Brain areas

Unlike aniracetam, pramiracetam does not appear to interact with dopaminergic, serotonergic, or adrenergic neurotransmission (72). The agent inhibits prolylendopeptidase in certain brain areas, but its inhibition constant, iC, is only 11 ]lM (69). The absence or weak activity of this compound with various neuronal systems appears to make it less likely to be of significant therapeutic value than other members of this class of agents. 

Altered synaptic properties Numerous changes in the properties of inhibitory (GABAergic) and excitatory (glutamatergic) synapses have been reported. While the simple adage of an imbalance between inhibitory and excitatory neurotransmission in epilepsy is not generally applicable, some forms of inhibition are lost or impaired in epilepsy. Likewise, an increased function of glutamate receptors has been demonstrated in some brain areas. 

High amounts of somatostatin are found in the CNS, the peripheral nervous system, the gut and the endocrine pancreas whereas the kidneys, adrenals, thyroid, submandibular glands, prostate and placenta produce rather low amounts. In particular, the hypothalamus, all limbic structures, the deeper layers of the cerebral cortex, the striatum, the periaqueductal central grey and all levels of the major sensoty pathway are brain areas that are especially rich in somatostatin. Eighty percent of the somatostatin immunoreactivity in the hypothalamus is found in cells of the anterior periventricular nucleus (Fig. 1, [1]). The gut 5 cells of the mucosa and neurons, which are intrinsic to the submucous and... 

The rate of synthesis is similar for trace amines and monoamine neurotransmitters, however, trace amines undergo a more rapid turnover due to their higher affinity to MAO and the lack of comparable cellular storage. Thus, the tissue concentration of trace amines in the vertebrate central nervous system is estimated to be in the range of 1-100 nM, depending on the trace amine and brain area, in contrast to micromolar concentrations of classic monoamine neurotransmitters. 

The distribution of endosulfan and endosulfan sulfate was evaluated in the brains of cats given a single intravenous injection of 3 mg/kg endosulfan (Khanna et al. 1979). Peak concentrations of endosulfan in the brain were found at the earliest time point examined (15 minutes after administration) and then decreased. When tissue levels were expressed per gram of tissue, little differential was observed in distribution among the brain areas studied. However, if endosulfan levels were expressed per gram of tissue lipid, higher initial levels were observed in the cerebral cortex and cerebellum than in the spinal cord and brainstem. Loss of endosulfan was most rapid from those areas low in Upid. Endosulfan sulfate levels peaked in the brain at 1 hour postadministration. In contrast, endosulfan sulfate levels in liver peaked within 15 minutes postadministration. The time course of neurotoxic effects observed in the animals in this study corresponded most closely with endosulfan levels in the central nervous system tissues examined. 

Acute exposure to large amounts of endosulfan results in frank effects manifested as hyperactivity, muscle tremors, ataxia, and convulsions. Possible mechanisms of toxicity include (a) alteration of neurotransmitter levels in brain areas by affecting synthesis, degradation, and/or rates of release and reuptake, and/or (b) interference with the binding of those neurotransmitter to their receptors. 

An additional study reported age-dependent effects. Lakshmana and Raju (1994) found that oral treatment of rat pups with endosulfan from postnatal days 2-10 resulted in changes in the concentration of noradrenalin, dopamine, and serotonin in various brain areas that differed either in magnitude or direction from changes seen in pups treated from postnatal days 2-23. While the results from this study do not necessarily indicate that neonates are more sensitive to the toxic effects of endosulfan, they do show that the duration of exposure in neonates is an important parameter to consider. 

Markman, S., Leitner, S., and Catchpole, C. et al. (2008). Pollutants Increase Song Complexity and the Volume of the Brain Area HVC in a Songbird. PLoS ONE 3, el674. 

Figure 1.8 Some basic neuronal systems. The three different brain areas shown (I, II and III) are hypothetical but could correspond to cortex, brainstem and cord while the neurons and pathways are intended to represent broad generalisations rather than recognisable tracts. A represents large neurons which have long axons that pass directly from one brain region to another, as in the cortico spinal or cortico striatal tracts. Such axons have a restricted influence often only synapsing on one or a few distal neurons. B are smaller inter or intrinsic neurons that have their cell bodies, axons and terminals in the same brain area. They can occur in any region and control (depress or sensitise) adjacent neurons. C are neurons that cluster in specific nuclei and although their axons can form distinct pathways their influence is a modulating one, often on numerous neurons rather than directly controlling activity, as with A . Each type of neuron and system uses neurotransmitters with properties that facilitate their role...

It is generally felt that a substance is more likely to be a NT if it is unevenly distributed in the CNS although if it is widely used it will be widely distributed. Certainly the high concentration (5-10 pmol/g) of dopamine, compared with that of any other monoamine in the striatum or with dopamine in other brain areas, was indicative of its subsequently established role as a NT in that part of the CNS. This does not mean it cannot have an important function in other areas such as the mesolimbic system and parts of the cerebral cortex where it is present in much lower concentrations. In fact the concentration of the monoamines outside the striatum is very much lower than that of the amino acids but since the amino acids may have important biochemical functions that necessitate their widespread distribution, the NT component of any given level of amino acid is difficult to establish. 

Figure 4.6 The tip of a microdialysis probe, expanded to show dialysis tubing around a steel cannula through the base of which fluid can flow out and then up and over the membrane. The length of membrane below the probe support can be altered (1-10 mm) to suit the size of the animal and the brain area being studied. Flow rates are normally below 2 pl/min...

Toxins that gain access to a neuron through its uptake process and then destroy it in some way. This approach has been used mainly to destroy monoamine neurons with 5,6 or 5,7-dihydroxytryptamine targeting 5-HT neurons, 6-hydroxydopamine for dopamine (and to a lesser extent noradrenergic) neurons and MPTP for dopamine neurons (see Chapter 7). Only the latter is fully specific and effective systemically. The others need to be administered directly into the appropriate brain areas and while they may only affect the intended NT neurons, the injection may not affect all of them. 

Because DA is very much localised to one brain area (striatum) and as there is such a pronounced DA pathway from the substantia nigra to the striatum it would be reasonable to assume that the effect of this pathway on striatal neuron activity is well established. Unfortunately this is not the case. 

In other brain areas which receive a DA input, such as the nucleus accumbens and prefrontal cortex, it appears to be inhibitory and predominently D2-mediated. This is clear from Fig. 7.5 which shows inhibition by apomorphine (mixed D2, Di agonists) of the firing of neurons in the medial prefrontal cortex of the anaesthetised rat and its antagonism by the D2 antagonist haloperidol. 

It is perhaps easier to identify some of the central functions of DA than that of the other monoamines because not only does it have distinctive central pathways associated with particular brain areas, but it has few peripheral actions. Also the actions of its antagonists reveal its central effects. These are summarised in Table 7.4. 

Many brain areas are innervated by neurons projecting from both the locus coeruleus and the lateral tegmental system but there are exceptions (Fig. 8.3). The frontal cortex, hippocampus and olfactory bulb seem to be innervated entirely by neurons with cell bodies in the locus coeruleus whereas most hypothalamic nuclei are innervated almost exclusively by neurons projecting from the lateral tegmental system. The paraventricular nucleus (and possibly the suprachiasmatic nucleus, also) is an exception and receives an innervation from both systems. 

In short, although the 5-HT system seems to have a rather non-specific influence on overall brain function, in terms of the brain areas to which these neurons project, there is clearly much to be learned about possible functional and spatial specialisations of neurons projecting from different nuclei. 

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