Mesolimbic pathway

Initiation of behaviour Mesolimbic pathway to nucleus accumbens from VTA (AIO) Mesocortical pathways to prefrontal cortex from VTA (AIO) Animals Increases locomotor activity and intracranial self-stimulation Humans Hallucinations, psychoses (reward, reinforcement) Animals Decreases activity and self-stimulation Humans Reduces positive symptoms of schizophrenia D2 ... 

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... 

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. 

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. 

There appear to be important exceptions to the rule that a decrease in the availability of 5-HT in the mesolimbic pathway leads to increases in locomotor and investigatory activity. In contrast to the dramatic and pervasive hyperactivity produced by electrolytic lesions of the median raphe, similar depletions of 5-HT following the neurotoxic dihydroxytryptamines produce relatively subtle effects that appear to be related to the environmental context in which the behavior is monitored. For instance, microinjections of 5,7-DHT into the median raphe had no effect on the level of activity in a novel environment, whereas the same animals were hyperactive in a familiar environment (54). 

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. 

It has been suggested that abnormalities in attention-deficit/hyperactivity disorder in children and adults may be similar to those seen in early stages of PD (McCracken 1991). Of interest is that nicotinic mechanisms interact closely with dopamine systems (Kirch et al. 1988) and that nicotinic receptors may serve to regulate dopamine release (Clarke and Pert 1985 Rapier et al. 1990) in striatal and mesolimbic pathways. Nicotine is now being tried as an experimental treatment for attention-deficit/hyperactivity disorder in adults (Levin et al. 1995). 

Dopaminergic neuromodulatory system. The neurons that synthesize dopamine (structural formula in box) are found in the midbrain, from which they project to the limbic system (the mesolimbic pathway), the cerebral cortex (the mesocortical pathway), as well as to the extrapyramidal motor system (the nigrostriatal pathway). 

The net effect is to push the brain in a very REM dream-like direction. PET studies of schizophrenic patients brains show deficient frontal cortical activation and limbic overactivation. The working hypothesis of schizophrenia investigators is that psychosis results when the overactive mesolimbic pathway is released from deficient cortical control. This is formally identical to our hypothesis of dream psychosis the dorsolateral prefrontal cortex is deactivated and the limbic system is hyperactivated. 

The Mesolimbic Pathway and the Pharmacology of Improved Positive Symptoms... 

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. 

Apart from the lateral septum, there is no indication that dysbindin-1 is enriched in hippocampal or subicular output to extrinsic structures. Nor is there any evidence that the protein is enriched in extrinsic input to the hippocampal formation, except perhaps for minor dopaminergic input from the mesolimbic pathway originating in the ventral tegmental area of the midbrain (Murotani et al., 2007 see O Section 2.2.6A.2.7). Otherwise, dysbindin-1 neuropil in the hippocampal formation appears to be selectively concentrated in the intrinsic associational and commissural projections of that structure. 

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