Nonhuman behavioral models in the genetics of disturbed behavior

0022-3956/92 $5 00 f IN 1992 Pergamon Prc\r I td

NONHUMAN

BEHAVIORAL

MODELS

DISTURBED

IN THE GENETICS

OF

BEHAVIOR

ALBERTO OLIVERIO,* SIMONA CABIB and STEFANO PUGLISI-ALLEGRA Istltuto dl Pslcoblologla e Pslcofarmacologla, C N R , Roma, Italy, and Dlpartlmento dl Genetlca e Blologla Molecolare (A 0 ) and Dlpartlmento dl Pslcologla (S P -A ), Umverqlta dl Roma “La Saplenza”, Roma, Italy Summary-The development of the assoclatlon method m which genetIc markers match quantltatlbe traits has led to quantltatlve trait IOCI (QTL) Interval mappmg The assoclatlon method hat been extensively used mammal behavior genetlcs Ammal research allows more smtable hnkage studies and detailed assessment of cellular and subcellular components of the central nervous system that may play a crucial role m the development susceptlblhty to behabloral disorders Moreover, experlmental designs I” the laboratory settmg allow genotype x environment mteractlons to be controlled, thus possibly provldmg more mformatlon on the role of nongenetlc factors In gene expression ExperImental results are dlscussed which mdlcate that ammal studies will probIde a sort of test for hypotheses arlsmg m chmcal settmgs, allowmg gene-product and product-behavior pathways to be exammed at molecular levels when the gene accounts for a very small amount of genetlc variance In such a perspective, new molecular biology approaches and behavior genetIcs m nonhuman species could provide useful tools in the assessment of the genetlL as well as nongenetlc factors that lead to psychopathology

Behavior

Genetic

and Psychopathology

THE LAST decade has seen major developments m the genetic analysis of behavioral disorders These developments have been considered, to some extent, to be a reaction to the views predommatmg m the early 1970s which reJected the psychiatric view of mental illness and its possible blologlcal bases and pointed to soclocultural factors as responsible for any maladaptlve behavior (Hay, 1985) The result may be an overestimation of the role of heredity and of the blologlcal substrate when simple Mendehan genetic factors are claimed determinants m the etiology of disturbed behavior. as “unique” Behavioral dimensions and disorders are unlikely to be the ObJect of genetic analysis since they are the most complex phenotype that can be studied In fact, behavior IS the expression of the functlonmg of the whole organism and changes m response to the environment Moreover, unlike the characteristics studied by Mendel m the pea, behaviors are not distributed m either/or dlchotomles. Many single-gene mutations, such as Huntington’s disease of phenylketonurla can disrupt normal behavior, causing mental retardation, without being influenced by other genes or environmental background However, single genes do not account for slgmflcant varlablhty for complex traits, such as behavioral traits, which appear to be influenced by a system of many genes, each with small effects, as well as by environmental influences. Therefore, most behavioral genetic studies are based on the theory and methods of quantitative genetics which identify genetic influence even when many genes and substantial *Author to whom correspondence Reno 1, I-00198 Rome, Italy

should be addressed

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environmental varlatlons are Involved Quantltatlve genetlc theory emerged in the early 1900s as a resolution of the dispute between Mendehans, who had redlrcovered Mendel’s laws derived from studies on quahtatlve characterlstlcs on pea plants, and blometrlclans who felt that Mendel’s laws on Inheritance were not apphcable to the complex traits ot higher organisms that are distributed quantltatlbeely over a normal bell-shaped curve The essence of quantitative genetics theory 1s that Mendel’s mechamsms of discrete Inheritance also apply to normally distributed complex characterlstlcs if we assume that the small effects of many genes are summed to produce observable differences among mdlvlduals In a population However, quantitative genetic studies do not give any lnformatlon as to which genes are responsible tor genetic Influence, and merely determme the sum of heritable genetlc influence on behavior, regardless of the complexity of genetlc mode of actlon or the number of genes Involved Behavioral genetic research has reaped the benefit of experimental methods avallable m the field of animal studies, such as artlflclal selectlon or inbred strains (see below) These methods are not available for human behavloral genetics, which relies on family, adoptlon or twm designs, methods that are also used m nonhuman ammal research Behavioral geneticists have combined family, twm and adoption designs m order to mcorporate ar much lnformatlon as possible m their analysis, trying m this way to overcome the hmtts that characterize each of these methods A typlcal example is the Colorado Adoptlon Project which combines the family and adoptlon designs by studymg resemblances between blologlcal parents and their adopted-away offsprmg, adoptive parents and their adopted children, and matched nonadoptlve parents and their natural children (Plomm & DeFrles, 1985) It must be taken into account, however, that when data from several designs are analyzed m conJunction, the mterpretatlon of results becomes more dlfflcult Nevertheless, m the genetics of psychopathology this approach facilitated the reasonable and important first step being taken of askmg the extent to which behavloral differences observed among mdlvlduals are related to genetic differences among them Most research focused on schizophrenia and affective disorders, which mclude major depressive and manic-depressive disorders Schizophrenia, hke all psychlatrlc disorders, 1s a threshold trait That means that behavior must exhlblt more than a particular degree of abnormahty before the person 1s classlfled as “ill” This threshold 1s determined m part by social practices and m part by the current diagnostic practices. In many cases, differences m the dlagnostlc categories among countries or inside the same country have posed additional problems to behavioral genetlclsts (for a dlscusslon see Hay, 1985, Vandenberg, Manes Singer, & Pauls, 1986) The results of 14 studies m which more than 18,000 first relatives of schizophrenics were considered, showed that their risk was 8%, a value eight times larger than the base rate found m the population (Gottesman & Shields, 1982) In a recent study, mvolvmg male twins who were veterans of the World War II (Kendler & Robmette, 1983), a concordance rate of 30 9% for 164 pairs of ldentlcal twms was found compared with 6 5% and 268 pairs of fraternal twins Adoption studies support the twin results pomtmg to genetlc influence m the etiology of schlzophrema Therefore, familial resemblance for this illness seems to be due to heredity rather than to a shared family environment, suggesting that inheritance also plays a maJor role However, the studies also Indicate that nongenetlc factors

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are of crrttcal importance as well In fact, although a rusk of 30% for an tdentrcal cotwm of a schtzophremc far exceeds the populatton rusk of l%, it IS very far from the 100% concordance expected if schrzophrema were an entnely transmissible genetic disease This substantial dtscordance m the case of identical twins for schtzophrema as currently dragnosed cannot be explained other than by nongenettc factors (Plomm, 1990). Gottesman and Shtelds (1982) presented a detarled method for viewing the varrous determmants of the drstrtbutron of habihty where schrzophrema forms one extreme of a continuum throughout the populatton. In addttton to genes specific to the psychopathology, their model mcorporates more general genetic and envnonmental assets and habthties The most important feature of the complex of determinants m this model 1s that people hvmg m the same environment will not necessarily all exhibit schtzophrema, nor ~111people with tdenttcal genotypes such as tdentrcal monozygotrc (MZ) twins, if they live in different environments Stmtlar results come from studres on affective dtsorders, although any related genetic effects appear to be independent of genettc effects on schizophrenia Moreover, genetic factors affecting umpolar depression have been suggested to be distinct from those affecting bipolar manic-depression (Vandenberg et al., 1986). Recent family studies have diagnosed major depression for 13-30% of male and female relattves respectively, which exceeds the base rate m the populatton, while a lower rusk (6070) was found for bipolar tllness with no gender differences, compared with a rate of 1% m the control group (Rice, 1987) Different results have been obtained m twin or adoptton studies, the first pomtmg to a greater genetrc influence for affective disorders than for schtzophrema, whtle less genetic influence has been shown by adoption designs (Loehhn, Wtllerman, & Horn, 1988; Wender, Kety, Rosenthal, Schulsmger, & Ortmann, 1986). The methods discussed thus far are the usual first step to take m demonstrating genettc effects on behavioral traits Once a genettc component has been established, the next step 1s to attempt to determine the mode of inheritance of that genetic component One of the simplest models of genetic transmission IS that the tract 1s largely controlled by a single genetic locus One of the strongest pieces of evidence for a single genetic factor 1s the demonstration of genetic linkage MaJor methodologtcal problems m detecting hnkage in human studies are small famrly size, the mabthty to control matmgs, and the small prior probabrhty that the two loci are linked The small number of polymorphrc genetic markers avatlable for humans has hmtted the apphcabthty of this method. However, recent advances m molecular biology, m particular the development of recombinant DNA techmques, have changed this picture. A new class of polymorphtsms has been identified, which are referred to as “restriction fragment length polymorphrsms” (RFLPs), because they are visualized as mhertted variattons m the length of defined fragments of DNA when the latter 1s digested with specific restrtctton enzymes. Psychopathology was the first behavioral domain m whtch RFLPs markers were used and major-gene linkages have been reported. In 1987, Egeland and coworkers (1987) observed that the bipolar manic-depressive disorder was linked to a dommant gene on the short arm of the chromosome 11 m an Amish pedigree of 81 mdrviduals, 19 of whom were affected. However, a subsequent study of the ortgmal Amish pedigree led to two new diagnoses of mamc-depressive drsorder, which provided evtdence

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for linkage The original results could not be replicated by an extension of the original pedigree nonslgmflcant (Baron et al., 1987) Slmllarly, linkage to a dominant gene on chromosome 5 has been reported by Sherrmgton and coworkers (1988) for five lcelandlc and two English families, with a high incidence for schizophrenia, but these results were not confirmed by subsequent studies (Plomm, 1990, for a review) Failure to fmd major-gene linkages for human mental illness to date does not mean that this hypothesis might not be successful m the future, when closely spaced markers will be available for nearly all human chromosomes However, it seems more plausible that, although any one of many genes can disrupt behavior, the normal range of behavioral variation is modulated by a system of many genes, each having a light effect Although linkage 1s a powerful method for ldentlfymg the chromosomal location of a disorder caused by a smgle gene whose effects are not dependent on a genetic or environmental background, as m Huntington’s disease, linkages have not been demonstrated for schlzophrema and manic depression This 1s thought to be due to what behavior genetics research m humans as well as m nonhuman species has indicated, 1 e that genetic influence on behavior mvolves multiple genes rather than one or two major genes and that nongenetic sources of variance are as important as genetic factors (Plomm, 1990) Therefore, molecular biology strategies are needed to detect DNA markers accountmg for small amounts of behavioral variation It 1s worth noting also that genetic research m different domains such as plant genetics has shown that a very large number of genes with very small effects are responsible for genetic influence on complex characteristics As recently pointed out by Plomm (1990) “ we need to fmd many tmy needles m the haystack” The development of the association method m which genetic markers match quantitative traits has led to quantitative trait loci (QTL) interval mapping. The method 1s based on assoclatlons with many closely spaced RFLPs simultaneously by the use of the interval between marker5 rather than the markers themselves (Patterson et al., 1988; Gora-Maslak et al , 1991) Assoclatlon studies, also called linkage dlsequlhbrmm, are based upon the covarlatlon between allehc variation m a marker and phenotyplc variation among mdlvlduals m a population In this line, as the human genome project proceeds, it will be possible to ldentlfy many markers and genes that possibly play a role m genetic variation m behavior Quantitative genetic techniques might therefore become an important approach to behavioral variation and to mental illness The association method has been extensively used m animal behavior genetics Animal research allows more suitable linkage studies, since inbreeding or selection give more linkage at the same chromosome as well as the posslblhty to manipulate genetic variables by crossing Moreover, the use of animals allows detailed studies on cellular and subcellular components of the central nervous system that may play a crucial role m the development of “weak” points underlying susceptlbihty or vulnerablhty Lastly, experimental designs m the laboratory set allow genotype x environment interaction to be controlled, thus possibly provldmg more mformatlon on the role of nongenetic factors m gene expression In the next paragraph the validity of animal models m behavior genetics and m preclmlcal studies of behavioral disorders will be considered

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Apphed

Behavior

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Behavior

The history of animal behavror genetics reflects a gradual conceptual transformation The mrtial steps m this area were mostly characterized by a tendency to concentrate on the role played by single genes, on biometric analyses and on the modes of inheritance of specrftc behavioral traits These genetic approaches were undertaken for different reasons: first, they were m hne with a consolidated genetic tradition and analysis of other nonbehavioral phenotypes; second, they seemed to represent the best way of opposmg the “behavrorrst dogma” smce they might prove that behavior was shaped by brologrcal forces and not by the environment alone, as suggested by radical behaviorists Two approaches were critical m this regard the first one involved screening single-gene mutations or chromosomal abnormahtres m the fruit fly or the laboratory mouse; the second was based on drallele crosses between inbred strains. The frrst approach, e g. the screening of smglegene mutations, resulted m fmdmgs mdrcatmg that although (single) gene-behavior relationshrps existed, they were the exception, and not ubiquitous as was mitrally believed Although many clearcut fmdmgs were obtamed by Seymour Benzer (Benzer, 1973), who was able to establish the relationships between chromosomal or genetic mutations and a number of neurobehavroral patterns, the inadequacy and complexrty of the single-gene approach appeared when many mutations were screened for their possible pleiotropic effects upon behavior (Lmdzey & Thiessen, 1970) For example, m one study 27 coat-color alleles and four other mutations on the same Inbred background (C57BL/6J mice) were studied for their effects on avoidance, maze learning and activity (Ohverro & Messeri, 1973) A number of mutations resulted m modrftcatrons of either avoidance learning or activity, thus mdicatmg that these behaviors are specifically or nonspecifically influenced by genes at many loci. Presumably, other genes exert and affect these behaviors since only 31 mutations out of many possible thousands were screened A second genetic strategy was used m order to show that many behavioral traits responded to the same genetic rules controlling other phenotypes and were regulated by Mandehan laws. by crossing m a diallele design inbred strains characterized by opposite behavioral patterns it was shown that dominance, intermediate dominance, no dominance or heterosrs could be the mode of inheritance of a given behavioral trait as assessed m the Fl hybrids When the F2 generation was considered, it was shown that the total variance contamed a significant genetic component, thus further supporting the fact that genetic mechanisms modulate a number of behavioral traits (Oliverio, 1983). In addition to that, drallele studies also allowed us to make estimates of the magnitude of the genetic effect, that it to say, to attempt to measure the heritabihty, a descriptive statistic that estimates the extent to which observed variabihty is due to genetic varrabihty However, by using drfferent approaches (drallele studies, F2-F3 correlations or artificial selection, see De Fries, Gervars, & Thomas, 1978) herrtabrhty estimates were nearly always less than 50%, thus mdrcatmg that most behavioral variability 1s not genetic m origin In conclusion, while these approaches were m line with classic Mendehan genetics since they provided dramatic evidence of the existence of genetic influence on behavior, they also indicated that many rather than single genes appear to affect behavior and that geneenvironment mteractions play a crucial role, thus pomtmg to the necessity of lookmg m

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a different way at the genetlc determinants of behavior The more recent approaches of behavior genetlcs were therefore concentrated on two critIca pomts implying that (1) genetlc influence on behavior involves multiple genes rather than one or two malor genes, and (2) nongenetic sources of variance are at least as important as genetic factors when behavioral ontogeny and neurophyslologlcal organizations are concerned (Edelman, 1987) The development of new genetic tools such as recombmant mbred (RI) strams and fmdmgs wlthm plant genetics suggesting that a very large number of genes with very small effects are responsible for genetic influence on complex traits (Edwards, Stuber, & Wendel, 1987) contributed to spurring on this conceptual revolution RI strains represent a powerful genetic tool derived from studies on mbred lmes Durmg the 1960s most behavior genetic experiments were based on the use of mbred strains of mice created by mating brother and sister for at least 20 generations This severe inbreeding ehmmates heterozygoslty and results m animals that are virtually identical genetically The genetic differences characterlzmg different inbred strains of mice results m clear behavioral differences, m that various strains often attain contrasting exploratory, wheel running, avoidance of maze learning levels and are also characterized by contrasting patterns of sexual, maternal, aggressive, sleeping or stereotyped actlvltles (Fuller & Slmmel, 1983, Oliverio, 1983). This strain approach further pomted to a slgmflcant genetlc influence on most behaviors that have been examined and gave birth to a number of models wlthm the neurosclences Crosses and backcrosses between inbred strams and their progeny were also used to assess the patterns of inheritance and to calculate estimates of hentablhty for a given behavioral trait this approach, however, has httle power to dlscrlmlnate smglegene from multiple-gene transmission while RI strams represent a very useful strategy for this purpose Recombmant inbred strains (Bailey, 1971) are derived from a cross between two unrelated but highly inbred progenitor strams, followed by strict mbreedmg from the F2 generation onward This procedure genetically fixes the chance recomblnatlon of the genes that occurs, although m ever-decreasing amounts, m each succeeding generatlon after Fl The resulting battery of strains can be looked upon, m a sense, as a rephcable recombinant population If a single gene 1s responsible for a behavior that differs between the two parental strains, half of the RI strains should be hke one parent and half hke the other In other words, there should be no intermediate phenotypes However, behaviors studied m RI strains show no clearcut single-gene effects, though a few major-gene effects have been suggested (Oliveno, 1979) Despite the lack of evidence for single-gene effects when sophlstlcated mammalian behaviors are concerned, the RI approach presents many advantages for the lsolatlon multiple-gene influences, called quantitative trait loci (QTL) As indicated by Plomm (1990) the classical polygemc model of a very large number of genes, each with an equal and minuscule effect may be correct for some genetic effects However, as mdlcated by recent fmdmgs from plant genetlcs (Edwards et al , 1987) quantitative traits are generally influenced by several genes of intermediate magnitudes of influence. In this regard RI strains are very valuable for mdentlfymg the QTL associated with quantitative traits In the past, the stram dlstrlbutlon patterns (SDP) of different marker 1oc1 (hlstocompatlblhty, lsozymes, etc ) were determined m specific RI strams and the SDP method was primarily used m order

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to map single genes More recently, however, accumulated data on SDPs has provided a valuable resource for the detection of QTL associated with quantitative traits The essence of QTL association analysis for a quantrative trait is to correlate allehc varratton with phenotyprc varrabrhty m a segregatmg population. When applied to published data on genetic markers and on behavioral or psychopharmacological patterns evident m RI strains, the RI QTL approach tdenttfred several associations beyond known major gene effects (Gora-Maslak et al., 1991). The RI QTL approach is interesting since, when sigmfrcant assocratrons are found, they can be presented u-r relation to the mouse linkage map m order to determine the extent to which srgmficant assocrations are clustered on a particular chromosome and to take mto account linkage among markers Animal

Models

of Psychopathology

Research on the neurobiology of disturbed behavior has always used nonhuman models for methodologrcal as well as ethical reasons. In order to extrapolate results from the animal to man, experiments have to be conducted wrthm the framework of animal models bearing both analogies and homologres with pathological behavior m humans Analogies refer to srmrlarrtres between behavioral responses observed m animals wnhm the experimental setting and symptomatology described by clinical studies. The tdentificatlon of these analogies 1s a very difficult task since the symptom profile of some psychopathologres tends to change over time with the development of more refined dragnostrc techniques and the modrfrcatron of the socral context m which the patient 1s maintained. Moreover, symptoms which involve hngmstrc or thought disturbances are almost impossible to model m animals. Homology refers to the identity between the biological alterations which may be responsible for behavioral disturbances m humans and the biological basis of experimentally induced behavior m animals Of course the rdentrfication of a biologrcal basis for human psychopathology IS scarce and clmrcal evidence m thus regard 1s limited and usually contradrctory. Thus m most cases homologres refer to the brologrcal effects of therapeutic actrve substances tested m animals. For this reason, and for the use of animal models for psychopharmacological screening, most ammal models rely heavily on pharmacologrcal validation, i.e. then responsiveness to well-known pharmacological therapies Nevertheless, recent evidence indicates that some of the most important models may have potential heuristic value for the study of the mteractton between envrronmental and genetic factors m the etiology of disturbed behavior Stereotypic behavror 1s a response that 1s readily induced by psychostimulants m the mostused laboratory species, the rat Moreover, its use has been suggested for modellmg m animals the stereotypic alteration of behavior observed m schlzophremc patients. Finally, a strong correlation has been shown between the therapeutic potency of the majority of antrpsychotrc drugs (neuroleptrcs), their ability to block brain dopamme (DA) receptors, and to antagonize psychostrmulant-induced stereotypes m animals For these reasons psychostrmulant-induced stereotyped behavior has long been considered as the best animal model of schrzophremc syndromes (Cooper & Dourrsh, 1990). Quantrtatrve genetic research has been conducted on three maJor lines. First, maJor stramdependent differences have been detected for the behavioral response to psychostimulants

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(see Cablb, Algeri, Perego, & Pughsl-Allegra, 1990 and Robinson, 1988 for a review); second, both stram comparisons and selection Ftudles conducted on sensltlvlty to neuroleptlcs have led to the conclusion that genetic factors do actually regulate this sensltlvlty (see Hltzeman, Dams, Bier-Langmg, & Zahmser, 1991 for a review) Finally, a number of genotype-dependent differences m bram DA functlomng have been observed m mice and rats In particular, some evidence of correlations between behavioral sensltlvlty to DA active substances and variations m the number and dlstnbutlon of DA receptor sites or functioning of rate hmltmg factors m DA synthesis and metabolism has been collected (Claranello & Boheme, 1982) Nevertheless, this model has some major limits First, the analogy between psychostlmulant-induced stereotypic behavior and behavioral alterations m humans 1s very feeble and highly questionable Moreover, the homology based on the hypothesis of a possible mvolvement of altered brain DA functlomng m schlzophremc patients, and the effect of psychostlmulants on brain DA functlomng has yet to receive sufficient experimental and clmlcal support. Finally, this model 1~ of no use m elucidating the factors involved m the production of pathological behavior m humans due to its pharmacological basis The problem of modelhng etlologlcal factors has been the mam concern of researcher5 involved m the development of animal models of human depressive states. These researches have attempted to produce a behavioral syndrome m animals bearing analogies with depression states m humans by means of environmental constramts, 1 e stress The contrlbutlon of stress m the mductlon or exacerbation of depression has been increasingly emphasized m recent years (Bldzmska, 1984, Corwell, Mllden, & Shlmp, 1985). In animal studies it has been shown that uncontrollable stress induces remarkable behavioral deflclts m motor activity and learning performances, reduces food and water consumption, autostlmulatlon of rewarding areas and normal aggression or competltlon levels These disturbances bear slmllarltles to clinical depression with respect to susceptlblhty to treatment and symptomatology (Amsman & Zacharko, 1989, 1990, Weiss & Goodman-Slmson, 1985) Stress-induced behavioral disturbances m ammals used as models for human psychopathological outcomes have a maJor advantage for genetic studies smce these account for the role played by environmental factors m promotmg pathology m genetically susceptible mdivlduals Preclmlcal studies have revealed that exposure to a stressor may induce profound behavioral disturbances in some animals, while m others these behaviors seem hardly affected by the stressor Thus, the “symptom proflle” associated with a stressor (1 e the behaviors disrupted by the stressor) as well as the effectiveness of antidepressants in ameliorating the behavloral disturbances, may vary across strains of mice (Shanks & Amsman, 1989; Zacharko, Lalonde, Kaslan, & Amsman, 1987) Finally, exposure to uncontrollable stress provokes a marked mcrease of plasma corticosterone concentration m animals and there IS reason to suspect that ACTH and cortlcosterolds may be related to depression m humans (Stokes & Slkes, 1987) Thus the observations that the magnitudes of the cortlcosterone increase, as well as the times required to return to control values, vary appreciably across strains of mice, supports the view of genetically determined susceptlblhty to stress responses (Cablb et al , 1990, Shanks, Griffits, Zalcman, Zacharko, & Amsman, 1990) As far as the relationship between physlologlcal and behavloral alterations induced by stress 1s concerned, some convmcmg hypotheses have been recently put forward which

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involve bram norepmephrme (NE) It has been argued that upon exposure to an uncontrollable stressor the utlhzatton of this amme may exceed its synthesis, resulting in a net decline of the neurotransmltter levels, thus rendering the organism less capable of dealing wtth environmental demands (Amsman & Zacharko, 1990; Weiss 8z GoodmanStmon, 1985) Given that the impact of stressor on behavior varres across strains, it has been suggested that strain-specific differences may exist with respect to the relative vulnerabthty of different neurotransmttters as well as the brain regions m which these occur. In fact, it was observed that marked strain differences exist with respect to NE, dopamme (DA) and serotomn (5HT) alterattons induced by a stressor, as well as the bram regions m which these occur (Cablb, Kempf, Schleef, Ohveno, & Puglist-Allegra, 1988; Shanks et al., 1991) Although promtsmg, the model described above has a major hmltatton m that a reduction of the behavioral and blochemtcal effects of uncontrollable stress has been observed upon repeated exposure to the stressor This decay of the effects appears to be due to progresstve habituation, possrbly mediated by adaptive changes of brain NE receptors (Stone, 1990) The orgamsm’s capabrhty to habituate to stress, thus reducing the negative effects on behavior, seems to be m contradictton with the fact that depressive states do not ameliorate but are actually worsened m condtttons of chronic or repeated stress On the other hand rt 1s suggested that these adaptive processes may represent an important ground for genetrc and envtronmental factors to interact m, thereby producing pathologtcal outcomes It 1s mterestmg to note, m this regard, that opposite adaptation to the mhtbltory effects of restraint stress on behavior (decrease vs increase) has been observed m two inbred strains of mice (Pughsr-Allegra, Cabtb, & Badram, 1990a) Rats exposed chronically to a variety of mild unpredictable stressors showed deficits m motor performances, and hormonal changes which could be prevented by concurrent admmlstratlon of a wide range of antrdepressant drugs but not by drugs of other classes (Katz, 1982). Furthermore, prolonged exposure to this same stress regimen was shown to reduce both consumption and preference for palatable drinks Thus deficit outlasted stress termination and was overcome only by chrome treatment with the trlcychc antidepressant DMI (Katz, 1982; Wrllner, Towell, Sampson, Sophokleous, & Muscat, 1987) Thus is a particularly mterestmg fmdmg, as tt tmphes a defective reward system, and models the anhedoma, which 1s a central feature of endogenous depressron There are good reasons to believe that the mesohmbrc DA system mediates experimental anhedoma induced by chrome stress. The mesohmblc DA system is constdered to play a basic role m the emotronal responses to rewarding strmuh (Le Moal & Simon, 1991, Wrse, 1980) Uncontrollable stress has been shown to suppress the ability of strmulatlon of the ventral tegmental area (the area of ortgm of the mesohmblc DA system) to remforce behavior, while not affecting responses for stlmulatron of the substantta mgra (the area of origin of the other major brain DA system-the mgrostriatal) (Zacharko, Bowers, Kokkmrdts, & Amsman, 1983). Fmally, rt was shown that chronic mild unpredictable stress decreases specific bmdmg to dopamme D2 receptor m the rat hmbrc forebram (Wrllner, Golembrowska, Khmek, & Muscat, 1991) The mesohmbic DA system 1s not only involved m reward but also m the response to arousing or stressful sttmuh Arousing stimuli have been shown to stimulate DA release

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in the nucleus accumbens (the major projectmg area of the mesollmblc system) (Imperato, Pughsl-Allegra, Casohnl, Zocchl, & Angeluccl, 1989, Pughsl-Allegra et al , 1990a, 1991) In contrast, exposure to uncontrollable stressors has been shown to decrease DA release m this same area (Cablb et al , 1988, Pughsl-Allegra et al , 1991) It is mterestmg to note that bram stlmulatlon appears to be potentlated by arousing stirnull and reduced by uncontrollable stressors (Katz & Roth, 1979, Zacharko et al , 1983) It 1s thus conceivable that adaptation to repeated stress exposure may involve adaptation of the DA mesohmblc system, possibly through changes m sensltlvlty of DA receptors Studies on inbred strains of mice have revealed that repeated stress may induce complex genotype-dependent alterations of mesohmblc DA functlonmg involving different types of DA receptors DA systems bear two classes of receptors The first class IS located on cell bodies postsynaptlcally to the DA neurons and responsible for DA-dependent effects Another class of receptors, called autoreceptors, are located on DA terminal and cell bodies, where they play an mhlbltory role on the synthesis and the release of the neurotransmltter, thus acting as feedback control for DA overactlvatlon (see Martres et al , 1977 for a review) Following repeated stress C57BL/6 (C57) mice show a marked increase of mesohmblc DA autoreceptor activity which would reduce DA released m the synaptic cleft (Cablb, PughsiAllegra, & Oliverlo, 1985, Cablb & Pughsl-Allegra, 1991) (Figure 1) These Same strains 3_

u7 E

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FIgwe 1 Effects of repeated stress experlemes on the behaworal and neurochemlcal effects of autoreceptorselectwe doses of the dopamme agonist apomorphme m two strains of mice Results are expressed as percent changes of 3-methoxytyramme/dopamlne ratlo (upper panel) as Index of dopamme release, and chmbmg score\ * = stgmflcantly different @ < 0 01) In comparison wth (lower panel) as Index of dopamme-medlated behawor response m unstressed mice

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of mice show also a dramatic reduction of postsynapttc mesohmbrc DA D2 receptors (Puglist-Allegra et al , 1990a) In contrast, mice of the DBA/2 (DBA) strain show a decreased ability of the mesohmbrc DA receptors to regulate the activity of the system and a reduction of postsynaptic DA D2 receptor by far less pronounced than C57 mice (Cabrb et al , 1985, Cabrb & Pughsr-Allegra, 1991, Puglist-Allegra et al , 1990a). Quantitative analysis of repeated stress effects on Fl and F2 hybrids and backcross populations revealed that stress-induced changes m DA autoreceptor sensmvrty characterrstrc of the C57 parental stram are mherrted m a dominant fashion and that a major genotype x stress mteractron regulate the expression of this phenotype (Cabrb et al , 1985) (Figure 2). A further analysis

Pl

Bl

Fl

B2

P2

BehavIoral response (chmbmg scores) to an autoreceptor-selectwe dose of the dopamme agomst apomorphme m chromcally stressed mice observed and expected population means Open circles = expected values FIlled m circles = observed values P 1 C57, P2 = DBA, Fl, F2 = first and second generatlon hybrids, Bl = backcross to Pl, B2= backcross to P2

Flgure

2

mvolvmg RI strains showed that the dlstrrbutron for responsrvrty to apomorphme challenge after chronic stress was neither brmodal nor contmuous, thus suggesting a polygemc influence (Figure 3) The decreased ability of the mesohmbrc DA autoreceptors to regulate the activity of the system shown by repeatedly stressed DBA mice, may compensate for the slight reduction m sensmvny of postsynaptic DA receptors produced by stress m this strain suggesting a sort of homeostatrc regulatron. By contrast, m the C57 mice the increased sensitivity of mesohmbic DA autoreceptor may reduce the DA available for a greatly reduced number of postsynaptrc receptors producing a marked impairment of mesohmbrc DA transmrssron Consequently, genetic factors influence adaptive changes induced by stress leading to opposite outcomes. This 1s confirmed by behavioral results showing that repeated stress exposure enhances the mhrbrtory effects of stress on behavior m C57 mice but reduces these same effects m DBA mice (Pughsi-Allegra et al., 1990a). In conclusron, the organism’s ability to habituate to stress through adaptive changes of mesolimbrc DA system is controlled by genetic factors. It is worth noting that m different

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15 Climbing Egure 3 Frequency scores)

histogram

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25

30

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drawn from means of BXD RI strams for apomorphme-Induced

behawor

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studies rt was demonstrated that the types of adaptive changes developed during stress exposure do not depend on the mural response to stress, which suggests that genotype plays its controlling role through the mechanisms Involved m adaptation processes (Cabib et al , 1988) The fact that impaired mesohmbrc DA transmission may produce behavioral alterations bearing some srmrlarmes with depressive symptoms should not lead to the conclusion that the opposite adaptation to stress 1s devoid of possible pathologrcal outcomes In fact, the strain of mice which appear to habituate to repeated stress experiences also develops behavioral sensmzatron The term sensrtrzatron 1s generally used to refer to long-lasting increments m response occurrmg upon repeated presentation of a stimulus that, at us mrtral presentation, reliably elicits a response. This is a ublqurtous brologrcal phenomenon which has been used to describe the enhancement of reflexive responses followmg repeated elmtatron, the growth m the response to repeated epileptic discharge, and the increased responsrvrty of the immune system following the mitral exposure to an antigen (Groves & Thompson, 1970; Kahvas & Barnes, 1988). Behavioral sensitization 1s classically described following chronic intermittent amphetamine treatment. In animals that have been previously exposed to amphetamine, subsequent amphetamine treatment produces more intense stereotyped behavior, a reduced time to the onset of stereotypy followmg mIectron of the test dose, or the development of stereotyped responses to doses previously devoid of this behavioral effect (Kalavrs & Barnes, 1988; Robinson & Becker, 1986) The sensitization to amphetamme does not seem to be a species-specific phenomenon. An endurmg behavioral sensitization to repeated intermittent amphetamine admmrstratron has been described m rats, mice, cats, guinea pigs, dogs, nonhuman primates and humans (Robinson & Becker, 1986).

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Vutually all known chronic or repeated experimental stressors have been shown to produce behavioral senstttzatton to amphetamine Moreover, stereotypic behavior induced by certain stressors IS progressrvely enhanced by repeated exposure either to the stressor or to amphetamine. Finally, rats reared m tsolatron, exhibit enhanced amphetammeand stress-induced stereotypes (see Antelman & Chrodo, 1983; Robbms, Mrttelman, O’Brien, & Wmn, 1990 for review). The mterchangeabthty between stress and amphetamine m producing behavioral sensitization has led to the hypothesis that a similar adaptation mechanism 1s triggered by chronic or repeated exposure to both treatments. Since increasing evidence has been collected on a major mvolvement of brain DA system m this mechamsm, tt has been suggested that behavioral sensttrzatton depends on altered brain DA functronmg (Robinson, 1988). The ability of repeated stress experiences to induce stereotyped behavior m undrugged organisms and to enhance amphetamine-induced stereotyptes possibly through altered brain may give a new perspective to the animal model of human DA functioning, psychopathologres based on psychostimulant-induced stereotyptes. Furthermore, envuonmentally induced stereotypres represent the most relevant behavioral pathology m domestic animals, suggesting that behavioral sensttrzatton processes may be an etrologtcal factor m a wide range of species. Strain-dependent drfferences in the suscepttbrhty to amphetamine-induced behavioral sensrtrzatron have been revealed m rodents (Robmson, 1988, for a review). Most importantly, the impairment of mesohmbtc DA transmission induced by stress m certain genotypes seems to protect agamst the development of behavtoral sensmzatron, while adaptive changes which appear to accompany habituation to some negative effects of stress favor the development of this response (Pughsr-Allegra, Cabtb, & Badram, 1990b) However, as previously observed, rmpau-ment of mesohmbrc DA transmission may also produce behavioral alterations which bear simtlarrttes to clmtcal depression m that susceptrbrhty to treatment and symptomatology are concerned. Thus, although rt 1s possible to show at experimental levels that adaptation to stress may produce opposite outcomes depending on genotype, these seem to be costly in terms of susceptibihty to behavioral pathologies In conclusron, animal models for preclimcal studies on psychopathology may offer a wealth of mformatton about the mvolvement of genetic factors m the etiology of human behavioral disturbance. Above all they are increasingly capable of reproducing, wtthm the experimental setting, complex interactions between genotype and environment which lead to drfferent behavioral dysfunctions. Moreover, experimental models allow the rdenttftcatton of some specific brain subsystem (1 e the mesolimbtc DA system) as the possible locus of these Interactions, as well as subcellular mechanisms involved m then functronmg. This 1s an important starting point for an experimental approach on genetic determinants of behavior disorders. Recently, an approach in the domam of psychopathology has been proposed that attempts to correlate biological variables with psychologtcal dysfunctions, which are considered to be the basrc units of classrftcatron in psychopathology. According to this view the basic units of classtficatron in psychopathology are not syndromes or nosologrcal entitles, but psychological dysfunctions, such as disturbances m perception, cognition, memory, or information processmg and others (van Praag et al , 1991). Such psychologtcal dysfunctions

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would be the elementary constituents of psychlatrlc syndromes In the research on the blologlcal basis of behavior disorders, correlations between blologlcal and psychological dysfunctions should be investigated This approach is, to some extent, consistent with the view stemming from behavior genetics and pointing to polygemc factors m the etiology of psychotic syndromes and to small contrlbutlons of many genes toward behavloral varlablhty and vulnerablhty The functlonmg of bram systems related to psychic functions such as emotion, cogmtlon or perception may be dlsrupted by a few or many alterations mvolvmg a number of genes controlling, for Instance, enzymes regulatmg neurotransmltter metabolism, or receptor complexes for neurotransmltters, or messengers within pre- or postsynaptic neurons These all may be blologlcal factors underlying “weakness” and therefore susceptlblhty or vulnerablhty to pathology In this framework, animal studies will provide a sort of test for hypotheses arising m chmcal sets, allowmg gene-product and product-behavior pathways to be examined at molecular levels when the gene accounts for a very small amount of genetic variance Accordmgly, animal studies are to be considered as both prechmcal and “postchmcal” research In such a perspective, new molecular biology approach and behavior genetics m nonhuman species could provide useful tools in the assessment of the genetic as well as nongenetic factors that lead to some mdlvlduals being broken down by envu-onmental pressures that are overcome by others In future more sophisticated quantltatlve and molecular genetic methods will possibly allow these factors to be found m the human species References Am\man, H , & Zacharko, R M (1989) PharmaLologlcal blochemlcal and behavIoral analyses of dcpreaslon ammal models In G F Koob, C L Ehlers, & D J Kupfer (Eds ), Anrmal models ofdepressron (pp 204-238) Blrkhauser, Boston Amsman, H , & Zacharko, R M (1990) MultIpIe neurochemlcal and behawora! consequenx\ of stressolr lmpllcatlons for deprewon Pharmatologrcul Therapy, 46, 119-136 Antelman, S M , & Chlodo, L S (1983) Amphetamme as a stressor In I Creese (Ed ), S/rmu/unts neurochemrcul, behavroral and clrnrcal perspecfrves (pp 269-299) Raven Press, New York Bailey, D W (1971) Recombmant Inbred strams Trunsplanfatron, 11, 325-327 Baron, M , Rlsch, N , Hamburger, R , Mandel, B , Kushner, S , Newman, M , Drumer, D , & Belmaker, R H (1987) Genetlc !mkage between X-chromosome markers and bipolar affectlbe Illness Narure, 326, 289-292 Benzer, S (1973) GenetIc dIssectIon of behawor Screntgfrc Amerrcan, 229, 24-37 Bldzmska, E .I (1984) Stress factors m affective disorders Brrtlsh Journal of Psychratry, 144, 161-166 Cablb, S , Algerl, S , Perego, C , & PughwAllegra. S (1990) BehavIoral and biochemical changes momtored m two Inbred strams of mace during exploration of an unfamlhar enwronment Physmlogy ofBehavror, 47, 749-753 Cablb, S , Kempf, S , Schleef, C , Ohverlo, A , & PughwAllegra, S (1988) Eftects of lmmobdwatlon Ftress on dopamme and Its metabohtes m different bram areas of the mouse role of genotype and stress duration Bram Research, 441, 153-160 Cablb, S , & PughwAllegra, S (1991) Genotype-dependent effects of chrome stress on strlatal and mesollmblL dopamme metsbohsm m response to apomorphme Bram Research. 542, 91-96 Cablb, S , Pugllsl-Allegra. S , & Ohverlo, A (1985) A genetlc analysis of stereotypy m the mouse Behavioral Neurological Biology, 44, 239-248 Claranello, R D , & Boheme, R (1982) Genetlc regulation of neurotranbmltter enzyme and receptors relatlonshtp to the mherltance of psychlatrx disorders Behaworal Genetu, 12, 11-215 Cooper, S J , & Dourlsh, C T (1990) Neurobrology of stereotyped behavrour Ciarendon Press, Oxford

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