Dopamine pathways in the brain

Mesocortical A neural pathway that connects the ventral tegmentum to the cortex, particularly the frontal lobes. It is one of the major dopamine pathways in the brain. 

Four well-defined dopamine pathways in the brain are shown in Figure 10—7. They include the mesolimbic dopamine pathway, the mesocortical dopamine pathway, the nigrostriatal dopamine pathway, and the tuberoinfundibular dopamine pathway. 

The four major dopamine pathways in the brain have been described. The me-solimbic dopamine system, which may mediate the positive symptoms of psychosis the mesocortical system, which may mediate the negative symptoms and cognitive symptoms of psychosis the nigrostriatal system, which mediates extrapyramidal... 

It should now be obvious that the use of conventional antipsychotic drugs presents a powerful dilemma. That is, there is no doubt that conventional antipsychotic medications have dramatic therapeutic actions on positive symptoms of psychosis by blocking hyperactive dopamine neurons in the mesolimbic dopamine pathway. However, there are four dopamine pathways in the brain, and it appears that blocking dopamine receptors in only one of them is useful, whereas blocking dopamine receptors in the remaining three pathways may be harmful. 

What is an atypical antipsychotic From a pharmacological perspective, the atypical antipsychotics as a class may be defined in part as serotonin-dopamine antagonists (SDAs) (Fig. 11 — 16). Several other distinguishing pharmacological characteristics will be discussed in the following section. In this section, we will first discuss how the atypical antipsychotics all derive some of their atypical clinical properties from exploiting the different ways that serotonin and dopamine interact within the four key dopamine pathways in the brain. Thus, it is very important to understand serotonin-dopamine interactions in each of the four dopamine pathways. 

The time spent reviewing the dopamine pathways in the brain was just right. ... 

It could not be anticipated that the extension of the alpha-methyl of MDMA to an alpha-ethyl would also attenuate the effects of the compound on dopaminergic pathways in the brain. In contrast to MDMA, MBDB has no significant effect either on inhibition of uptake of dopamine into striatal synaptosomes (Steele et al. 1987) or on release of dopamine from caudate... 

The pleasure derived from using tobacco is linked to the stimulation of dopamine-dependent neurotransmitter pathways in the brain, particularly in the meso-limbic system. The precise nature of this link remains controversial, but many of the neurophysiological processes underlying nicotine addiction are common to other addictive drugs with diverse pharmacological actions such as opiates, cannabis, alcohol and cocaine. 

That conclusion is correct and has been known for quite some time. Back in 1960, examination of the brains of parkinsonism victims revealed that a pathway in the brain termed the nigrostriatal pathway had degenerated. This pathway proceeds from a group of cells called the substantia nigra to the striatum and is known to be important for the control of movement. The neurotransmitter employed in this pathway is dopamine. 

Dopamine Pathways. Before we describe the typical antipsychotics in any detail, we should digress briefly to talk about the role of dopamine in the brain and how these medications affect it. First, there are four key pathways of dopamine activity in the brain, and each pathway has a particular significance ... 

Figure 4.3 The reward pathway is the pathway in the brain that positively reinforces pleasurable behavior. When the brain receives a rewarding stimulus, the neurons in the ventral tegmental area release dopamine. The dopamine, in turn, affects neurons in the nucleus accumbens and the prefrontal cortex.

The distribution of dopamine in the brain is very non-uniform. There is some in the limbic system, and a large proportion is found in the corpus striatum - a part of the extrapyramidal motor system which is concerned with the coordination of movement. Dopamine-containing nerves are found in three main pathways in the brain. The nigrostriatal pathway contains about 75% Of the dopamine in the brain, and the cell bodies lie in the substantia nigra and the nerves terminate in the corpus striatum. The second important pathway is the mesolimbic pathway, the cell bodies of which lie in the mid-brain and project to parts of the limbic system, particularly the nucleus accumbens. The third, the tubero-infundibular system, consists of short neurons that run from the arcuate nucleus of the hypothalamus to the median eminence and the pituitary gland, the secretions of which they regulate. 

Nonetheless, there is a vast body of literature documenting interactions between dopamine and serotonin pathways in the brain (109-111). Clearly, however, if a drug (e.g., cocaine)releases multiple transmitters, then a behavioral interaction is not surprising. Inhibition of presynaptic reuptake of serotonin, for example, could lead to postsynaptic activation of a variety of other receptors, some of which could modulate dopamine function. In addition to potential effects on 5-HT receptors, other studies have implicated serotonin 5-HT, receptors (112), 5-HT receptors (113), and 5-HT receptors (114). 5-HT receptors can also modulate the locomotor effects of cocaine (115). 

The basic addiction pathway in the brain is a dopamine pathway. Activation of this pathway accounts for the positive reinforcement feeling and makes us want to repeat the action that triggered that feeling. 

The mesolimbic dopaminergic system is the principal reward pathway in the brain. Amphetamine, cocaine, and opiates cause dopamine release in the nucleus accumbens. Food seeking and sexual behavior do so as well. 

There are three dopaminergic pathways in the brain the nigrostriatal, the mesolimbic-mesocortical and the tuberculoinfundibular. In addition to being a neurotransmitter, dopamine is a precursor of noradrenahne and adrenaline. 

The nigrostriatal tract is one of the four main dopaminergic pathways in the central nervous system. About 75% of the dopamine in the brain occurs in the nigrostriatal pathway with its cell bodies in the substantia nigra, whose axons project in the corpus striatum. Degeneration of the dopaminergic neurons in the nigrostriatal system results in Parkinsons disease. 

This peptide itself has no selectivity for the two CCK receptors, CCK-A and B, which have so far been established to stimulate IP3/DAG while, like substance P, can close potassium channels to increase neuronal activity. The CCK-B receptor is thought to predominate in the CNS but species differences may make this interpretation difficult. It has a wide distribution in the CNS but is also found in the gut whereas the CCK-A receptor is more restricted but is found in the hypothalamus, hippocampus and in the brainstem. There are high levels of the natural peptide, CCK-8 in cortex, hippocampus, hypothalamus, ventral tegmentum, substantia nigra, brainstem and spinal cord. CCK is one of the most abundant peptides in the brain and CCK co-exists with dopamine, substance P, 5-HT and vasopressin. Interestingly, in the dopamine areas, CCK co-exists in the mesolimbic pathways but in the nigrostriatal projections, the peptide and... 

Parkinsonism is unique among diseases of the CNS, in that it results from the known loss of a particular NT, i.e. DA, resulting from the degeneration of a particular pathway, the nigrostriatal. Dopamine also has a relatively limited distribution in the brain and few peripheral effects. It should therefore be amenable to therapy based on augmenting its function. Also since the role of DA appears to be to maintain a tonic inhibitory control on GABA output pathways from the striatum, possibly in part by an extra synaptic action (Chapter 6), it may not be necessary for it to be released physiologically from nerve terminals. Thus it may be adequate to just provide DA extracellularly. 

The extrapyramidal motor system controls muscle movement through a system of pathways and nerve tracts that connect the cerebral cortex, basal ganglia, thalamus, cerebellum, reticular formation, and spinal neurons. Patients with PD lose dopamine neurons in the substantia nigra, which is located in the midbrain within the brain stem. The substantia... 

The majority of DDC-expressing cells in the brain lobes are dopamine cells. Most of these dopamine cells have axons that project into a common axonal fiber extending anteriomedially within the brain lobe and then separating into finer fibers that cross between the lobes. The dopamine cells occur in small clusters of two to six cells, which suggests that these cells might share common lineages. The serotonin cells within the lobes are also found in pairs, and each pair projects axons into closely associated tracts. The pathways of the serotonin tracts often parallel those of the dopamine cells but are distinct (Lundell and Hirsh, 1994). 

Once returned to the presynaptic terminal, dopamine is repackaged into synaptic vesicles via the vesicular monoamine transporter (VMAT) or metabolized to dihydroxyphenylacetic acid (DOPAC) by monoamine oxidase (MAO). Two alternative pathways are available for dopamine catabolism in the synapse, depending on whether the first step is catalyzed by MAO or catechol-O-methyltransferase (COMT). Thus, dopamine can be either deaminated to 3,4-dihydroxyphenylacetic acid (DOPAC) or methylated to 3-methoxytyramine (3-MT). In turn, deamination of 3-MT and methylation of DOPAC leads to homovanillic acid (HVA). In humans, cerebrospinal fluid levels of HVA have been used as a proxy for levels of dopaminergic activity within the brain (Stanley et al. 1985). 

Unlike many chemicals in the brain, neurotransmitters are not homogeneously distributed, but concentrated in certain regions. For example, almost two-thirds of the dopamine in the brain is found in the bilateral nigrostriatal (mesostriatal) tract (pathway), where the neuronal cell bodies are located in the substantia nigra and the axons terminate in the corpus striatum. When over 85% of these dopaminergic neurons are lost, the characteristic motor dysfunction of Parkinson s disease is seen. 

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