سوء تغذیه و واکنش پذیری به بازیگری مواد مخدر در سیستم عصبی مرکزی

Abstract ALMEIDA, S. S.; J. TONKISS AND J. R. GALLER. Malnutrition and reactivity to drugs acting in the central nervous system. NEUROSCI BIOBEHAV REV 20(3) 389–402, 1996.—There is a well-established body of data demonstrating that protein or protein-calorie malnutrition experienced early in life is associated with neuroanatomical, neurochemical, as well as behavioral alterations in both animals and humans. A number of studies has focused on the following question: are the neuroanatomical and/or neurochemical changes produced by early malnutrition responsible for the altered behaviors reported in malnourished animals? A tool that has been used to help answer this question is the administration of drugs with specific actions in the various neurotransmitter systems in the central nervous system (CNS). This neuropharmacological approach has produced a considerable amount of data demonstrating that malnourished animals react to drugs differently from controls, suggesting that the altered behavioral expression of these animals could be partly explained by the alterations in the brain function following malnutrition. The present review will provide an overview of the literature investigating the reactivity of malnourished animals to psychoactive drugs acting through GABAergic, catecholaminergic, serotonergic, opioid and cholinergic neurotransmitter systems. Altered responsiveness to psychoactive drugs in malnourished animals may be especially relevant to understanding the consequences of malnutrition in human populations. Copyright © 1996 Elsevier Science Ltd.

1. INTRODUCTION THE EFFECTS of protein and protein-calorie malnutrition in animals and humans have been studied for the past 30 years (for reviews see 25, 50, 54, 93, 111, 112, 113, 134, 141, 155 and 166). The earliest studies focused on the effects of deficient diets on body and brain morphology (for reviews see 113, 132 and 137). These were followed by studies focused on malnutrition and brain neurochemistry, primarily investigating the cholinergic, noradrenergic, dopaminergic, serotonergic and GABA (gamma-aminobutyric acid)ergic neurotransmitter systems (for reviews see 41, 113, 117, 137 and 165). As results, derived mainly from animal studies, increased the knowledge of the effects of protein malnutrition on these parameters, the number of studies investigating the effects of malnutrition on mental function and behavior also increased in both animals and humans (for reviews see 54, 58, 66, 91, 99, 113, 126, 136, 140, 141 and 166). However, data produced by these different studies remained unintegrated for many years although the need for an interdisciplinary approach gained attention as early as 1978 [92]. The question was: What is the significance of the relationship between malnutrition and brain changes if little is known about what these brain changes mean in terms of brain function? Thus, studies in malnutrition were designed to investigate different aspects of morphology and/or biochemistry as well as behavior within the same model. Similarly, studies focusing on aspects of molecular neurobiology and neurophysiology following protein or protein-calorie malnutrition were conducted as new technologies made them possible (for reviews see 111, 112, 113 and 153). However, most of these studies have only established correlations between a particular behavioral change and a particular neuroanatomical and/or neurochemical change produced by malnutrition as assessed by post-mortem analysis. Thus, causality could not be substantiated. Although these correlational studies produced a substantial mount of data, the functional significance of any neuroanatomical and/or neurochemical alterations produced by malnutrition needed a more direct approach. Some advances have come with interdisciplinary neuropharmacological studies which use centrally acting drugs to investigate the question of which particular neuroanatomical and/or neurochemical brain alteration could be underlying changes in behavioral expression. Specifically, we know the mechanisms of action of several drugs acting in the central nervous system (CNS) that alter a large class of behaviors. Because the specificity of these drugs to a particular neurotransmitter system or even to a particular receptor subtype in that system is known, these drugs can be used as a tool to investigate whether malnutrition induced an alteration in a particular neurotransmitter system. Evidence for this would be indicated by a differential behavioral change in response to the drug. This neuropharmacological approach has the advantage of assessing the consequences of altered neuroanatomical and/or neurochemical parameters in rats with a history of malnutrition while the animals are behaving in a particular test chosen to measure specific aspects of behavior. In this paper, we review studies on the effects of psychoactive drugs acting through the GABAergic, catecholaminergic, serotonergic, opioid and cholinergic neurotransmitter systems in protein- and protein-malnourished animals.

CONCLUSIONS An analysis of the above data leads to four major conclusions. First, drugs of central action are useful tools in our effort to understand how early protein or protein-calorie malnutrition can alter neuroanatomical and/or neurochemical aspects of the CNS and ultimately produce alterations in behavioral expression. This approach has the advantage of enabling investigators to study a particular brain region (i.e., with central drug injections) and/or a particular central neurotransmitter system or even a subtype of receptor present in this system. Second, with few exceptions, most studies into the response of malnourished animals to psychoactive drugs have used the method of protein malnutrition during postnatal or prenatal and postnatal development, used male Wistar rats as subjects, and tested adult animals. Thus, the conclusions of the present review are restricted to rats subjected to these malnutrition procedures, and any attempt to generalize these data to another experimental situation and/or subject should be conducted with caution. Third, the above data also showed that, independent of some discrepancies among the various studies (a result that could be due to differences in the malnutrition model, species, sex of subjects and/or schedule of administration and dose of drug used), protein or protein-calorie malnutrition early in life leads to similar changes (mainly hyporeactivity) in responsiveness to centrally active drugs. Malnutrition-induced changes in the reactivity to this class of drugs must be weighed against the paucity of knowledge about the pharmacokinetic and pharmacodynamic aspects of most of these psychoactive drugs in early malnourished animals. Nevertheless, it has been shown that, at least regarding the reported hyporeactivity of malnourished animals to ETOH, differences due to diet upon the elimination could not explain the differences in responsiveness to this drug since malnourished animals did not differ from controls in ETOH clearance rates 42 and 44. When a difference was found, it was in the direction of a failure of ETOH elimination in malnourished rats, i.e., removal of ETOH from blood is markedly decreased in postnatally malnourished rats to less than half that in control rats [47], which could predict increased behavioral reactivity to ETOH rather than the lower reactivity described in the literature. Interestingly, healthy human subjects consuming an energy- or protein-deficient diet also showed a reduced clearance rate and a prolonged half-life for oxazepam 62 and 145. As oxazepam is almost exclusively metabolized by glucuronidation [59] these results indicate that both low energy and low protein diets decrease the glucuronidation of this BZ. Unfortunately, the data available in the literature only describe the effects of malnutrition on the absorption, disposition, biotransformation and excretion of drugs normally used to counteract some physical illnesses frequently associated with chronic malnutrition. Thus, most of these studies focused on the effects of malnutrition on efficacy and/or toxicity of antibiotic, antipyretic, antiparasitic, diuretic, and antidiarrhoeal agents, as well as other drugs acting in the pathophysiology of illness commonly associated with protein-calorie malnutrition (for reviews see 8, 9, 12, 28, 35, 46, 81, 82, 83, 84, 87, 106 and 107). In addition, most of these studies of the pharmacokinetics and pharmacodynamics of drugs pertaining to animals or humans were tested under conditions of chronic protein or protein-calorie malnutrition 7, 8, 16, 28, 29, 35, 47, 73, 83 and 106. Metabolic conditions in subjects nutritionally rehabilitated from malnutrition are likely to differ substantially from those still being malnourished. One way to avoid any possible confounding factors due to differences in the absorption, distribution and elimination of psychoactive drugs in malnourished animals is to inject these brain active substances directly into the cerebral ventricles or specific brain structures. Using such a procedure, malnourished animals have been described as hyporeactive to a drug injected directly into a brain inhibitory system (glycinergic), thus removing any confounding of the drug effect by dietary interactions due to differences in body weight or liver metabolism of the drug. Postnatally malnourished rats showed a decreased susceptibility to strychnine (a competitive inhibitor for glycine receptors in the CNS) as measured by changes in peak-to-peak amplitude of prefrontal cortex-evoked responses, indicating functional disturbances of glycinergic synapses [121]. While additional studies injecting drugs directly into the brain are needed, it is reasonable to work with the idea that it is the direct effects of malnutrition on the brain neuroanatomy and/or neurochemistry systems that produce changes in the reactivity of malnourished animals to psychoactive drugs. Finally, human studies have suggested generalized malnutrition or early protein malnutrition to be a potential risk factor in the incidence of personality and psychiatric disorders 24, 149 and 150, mainly schizophrenias 26, 149 and 150 and depression [24]. In this review, we have also addressed the potential usefulness of early malnutrition as a model of panic disorder. This further emphasizes the need to improve our knowledge of how early protein malnutrition could affect the response of the CNS to psychoactive drugs. However, contrary to the studies described above in animals, the analysis of how malnourished humans react to psychoactive drugs is much more complex. In the human population we do not have any information about the type, the level, the period and the duration of the malnutrition episode. Additionally, malnutrition does not occur in human societies in the absence of a poor social and cultural environment. The importance of these social factors associated with malnutrition in human studies has been largely discussed in the literature, and previously reported results showed difficulties in demonstrating behavioral deficits in malnourished children living in good social and cultural conditions [58]. As a result of these difficulties, no experimental data have been reported concerning the use of psychoactive drugs in humans malnourished early in life. Thus, animal studies are frequently used to improve our knowledge of the consequences of malnutrition to humans. However, the assumption that alterations in drug response reflect changes in brain function, which has functional significance in animals, should not be naïvely generalized to humans, since we do not know whether these changes have any functional significance for the human population. These problems, associated with ethical questions relating to the administration of psychoactive agents to humans in experimental studies, reinforce the need for animal models in this area of research. The use of these models, as discussed in the present review, has presented a large body of data suggesting that the response to psychoactive drugs can be a good indicator of functionally significant brain changes in malnourished animals