is well known that temporal lobe epilepsy, a type of hyperactivity
of the hippocampus, has been associated with schizophrenia
symptoms in humans (Ounsted and Lindsay, 1981). Together,
these data are consistent with the model derived from the present
study, in which a hyperactive vHipp drives a DA hyperfunction.
However, whether this hyperactivity has its origin as a result of
pathology within the ventral hippocampus, or is driven abnor-
mally by another region, is not known at this time.
At face value, the hippocampal hyperactivity model of schizo-
phrenia may appear to be inconsistent with the neonatal ventral
hippocampal lesion (NVHL) model (Lipska et al., 1993). How-
ever, we suggest that both models may actually be producing a
similar pathology, but via different means. Thus, Swerdlow et al.
(2001) have demonstrated that the enhanced behavioral respon-
sivity to amphetamine in the NVHL model is attenuated with
extensive lesions encompassing the entire dorsal and ventral re-
gions of the hippocampus. On this basis, it has been suggested
that the behavioral abnormalities in the NVHL model reflect, at
least in part, aberrant function within spared elements of the
hippocampal complex (Swerdlow et al., 2001). Therefore, al-
though this increase in hippocampal activity has not been dem-
onstrated in the NVHL model, it is possible that in both models
the enhanced response to amphetamine derives from a hyperac-
tivity within hippocampal tissue.
The present study demonstrates that the pathological increase
in tonic DA transmission and aberrant responsivity to psy-
chomotor stimulants observed in MAM rats is likely attributable
to hyperactivity within the ventral hippocampus. Moreover, we
propose that the hippocampal dysfunction consistently observed
in schizophrenia patients is the basis for the dopamine dysregu-
lation in this disorder. We are of course aware that the adminis-
tration of a toxin to a developing rat is not an accurate recapitu-
lation of the etiology of schizophrenia in humans, nor is the
presence of simple deficits in sensory gating and executive func-
tion a necessary parallel to the complex cognitive and affective
deficits distinctive of this disorder. Nonetheless, we posit that at
the core of this disorder is a disruption of systems interactions
that can be modeled in animals, but when placed in the context of
complex human brain and behavioral patterns, yields the com-
plex pattern of psychopathology recognized as schizophrenia.
Such an understanding of the functional interactions among
these systems and how disruption within these circuits affects
information processing is central to gaining a better understand-
ing of disease pathophysiology and developing better pharmaco-
Abi-Dargham A (2004) Do we still believe in the dopamine hypothesis? New
data bring new evidence. Int J Neuropsychopharmacol 7:S1–S5.
Ambrogi Lorenzini CG, Baldi E, Bucherelli C, Sacchetti B, Tassoni G (1997)
Role of ventral hippocampus in acquisition, consolidation and retrieval of
rat’s passive avoidance response memory trace. Brain Res 768:242–248.
Berridge KC, Robinson TE (1998) What is the role of dopamine in reward:
hedonic impact, reward learning, or incentive salience? Brain Res Rev
Breier A, Su TP, Saunders R, Carson RE, Kolachana BS, de Bartolomeis A,
Weinberger DR, Weisenfeld N, Malhotra AK, Eckelman WC, Pickar D
(1997) Schizophrenia is associated with elevated amphetamine-induced
synaptic dopamine concentrations: evidence from a novel positron emis-
sion tomography method. Proc Natl Acad Sci USA 94:2569 –2574.
Chergui K, Akaoka H, Charlety PJ, Saunier CF, Buda M, Chouvet G (1994)
Subthalamic nucleus modulates burst firing of nigral dopamine neurones
via NMDA receptors. NeuroReport 5:1185–1188.
Degroot A, Treit D (2004) Anxiety is functionally segregated within the
septo-hippocampal system. Brain Res 1001:60–71.
Flagstad P, Mork A, Glenthoj BY, van Beek J, Michael-Titus AT, Didriksen M
(2004) Disruption of neurogenesis on gestational day 17 in the rat causes
behavioral changes relevant to positive and negative schizophrenia symp-
toms and alters amphetamine-induced dopamine release in nucleus ac-
cumbens. Neuropsychopharmacology 29:2052–2064.
Floresco SB, Todd CL, Grace AA (2001) Glutamatergic afferents from the
hippocampus to the nucleus accumbens regulate activity of ventral teg-
mental area dopamine neurons. J Neurosci 21:4915– 4922.
Floresco SB, West AR, Ash B, Moore H, Grace AA (2003) Afferent modula-
tion of dopamine neuron firing differentially regulates tonic and phasic
dopamine transmission. Nat Neurosci 6:968–973.
Goto Y, Grace AA (2005) Dopamine-dependent interactions between lim-
bic and prefrontal cortical plasticity in the nucleus accumbens: disruption
by cocaine sensitization. Neuron 47:255–266.
Goto Y, Grace AA (2006) Alterations in medial prefrontal cortical activity
and plasticity in rats with disruption of cortical development. Biol Psy-
chiatry 60:1259 –1267.
Gourevitch R, Rocher C, Le Pen G, Krebs MO, Jay TM (2004) Working
memory deficits in adult rats after prenatal disruption of neurogenesis.
Behav Pharmacol 15:287–292.
Grace AA (1991) Phasic versus tonic dopamine release and the modulation
of dopamine system responsivity: a hypothesis for the etiology of schizo-
phrenia. Neuroscience 41:1–24.
Grace AA (2000) Gating of information flow within the limbic system and
the pathophysiology of schizophrenia. Brain Res Rev 31:330 –341.
Grace AA, Bunney BS (1983) Intracellular and extracellular electrophysiol-
ogy of nigral dopaminergic neurons. I. Identification and characteriza-
tion. Neuroscience 10:301–315.
Grace AA, Moore H (1998) Regulation of information flow in the nucleus
accumbens: a model for the pathophysiology of schizophrenia. In: Ori-
gins and development of schizophrenia: advances in experimental psy-
chopathology (Lenzenweger MF, Dworkin RH, eds), pp 123–157. Wash-
ington, DC: American Psychological Association.
Grace AA, Floresco SB, Goto Y, Lodge DJ (2007) Regulation of firing of
dopaminergic neurons and control of goal-directed behaviors. Trends
Neurosci 30:220 –227.
Harrison PJ (1999) The neuropathology of schizophrenia. A critical review
of the data and their interpretation. Brain 122:593– 624.
Harrison PJ (2004) The hippocampus in schizophrenia: a review of the neu-
ropathological evidence and its pathophysiological implications. Psycho-
Heckers S, Rauch SL, Goff D, Savage CR, Schacter DL, Fischman AJ, Alpert
NM (1998) Impaired recruitment of the hippocampus during conscious
recollection in schizophrenia. Nat Neurosci 1:318 –323.
Johnson PI, Napier TC (1997) GABA- and glutamate-evoked responses in
the rat ventral pallidum are modulated by dopamine. Eur J Neurosci
Krieckhaus EE, Donahoe JW, Morgan MA (1992) Paranoid schizophrenia
may be caused by dopamine hyperactivity of CA1 hippocampus. Biol
Psychiatry 31:560 –570.
Lahti AC, Weiler MA, Holcomb HH, Tamminga CA, Carpenter WT, McMa-
hon R (2006) Correlations between rCBF and symptoms in two inde-
pendent cohorts of drug-free patients with schizophrenia. Neuropsycho-
Laruelle M, Abi-Dargham A (1999) Dopamine as the wind of psychotic fire:
new evidence from brain imaging studies. J Psychopharmacol
Laruelle M, Abi-Dargham A, Van Dyck CH, Gil R, D’Souza CD, Erdos J,
McCance E, Rosenblatt W, Fingado C, Zoghbi SS, Baldwin RM, Seibyl JP,
Krystal JH, Charney DS, Innis RB (1996) Single photon emission com-
puterized tomography imaging of amphetamine-induced dopamine re-
lease in drug-free schizophrenic subjects. Proc Natl Acad Sci USA
Legault M, Wise RA (1999) Injections of N-methyl-D-aspartate into the
ventral hippocampus increase extracellular dopamine in the ventral teg-
mental area and nucleus accumbens. Synapse 31:241–249.
Lipska BK, Jaskiw GE, Weinberger DR (1993) Postpubertal emergence of
hyperresponsiveness to stress and to amphetamine after neonatal excito-
toxic hippocampal damage: a potential animal model of schizophrenia.
Lodge DJ, Grace AA (2006a) The hippocampus modulates dopamine neu-
Lodge and Grace • The Hippocampus, Dopamine, and Schizophrenia J. Neurosci., October 17, 2007
• 27(42):11424–11430 • 11429