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A possible role of hippocampal dysfunction in schizophrenic symptomatology
BIOL PSYCHIATRY 1990;28:87-91
COMMENT
A Possible Role of Hippocampal Dysfunction in Schizophrenic Symptomatology Daniel J. Luchins
The author proposes a pathogenesis for the bizarre, repetitive behaviors frequently seen in deteriorated schizophrenb:, i.e., polydipsia, hoarding, pacing, etc. It is argued that such behaviors may have a neurobiology similar to schedule-induced behaviors or incentive-conditioned behaviors described in animal models, which involve the hippocampus, nucleus accumbens, and the neurotransmitter dopamine. Such behaviors are aug~. m~nted by hippocampal lesions, stress, tncreased drive state, or doparninergic agents, and reduced by 6-OH dopamine lesions to nucleus accumbens or ant|psychotic agents. Thes~~repetitive behaviors tray. reflect the failure of hippocampus to modulate the impao of mesolimbic dopaminergic activity on che n.,~cleus accumbens and thus on motor behavior. Such a hypothesis is consistent with a growing body of neuropathological and brain imaging re'~ults demonstraffng hippocampal lesions in chronic z~'hizophrenics.
Introduction Over the last decade, discussions of schizophrenic psychopathology h~ve tended to emphasize either positive (delusions, hallucinations, formal thought disorder) or negative [alogia, anhedonia, flat affect, asocialty, and abulia (Crow 1980~ Andreasen 1982)] symptoms. However, particularly among chronically ~stitutiona!lized schizophrenics, there is a group of symptoms not easily subserved by either of these categories. These symptoms are often described as "bizarre behaviors" and include polydipsia, pacing, constant smoking, strange grooming patterns, hoarding, stereotypies, and mannerisms (Bleu!er !9~0; Arieti !97~.). Unlike most positive or negative symptoms, many of these bizarre behaviors can be reproduced in animal models, possibly throwing light on the symptoms' pathophysiology in humaas. High rates of polydipsi~, stereotypies, and bizarre behaviors can be established in animals (Wallace and Singer 1~76) and normal humans (Wallace et al. 1975) by ~aintaining them on brief, fixed interv~ schedules of reinforcement (usually less than 2-rain intervals). The neurobiology of this phenomenon, termed "scbedule-induced behavior," appears to involve the hippocampus, nucleus accumbens, and the neurotrans-
From the Department of Psychiatry, Pritzker School of Medicine, University of Chicago; and Illinois State Psychiatric Institute, Chicago, IL. Supported in part by the Brain Research Foundation, an Af'iliate of the University of Chicago. Addres.,, repot ~:qttesis ~ Dr. D~ufiei J. L~hirls, Dep~,~-~erlt of ~sych~L~y, ~t~.ke~ ~choo| o~ ~,,~edicme, Uaive~i~'y of Chicago, 5841 South Maryland Avenue, Chicago, IL 606~?. Received August 19, 1989; revised Decem.t~e.-10, i989. © 1990 Society of Biological psychiatry
0006-3223/90/~03.50
88
BIOL PSYCIHATRY
D.J. Luchins
1990;28:87-91
mitter dopamine. Hippocampal lesions in rats facilitate the acquisition of schedule-induced polydipsia (Devenport 1978) whereas 6-OH dopamine lesions of nucleus accumbens (Robbins and Koob 1980), but not prefrontal cortex (Christie et al. 19~.6), block sche(Jule~ndaced polydipsia as well as other forms of schedule-induced behaviors (Wallace et al. 1983). The obvious criticism of schedule-induced behaviors as a model of schizophrenic symptoms is that there is cth-rently no evidence that the behavior of patients reflects brief, fixed interval schedules of reinforcement. However, there is a related form of behavior ("incentive-conditioned"), with a similar neurobiology, that may provic]e a more suitable model. Devenport et al. (1981) have shown that if deprived of food and fed once daffy, hippocampally lesioned rats exhibit increases in motor behavior and stereotypic movements associated with the feeding. Such behavio~ are blocked by haloperidol. Interestingly, nonlesioned animals will develop similar responses if made very hungry (personal communication) or given d-amphetamine (Devenport et al. 1981). Thi:s effex:t has been explained by assuming that the hippocampus normally holds in check supefltuoas behaviors associated with incentive conditioning, and promotes the selective association of such conditioning with useful behaviors. Neurobiologically~ it may we!! be that the hippocampus, through excitatory glutaminergic pathways, opposes the inhibiting effect of ventral tegmental dopamine at the nucleus accumbens (Schmajuk and Tyberg 1989). An intact hippocampus would inhibit the tendency of dopamine to increase motor activity. The idea that hippocampal lesions are relevant to schizophrenia was probably first proposed by Heath (1954) and was formally stated by Mednick (1970), who noted histories of pcrinatal insult and abnormal galvanic skin responses with decreased latency and habituation in the children of schizophrenic mothers who go on to develop schizophrenia. The hippocampus is extremely sensitive to anoxia (Friede 1966), a possible concomitant. of perinatal insult, and rats with ablated hippocampus show decreased galvanic skin response latencies (Rabe and Haddad 1969), with poor habituation (Kimble 1968). Recently, evidence for a tdppocampal or related abnormality in schizophrenia has been reported by four different groups engaged in postmortem study of the brains of schizophrenics. Bogerts et al. (1985) noted a decreased volume of the amygdala and hippocampus, and of the parahippocampal g)~us, with decreased cell number in hippocampus (Falkai and Bogerts 1986) and entorhinal cortex (Falkai et al. 1988) compared with normals. Jakob and Beckmann (1986) noted disturbances of both the temporal cortical sulcogyral pattern and entorhinal g y ~ . cytoarchitectonics, primarily on the left. Brown et all. (!986) found, compared with a!~ective disorder controls, thimter parahippocampal gyri in the schizophrenics, again primarily on the left. Jeste and Lohr (1989) also noted decreased hippocampal volume and cell density in CA4, especi~y in the left, in the brains of schizophre.nics compared with normals or nonschizophrenic p~tients. Utilizing magnetic resonance imaging (MR0, these findings have been partially corroborated in living patients. Suddath et al. (1989s.) have reported decreased temporal grey in 17 schizophrenics when compared with 17 age-matched controls. When specifically co~paring 12 schizophrenics who had histories of polydipsia and hyponatremia with 12 schizophrenics without suc~ histories (matched for age, gender, and age of onset), the same investigators noted decreased temporal grey, and smaller hippocampus and amygdala in the former group (Suddath et al. 1989b). How can we tie all this together? I would argue that in at least some, possibly most, "regressed" schizophrenics, there is a hippocamp~l abnormality, particularly in the left hemisphere (Flor-Henry 1983). These lesions interfere with the ability to respond selec-
Hippocampal Dysfunction in Schizophrenia
BIOL PSYCHIATRY
1990;28:87-91
89
tively to environmental cues associated with reward or arousal. This leads to the development of unselected stereo,'ypic responses including drinking, pacing, smoking, and odd grooming. Such symptoms would reflect a failure of the hippocampus to modulate the impact of mesolimbic dopaminergic activity on the nucleus accnmbens. Like incentiveconditioned behaviors in animals, they could b~ augmented by increases in drive state or stress (McLev3an and Maier 1987) and by dopaminergic drugs such as amphetamines, or reduced by d o p ~ i n e antagonists such as antipsychotics~ How does this theery compare with other current theories of the neurobiology of schizophrenic symptoms7 Weinberger (1987) has argued that the primary defect in schizophrenics is in the dorsal lateral prefrontal cortex (DIAl), as evidenced by an inability to activate this area when faced with cognitive tasks such as the Wisconsin Card Sorting Tests (Weinberger et al. 1986). Weinberger argued that this DLPC deficit is associated with the negative symptoms of schizophrenia. To explain the positive symptoms he invokes animal data by Pycock et al. (1980) showing that lesions to the dopamine afferents to frontal cortex in rats induced increased subcortical dopamine (i.e., increased mesolimbic and striatal dopamine). However, the theory does not explain how increased subcortical dopamine produces positive symptoms, and tends to rely hearty on the existence of a DLPC abnormelity. Evidence for DLPC slruc~.~ral abnormalities in schizophrenia is rare (Shelton et al. 1988). Furthermore, as an increwe i~ subco~.ical dopamine can occur after temporal or parietal lobe cortical lesions (Bracha et al. 1989), a lesion in prefrental areas may not be necessary to explain increased subcortical dopamine in schizophrenics. In fact, subcortical injury such as that to the caudate in ~ n a l ~ed_~llary _txansp!¢nt experiments (Fiandaca et al. 1988) can also elicit sprouting of dopaminergic neurons and may be another source of increased subcortical dopaminergic activity. A hippocampal theory would support increased study of hippocampal structure and function in schizophrenics, particularly those with the bizarre behaviors previously discussed. What is the exact location - ~ nature of anatomical abno:malities that can be detected on autopsy or through brain imaging? Can the severity of hippocampal neuropathology be indirectly quantified, using event-related po~:fials (Wood et al. 1988), and will this relate to form or degree of psychopathology? Are there functional deficits, particularly left sided, in memory or more basic conditioning paradigms associated with hippocampal function (Schmajuk and Tyberg 1989) detectable in these patients? I would like to thank Morris GolcLman, M.D. for his thoughtful suggestions,
References Andreasen NC (1982): Negative symp~orn~in schiz,Jphrenia. Arch Gen Psychiatry 39:784-788. Adefi $ (1974): Interpretation of Schiz~,phrenia (ed 2). New York: Basic Books, Inc., pp 415422. Bleuler E (1950): Dementia Precox or the Group of Schi,,op~renics. New York: International Universities Press. Bogerts B, Meertz E, Schonfeld-Bausch R (1985): Basal ganglia and limbic system pa~,~logy in schizophrenia. Arch Gen Psychiatry 42:784-791. B~cha HS, Lyden PD, Klumsaria S (1989): Delayed emergency of ~atal dopaminergic hyperactivity after anterolateral ischemic co~.~icallesions in h~mans: Rvider~'efrom turning behavior. 8ioi Psychiatry 25:265-274.
BIOLPSYCHIATRY 1990;28:87-91
D.J. Luchins
Brown K, Col~er N, Corsellis JA, et al. (1986): Postmortem evideace of structural brain changes in schizophrenia. Arch Gen Psychiatry 43:36-42. Christie MJ, Beart PM, Louis WH, Gibson SJ, Singer G, Papasava M (1986): 6-Hy~-oxydo~,~ and excitatory lesions of medial pre-frontal cortex fail to affect ~hedule-induced drinking in the rat. Belmv Brain Res 10:183-186. Crow TJ (1980): Molecular pathology of schizophrenia: More than one disease process. Br Med J [Clin Res] 2~1~:1-9. Devenport LD (! 978): Schedule-induced polydipsia in rats: Adreno-cortical and hippocampa~ rood-. ulation. J Comp Physiol Psycho192:65 !-660. Devenport LD, Devenport JA, Holloway FA (1981): Reward-induced stereotypies: Modulation by the hippocampus. Science 212:1288-1289. F~a~kaiP, Bogerts B 0986): Cell loss in the hippocampus of schizophrenics. Eur Arch Psychiatry Neurol Sci 236:154-161. Falkai P, Bogerts B, Rozumik M (1988): Limbic pathology in schizophrenia: The entorhinal region~A morphometric study. Biol P~chiatry 24:515-521. Fian0aca MS, Kordower JH, Hansen JT, Jiao SS, Gash DM (1988): Adrenal medullary autographs into the basal ganglia of cebus monkeys: Injury-induced regeneration. Exp Neurol 102:76-91. Flor-Henry P (1983): The Cerebral B~sis of Psychopathology. Littleton, MA: Wright PSG. Ffiede R (1966): The histochemical architecture of Ammons horn as it relates to its selective vulnerability. Acta Neuropathol (Bed) 6:1-13. Heath RG (1954): Studies in Schizophrenia. Carabridge, MA: Harvard University Press. Jacob H, Beckmann H (1986): Prenatal development disturbances in Se limbic allocortex in schizophrenics. J Neurol Trans 65:303-326. ]este DV, Lohr JB (1989): Hippocampal pathologic findings in schizophrenia. Arch Gen Psychiatry 46:1019-1024. Kimble DP (1968): Hippocampus and internal inhibition. Psych Bull 70:285-295. McLennan A.I, Maier S (1987): Coping and stress-induced potentiation of stimulant stereotypy in the rat. Science 219:1091-1094. Mednick SA (1970): I~reakdown in individuals at high risk for schizophre:nia: Possible predispo~ sitional perinatal factors. Ment Hygiene 54:50-63. Pycock CJ, Kerwin RW, Carter JC (1980): Effect of lesions of cortical ~iopaln~e terminals on subeortical dopamine in rats. Nature 286:74-77. Rabe A, Hadda_dRK (19~9): Acquisition of 2-way shuttle box avoidance, ~ter selecti-,~eb~ppocampal lesions. Physiol Beb.av 4:319-323. Robbins TW, Koob GF (1980): Selective disruption of displacement behavior by lesions of the mesolimbic dopamine system. Na.'~ure285:409-412. Schmajnk NA, Tyberg M (1989): The hippocampal lesion model of schizophrenia. In Boulton ,~A, Baker GB, Martin-lverson MT (eds) Neummethods, vol. 19. Animal Models in Psychiatry. I. Clifton, NJ: Humana Press. Sheltoa RC, Karson RC, Doran AR, Pickar D, Bigelow LB, Weinberger DR (1988): Cerebral structural pathoiogy ~n schizophrenia: Evidence for a selective prefrontal cortical defect. Am J Psychiatry 145:15~-163. Suddath RL, Casanova MF, Goldberg TE, Daniel DG, Kelsoe JR, Weiuberger DR f1989a): Temporal lobe pathology in schizophrenia: A quantitative magnetic resonance imaging study. Am J Psychiatry 146:464-472. Suddath RL, Foote M, Godelski L, Viewig VR, Weinberger DR, Kirch DG (1989b): MRI of polydipsia-hyponatremia. Presented at 14th Annual Meeting of ~ e r i c a n Psychiatric Association. San Francisco, CA. Wallace M, Singer G, Wayner MJ, Cook P (1975): Adjunctive behavior in humans during game playing. Physiol Behav 14:651-654,
Hippocampal Dysfunction in Schizophrenia
BIOLPSYCHIATRY 1990;28:87-91
91
W~ace M, Singer (3 (1976): Schedule-induced behavior: A review of ;-ts generality, determinants and pharmacological data. Pharm Biochem Behav 5:483-~.~0. Wallace M, Singer (3, Finlay ~I, (3ibson S (1983): The effect of 6-Of-IDA lesions of the nucleus accumbens septum on schedule-induced drinking, wheel nmning and corticosterone levels in rats. "Pharmacol Biochem Behav 18:129--136. Weinberger DR (1987): L,nplica~_s of normal brain development for the pathogenesis of schizophrenia. Arch Gen P~chiatry 44:660-669. Weinberger DR, Berman KF, Zec RF (1986): Physiological dysfunction of dorsolateral pre,~'rontal cortex in schizophrenia: Regional cerebral blood flow (rCBF) evidence. Arch Gen Psychiatry 43:114-125. Wood CC, McCarthy G, Kiro HI, Spencer DD, Will~_~nsonPD (1988): Abnormalities in temporal lobe. event-related potentials predict hip!mcampal cell loss in temporal lobe epilepsy (Abstract). Soc Neurosci 14:5.
COMMENT
A Possible Role of Hippocampal Dysfunction in Schizophrenic Symptomatology Daniel J. Luchins
The author proposes a pathogenesis for the bizarre, repetitive behaviors frequently seen in deteriorated schizophrenb:, i.e., polydipsia, hoarding, pacing, etc. It is argued that such behaviors may have a neurobiology similar to schedule-induced behaviors or incentive-conditioned behaviors described in animal models, which involve the hippocampus, nucleus accumbens, and the neurotransmitter dopamine. Such behaviors are aug~. m~nted by hippocampal lesions, stress, tncreased drive state, or doparninergic agents, and reduced by 6-OH dopamine lesions to nucleus accumbens or ant|psychotic agents. Thes~~repetitive behaviors tray. reflect the failure of hippocampus to modulate the impao of mesolimbic dopaminergic activity on che n.,~cleus accumbens and thus on motor behavior. Such a hypothesis is consistent with a growing body of neuropathological and brain imaging re'~ults demonstraffng hippocampal lesions in chronic z~'hizophrenics.
Introduction Over the last decade, discussions of schizophrenic psychopathology h~ve tended to emphasize either positive (delusions, hallucinations, formal thought disorder) or negative [alogia, anhedonia, flat affect, asocialty, and abulia (Crow 1980~ Andreasen 1982)] symptoms. However, particularly among chronically ~stitutiona!lized schizophrenics, there is a group of symptoms not easily subserved by either of these categories. These symptoms are often described as "bizarre behaviors" and include polydipsia, pacing, constant smoking, strange grooming patterns, hoarding, stereotypies, and mannerisms (Bleu!er !9~0; Arieti !97~.). Unlike most positive or negative symptoms, many of these bizarre behaviors can be reproduced in animal models, possibly throwing light on the symptoms' pathophysiology in humaas. High rates of polydipsi~, stereotypies, and bizarre behaviors can be established in animals (Wallace and Singer 1~76) and normal humans (Wallace et al. 1975) by ~aintaining them on brief, fixed interv~ schedules of reinforcement (usually less than 2-rain intervals). The neurobiology of this phenomenon, termed "scbedule-induced behavior," appears to involve the hippocampus, nucleus accumbens, and the neurotrans-
From the Department of Psychiatry, Pritzker School of Medicine, University of Chicago; and Illinois State Psychiatric Institute, Chicago, IL. Supported in part by the Brain Research Foundation, an Af'iliate of the University of Chicago. Addres.,, repot ~:qttesis ~ Dr. D~ufiei J. L~hirls, Dep~,~-~erlt of ~sych~L~y, ~t~.ke~ ~choo| o~ ~,,~edicme, Uaive~i~'y of Chicago, 5841 South Maryland Avenue, Chicago, IL 606~?. Received August 19, 1989; revised Decem.t~e.-10, i989. © 1990 Society of Biological psychiatry
0006-3223/90/~03.50
88
BIOL PSYCIHATRY
D.J. Luchins
1990;28:87-91
mitter dopamine. Hippocampal lesions in rats facilitate the acquisition of schedule-induced polydipsia (Devenport 1978) whereas 6-OH dopamine lesions of nucleus accumbens (Robbins and Koob 1980), but not prefrontal cortex (Christie et al. 19~.6), block sche(Jule~ndaced polydipsia as well as other forms of schedule-induced behaviors (Wallace et al. 1983). The obvious criticism of schedule-induced behaviors as a model of schizophrenic symptoms is that there is cth-rently no evidence that the behavior of patients reflects brief, fixed interval schedules of reinforcement. However, there is a related form of behavior ("incentive-conditioned"), with a similar neurobiology, that may provic]e a more suitable model. Devenport et al. (1981) have shown that if deprived of food and fed once daffy, hippocampally lesioned rats exhibit increases in motor behavior and stereotypic movements associated with the feeding. Such behavio~ are blocked by haloperidol. Interestingly, nonlesioned animals will develop similar responses if made very hungry (personal communication) or given d-amphetamine (Devenport et al. 1981). Thi:s effex:t has been explained by assuming that the hippocampus normally holds in check supefltuoas behaviors associated with incentive conditioning, and promotes the selective association of such conditioning with useful behaviors. Neurobiologically~ it may we!! be that the hippocampus, through excitatory glutaminergic pathways, opposes the inhibiting effect of ventral tegmental dopamine at the nucleus accumbens (Schmajuk and Tyberg 1989). An intact hippocampus would inhibit the tendency of dopamine to increase motor activity. The idea that hippocampal lesions are relevant to schizophrenia was probably first proposed by Heath (1954) and was formally stated by Mednick (1970), who noted histories of pcrinatal insult and abnormal galvanic skin responses with decreased latency and habituation in the children of schizophrenic mothers who go on to develop schizophrenia. The hippocampus is extremely sensitive to anoxia (Friede 1966), a possible concomitant. of perinatal insult, and rats with ablated hippocampus show decreased galvanic skin response latencies (Rabe and Haddad 1969), with poor habituation (Kimble 1968). Recently, evidence for a tdppocampal or related abnormality in schizophrenia has been reported by four different groups engaged in postmortem study of the brains of schizophrenics. Bogerts et al. (1985) noted a decreased volume of the amygdala and hippocampus, and of the parahippocampal g)~us, with decreased cell number in hippocampus (Falkai and Bogerts 1986) and entorhinal cortex (Falkai et al. 1988) compared with normals. Jakob and Beckmann (1986) noted disturbances of both the temporal cortical sulcogyral pattern and entorhinal g y ~ . cytoarchitectonics, primarily on the left. Brown et all. (!986) found, compared with a!~ective disorder controls, thimter parahippocampal gyri in the schizophrenics, again primarily on the left. Jeste and Lohr (1989) also noted decreased hippocampal volume and cell density in CA4, especi~y in the left, in the brains of schizophre.nics compared with normals or nonschizophrenic p~tients. Utilizing magnetic resonance imaging (MR0, these findings have been partially corroborated in living patients. Suddath et al. (1989s.) have reported decreased temporal grey in 17 schizophrenics when compared with 17 age-matched controls. When specifically co~paring 12 schizophrenics who had histories of polydipsia and hyponatremia with 12 schizophrenics without suc~ histories (matched for age, gender, and age of onset), the same investigators noted decreased temporal grey, and smaller hippocampus and amygdala in the former group (Suddath et al. 1989b). How can we tie all this together? I would argue that in at least some, possibly most, "regressed" schizophrenics, there is a hippocamp~l abnormality, particularly in the left hemisphere (Flor-Henry 1983). These lesions interfere with the ability to respond selec-
Hippocampal Dysfunction in Schizophrenia
BIOL PSYCHIATRY
1990;28:87-91
89
tively to environmental cues associated with reward or arousal. This leads to the development of unselected stereo,'ypic responses including drinking, pacing, smoking, and odd grooming. Such symptoms would reflect a failure of the hippocampus to modulate the impact of mesolimbic dopaminergic activity on the nucleus accnmbens. Like incentiveconditioned behaviors in animals, they could b~ augmented by increases in drive state or stress (McLev3an and Maier 1987) and by dopaminergic drugs such as amphetamines, or reduced by d o p ~ i n e antagonists such as antipsychotics~ How does this theery compare with other current theories of the neurobiology of schizophrenic symptoms7 Weinberger (1987) has argued that the primary defect in schizophrenics is in the dorsal lateral prefrontal cortex (DIAl), as evidenced by an inability to activate this area when faced with cognitive tasks such as the Wisconsin Card Sorting Tests (Weinberger et al. 1986). Weinberger argued that this DLPC deficit is associated with the negative symptoms of schizophrenia. To explain the positive symptoms he invokes animal data by Pycock et al. (1980) showing that lesions to the dopamine afferents to frontal cortex in rats induced increased subcortical dopamine (i.e., increased mesolimbic and striatal dopamine). However, the theory does not explain how increased subcortical dopamine produces positive symptoms, and tends to rely hearty on the existence of a DLPC abnormelity. Evidence for DLPC slruc~.~ral abnormalities in schizophrenia is rare (Shelton et al. 1988). Furthermore, as an increwe i~ subco~.ical dopamine can occur after temporal or parietal lobe cortical lesions (Bracha et al. 1989), a lesion in prefrental areas may not be necessary to explain increased subcortical dopamine in schizophrenics. In fact, subcortical injury such as that to the caudate in ~ n a l ~ed_~llary _txansp!¢nt experiments (Fiandaca et al. 1988) can also elicit sprouting of dopaminergic neurons and may be another source of increased subcortical dopaminergic activity. A hippocampal theory would support increased study of hippocampal structure and function in schizophrenics, particularly those with the bizarre behaviors previously discussed. What is the exact location - ~ nature of anatomical abno:malities that can be detected on autopsy or through brain imaging? Can the severity of hippocampal neuropathology be indirectly quantified, using event-related po~:fials (Wood et al. 1988), and will this relate to form or degree of psychopathology? Are there functional deficits, particularly left sided, in memory or more basic conditioning paradigms associated with hippocampal function (Schmajuk and Tyberg 1989) detectable in these patients? I would like to thank Morris GolcLman, M.D. for his thoughtful suggestions,
References Andreasen NC (1982): Negative symp~orn~in schiz,Jphrenia. Arch Gen Psychiatry 39:784-788. Adefi $ (1974): Interpretation of Schiz~,phrenia (ed 2). New York: Basic Books, Inc., pp 415422. Bleuler E (1950): Dementia Precox or the Group of Schi,,op~renics. New York: International Universities Press. Bogerts B, Meertz E, Schonfeld-Bausch R (1985): Basal ganglia and limbic system pa~,~logy in schizophrenia. Arch Gen Psychiatry 42:784-791. B~cha HS, Lyden PD, Klumsaria S (1989): Delayed emergency of ~atal dopaminergic hyperactivity after anterolateral ischemic co~.~icallesions in h~mans: Rvider~'efrom turning behavior. 8ioi Psychiatry 25:265-274.
BIOLPSYCHIATRY 1990;28:87-91
D.J. Luchins
Brown K, Col~er N, Corsellis JA, et al. (1986): Postmortem evideace of structural brain changes in schizophrenia. Arch Gen Psychiatry 43:36-42. Christie MJ, Beart PM, Louis WH, Gibson SJ, Singer G, Papasava M (1986): 6-Hy~-oxydo~,~ and excitatory lesions of medial pre-frontal cortex fail to affect ~hedule-induced drinking in the rat. Belmv Brain Res 10:183-186. Crow TJ (1980): Molecular pathology of schizophrenia: More than one disease process. Br Med J [Clin Res] 2~1~:1-9. Devenport LD (! 978): Schedule-induced polydipsia in rats: Adreno-cortical and hippocampa~ rood-. ulation. J Comp Physiol Psycho192:65 !-660. Devenport LD, Devenport JA, Holloway FA (1981): Reward-induced stereotypies: Modulation by the hippocampus. Science 212:1288-1289. F~a~kaiP, Bogerts B 0986): Cell loss in the hippocampus of schizophrenics. Eur Arch Psychiatry Neurol Sci 236:154-161. Falkai P, Bogerts B, Rozumik M (1988): Limbic pathology in schizophrenia: The entorhinal region~A morphometric study. Biol P~chiatry 24:515-521. Fian0aca MS, Kordower JH, Hansen JT, Jiao SS, Gash DM (1988): Adrenal medullary autographs into the basal ganglia of cebus monkeys: Injury-induced regeneration. Exp Neurol 102:76-91. Flor-Henry P (1983): The Cerebral B~sis of Psychopathology. Littleton, MA: Wright PSG. Ffiede R (1966): The histochemical architecture of Ammons horn as it relates to its selective vulnerability. Acta Neuropathol (Bed) 6:1-13. Heath RG (1954): Studies in Schizophrenia. Carabridge, MA: Harvard University Press. Jacob H, Beckmann H (1986): Prenatal development disturbances in Se limbic allocortex in schizophrenics. J Neurol Trans 65:303-326. ]este DV, Lohr JB (1989): Hippocampal pathologic findings in schizophrenia. Arch Gen Psychiatry 46:1019-1024. Kimble DP (1968): Hippocampus and internal inhibition. Psych Bull 70:285-295. McLennan A.I, Maier S (1987): Coping and stress-induced potentiation of stimulant stereotypy in the rat. Science 219:1091-1094. Mednick SA (1970): I~reakdown in individuals at high risk for schizophre:nia: Possible predispo~ sitional perinatal factors. Ment Hygiene 54:50-63. Pycock CJ, Kerwin RW, Carter JC (1980): Effect of lesions of cortical ~iopaln~e terminals on subeortical dopamine in rats. Nature 286:74-77. Rabe A, Hadda_dRK (19~9): Acquisition of 2-way shuttle box avoidance, ~ter selecti-,~eb~ppocampal lesions. Physiol Beb.av 4:319-323. Robbins TW, Koob GF (1980): Selective disruption of displacement behavior by lesions of the mesolimbic dopamine system. Na.'~ure285:409-412. Schmajnk NA, Tyberg M (1989): The hippocampal lesion model of schizophrenia. In Boulton ,~A, Baker GB, Martin-lverson MT (eds) Neummethods, vol. 19. Animal Models in Psychiatry. I. Clifton, NJ: Humana Press. Sheltoa RC, Karson RC, Doran AR, Pickar D, Bigelow LB, Weinberger DR (1988): Cerebral structural pathoiogy ~n schizophrenia: Evidence for a selective prefrontal cortical defect. Am J Psychiatry 145:15~-163. Suddath RL, Casanova MF, Goldberg TE, Daniel DG, Kelsoe JR, Weiuberger DR f1989a): Temporal lobe pathology in schizophrenia: A quantitative magnetic resonance imaging study. Am J Psychiatry 146:464-472. Suddath RL, Foote M, Godelski L, Viewig VR, Weinberger DR, Kirch DG (1989b): MRI of polydipsia-hyponatremia. Presented at 14th Annual Meeting of ~ e r i c a n Psychiatric Association. San Francisco, CA. Wallace M, Singer G, Wayner MJ, Cook P (1975): Adjunctive behavior in humans during game playing. Physiol Behav 14:651-654,
Hippocampal Dysfunction in Schizophrenia
BIOLPSYCHIATRY 1990;28:87-91
91
W~ace M, Singer (3 (1976): Schedule-induced behavior: A review of ;-ts generality, determinants and pharmacological data. Pharm Biochem Behav 5:483-~.~0. Wallace M, Singer (3, Finlay ~I, (3ibson S (1983): The effect of 6-Of-IDA lesions of the nucleus accumbens septum on schedule-induced drinking, wheel nmning and corticosterone levels in rats. "Pharmacol Biochem Behav 18:129--136. Weinberger DR (1987): L,nplica~_s of normal brain development for the pathogenesis of schizophrenia. Arch Gen P~chiatry 44:660-669. Weinberger DR, Berman KF, Zec RF (1986): Physiological dysfunction of dorsolateral pre,~'rontal cortex in schizophrenia: Regional cerebral blood flow (rCBF) evidence. Arch Gen Psychiatry 43:114-125. Wood CC, McCarthy G, Kiro HI, Spencer DD, Will~_~nsonPD (1988): Abnormalities in temporal lobe. event-related potentials predict hip!mcampal cell loss in temporal lobe epilepsy (Abstract). Soc Neurosci 14:5.