Neurotransmitters and Drugs of Abuse

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Dopamine

Synthesis and Metabolism

Phenylalanine ---> Tyrosine ---> DOPA ---> Dopamine (DA)


Anatomy

  • Synthesized mainly in neurons located in the ventral midbrain (substantia nigra pars compacta & ventral tegmental area)
  • Three projection systems:
    • Nigrostriatal Pathway: Substantia nigra to caudate and putamen (implicated in Parkinson’s)
    • Mesolimbic Pathway: Midbrain to limbic structures (implicated in positive symptoms of psychosis)
    • Mesocortical Pathway: Midbrain to prefrontal cortex (implicated in working memory and other executive skills and cognitive deficits and negative symptoms of Schizophrenia)


Conditions Due to Deficits in Dopamine Synthesis

Phenylketonuria (PKU)

  • Inherited disorder of enzyme that breaks down phenylalanine into tryrosine
  • Results in excessive phenylalanine (excreted in urine) and dopamine depletion
  • If not put on very low phenylalanine diet, the individual will develop mental retardation. Even on diet, executive functioning deficits occur.

Parkinson’s Disease

  • Deficit in conversion of precursors into DOPA, which results in diminished DA
  • Involuntary movement disorder with both “positive symptoms” (e.g., tremor, especially when on L-Dopa), and “negative symptoms” (e.g., bradyphrenia, bradykinesia)
  • Treated with L-Dopa (which boosts DOPA levels), drugs that reduce L-Dopa metabolism outside of the CNS (which allows for lower L-Dopa doses and fewer systemic side effects), or DA agonists


Conditions Due to Excessive Dopamine Activity

Synthetic Causes

  • Excessive L-dopa
  • Cocaine
  • Amphetamines

Endogenous Causes

  • Tardive Dyskinesia Probable increased DA sensitivity due to antipsychotics. Results in visual hallucinations, psychosis, hyperkinetic movement disorders (e.g., dystonia, chorea)


Norepinephrine (NA) and Epinephrine

(norepinephrine is also known as noradrenaline)

Synthesis and Metabolism

Dopamine ---> Norepinephrine ---> Epinephrine


Anatomy

  • NA synthesized primarily in locus ceruleus (located near fourth ventricle in the rostral/dorsal pons)
  • Projects to the entire forebrain through the thalamus
  • Ascending norepinephrine projection system implicated in modulation of attention, sleep-wake states, mood
  • Epinephrine synthesized in adrenal gland
  • Outside CNS, major neurotransmitters in the sympathetic nervous system


Related Disorders

  • ADHD: Psychostimulant or SNRI (Strattera) treatment enhances noradrenergic transmission and/or reduces reuptake
  • Neuronal depletion of locus ceruleus in Parkinson’s can lead to depression and sleep disorders
  • Noradrenergic transmission also seems to be important in mood disorders including depression and bipolar and anxiety disorders
  • NA depletion can result in orthostatic hypotension and other symptoms of reduced sympathetic n. system activity
  • Excessive NA causes tremor, sympathetic nervous system overactivity (e.g., bronchodilation, arterial dilation)


Serotonin

Synthesis and Metabolism

Tryptophan ---> 5-Hydrotryptophan ---> Serotonin (5-Hydrotryptamine or 5-HT)


Anatomy

  • Synthesized in dorsal raphe nuclei of the midbrain and pons
  • Projects to entire forebrain including cortex, thalamus, and basal ganglia
  • Many different receptor types result in a variety of symptoms/behaviors associated with 5-HT disorders


Related Disorders

  • Low 5-HT ---> depression, anxiety, OCD. Also found in Parkinson’s (esp. if depressed) and Alzheimer’s
  • Excessive 5-HT ---> LSD and Ecstasy are serotonin agonists that cause psychosis and hallucinations


Acetylcholine

Synthesis and Metabolism

Acetyl CoA + Choline ---> Acetylcholine (ACh)


Anatomy

  • Synthesized mainly in nucleus basalis of Meynert and adjacent nuclei in the basal forebrain
  • Two kinds of receptors:
    • Nicotinic: Involved almost exclusively at neuromuscular junction
    • Muscarinic: Involved in cerebral cortex (especially in arousal and memory functioning)


Related Disorders

  • Alzheimer’s Disease: Deterioration of nucleus basalis of Meynert implicated in memory dysfunction. Anticholinesterases (e.g., Cognex, Aricept) show some effectiveness in slowing progression a bit.
  • Botox inhibits Ach release from presynaptic neuron, resulting in localized loss of muscle tone
  • Neuroleptics can cause anticholinergic side effects (e.g., confusion, drowsiness, dry mouth); those that tend to produce the least extrapyramidal symptoms (see DA, above) tend to have more anticholinergic side effects.


Glutamate

Synthesis and Metabolism

Glutamine ---> Glutamate


Anatomy

  • Major excitatory amino acid; NMDA receptor modulates Calcium channel flow
  • Projects throughout central nervous system


Related Disorders

  • Excessive Glutamate: Causes excitotoxicity, a probable cause of cell death in TBI, stroke, other disorders.


Gamma-Aminobutyric Acid (GABA)

Synthesis and Metabolism

Glutamine ---> GABA


Anatomy

  • Major inhibitory transmitter; opens Chloride (Cl-) channels and closes Calcium channels, hyperpolarizing cells
  • Widespread in entire central nervous system, but highest in striatum, hypothalamus, spinal cord, and temporal lobes.


Related Disorders

  • GABA Deficiency: Implicated in epilepsy and, sometimes, chorea
  • Many antiepileptic medications increase GABA activity


Several Drugs of Abuse

(not including alcohol)

Cocaine


Pharmacology

  • CNS Stimulant
  • Blocks re-uptake of DA, NA, and serotonin, while also causing release of DA into synaptic cleft

Desired Effects

  • Euphoria
  • Increased vigilance

Overdose

  • Agitation, paranoia, delusions, hallucinations
  • Strokes (or heart attacks) and seizures
  • Long-term use: involuntary movement disorders (e.g., “crack dancing”: inability to stand still)

Withdrawal

  • Emotional “crash”: dysphoria, anhedonia, strong craving for drug
  • Rebound of REM sleep (which was suppressed while on drug), resulting in vivid, disturbing dreams


Amphetamine


Pharmacology

  • CNS Stimulant, lasting much longer than cocaine
  • Blocks re-uptake of DA while also causing release of DA into synaptic cleft

Desired Effects

  • Euphoria
  • Increased vigilance (many ADHD drugs are amphetamines or amphetamine-like)

Overdose

  • Paranoia, delusions, hallucinations
  • Strokes (or heart attacks) and seizures
  • Long-term use: involuntary movement disorders

Withdrawal

  • Emotional “crash”: dysphoria, anhedonia, strong craving for drug
  • Rebound of REM sleep (which was suppressed while on drug), resulting in vivid, disturbing dreams


Opioids


Pharmacology

  • Can affect DA and other neurotransmitters, but primary effect at opiate receptors

Desired Effects

  • Pain reduction
  • Anxiety reduction
  • Sleepiness

Overdose

  • Coma, “pin-point pupils” (miosis), and respiratory depression
  • Cerebral hypoxia
  • Rarely associated with seizures or cerebral hemorrhages

Withdrawal

  • Strong craving for drug
  • Dysphoria, autonomic hyperactivity


PCP (Phencyclidine)


Pharmacology

  • Central analgesic, depressant, and hallucinogen
  • Blocks re-uptake of DA, NA, and serotonin, prevents glutamate from activating NMDA receptor

Desired Effects

  • Low doses like alcohol use
  • Higher doses cause both positive and negative symptoms of schizophrenia

Overdose

  • Muscle rigidity, vertical nystagmus, stereotypies, blank stare, unresponsiveness
  • Seizures that can lead to status epilepticus
  • Violent, psychotic behavior


Marijuana


(especially the THC in it)

Pharmacology

  • Affects THC receptors in cortex, basal ganglia, hippocampus, and cerebellum

Desired Effects

  • Calming
  • Reduced nausea or vomiting
  • Mood elevation

Negative Effects

  • Slowed mentation
  • Sedation
  • Sometimes hallucinations at high doses
  • Sometimes lasting inattention
  • Fluency problems
  • Impaired executive functioning



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