology of Stimulants
Methylxanthines
Indirect-acting sympathomimetics: stimulant compounds mimic the effect of endogenous agonists of the sympathetic nervous system
Pharmacology of Methylxanthines
Antagonize adenosine receptors
Inhibit phosphodiesterases: increase cAMP (potentiate Gs-linked receptors)
Increase activity of ryanodine receptors, increasing intracellular Ca2+
Adenosine Receptors
A1 - Gi/o-linked, pre and post synaptic; inhibitory modulation of many neurotransmitters
Located in cerebral cortex, hippocampus, cerebellum, thalamus, brain stem, and spinal cord.
CNS Activation: sedation, neuroprotection, anxiolysis, temperature reduction, anticonvulsant activity, and spinal analgesia.
Peripheral Activation: bronchoconstriction, decreased glomerular filtration, decreased heart rate, slowed atrioventricular conduction, and decreased atrial myocardial contractility.
Adenosine Receptors Cont.
A2A - Gs-linked pre and post synaptic: located in cerebral vasculature and striatum; vasodilation
Heterodimerize with A1 and D2 dopamine receptors
A2B - Gs-linked, mostly on glial cells function unknown
A3 - Gq-linked, hippocampus and thalamus (only activated in states of excessive catabolism; e.g., seizures, hypoglycemia, stroke; not antagonized by methylxanthines)
Pharmacology of Methylxanthines Cont.
Mild cortical arousal
Increased alertness
Decreased fatigue
Nervousness/insomnia
Ionotropic/ chronotropic effects
Vasoconstriction (cerebral vessels)
Smooth muscle relaxation
Diuretic actions
Pharmacology of Stimulants: indirect-acting sympathomimetics
NET: norepinephrine transporter/NE reuptake
VMAT: vesicular monoamine transporter
Reward Pathways
potential for abuse
prefrontal cortex, nucleus accumbens, ventral tegmental area
Monoamine transporters
dopamine, NE, serotonin
Indirect-acting sympathomimetics: cocaine (3-phenyltropanes)
Alkaloid from leaves of Erythroxylon coca
Inhibit (blockade only) monoamine transporters (NE, 5-HT, DA)
Used as local anesthetic
Highly rewarding and addictive
Indirect-acting sympathomimetics: amphetamines
Pharmacology of Amphetamines
Non-selective activation of monoamines (exception MDMA “ecstasy/molly/love drug” which is more selective for 5-HT; research use: may increase sociability, “psychedelic revival”)
Wakefullness, alertness, increased ability to concentrate
Highly rewarding = abuse potential
High doses can elicit psychotic behaviors
Abuse: Increase with increased prescribing
