Mesolimbic DA pathway

Alterations in dopamine (DA) levels are associated with the rewarding effects of abused substances including cigarettes. Specifically, the mesolimbic DA pathway, which originates in the... 

Studies of brain mechanisms have tended to focus primarily on structures associated with the mesolimbic DA pathway. Ideally, all brain regions with major concentrations of nicotinic acetylcholine receptors should be probed with nicotinic... 

Figure 17.9 Schematic representation of the proposed activity profile of an ideal neuroleptic. The figure shows DA pathways to the prefrontal cortex, mesolimbic nucleus accumbens and striatum the effects required for an ideal drug on the DA influence and symptoms there and to what extent they are met by most typical and atypical neuroleptics and by clozapine. Note that while all atypical neuroleptics induce few extrapyramidal w side-effects (EPSs) few of them, apart from clozapine, have much beneficial effect in overcoming negative symptoms of schizophrenia ...

Naloxone precipitation, nnlike nicotine-antagonist challenge, fails to decrease DA-activity, yet still precipitates somatic signs (Carboni et al. 2000). Thus the aversiveness of nicotine withdrawal can be dissociated in part from those effects on the mesolimbic-DA reinforcement pathway that have sometimes been proposed to account for the affective aspects of withdrawal (Balfour 2004 Paterson et al. 2007). 

It is well established that nicotine stimulation of the mesolimbic dopamine (DA) pathway is essential to the reinforcing action of nicotine (Balfour 2004 Corrigall and Coen 1991). Considerable evidence suggests that alterations in this pathway may also be essential to the nicotine abstinence syndrome, particularly to its depression-like dimension. During withdrawal from continuous nicotine infusion, rats displayed reduced activity levels and reduced DA content in the striatum... 

Postmortem studies of patients with idiopathic Parkinson s disease demonstrate cell loss in the striatal system (A-9), directly implicating this tract vis-a-vis the neuroleptic-induced pseudoparkinsonian side effects. The assumption that psychosis is related to the A-10 system is made by exclusion. Evidence also indicates that clozapine may differentially block DA pathways. Specifically, it seems to act on the mesolimbic dopaminergic system (A-10), while being relatively inactive in the striatal system (A-9) however, this remains controversial. Chronic administration of clozapine decreases the firing rate of A-10 mesocortical tract dopamine neurons... 

Unfortunately, it is not possible to block just these D2 receptors in the mesolimbic dopamine (DA) pathway with conventional antipsychotics because these drugs are delivered throughout the entire brain after oral ingestion. Thus, conventional antipsychotics will seek out every D2 receptor throughout the brain and block them... 

As with many neurons (e.g. NA) there are presynaptic autoreceptors on the terminals of dopamine neurons whose activation attenuate DA release. Although most of these receptors appear to be of the D2 type, as found postsynaptically, D3 receptors are also found. It is possible that in addition to the short-term control of transmitter release they may also be linked directly to the control of the synthesising enzyme tyrosine hydroxylase. It seems that autoreceptors are more common on the terminals of nerves in the nigrostriatal (and possibly mesolimbic) than mesocortical pathway. 

The mechanism by which 5-HT2 antagonism could ameliorate schizophrenic symptoms and what effect 5-HT has on mesolimbic and mesocortical pathways through A10 neurons is even less certain. It is more likely that 5-HT s action occurs postsynaptically in the limbic system or PFC. The probability that neuroleptics benefit from a particular balance of DA and 5-HT2A antagonism is developed later. 

In this regard, considerable evidence shows that PCP increases dopaminergic transmission in the striatum (Johnson 1983) and, more recently, evidence indicates that DA function is increased in the mesolimbic and mesocortical pathways as well. For example, PCP administration has been shown to inhibit the firing of cells found in the ventral tegmental area (Freeman and Bunney 1984) similar to that observed in the substantia nigra (Raja and Guyenet 1980). 

The role of DA. Several reviews suggest that increased DA neurotransmission in the mesolimbic pathway may be related to the mechanism of action of antidepressants. 

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