Dopamine action, synthesis, and pathways:
Dopamine's synthetic precursor is 3,4-dihydroxyphenylalanine (L-DOPA). If you have seen the movie Awakenings or read Oliver Sacks's novel on which the movie is based, you may remember that L-DOPA was the drug the new doctor on the ward administered to catatonic patients and that it prompted their awakening from decades-long bouts of catatonia. Their illness was caused by an outbreak of viral encephalitis that destroyed dopamine-producing neurons in their brains. We will discuss postencephalitic Parkinsonism further when we talk about neurotransmitter-related illnesses.
Action: In Affective Neuroscience: The Foundations of Human and Animal Emotions (1998), Jaak Panksepp explains that the overall functions of the basal ganglia [corpus striata] "are under the control of one major 'power switch'—ascending brain dopamine…." Panksepp points out that dopamine circuits "appear to be major contributors to our feelings of engagement and excitement as we seek the material resources needed for bodily survival, and also when we pursue the cognitive interests that bring positive existential meanings into our lives." He explains that without dopamine, "human aspirations remain frozen…." He goes on to say that when dopamine is abundant in synapses, "a person feels as if he or she can do anything." Panksepp asks: "Is it any wonder that humans and animals eagerly work to artificially activate this system whether via electrical or chemical means? Cocaine and amphetamines are psychologically addicting because they facilitate activity in brain DA [dopamine] systems."
In Part 1 of CorticalBrain.com, in The corpus striata (basal ganglia) complex, we discuss how the corpus striata, often called the basal ganglia, are ancient protoreptilian structures. In Brainscapes: An Introduction to What Neuroscience Has Learned about the Structure, Function, and Abilities of the Brain (1995), Richard M. Restak points out that the corpus striata mediate the "initiation, smoothness, and precision of movement." When dopamine is available in normal amounts, the corpus striata efficiently manage the flow of sensory information from the neocortex, repeatedly recirculating information back to the cortex through the thalamus. Restak goes on to say that the corpus striata are "responsible for the automatic movements we make without thinking." And there are indications that the corpus striata—prompted by dopamine—are involved in compulsive behaviors as well as obsessions.
Synthesis: Dopamine is synthesized in cell groups in the midbrain's substantia nigrae and ventral tegmental areas (VTA). The midbrain is labeled 3 in the picture below. The term tegmental comes from tegmentum, which is Latin for "covering." MedlinePlus Dictionary defines tegmentum as "the part of the ventral midbrain above the substantia nigra formed of longitudinal white fibers with arched transverse fibers and gray matter." The term ventral refers to the part of the tegmentum located toward the front of the human body rather than the rear.
If you look carefully at the image below, you can see two blackish areas, mirror images of each other, in the area labeled 3. These are the substantia nigrae. The VTA structures are located just above the substantia nigrae. The corpus striata surrounds the centrally located thalami (labeled 2), so you can see that axonal connections from the substantia nigrae could easily innervate the corpus striata. these connections are discussed, referred to as the nigrostriatal pathway, as well as VTA pathways, later in this narrative. The image below is from John A Beal, Department of Cellular Biology and Anatomy, Louisiana State University.
Medial Forebrain Bundle: The medial forebrain bundle (MFB) is a prominent tract of nerve fibers, both ascending and descending, that connects areas of the brain stem with subcortical areas of the brain. Within this larger and longer pathway are several shorter pathways including the nigrostriatal pathway, the mesolimbic pathway, and the mesocortical pathway—all extending from dopamine-producing neurons.
The position of the medial forebrain bundle is illustrated in the image below from the HOPES Brain Tutorial, a project of Stanford University. In real tissue, the bundle would appear white. As we discuss in Part 1 of CorticalBrain.com, in Gray matter, white matter, glial cells, when multitudes of axons are grouped together, they appear as white matter.
Nigrostriatal Pathway: The axons of neurons in the substantia nigrae ascend via the MFB but terminate in the caudate-putamen areas of the corpus striata complex. These axons are together named the nigrostriatal pathway. This pathway is particularly associated with movement. Depletion of dopamine in the nigrostriatal pathway causes Parkinson's disease. We will discuss Parkingon's disease in the next page of CorticalBrain.com, Brain Neurotransmitters and Illness
Mesolimbic Pathway: The axons of a subset of neurons in the VTA ascend via the MFB but terminate in the nucleus accumbens (also part of the corpus striata complex). These axons are together named the mesolimbic pathway. The prefix "meso" is Greek for "middle." So the term "mesolimbic" means from the middle-brain, or mid-brain as we now call it, to a part of the limbic system. We discuss the naming of brain structures in Part 1 of CorticalBrain.com in Broca's Limbic Lobe, Papez's Circuit, and MacLean's Limbic System.
Regarding the nigrostriatal pathway and the mesolimbic pathway, Panksepp explains in Affective Neuroscience that reciprocating, descending nerve pathways exit the corpus striata and run back to respective cell groups in the substantia nigrae and VTA structures. These reciprocating loops are probably intended, explains Panksepp, "to help protect the system from excessive arousal when it is perturbed by an overabundance of incoming stimulation."
Mesocortical Pathway: The axons of a second subset of neurons in the VTA ascend via the MFB into the nucleus accumbens (within the corpus striata) and continue on to innervate the frontal cortex. These axons are together named the mesocortical pathway.
Tuberoinfundibular Pathway: In addition to the mid-brain, dopamine-producing neurons are also found in the tuberal nuclei, an anatomically specific region of the hypothalamus. Axons from these neurons project to an anatomically specific area of the pituitary gland called the infundibulum. Thus, in very general terms, the tuberoinfundibular pathway connects the hypothalamus with the pituitary gland.
In the Color Atlas of Neuroscience: Neuroanatomy and Neurophysiology, Adam Greenstein explains that the tuberoinfundibular pathway projects "from the hypothalamic arcuate nucleus to the median eminence, where the terminals release DA [dopamine] into the pituitary portal blood. The released DA has a hormonal role, suppressing prolactin release." Antipsychotic drugs aimed at decreasing dopamine transmission in other pathways may also decrease dopamine transmission in the tuberoinfundibular pathway. The use of these drugs always comes with a caution since higher doses result in a greater likelihood that increased blood prolactin levels (hyperprolactinaemia) will develop. In both men and women, hyperprolactinaemia may produce breast lactation and result in loss of bone mineral density leading to osteoporosis. Hyperprolactinaemia may also disrupt the menstrual cycle in women. In men, the condition may reduce testosterone as well as contribute to erectile dysfunction and infertility.
Generally, very low doses of antipsychotics are recommended for OCD (e.g., 0.25 – 0.5 mg haloperidol, titrated slowly to 2 – 4 mg) according to McDougle and Walsh, "Treatment for Refractory OCD," (2001), In: Fineberg, Marazitti, and Stein (eds), Obsessive Compulsive Disorder: A Practical Guide.
Lower doses of dopamine antagonist drugs are less likely to produce side-effects such as hyperprolacti naemia. Side effects have to be weighed against benefits. From personal experience, many patients with OCD would benefit from very low doses of medication (e.g., 0.25 – 0.5 mg haloperidol) that mitigate symptoms. Part 3 of CorticalBrain.com includes more information in the section titled OCD Treatments Including Antipsychotic Medications
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