Dopamine pathway

Of course, while the identification of these distinct systems may be useful there are many neural pathways that would not fit easily into one of them. Thus some inhibitory pathways, such as that from the caudate nucleus to substantia nigra, utilising GABA, are not intrinsic neurons. The dopamine pathway from the substantia nigra to striatum may start from a small nucleus but unlike other monoamine pathways it shows little ramification beyond its influence on the striatum. The object of the above classification is not to fit all neural pathways and mechanisms into a restricted number of functional categories but again to demonstrate that there are different forms of neurotransmission. 

Figure 7.7 Dopamine-induced rotation in the rat in which one (left) nigrostriatal dopamine pathway from the substantia nigra (SN) to the caudate putamen (CP) has been lesioned by a prior injection (14 days) of 6-hydroxydopamine. Amphetamine, an indirectly acting amine, releases DA and so can only act on the right side. Since the animal moves away from the dominating active side it induces ipsilateral rotation (i.e. towards the lesioned side). By contrast, the development of postS5maptic supersensitivity to DA on the lesioned side ensures that apomorphine, a directly acting agonist, is actually more active on that side and so the animal turns away from it (contralateral rotation)...

ANSWER Yes, 6-hydroxydopamine by itself elevates neurotensin levels. When you combine it with methamphetamine, you do not get any additivity. It is just a 6-hydroxydopamine action. It is a bit complicated to interpret, but it appears that it is still the nigral striatal dopamine pathway that is mediating the methamphetamine effect. 

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. 

Lindvall O., Bjorklund A. (1982). Neuroanatomy of central dopamine pathways review of recent progress. In M Real, editor. Advances in Dopamine Research. Oxford and New York Pergamon Press pp. 297-311. 

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. 

We are still confronted by a list of interesting and important questions that have not been answered. To what extent are dopamine pathways involved in hallucinogenic drug action What is the relative importance of presynaptic versus postsynaptic serotonergic action Is the release of endogenous neurotransmitters... 

Triple reuptake inhibitors (TRIs), which inhibit reuptake at all three transporters, have attracted considerable interest in recent years [77]. The involvement of dopamine reuptake in the etiology of depression and other CNS disorders has been recognized [29,30]. As a result, TRIs have been proposed to offer a faster onset of action and improved efficacy for depression over currently prescribed single or dual action monoamine reuptake inhibitors. Historically, the mesocorticolimbic dopamine pathway is thought to mediate the anhedonia and lack of motivation observed in depressed patients [78,79]. In addition, methylphenidate, both immediate release and extended release formula, has been found to be effective as an augmenting agent in treatment-resistant depression [4]. Furthermore, clinical studies using the combination of bupropion and an SSRI or SNRI have showed improved efficacy for the treatment of MDD in patients refractory to the treatment with SSRIs, SNRIs, or bupropion alone [5,80,81]. 

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... 

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 ... 

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. 

In contrast, it is often hypothesized that the negative symptoms of schizophrenia are a result of decreased activity of the mesocortical dopamine pathway. Unfortunately, dopamine blocking by typical antipsychotics in the mesocortical pathway does not improve the negative symptoms, and may even worsen them. 

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 neurotransmitter 5-hydroxytryptamine (5-HT, serotonin) is formed from tryptophan by hydroxylation then decarboxylation, paralleling the tyrosine — dopamine pathway. The non-specific enzyme aromatic amino acid decarboxylase again catalyses the decarboxylation. 

The linkage HA-NO-blood pressure was also demonstrated in rats that had been administered HA intracerebroventricularly into a particular forebrain area, in doses ranging from 0.01 to 0.5 mg . A dose-dependent increase in NO release and a concomitant decrease in arterial blood pressure promoted the understanding of the role of NO in central regulation of blood pressure, and further substantiated the contention that endogenous HA may serve as a source of NO. The intracranial administration of HA into rats was also used to demonstrate the existence of an NO-dopamine pathway that is likely to be involved in control of blood pressure . 

Inputs from ascending dopamine pathways originating in the substania nigra, pars compacta, play a crucial role in coordinating the output from the striatum (Aosaki et ah, 1994). Explicit dopamine hypotheses for Tourette s syndrome posit either an excess of dopamine or an increased sensitivity of D2 dopamine re-... 

In the central nervous system, there are close associations between NT and dopamine systems, and NT may be involved in clinical disorders involving dopamine pathways such as schizophrenia, Parkinson s disease, and drug abuse. Consistent with this, it has been shown that central administration of NT produces effects in rodents similar to those produced by antipsychotic drugs. 

Nestler, Eric J. 1993. "Molecular Mechanisms of Drug Addiction in the Meso-Hrnbic Dopamine Pathway." Seminars in the Neurosciences 5 369-76. 

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. 

III. Four key dopamine pathways and the biological basis of schizophrenia... 

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

Four Key Dopamine Pathways and the Biological Basis of Schizophrenia... 

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)-... 

---