Dopamine mesolimbic pathway

The localisation of a particular peptide to a particular brain area and possibly associated with a particular transmitter (e.g. CCK with dopamine in mesolimbic pathways) has often prompted a prediction of function (e.g. CCK may have a role in schizophrenia). Animal studies in which the peptide has been injected into the appropriate brain area or tested on slices taken from the brain area have sometimes been taken to confirm such hypotheses. These approaches have lined up the peptides for a whole range of potential roles, some of which are listed in Table 12.4. Whether these predictions are realities will depend on the availability of chemical agents and their evaluation, not only in animals but also in humans. 

Ferrari, R., Le Novere, N., Picciotto, M.R., Changeux, J.P., Zoli, M. Acute and long-term changes in the mesolimbic dopamine pathway after systemic or local single nicotine injections. Eur. J. Neurosci. 15 1810, 2002. 

Mesolimbic dopamine pathways are thought to be involved in the rewarding effects of drugs of abuse and an imbalance of this pathway is thought to be causal in psychoses. Several studies have revealed that 5-HT3 receptor antagonists can correct such imbalances. Thus, ondansetron inhibits the behavioural hyperactivity resulting from direct stimulation of this... 

In admittedly oversimplified terms, it is believed that hyperactivity of dopamine neurons in the mesolimbic pathway contribute to the positive symptoms of schizophrenia. All the typical antipsychotics are believed to work by reducing the activity of the mesolimbic dopamine pathway. More specifically, they do this by blocking dopamine receptors on the nerve cells. Over a period of 1-3 weeks, the dopamineblocking effect of the typical antipsychotic begins to relieve the positive symptoms of schizophrenia. 

The Four Dopamine Pathways. There are four major dopamine circuits in the mammalian brain. They are known as the mesolimbic, mesocortical, tuberoinfun-dibnlar, and nigroneostriatal pathways. The mesolimbic pathway arises in the midbrain and projects to the so-called limbic structures. The mesocortical pathway arises in the midbrain and projects to frontal and temporal areas of the brain s cerebral cortex. 

The first generation antipsychotics, now known as typical drugs, were all D2 receptor blockers and, as such, very likely to produce Parkinsonian side effects. Because antipsychotic potency was associated with D2 receptor affinity, it was assumed that dopamine overactivity was the essential defect in schizophrenia and that a direct dopamine blockade was the definitive route to treatment. But these drugs affected both the target dopamine pathways of the mesolimbic projection and the uninvolved nigrostriatal projection. Unfortunately, that meant that movement disorders were the price that had to be paid for antipsychosis. 

A. Mesolimbic dopamine pathway and the dopamine hypothesis of the positive symptoms of psychosis... 

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. 

Mesolimbic Dopamine Pathway and the Dopamine Hypothesis of the Positive Symptoms of Psychosis... 

The mesolimbic dopamine pathway projects from dopaminergic cell bodies in the ventral tegmental area of the brainstem to axon terminals in limbic areas of the brain, such as the nucleus accumbens (Fig. 10—8). This pathway is thought to have an important role in emotional behaviors, especially auditory hallucinations but also delusions and thought disorder (Fig. 10—9)-... 

A pathway related to the mesolimbic dopamine pathway is the mesocortical dopamine pathway (Fig. 10—10). Its cell bodies arise in the ventral tegmental area of the brainstem, near the cell bodies for the dopamine neurons of the mesolimbic dopa-... 

FIGURE 10-8. This diagram shows the mesolimbic dopamine pathway, which is thought to be hyperactive in schizophrenia and to mediate the positive symptoms of psychosis. 

FIGURE 10-9. The dopamine hypothesis of psychosis. Hyperactivity of dopamine neurons in the mesolimbic dopamine pathway theoretically mediates the positive symptoms of psychosis, such as delusions and hallucinations. This pathway is also involved in pleasure, reward, and reinforcing behavior, and many drugs of abuse interact here. 

FIGURE 11 — 2. The dopamine receptor antagonist hypothesis of antipsychotic drug action for positive symptoms of psychosis in the mesolimbic dopamine pathway is shown here. Blockade of postsynaptic dopamine 2 receptors by a dopamine 2 antagonist acting in the mesolimbic dopamine pathway is hypothesized to mediate the antipsychotic efficacy of the antipsychotic drugs and their ability to diminish or block positive symptoms. 

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. 

Serotonin 2A antagonism fortunately fails to reverse D2 antagonism in the mesolimbic system. If serotonin 2A antagonism reverses, at least in part, the effects of D2 antagonism in several dopamine pathways, then why does it not reverse the antipsychotic actions of D2 blockade in the mesolimbic dopamine pathway Evidently, the antagonism by serotonin of the effects of dopamine in this pathway is not robust enough to cause the reversal of D2 receptors by atypical antipsychotics or to mitigate the actions of atypical antipsychotics on positive symptoms of psychosis. 

In summary, for conventional antipsychotics dopamine blockade wins the tug-of-war in every dopamine pathway, resulting in antipsychotic actions for positive symptoms, but at a cost of worsened, or at least not improved, negative symptoms, production of EPS, tardive dyskinesia, and hyperprolactinemia. On the other hand, it appears that atypical antipsychotics let you have your cake and eat it too, that is, dopamine blockade wins the all important tug of war over dopamine release where it must win to treat disruptive positive symptoms, namely, in the mesolimbic dopamine... 

On the dopamine side of the equation, one of the most promising agents in late clinical development is aripiprazole, theoretically a presynaptic D2 autoreceptor agonist. This compound is postulated to exert its antipsychotic actions in a manner far different from serotonin-dopamine antagonism that is, it may shut off the presynaptic dopamine terminal and stop dopamine release in the mesolimbic dopamine pathway by stimulating presynaptic D2 receptors. The agents Cl-1007 and DAB-... 

FIGURE 13—1. The mesolimbic dopamine pathway mediates the psychopharmacology of reward, whether that is a natural high or a drug-induced high. 

The reinforcing actions of nicotine are very similar to those of cocaine and amphetamine, since dopaminergic cells in the mesolimbic dopamine pathway receive direct nicotinic cholinergic input, which is stimulated by cigarette smoking (Figs. 

We have described the mesolimbic dopamine pathway and the neuropharmacology of reward and have specifically emphasized the mechanism of action of several classes of dmgs of abuse, including stimulants (cocaine and amphetamines), hallucinogens, designer drugs and phencyclidine, nicotine, marijuana, opiates, alcohol, benzodiazepines, and sedative-hypnotics. We have even mentioned how receptors and the mesolimbic dopamine pathway could play a role in the psychopharmacology of obesity. 

Movement disorders are mediated by abnormalities in the mesolimbic dopamine pathway. True or False. 

Schizophrenia appears to be caused by an overactivity of dopamine pathways in certain parts of the brain such as the limbic system.2,23 This idea is based primarily on the fact that most antipsychotics block dopamine receptors, thereby reducing dopaminergic hyperactivity in mesolimbic pathways and other limbic structures (see the next section of this chapter). The increased dopamine influence underlying psychosis could be caused by excessive dopamine synthesis and release by the presynaptic neuron, decreased dopamine breakdown at the synapse, increased postsy-naptic dopamine receptor sensitivity, or a combination of these and other factors. 

Alan Mackay-Sim, Francois Feron, Darryl Eyles, Thomas Bume, and John McGrath Possible Contributions of Myelin and Oligodendrocyte Dysfunction to Schizophrenia Daniel G. Stewart and Kenneth L. Davis Brain-Derived Neurotrophic Factor and the Plasticity of the Mesolimbic Dopamine Pathway Oliver Guillin, Nathalie Griffon, Jorge Diaz,... 

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