Limbic region

D3 Much less abundant than D2. Mainly in limbic regions (nucleus accumbens and olfactory tubercle) but also in hypothalamus. Some in caudate and cortex and also expressed on DA neurons in substantia nigra, presumably as autoreceptors. No effect on adenylate cyclase but inhibits Ca + entry (autoreceptor role). High affinity for DA (Ali 25nM). 

Dopamine receptor blocking agents. Many of the neuroleptics used in the treatment of schizophrenia frequently produce parkinsonian symptoms as unwanted effects. Neuroleptics block dopamine receptors and their therapeutic effect seems to be related to this action. Although these drugs act on DA systems without distinction, some are more selective. Thioridazine, clozapine and molindone, for example, have electrophysiological effects in the limbic region of the brain but little action in the nigro-striatal area. This selectivity may be related to receptor subtype specificity (see Chs 12 and 54). 

Carboni et al. (2000) reported increased DA output in the prefrontal cortex during mecamylamine-precipitated withdrawal. The striatum appears to become insensitive to nicotine during withdrawal, as indicated by loss of the cFos response to nicotine. This was also true of a limbic region, the cingulate gyrus (Salminen et al. 1999). 

Increased density of 5-HT2a receptors in limbic regions... 

There is also evidence that the density of muscarinic receptors is increased in limbic regions of depressed patients who have committed suicide. If it is assumed that such a change reflects an increased activity of the cholinergic system, it could help to explain the reduced noradrenergic function as there is both clinical and experimental evidence to suggest that increased central cholinergic activity can precipitate depression and reduce noradrenergic activity. 

The role of serotonin (5-hydroxytryptamine, 5-HT) has also been extensively studied in depressed patients. Whereas the overall psycho-physiological effects of noradrenaline in the CNS appear to be linked to drive and motivation, 5-HT is primarily involved in the expression of mood. It is not surprising therefore to find that the serotonergic system is abnormal in depression. This is indicated by a reduction in the main 5-HT metabolite, 5-hydroxy indole acetic acid (5-HIAA), in the cerebrospinal fluid of severely depressed patients and a reduction in 5-HT and 5-HIAA in the limbic regions of the brain of suicide victims. The 5-HT receptor function also appears to be abnormal in depression. This is indicated by an increase in the density of cortical 5-HT2a receptors in the brains of suicide victims and also on the platelet membrane of depressed patients. Platelets may be considered as accessible models of the nerve terminal. 

Stressful stimuli of many types produce marked increases in brain noradrenergic function. Stress produces regional selective increases in NE turnover in the locus coeruleus (LC), limbic regions (hypothalamus, hippocampus, and amygdala), and cerebral cortex. These changes can be elicited with immobilization stress, foot-shock stress, tail-pinch stress, and conditioned fear. Exposure to stressors from which the animal cannot escape results in behavioral deficits termed learned helplessness. The learned helplessness state is associated with depletion of NE, probably reflecting the point where synthesis cannot keep up with demand. These studies have been reviewed elsewhere in detail (Bremner et al. 1996a,b). 

Five subtypes of dopamine receptors have been described they are the Dj-like and Dj-like receptor groups. All have seven transmembrane domains and are G protein-coupled. The Dj-receptor increases cyclic adenosine monophosphate (cAMP) formation by stimulation of dopamine-sensitive adenylyl cyclase it is located mainly in the putamen, nucleus accumbens, and olfactory tubercle. The other member of this family is the D5-receptor, which also increases cAMP but has a 10-fold greater affinity for dopamine and is found primarily in limbic regions. The therapeutic potency of antipsychotic drugs does not correlate with their affinity for binding to the Dj-receptor. 

The most obvious hypothesis is that in mania, as in dream psychosis with elation and grandiosity, it is possible to raise to very high levels the general activation of the brain and the specific activation of the positive emotion generator in the medial septum and other limbic regions. Because this effect can be artificially accomplished by taking amphetamines, it is reasonable to propose that excessive endogenous dopamine release (or increased receptor sensitivity) may be involved. 

From such studies, it may be concluded that physical stress leads to an activation of endogenous opioid systems, which raises the pain threshold. The euphoriant effect of physical exercise may also be attributed to the effects of these opioids acting on limbic regions of the brain. 

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