■ 8 44 



II \M)li( K iK HI-' I'HYSK 1LOGV 



Xlil'ROIMlYSIOI.OGY III 



iblc changes. In these circumstances, metabolism 

 does not cease. The metabolic rate is slowed, but 

 chemical processes, obviously abnormal since they 

 lead to irreversible functional changes, persist. In 

 vitro studies, in which tissue blood flow is necessarily 

 nonexistent, are particularly susceptible to the ap- 

 pearance ol such artifactual chemical processes. 

 An additional peculiarity of the central nervous 

 system which operates only in the normal in situ 

 state is the so-called blood-brain barrier. Metabolites 

 i apable of being utilized by the tissues of the nervous 

 system, as indicated by /// vitro studies, cannot pene- 

 trate into these tissues from the blood because of the 

 selective permeability of this barrier. In in vitro 

 studies the blood-brain barrier is bypassed so that 

 the results indicate only the potential capabilities of 

 the enzymatic systems within the tissues of the central 

 nervous system. It remains for in vivo studies to de- 

 termine which of these capabilities are fulfilled in 

 the actual functional state. It is, therefore, indeed 

 fortunate that there are available in vivo methods 

 which are not only adequate, at least in regard to 

 the brain, but are also applicable to studies in con- 

 scious unanesthetized man. 



MK I III IDS 



Several techniques have been employed to study 

 the metabolism "I the central nervous system in 

 These varj considerably in complexity and in 

 the degrei to which the) yield quantitative results. 

 Some require such minimal operative procedures on 

 the experimental animal that no anesthesia is neces- 

 sary, and little or no interference with the tissue occurs 

 except for the effects of the experimental condition 

 under study. Others involve such extensive surgical 

 intervention thai the experiment approaches an 

 in vitro stud) in situ. 



Simple Behavioral-Chemical Correlation Techniques 



I In earliest and leasl complex of the techniques 

 for studying central nervous system metabolism in 

 i.i fcn ' n, perhaps, simpl) the observation of the 

 effects on the behavior of the animal of administering 

 chemical agents into the blood or spinal fluid. A more 

 refined variant ol this technique is the correlation 

 between blood or spinal fluid levels of chemical 



substances oj metabolites and behavior It is pre- 

 cisely bv such techniques, foi example the effect of 

 insulin administration on bl 1 glucose levels and 



consciousness and the restorative action of glucose, 

 that the vital role of glucose in the cerebral metabo- 

 lism was discovered (211, 122). 



Other, more objective criteria have been employed 

 as indicators of the effects of the chemical substances 

 studied. Changes in electroencephalographic pat- 

 terns, electrical responses or reflex functions have 

 thus been employed (16, 24, 81, 85, 190), the latter 

 two being particularly useful for studies on the spinal 

 cord in which functional changes are less manifested 

 by distinct behavioral alterations. 



The chief virtues of this group of methods are their 

 simplicity and their applicability under conditions 

 closely approximating the physiological state. Thev 

 are, however, gross and nonspecific, and do not 

 always distinguish between a direct effect of the 

 experimental agent on the metabolism of the nervous 

 system and one secondary to changes produced in 

 somatic tissues. Similarly, negative results arc often 

 inconclusive, for there always remains the possibility 

 of insufficient dosage, inadequate circulation or the 

 impermeability of the blood-brain barrier. 



Tissue Content and Incorporation Techniques 



The availability of suitable chemical analytical 

 techniques makes possible quantitative analysis of 

 central nervous tissue for specific metabolites at given 

 times during control periods or during or after ex- 

 posure of the animal to experimental conditions. 

 Although such methods require sacrifice of the animal, 

 thev arc in reality in vivo methods since they deter- 

 mine the state of the tissue while still in the animal. 

 For example, by such an approach the effects of 

 various conditions such as anesthesia or convulsions 

 on the adenosine triphosphate level of brain tissue 

 I 1 ;6, 182, 183), or the effects of insulin hypoglycemia 

 on brain carbohydrate Stores (90) have been de- 

 termined. 



The development of radioactive tracer techniques 

 has added much to the usefulness of these methods 

 (26) I he determination of the rate of incorporation 

 of radioactive compounds from the blood or spinal 

 fluid into the tissues of the central nervous system 

 leads to quantitative data on the penetrability of the 

 blood-brain barrier I >v the test substance as well as 

 its hall-life or turnover rate in the tissues. Similarly, 

 the incorporation of a radioisotope of the administered 

 compound into its metabolic products serves not only 

 to identify the intermediate pathways ol metabolism 

 but also to quantify the rates of synthesis and turn- 

 over ol the metabolites derived from the test sub- 



