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Amphetamine sensitization of hallucinatory-like behaviors is dependent on prefrontal cortex in nonhuman primates
Amphetamine Sensitization of Hallucinatory-like Behaviors Is Dependent on Prefrontal Cortex in Nonhuman Primates Stacy A. Castner and Patricia S. Goldman-Rakic Background: Repeated amphetamine (AMPH) exposure in nonhuman primates produces a chronic state of monoamine dysregulation and long-lasting changes in behaviors elicited by acute AMPH (including tracking, grasping “at thin air,” manipulating nonapparent stimuli, and hypervigilance) in a manner that bears a marked resemblance to symptoms of both amphetamine psychosis and paranoid schizophrenia. These abnormal responses have historically been referred to as psychotomimetic or hallucinatory-like. In contrast to negative symptoms and cognitive deficits, the positive symptoms of schizophrenia including hallucinations have not traditionally been linked to prefrontal dysfunction. Methods: The dorsomedial (9/8B), dorsolateral (46/8A), and inferior (45/12) sectors of prefrontal cortex were lesioned, singly or in combination. Lesioned and nonlesioned control monkeys were sensitized over a 6-week period using an intermittent schedule of escalating low doses of AMPH. Behavioral responses to acute AMPH after chronic exposure were compared with preexposure responses. Results: Bilateral lesions of prefrontal cortex performed before subchronic AMPH suppressed the sensitization of hallucinatory-like behaviors but markedly enhanced locomotor sensitization compared with control animals. Conclusions: These findings indicate that the primate prefrontal cortex may be a substrate for the development of the full complement of behaviors elicited by AMPH sensitization, including hallucinatory-like behaviors. Biol Psychiatry 2003;54:105–110 © 2003 Society of Biological Psychiatry Key Words: Prefrontal lesion, behavioral sensitization, monkey, schizophrenia, hallucination, positive symptoms
Introduction
D
ysfunction of the prefrontal cortex has commonly been associated with a deficit state in schizophrenia (Buchanan et al 1990; Crow 1985; Carpenter et al 1988;
From the Department of Neurobiology (SAC, PSG-R), Yale University School of Medicine, New Haven, Connecticut. Address reprint requests to Patricia S. Goldman-Rakic, Ph.D., Yale University School of Medicine, Section of Neurobiology, 333 Cedar Street, New Haven, CT 06510. Received October 2, 2002; revised March 11, 2003; accepted March 14, 2003.
© 2003 Society of Biological Psychiatry
Kirkpatrick and Buchanan 1990); however, an increasing number of functional magnetic resonance imaging studies of patients with schizophrenia have shown prefrontal areas to be activated during auditory hallucinations (Lennox et al 2000; McGuire et al 1993; Shergill et al 2000; Silbersweig et al 1995) and other positive symptoms (Sabri et al 1997). Furthermore, one of the putative therapeutic mechanisms of action of neuroleptics is through a reduction in activation of prefrontal cortex (Liddle et al 2000; Miller et al 1997; Ngan et al 2002; Potkin et al 1994; Vita et al 1995). Repeated amphetamine (AMPH) administration in the intact nonhuman primate has been shown to induce behaviors reminiscent of the hallmark symptoms of schizophrenia, including hallucinatory-like behaviors, long-lasting psychomotor depression, and cognitive deficits (Castner et al 2000, 2001; Castner and Goldman-Rakic 1999a; Ellinwood et al 1973; Ellison and Eison 1983; Ellison et al 1981; Ridley et al 1982). In monkeys, both chronic high dose and a sensitizing regimen of AMPH treatment elicit a subset of behaviors that have been variably referred to as psychotomimetic (Sams-Dodd and Newman 1997), psychotic-like (Machiyama 1992), abnormal (Schlemmer and Davis 1983), and hallucinatory-like (Ellison et al 1981; Ellison and Eison 1983; Nielsen et al 1983a, 1983b). These behaviors include hypervigilance, abnormal tracking, grasping, and checking the environment for stimuli that are not observable to the experimenter. Because, to all appearances, the animal’s behavior is mediated by imagined stimuli, it has commonly been analogized to visual or auditory hallucinations in both amphetamine psychosis and schizophrenia (Ellinwood 1967; Snyder 1972, 1973). Accordingly, we here refer to these behaviors as “hallucinatory-like” as the best descriptor of an exaggerated repertoire of responses that occur in the absence of any observable stimuli. In addition to its psychotomimetic effects, amphetamine sensitization also prominently affects locomotor activity. In rodents, lesions of the medial prefrontal cortex block the sensitization of hyperlocomotion, but 0006-3223/03/$30.00 doi:10.1016/S0006-3223(03)00292-0
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guidelines set by the Yale Animal Care and Use Committee and with federal standards for laboratory primates.
Surgical Procedures
Figure 1. Coronal sections across the rostral– caudal extent of the prefrontal cortex for each selective prefrontal lesion. Lesions are denoted by a dashed line. Panels depict either a dorsal (A) and (B) or ventral (C) reconstruction of each selective lesion. (A) shows a representative dorsomedial lesion encompassing both area 9 and parts of area 8B. In B, one of the two dorsolateral lesions is reconstructed. For both animals, this lesion was confined to areas 46 and 8A. In (C), a ventral view of an inferior lesion reconstruction is shown.
not stereotypy, following a sensitizing AMPH regimen (Wolf et al 1995). To our knowledge, the effects of prefrontal lesions on AMPH sensitization of locomotion and the hallucinatory-like behaviors have never been examined in a nonhuman primate. Because the prefrontal cortex is a major site of dysfunction in schizophrenia and amphetamine sensitization can be expected to alter the regulation of neural function in this brain region, we tested the hypothesis that the prefrontal cortex is an essential substrate of AMPH sensitization in this species. Our experiment examines the effects of selective lesions of prefrontal cortex on the development of sensitization, with the expectation that alterations in the normal expression of sensitization will provide further insight into the pathophysiology of dopamine dysfunctional states such as schizophrenia.
Methods and Materials Subjects The pattern of behavioral sensitization to AMPH was documented in 17 adult (5–12 years of age) rhesus monkeys (Macaca mulatta) of both sexes (males, n ⫽ 7; females n ⫽ 10). Monkeys were housed individually and maintained in accordance with
The animals were prepared for surgery under ketamine (5–10 mg/kg; administered intravenously [IV]) and atropine (.2 mg/kg; IV) and maintained during surgery under sodium pentobarbitol (25–30 mg/kg; administered intraventricularly). Using aseptic stereotaxic techniques, a midline scalp incision was made, and a 2–3 cm craniotomy was performed over the area to be lesioned. After duratomy, selective regions of the cortex were aspirated bilaterally. The dura was sutured closed, the skull incision was filled with sterile gelfoam, and the wound was closed in layers. The lesions were designed to explore regional susceptibilities to sensitization. Two monkeys received dorsomedial lesions (Walker’s areas 9 and 8B on the superior frontal gyrus), two monkeys received dorsolateral lesions (Walker’s areas 46 and 8A inclusive of the depths and banks of the principal sulcus and the anterior bank of the arcuate sulcus), and three animals received lesions of the inferior convexity (Walker’s areas 12 and 45; Walker 1940). The lesion of the inferior convexity extended from below the principal sulcus to the edge of the convexity and continued onto the ventral surface as far as the lateral orbital sulcus. The posterior part of this lesion included the anterior bank of the inferior ramus of the arcuate sulcus. One monkey received a combined lesion encompassing all three selective lesions (i.e., areas 9, 8A, 8B, 46, 12, 45, and part of 10). Reconstructions of representative lesions are shown in Figure 1, A–C. The animals used as controls in this study were also involved in ongoing studies on the effects of AMPH sensitization on cognition, and did not receive sham lesions.
Sensitization To induce behavioral sensitization, monkeys received intermittent, escalating low-doses of AMPH (.1–1.0 mg/kg twice daily, IV) over a 6-week period. (Data on AMPH sensitization for six of the nine nonlesioned monkeys were originally reported in Castner et al 2000). Behavioral sensitization was documented by comparing homecage responses to acute AMPH (.4 mg/kg, IV) before, at 21 days, and 6.5– 8 months after subchronic exposure. Behavioral responses were recorded on videotape and computer by focal time sampling with a program, MonkeyWatcher, during the first 2–3 hours postinjection and at regularly timed intervals until behavior returned to “baseline,” defined as prechallenge behavior. The software program, as developed by Jonathon Traupman, documents the occurrence, duration, and frequency of each behavior displayed. Behaviors were divided into three categories: 1) locomotor stereotypies (repetitive gross locomotor behaviors such as pacing, circling, somersaulting), 2) hallucinatory-like behaviors (tracking, grasping, or manipulating of nonapparent stimuli, hypervigilance, and checking in the absence of visible stimuli), and 3) other AMPH-induced behaviors that included fine-motor and oral stereotypies, parasitoticlike grooming, vocalizations, and static or catatoniclike posturing (for additional details, see Castner and Goldman-Rakic 1999a; Castner et al 2000).
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Lesion Analysis No earlier than 1 week after the last AMPH challenge, the lesioned monkeys received ketamine (5–10 mg/kg, IV) and atropine (.2 mg/kg, IV) for restraint followed by an overdose of sodium pentobarbitol (100 mg/kg, intraventricularly). Following transcardial perfusion with 2L .9% NaCl followed by 4 L of 4% paraformaledehyde in .1 mol/L phosphate buffer, the brains were removed, postfixed in 4% paraformaldehyde, blocked, and cryoprotected in sucrose (5%–20%). Blocks of frontal cortex were sectioned at 40 m on a freezing sliding microtome, and every 10th section was collected and stained for cresyl violet. Alternate cresyl violet stained sections (⬃800 m apart) were scanned and digitized by a CCD camera using an MCID system (Imaging Research, Brock University, St. Catherines, Ontario, Canada). All scanned sections in the lesioned animals were examined, and the lesioned area in each was outlined using Canvas software. Two-dimensional reconstructions of each lesion were compiled from serial drawings of the sections containing the lesion outlines.
Statistical Analyses One-, two-, and three-way factorial analysis of variance (ANOVA) was used to examine group (lesion vs. control), group ⫻ time, and group ⫻ time ⫻ type of behavior effects. Symbols (*) in Figure 2 indicate that the lesioned group differed significantly from control animals at an alpha level of .05, as indicated by one-way ANOVA with Scheffe post hoc comparisons.
Results Before sensitization, there was a striking group difference in the behavioral phenotype elicited by AMPH challenge, with lesioned monkeys showing a significant enhancement of locomotor stereotypies [F(1,15) ⫽ 4.82, p ⫽ .04; Figure 2A] and as a group a marked suppression of hallucinatorylike behaviors [F(1,15) ⫽ 7.07, p ⫽ .018; Figure 2B] compared with control animals. Interestingly, the process of sensitization only served to magnify this difference. Confirming our previous studies, nonlesioned control animals showed significant sensitization of hallucinatorylike as well as other AMPH-induced behaviors such as oral and fine-motor stereotypies and a virtual absence of sensitization of locomotion (Castner and Goldman-Rakic 1999a; Castner et al 2000), whereas the lesioned monkeys as a group showed the opposite result— dramatic and significantly enhanced locomotion and an almost complete suppression of the sensitization of hallucinatory-like behaviors including visual tracking, grasping, or manipulating nonapparent stimuli, as well as hypervigilance and checking in the absence of visible stimuli (Figure 2B). Hallucinatory-like behaviors did not sensitize even in the three lesioned monkeys that displayed significant levels of these behaviors in response to AMPH challenge before sensitization. Lesions of the prefrontal cortex also abol-
Figure 2. The mean percentage time spent by lesioned and control monkeys engaged in locomotor stereotypies (A) and in hallucinatory-like behaviors (B) in response to amphetamine (AMPH) challenge: pretreatment, early post (21 days posttreatment), and late post (6.5– 8 months posttreatment) is shown. Monkeys with prefrontal lesions (cross-hatch bars) exhibited a significant sensitization of AMPH-induced locomotion (A) and failed to show sensitization of AMPH-induced hallucinatory-like behaviors (B) in direct contrast to the pattern shown by nonlesioned control monkeys (solid bars). The apparent, although nonsignificant, increase in locomotor stereotypies shown in response to AMPH at the early post challenge by control monkeys was attributable to a dramatic increase in this behavior by one monkey that was not observed in response to subsequent challenges in this animal.
ished sensitization of parasitotic-like grooming (Table 1), a behavior that several studies in nonhuman primates have classified as hallucinatory-like (Ellinwood et al 1973; Ellison et al 1981; Ellison and Eison 1983; Ridley et al 1982). A three-way ANOVA revealed that there was indeed a differential effect of sensitization on locomotor versus hallucinatory-like behaviors as a function of group [effect of group ⫻ type of behavior: F(1,88) ⫽ 66.701; p ⬍ .0001; effect of group ⫻ time of challenge: F(2,88) ⫽
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Table 1. Mean ⫾ SEM Percentage Time Spent Engaged in Locomotor Stereotypies, Hallucinatory-like Behaviors, and Other Amphetamine-Induced Behaviors by Control and Lesioned Monkeys Condition Pre-AMPH Control Area 46/8A lesion Area 9/8B lesion Area 45/12 lesion Comprehensive Late, 6.5⫹ Months Post-AMPH Control Area 46/8A lesion Area 9/8B lesion Area 45/12 lesion Comprehensive
Locomotor
Hallucinatory-like
Other
4.78 ⫾ 3.25 2.20 ⫾ .70 22.30 ⫾ 9.50 24.73 ⫾ 9.78 80.20 ⫾ .00
27.44 ⫾ 6.72 6.95 ⫾ 4.35 5.25 ⫾ 2.05 11.92 ⫾ 3.07 2.70 ⫾ .00
16.59 ⫾ 8.21 70.00 ⫾ 10.80 12.00 ⫾ .70 15.10 ⫾ 2.72 0.00 ⫾ .00
4.98 ⫾ 2.40 50.97 ⫾ 7.03 43.75 ⫾ 6.25 45.68 ⫾ 45.68 99.90 ⫾ .00
56.36 ⫾ 8.82 21.48 ⫾ 3.38 13.55 ⫾ 6.55 7.81 ⫾ 1.81 12.00 ⫾ .00
62.20 ⫾ 7.37 4.37 ⫾ .07 58.90 ⫾ 15.90 28.71 ⫾ 28.39 49.50 ⫾ .00
Behaviors are in response to acute amphetamine (AMPH; .4 mg/kg, IV) administered either before (Pre-AMPH) or after (Late, 6.5⫹ months post-AMPH) repeated AMPH exposure.
3.115; p ⫽ .493; effect of group ⫻ time of challenge ⫻ type of behavior: F(2,88) ⫽ 3.240; p ⫽ .0439]. The effect on locomotion was long-lasting and still significant at more than 6.5 months postsensitization [pre: F(1,15) ⫽ 4.82, p ⫽ .04; early: F(1,15) ⫽ 11.86, p ⫽ .004; late: F(1,14) ⫽ 18.60, p ⫽ .0007; Figure 2A]. The difference between control and lesioned monkeys in hallucinatorylike behaviors was present at all challenges [pre: F(1,15) ⫽ 7.07, p ⫽ .018; early: F(1,15) ⫽ 9.71, p ⫽ .007; late: F(1,14) ⫽ 16.76, p ⫽ .001; Figure 2B]. In contrast to the monkeys with prefrontal lesions, the control monkeys expressed statistically significant sensitization of hallucinatory-like behaviors by the late AMPH challenge [effect of time of challenge: F(2,24) ⫽ 3.48; p ⫽ .047; pre vs. late: p ⫽ .049 by Scheffe post hoc comparison]. Although the numbers of animals in each selective lesion group were too small for statistical analysis, several interesting trends were observed regarding the relationship between behavioral sensitization phenotype and lesion site. Notably, the most dramatic effects of lesioning were observed in the monkey with complete removal of prefrontal cortex. After sensitization, this monkey responded to AMPH challenge by engaging in locomotion 99.9% of the time and showed the lowest incidence of AMPHinduced hallucinatory-like behaviors (Table 1). The only trend for an effect of lesion site on the pattern of AMPH sensitization was in regard to fine-motor stereotypy and parasitotic-like grooming. Interestingly, these behaviors were dramatically suppressed in the two monkeys with area 46/8A lesions in response to AMPH challenge following sensitization (Table 1).
Discussion The goal of this study was to identify and characterize the contribution of prefrontal cortex in the nonhuman primate
to the development of the AMPH-sensitized behavioral phenotype. In monkeys with prefrontal lesions, we found that an acute AMPH challenge significantly enhanced locomotion, whereas hallucinatory-like behaviors tended to be suppressed consistent with previous findings (Miller 1976). The process of sensitization augmented these effects, such that selective lesions of the prefrontal cortex enhanced AMPH sensitization of locomotion and suppressed sensitization of hallucinatory-like behaviors, compared with the profile of sensitized behaviors shown by nonlesioned animals. The loss of sensitization of hallucinatory-like behaviors after prefrontal lesions indicates that the development of the AMPH-sensitized behavioral phenotype in nonhuman primates requires circuitry that includes dorsomedial, dorsolateral, and inferior regions of the prefrontal convexities. A mechanism analogous to sensitization has been postulated to play an etiologic role in the emergence of positive symptoms of schizophrenia, including hallucinations, during adolescence and early adulthood (Lieberman et al 1997). The role of the prefrontal cortex in this putative sensitization is supported by the finding that subanesthetic doses of ketamine that produce activation of the homologous areas of prefrontal cortex, areas 46 and 9, in normal healthy adults (Vollenweider et al 1997a, 1997b) exacerbate positive symptomatology, including hallucinations, in neuroleptic-free patients with schizophrenia (Malhotra et al 1997). Indeed, one of the possible therapeutic mechanisms of action of neuroleptics in the treatment of schizophrenia is through decreased activation of prefrontal cortex (Miller et al 1997; Potkin et al 1994; Vita et al 1995). Recent studies have found that the increasing ability of risperidone to decrease glucose utilization in prefrontal cortex coincided with the dissipation of positive symptoms including hallucinations (Liddle et al 2000; Ngan et al 2002). Thus, the present findings suggest that the prefron-
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tal cortex, and aspects of corticostriatal transmission may be critical for the exacerbation of hallucinatory-like phenomena are consistent with these clinical studies. Although sensitization of hallucinatory-like behaviors was completely suppressed in the monkeys with prefrontal lesions, locomotor sensitization was profoundly enhanced compared with nonlesioned control animals. This sharp dissociation could be accounted for by one behavior inhibiting the other, possibly via disinhibition of the basal ganglia circuits involved in locomotion (Whishaw et al 1992). Each of the prefrontal cortical areas lesioned in this study projects heavily to the caudate nucleus (Selemon and Goldman-Rakic 1985; Yeterian and Pandya 1991), and the loss of these connections could help to explain the suppression of sensitization of hallucinatory-like behaviors. At the same time, this disconnection could contribute to the suppression of fine-motor stereotypies and parasitoticlike grooming observed in the monkeys with dorsolateral lesions. In contrast, the integrity of prefrontal-accumbens projections that arise predominantly from the medial and orbital regions of prefrontal cortex, mostly spared by these lesions, may have facilitated the development of locomotor sensitization in the monkeys with prefrontal cortical lesions (Haber et al 1995; Ongur and Price 2000). It is well documented that the nucleus accumbens plays a critical role in the expression of AMPH-induced hyperlocomotion, whereas the caudate nucleus is the major site for induction of AMPH-induced stereotyped behaviors (Clarke et al 1988; Kelly et al 1975). The differential effects of lesions of prefrontal cortex on AMPH sensitization in the nonhuman primate compared with the rodent may well reflect the differential pattern of projections to different regions of the basal ganglia between these two species. In direct contrast to the regions lesioned in our study, the medial prefrontal cortex in the rodent projects heavily to the nucleus accumbens (cf. Wolf et al 1995). In conclusion, our findings extend the evidence for a critical role of prefrontal cortex in the exacerbation of hallucinatory-like phenomena. Elucidating the cellular and molecular changes in the nonhuman primate prefrontal cortex and their relationship to those at the level of the basal ganglia produced by AMPH sensitization should help to identify suspect mechanisms for the etiology of both positive and negative symptoms of schizophrenia.
This work was supported by NIMH Grant MH44866 (PSG-R). The monkeys with dorsomedial and dorsolateral prefrontal lesions in this study were also subjects in a previous study on working memory by Drs. Levy and Goldman-Rakic (Levy and Goldman-Rakic 1999). We thank Dr. Levy for his cooperation in this study and for his assistance to PSG-R in producing the dorsomedial and dorsolateral lesions in the experimental animals. We also thank Heather A. Findlay and Tatyana A. Trakht for their expert technical assistance.
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References Buchanan RW, Kirkpatrick B, Heinrichs DW, Carpenter WT (1990): Clinical correlates of the deficit syndrome of schizophrenia. Am J Psychiatry 147:290 –294. Carpenter WT, Heinrichs DW, Wagman AMI (1988): Deficit and nondeficit forms of schizophrenia: The concept. Am J Psychiatry 145:578 –583. Castner SA, Al-tikriti M, Baldwin RM, Seibyl JP, Innis RB, Goldman-Rakic PS (2000): Behavioral changes and [123I]IBZM equilibrium measurement of AMPH-induced dopamine release in rhesus monkeys. Neuropsychopharm 22:4 – 13. Castner SA, Goldman-Rakic PS (1999a): Long-lasting psychotomimetic consequences of repeated low dose amphetamine exposure in rhesus monkeys. Neuropsychopharm 20:10 –28. Castner SA, Goldman-Rakic PS (1999b): Profound cognitive impairments in nonhuman primates exposed to amphetamine. Soc Neurosci Abstr 25:1563. Castner SA, Vosler PS, Goldman-Rakic PS (2001): Lowered dopamine turnover in amphetamine-sensitized monkeys: Development of a primate model of schizophrenia. Biol Psychiatry Abstr 49(suppl 8):124S. Clarke PBS, Jakubovic A, Fibiger HC (1988): Anatomical analysis of the involvement of mesolimbocortical dopamine in the locomotor stimulant actions of d-amphetamine and apomorphine. Psychopharmacol 96:511–520. Crow TJ (1985): The two-syndrome concept: Origins and current status. Schizophr Bull 11:471–485. Ellinwood, EH Jr (1967): Amphetamine psychosis. I. Description of the individuals and process. J Nerv Ment Dis 144:273–283. Ellinwood EH Jr, Sudilovsky A, Nelson LM (1973): Evolving behavior in the clinical and experimental amphetamine (model) psychosis. Am J Psychiatry 130:1088 –1093. Ellison G, Eison MS (1983): Continuous amphetamine intoxication: An animal model of the acute psychotic episode. Psychol Med 13:751–761. Ellison G, Nielsen EB, Lyon M (1981): Animal model of psychosis: Hallucinatory behaviors in monkeys during the late stage of continuous amphetamine intoxication. J Psychiatry Res 16:13–22. Haber SN, Kunishio K, Mizobuchi M, Lynd-Balta E (1995): The orbital and medial prefrontal circuit through the primate basal ganglia. J Neurosci 15:4851–4867. Kelly PH, Seviour PW, Iversen SD (1975): Amphetamine and apomorphine responses in the rat following 6-OHDA lesions of the nucleus accumbens septi and corpus striatum. Brain Res 94:507–522. Kirkpatrick B, Buchanan RW (1990): The neural basis of the deficit syndrome of schizophrenia. J Nerv and Ment Disease 178:545–555. Lennox BR, Park SBG, Medley I, Morris PG, Jones PB (2000): The functional anatomy of auditory hallucinations in schizophrenia. Psychiatry Res Neuroimaging Section 100:13–20. Levy R, Goldman-Rakic PS (1999): Association of storage and processing functions in the dorsolateral prefrontal cortex of the nonhuman primate. J Neurosci 19:5149 –5158. Liddle PF, Lane CJ, Ngan ETC (2000): Immediate effects of risperidone on cortico-striato-thalamic loops and the hippocampus. Br J Psychiatry 177:402–407.
110
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Lieberman JA, Sheitman BB, Kinon BJ (1997): Neurochemical sensitization in the pathophysiology of schizophrenia: Deficits and dysfunction in neuronal regulation and plasticity. Neuropsychopharm 17:205–229. Machiyama Y (1992): Chronic methamphetamine intoxication model of schizophrenia in animals. Schizophr Bull 18:107– 113. Malhotra AK, Pinals DA, Adler CM, Elman I, Clifton A, Pickar D, et al (1997): Ketamine-induced exacerbation of psychotic symptoms and cognitive impairment in neuroleptic-free schizophrenics. Neuropsychopharm 17:141–150. McGuire PK, Shah GMS, Murray RM (1993): Increased blood flow in Broca’s area during auditory hallucinations in schizophrenia. Lancet 342:703–706. Miller DD, Andreasen NC, O’Leary DS, Rezai K, Watkins GL, Ponto LL, et al (1997): Effects of antipsychotics on regional cerebral blood flow measured with positron emission tomography. Neuropsychopharmacology 17:230 –240. Miller MH (1976): Behavioral effects of amphetamine in a group of rhesus monkeys with lesions of dorsolateral frontal cortex. Psychopharmacology 47:71–74. Ngan ETC, Lane CJ, Ruth TJ, Liddle PF (2002): Immediate and delayed effects of risperidone on cerebral metabolism in neuroleptic naı¨ve schizophrenic patients: Correlations with symptom change. J Neurol Neurosurg Psychiatry 72:106 – 110. Nielsen EB, Eison MS, Lyon M, Iverson SD (1983a): Hallucinatory behaviors in primates produced by around-the-clock amphetamine treatment for several days via implanted capsules. Prog Clin Biol Res 131:79 –100. Nielsen EB, Lyon M, Ellison G (1983b): Apparent hallucinations in monkeys during around-the-clock amphetamine for seven to fourteen days. Possible relevance to amphetamine psychosis. J Nerv Ment Dis 171:222–233. Ongur D, Price JL (2000): The organization of networks within the orbital and medial prefrontal cortex of rats, monkeys, and humans. Cereb Cortex 10:206 –219. Potkin SG, Buchsbaum MS, Jin Y, Tang C, Telford J, Friedman G, et al (1994): Clozapine effects on glucose metabolic rate in striatum and frontal cortex. J Clin Psychiatry 55(suppl B):63– 66. Ridley RM, Baker HF, Owen F, Cross AJ, Crow TJ (1982): Behavioural and biochemical effects of chronic amphetamine treatment in the vervet monkey. Psychopharm 78:245–251. Sabri O, Erkwoh R, Schreckenberger M, Owega A, Sass H, Buell U (1997): Correlation of positive symptoms exclusively to hyperperfusion or hypoperfusion of cerebral cortex in nevertreated schizophrenics. Lancet 349:1735–1739. Sams-Dodd F, Newman JD (1997): Effects of administration regime on the psychotomimetic properties of d-amphetamine
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in the squirrel monkey (Saimiri sciureus). Pharmacol Biochem Behav 56:471–480. Schlemmer RF, Davis JM (1983): A comparison of three psychotomimetic-induced models of psychosis in nonhuman primate social colonies. In: Ethopharmacology: Primate Models of Neuropsychiatric Disorder. New York: Alan R. Liss, 33–78. Selemon LD, Goldman-Rakic PS (1985): Longitudinal topography and interdigitation of corticostriatal projections in the rhesus monkey. J Neurosci 5:776 –794. Shergill SS, Brammer MJ, Williams SCR, Murray RM, McGuire PK (2000): Mapping auditory hallucinations in schizophrenia using functional magnetic resonance imaging. Arch Gen Psychiatry 57:1033–1038. Silbersweig DA, Stern E, Frith C, Cahill C, Holmes A, Grootoonk S, et al (1995): A functional neuroanatomy of hallucinations in schizophrenia. Nature 378:176 –179. Snyder SH (1972): Catecholamines in the brain as mediators of amphetamine psychosis. Arch Gen Psychiat 27:169 –178. Snyder SH (1973): Amphetamine psychosis: A “model” schizophrenia mediated by catecholamines. Am J Psychiatry 130:61–67. Vita A, Bressi S, Perani D, Invernizzi G, Giobbio GM, Dieci M, et al (1995): High-resolution SPECT study of regional cerebral blood flow in drug-free and drug-naı¨ve schizophrenic patients. Am J Psychiatry 152:876 –882. Vollenweider FX, Leenders KL, Scharfetter C, Antonini A, Maguire P, Missimer J, et al (1997a): Metabolic hyperfrontality and psychopathology in the ketamine model of psychosis using positron emission tomography (PET) and [18F]fluorodeoxyglucose (FDG). Eur Neuropsychopharm 7:9 –24. Vollenweider FX, Leenders KL, Scharfetter C, Maguire P, Stadelmann O, Angst J (1997b): Positron emission tomography and flurodeoxyglucose studies of metabolic hyperfrontality and psychopathology in the psilocybin model of psychosis. Neuropsychopharm 16:357–371. Walker AE (1940): A cytoarchitectural study of the prefrontal area of the macaque monkey. J Comp Neurol 73:59 –86. Whishaw IQ, Fiorino D, Mittleman G, Castaneda E (1992): Do forebrain structures compete for behavioral expression? Evidence from amphetamine-induced behavior, microdialysis, and caudate-accumbens lesions in medial frontal cortex damaged rats. Brain Res 576:1–11. Wolf ME, Dahlin SL, Hu XT, Xue CJ, White K (1995): Effects of lesions of prefrontal cortex, amygdale, or fornix on behavioral sensitization to amphetamine: Comparison with N-methyl-D-aspartate antagonists. Neurosci 69:417–439. Yeterian EH, Pandya DN (1991): Prefrontostriatal connections in relation to cortical architectonic organization in rhesus monkeys. J Comp Neurol 312:43–67.
Introduction
D
ysfunction of the prefrontal cortex has commonly been associated with a deficit state in schizophrenia (Buchanan et al 1990; Crow 1985; Carpenter et al 1988;
From the Department of Neurobiology (SAC, PSG-R), Yale University School of Medicine, New Haven, Connecticut. Address reprint requests to Patricia S. Goldman-Rakic, Ph.D., Yale University School of Medicine, Section of Neurobiology, 333 Cedar Street, New Haven, CT 06510. Received October 2, 2002; revised March 11, 2003; accepted March 14, 2003.
© 2003 Society of Biological Psychiatry
Kirkpatrick and Buchanan 1990); however, an increasing number of functional magnetic resonance imaging studies of patients with schizophrenia have shown prefrontal areas to be activated during auditory hallucinations (Lennox et al 2000; McGuire et al 1993; Shergill et al 2000; Silbersweig et al 1995) and other positive symptoms (Sabri et al 1997). Furthermore, one of the putative therapeutic mechanisms of action of neuroleptics is through a reduction in activation of prefrontal cortex (Liddle et al 2000; Miller et al 1997; Ngan et al 2002; Potkin et al 1994; Vita et al 1995). Repeated amphetamine (AMPH) administration in the intact nonhuman primate has been shown to induce behaviors reminiscent of the hallmark symptoms of schizophrenia, including hallucinatory-like behaviors, long-lasting psychomotor depression, and cognitive deficits (Castner et al 2000, 2001; Castner and Goldman-Rakic 1999a; Ellinwood et al 1973; Ellison and Eison 1983; Ellison et al 1981; Ridley et al 1982). In monkeys, both chronic high dose and a sensitizing regimen of AMPH treatment elicit a subset of behaviors that have been variably referred to as psychotomimetic (Sams-Dodd and Newman 1997), psychotic-like (Machiyama 1992), abnormal (Schlemmer and Davis 1983), and hallucinatory-like (Ellison et al 1981; Ellison and Eison 1983; Nielsen et al 1983a, 1983b). These behaviors include hypervigilance, abnormal tracking, grasping, and checking the environment for stimuli that are not observable to the experimenter. Because, to all appearances, the animal’s behavior is mediated by imagined stimuli, it has commonly been analogized to visual or auditory hallucinations in both amphetamine psychosis and schizophrenia (Ellinwood 1967; Snyder 1972, 1973). Accordingly, we here refer to these behaviors as “hallucinatory-like” as the best descriptor of an exaggerated repertoire of responses that occur in the absence of any observable stimuli. In addition to its psychotomimetic effects, amphetamine sensitization also prominently affects locomotor activity. In rodents, lesions of the medial prefrontal cortex block the sensitization of hyperlocomotion, but 0006-3223/03/$30.00 doi:10.1016/S0006-3223(03)00292-0
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guidelines set by the Yale Animal Care and Use Committee and with federal standards for laboratory primates.
Surgical Procedures
Figure 1. Coronal sections across the rostral– caudal extent of the prefrontal cortex for each selective prefrontal lesion. Lesions are denoted by a dashed line. Panels depict either a dorsal (A) and (B) or ventral (C) reconstruction of each selective lesion. (A) shows a representative dorsomedial lesion encompassing both area 9 and parts of area 8B. In B, one of the two dorsolateral lesions is reconstructed. For both animals, this lesion was confined to areas 46 and 8A. In (C), a ventral view of an inferior lesion reconstruction is shown.
not stereotypy, following a sensitizing AMPH regimen (Wolf et al 1995). To our knowledge, the effects of prefrontal lesions on AMPH sensitization of locomotion and the hallucinatory-like behaviors have never been examined in a nonhuman primate. Because the prefrontal cortex is a major site of dysfunction in schizophrenia and amphetamine sensitization can be expected to alter the regulation of neural function in this brain region, we tested the hypothesis that the prefrontal cortex is an essential substrate of AMPH sensitization in this species. Our experiment examines the effects of selective lesions of prefrontal cortex on the development of sensitization, with the expectation that alterations in the normal expression of sensitization will provide further insight into the pathophysiology of dopamine dysfunctional states such as schizophrenia.
Methods and Materials Subjects The pattern of behavioral sensitization to AMPH was documented in 17 adult (5–12 years of age) rhesus monkeys (Macaca mulatta) of both sexes (males, n ⫽ 7; females n ⫽ 10). Monkeys were housed individually and maintained in accordance with
The animals were prepared for surgery under ketamine (5–10 mg/kg; administered intravenously [IV]) and atropine (.2 mg/kg; IV) and maintained during surgery under sodium pentobarbitol (25–30 mg/kg; administered intraventricularly). Using aseptic stereotaxic techniques, a midline scalp incision was made, and a 2–3 cm craniotomy was performed over the area to be lesioned. After duratomy, selective regions of the cortex were aspirated bilaterally. The dura was sutured closed, the skull incision was filled with sterile gelfoam, and the wound was closed in layers. The lesions were designed to explore regional susceptibilities to sensitization. Two monkeys received dorsomedial lesions (Walker’s areas 9 and 8B on the superior frontal gyrus), two monkeys received dorsolateral lesions (Walker’s areas 46 and 8A inclusive of the depths and banks of the principal sulcus and the anterior bank of the arcuate sulcus), and three animals received lesions of the inferior convexity (Walker’s areas 12 and 45; Walker 1940). The lesion of the inferior convexity extended from below the principal sulcus to the edge of the convexity and continued onto the ventral surface as far as the lateral orbital sulcus. The posterior part of this lesion included the anterior bank of the inferior ramus of the arcuate sulcus. One monkey received a combined lesion encompassing all three selective lesions (i.e., areas 9, 8A, 8B, 46, 12, 45, and part of 10). Reconstructions of representative lesions are shown in Figure 1, A–C. The animals used as controls in this study were also involved in ongoing studies on the effects of AMPH sensitization on cognition, and did not receive sham lesions.
Sensitization To induce behavioral sensitization, monkeys received intermittent, escalating low-doses of AMPH (.1–1.0 mg/kg twice daily, IV) over a 6-week period. (Data on AMPH sensitization for six of the nine nonlesioned monkeys were originally reported in Castner et al 2000). Behavioral sensitization was documented by comparing homecage responses to acute AMPH (.4 mg/kg, IV) before, at 21 days, and 6.5– 8 months after subchronic exposure. Behavioral responses were recorded on videotape and computer by focal time sampling with a program, MonkeyWatcher, during the first 2–3 hours postinjection and at regularly timed intervals until behavior returned to “baseline,” defined as prechallenge behavior. The software program, as developed by Jonathon Traupman, documents the occurrence, duration, and frequency of each behavior displayed. Behaviors were divided into three categories: 1) locomotor stereotypies (repetitive gross locomotor behaviors such as pacing, circling, somersaulting), 2) hallucinatory-like behaviors (tracking, grasping, or manipulating of nonapparent stimuli, hypervigilance, and checking in the absence of visible stimuli), and 3) other AMPH-induced behaviors that included fine-motor and oral stereotypies, parasitoticlike grooming, vocalizations, and static or catatoniclike posturing (for additional details, see Castner and Goldman-Rakic 1999a; Castner et al 2000).
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Lesion Analysis No earlier than 1 week after the last AMPH challenge, the lesioned monkeys received ketamine (5–10 mg/kg, IV) and atropine (.2 mg/kg, IV) for restraint followed by an overdose of sodium pentobarbitol (100 mg/kg, intraventricularly). Following transcardial perfusion with 2L .9% NaCl followed by 4 L of 4% paraformaledehyde in .1 mol/L phosphate buffer, the brains were removed, postfixed in 4% paraformaldehyde, blocked, and cryoprotected in sucrose (5%–20%). Blocks of frontal cortex were sectioned at 40 m on a freezing sliding microtome, and every 10th section was collected and stained for cresyl violet. Alternate cresyl violet stained sections (⬃800 m apart) were scanned and digitized by a CCD camera using an MCID system (Imaging Research, Brock University, St. Catherines, Ontario, Canada). All scanned sections in the lesioned animals were examined, and the lesioned area in each was outlined using Canvas software. Two-dimensional reconstructions of each lesion were compiled from serial drawings of the sections containing the lesion outlines.
Statistical Analyses One-, two-, and three-way factorial analysis of variance (ANOVA) was used to examine group (lesion vs. control), group ⫻ time, and group ⫻ time ⫻ type of behavior effects. Symbols (*) in Figure 2 indicate that the lesioned group differed significantly from control animals at an alpha level of .05, as indicated by one-way ANOVA with Scheffe post hoc comparisons.
Results Before sensitization, there was a striking group difference in the behavioral phenotype elicited by AMPH challenge, with lesioned monkeys showing a significant enhancement of locomotor stereotypies [F(1,15) ⫽ 4.82, p ⫽ .04; Figure 2A] and as a group a marked suppression of hallucinatorylike behaviors [F(1,15) ⫽ 7.07, p ⫽ .018; Figure 2B] compared with control animals. Interestingly, the process of sensitization only served to magnify this difference. Confirming our previous studies, nonlesioned control animals showed significant sensitization of hallucinatorylike as well as other AMPH-induced behaviors such as oral and fine-motor stereotypies and a virtual absence of sensitization of locomotion (Castner and Goldman-Rakic 1999a; Castner et al 2000), whereas the lesioned monkeys as a group showed the opposite result— dramatic and significantly enhanced locomotion and an almost complete suppression of the sensitization of hallucinatory-like behaviors including visual tracking, grasping, or manipulating nonapparent stimuli, as well as hypervigilance and checking in the absence of visible stimuli (Figure 2B). Hallucinatory-like behaviors did not sensitize even in the three lesioned monkeys that displayed significant levels of these behaviors in response to AMPH challenge before sensitization. Lesions of the prefrontal cortex also abol-
Figure 2. The mean percentage time spent by lesioned and control monkeys engaged in locomotor stereotypies (A) and in hallucinatory-like behaviors (B) in response to amphetamine (AMPH) challenge: pretreatment, early post (21 days posttreatment), and late post (6.5– 8 months posttreatment) is shown. Monkeys with prefrontal lesions (cross-hatch bars) exhibited a significant sensitization of AMPH-induced locomotion (A) and failed to show sensitization of AMPH-induced hallucinatory-like behaviors (B) in direct contrast to the pattern shown by nonlesioned control monkeys (solid bars). The apparent, although nonsignificant, increase in locomotor stereotypies shown in response to AMPH at the early post challenge by control monkeys was attributable to a dramatic increase in this behavior by one monkey that was not observed in response to subsequent challenges in this animal.
ished sensitization of parasitotic-like grooming (Table 1), a behavior that several studies in nonhuman primates have classified as hallucinatory-like (Ellinwood et al 1973; Ellison et al 1981; Ellison and Eison 1983; Ridley et al 1982). A three-way ANOVA revealed that there was indeed a differential effect of sensitization on locomotor versus hallucinatory-like behaviors as a function of group [effect of group ⫻ type of behavior: F(1,88) ⫽ 66.701; p ⬍ .0001; effect of group ⫻ time of challenge: F(2,88) ⫽
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Table 1. Mean ⫾ SEM Percentage Time Spent Engaged in Locomotor Stereotypies, Hallucinatory-like Behaviors, and Other Amphetamine-Induced Behaviors by Control and Lesioned Monkeys Condition Pre-AMPH Control Area 46/8A lesion Area 9/8B lesion Area 45/12 lesion Comprehensive Late, 6.5⫹ Months Post-AMPH Control Area 46/8A lesion Area 9/8B lesion Area 45/12 lesion Comprehensive
Locomotor
Hallucinatory-like
Other
4.78 ⫾ 3.25 2.20 ⫾ .70 22.30 ⫾ 9.50 24.73 ⫾ 9.78 80.20 ⫾ .00
27.44 ⫾ 6.72 6.95 ⫾ 4.35 5.25 ⫾ 2.05 11.92 ⫾ 3.07 2.70 ⫾ .00
16.59 ⫾ 8.21 70.00 ⫾ 10.80 12.00 ⫾ .70 15.10 ⫾ 2.72 0.00 ⫾ .00
4.98 ⫾ 2.40 50.97 ⫾ 7.03 43.75 ⫾ 6.25 45.68 ⫾ 45.68 99.90 ⫾ .00
56.36 ⫾ 8.82 21.48 ⫾ 3.38 13.55 ⫾ 6.55 7.81 ⫾ 1.81 12.00 ⫾ .00
62.20 ⫾ 7.37 4.37 ⫾ .07 58.90 ⫾ 15.90 28.71 ⫾ 28.39 49.50 ⫾ .00
Behaviors are in response to acute amphetamine (AMPH; .4 mg/kg, IV) administered either before (Pre-AMPH) or after (Late, 6.5⫹ months post-AMPH) repeated AMPH exposure.
3.115; p ⫽ .493; effect of group ⫻ time of challenge ⫻ type of behavior: F(2,88) ⫽ 3.240; p ⫽ .0439]. The effect on locomotion was long-lasting and still significant at more than 6.5 months postsensitization [pre: F(1,15) ⫽ 4.82, p ⫽ .04; early: F(1,15) ⫽ 11.86, p ⫽ .004; late: F(1,14) ⫽ 18.60, p ⫽ .0007; Figure 2A]. The difference between control and lesioned monkeys in hallucinatorylike behaviors was present at all challenges [pre: F(1,15) ⫽ 7.07, p ⫽ .018; early: F(1,15) ⫽ 9.71, p ⫽ .007; late: F(1,14) ⫽ 16.76, p ⫽ .001; Figure 2B]. In contrast to the monkeys with prefrontal lesions, the control monkeys expressed statistically significant sensitization of hallucinatory-like behaviors by the late AMPH challenge [effect of time of challenge: F(2,24) ⫽ 3.48; p ⫽ .047; pre vs. late: p ⫽ .049 by Scheffe post hoc comparison]. Although the numbers of animals in each selective lesion group were too small for statistical analysis, several interesting trends were observed regarding the relationship between behavioral sensitization phenotype and lesion site. Notably, the most dramatic effects of lesioning were observed in the monkey with complete removal of prefrontal cortex. After sensitization, this monkey responded to AMPH challenge by engaging in locomotion 99.9% of the time and showed the lowest incidence of AMPHinduced hallucinatory-like behaviors (Table 1). The only trend for an effect of lesion site on the pattern of AMPH sensitization was in regard to fine-motor stereotypy and parasitotic-like grooming. Interestingly, these behaviors were dramatically suppressed in the two monkeys with area 46/8A lesions in response to AMPH challenge following sensitization (Table 1).
Discussion The goal of this study was to identify and characterize the contribution of prefrontal cortex in the nonhuman primate
to the development of the AMPH-sensitized behavioral phenotype. In monkeys with prefrontal lesions, we found that an acute AMPH challenge significantly enhanced locomotion, whereas hallucinatory-like behaviors tended to be suppressed consistent with previous findings (Miller 1976). The process of sensitization augmented these effects, such that selective lesions of the prefrontal cortex enhanced AMPH sensitization of locomotion and suppressed sensitization of hallucinatory-like behaviors, compared with the profile of sensitized behaviors shown by nonlesioned animals. The loss of sensitization of hallucinatory-like behaviors after prefrontal lesions indicates that the development of the AMPH-sensitized behavioral phenotype in nonhuman primates requires circuitry that includes dorsomedial, dorsolateral, and inferior regions of the prefrontal convexities. A mechanism analogous to sensitization has been postulated to play an etiologic role in the emergence of positive symptoms of schizophrenia, including hallucinations, during adolescence and early adulthood (Lieberman et al 1997). The role of the prefrontal cortex in this putative sensitization is supported by the finding that subanesthetic doses of ketamine that produce activation of the homologous areas of prefrontal cortex, areas 46 and 9, in normal healthy adults (Vollenweider et al 1997a, 1997b) exacerbate positive symptomatology, including hallucinations, in neuroleptic-free patients with schizophrenia (Malhotra et al 1997). Indeed, one of the possible therapeutic mechanisms of action of neuroleptics in the treatment of schizophrenia is through decreased activation of prefrontal cortex (Miller et al 1997; Potkin et al 1994; Vita et al 1995). Recent studies have found that the increasing ability of risperidone to decrease glucose utilization in prefrontal cortex coincided with the dissipation of positive symptoms including hallucinations (Liddle et al 2000; Ngan et al 2002). Thus, the present findings suggest that the prefron-
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tal cortex, and aspects of corticostriatal transmission may be critical for the exacerbation of hallucinatory-like phenomena are consistent with these clinical studies. Although sensitization of hallucinatory-like behaviors was completely suppressed in the monkeys with prefrontal lesions, locomotor sensitization was profoundly enhanced compared with nonlesioned control animals. This sharp dissociation could be accounted for by one behavior inhibiting the other, possibly via disinhibition of the basal ganglia circuits involved in locomotion (Whishaw et al 1992). Each of the prefrontal cortical areas lesioned in this study projects heavily to the caudate nucleus (Selemon and Goldman-Rakic 1985; Yeterian and Pandya 1991), and the loss of these connections could help to explain the suppression of sensitization of hallucinatory-like behaviors. At the same time, this disconnection could contribute to the suppression of fine-motor stereotypies and parasitoticlike grooming observed in the monkeys with dorsolateral lesions. In contrast, the integrity of prefrontal-accumbens projections that arise predominantly from the medial and orbital regions of prefrontal cortex, mostly spared by these lesions, may have facilitated the development of locomotor sensitization in the monkeys with prefrontal cortical lesions (Haber et al 1995; Ongur and Price 2000). It is well documented that the nucleus accumbens plays a critical role in the expression of AMPH-induced hyperlocomotion, whereas the caudate nucleus is the major site for induction of AMPH-induced stereotyped behaviors (Clarke et al 1988; Kelly et al 1975). The differential effects of lesions of prefrontal cortex on AMPH sensitization in the nonhuman primate compared with the rodent may well reflect the differential pattern of projections to different regions of the basal ganglia between these two species. In direct contrast to the regions lesioned in our study, the medial prefrontal cortex in the rodent projects heavily to the nucleus accumbens (cf. Wolf et al 1995). In conclusion, our findings extend the evidence for a critical role of prefrontal cortex in the exacerbation of hallucinatory-like phenomena. Elucidating the cellular and molecular changes in the nonhuman primate prefrontal cortex and their relationship to those at the level of the basal ganglia produced by AMPH sensitization should help to identify suspect mechanisms for the etiology of both positive and negative symptoms of schizophrenia.
This work was supported by NIMH Grant MH44866 (PSG-R). The monkeys with dorsomedial and dorsolateral prefrontal lesions in this study were also subjects in a previous study on working memory by Drs. Levy and Goldman-Rakic (Levy and Goldman-Rakic 1999). We thank Dr. Levy for his cooperation in this study and for his assistance to PSG-R in producing the dorsomedial and dorsolateral lesions in the experimental animals. We also thank Heather A. Findlay and Tatyana A. Trakht for their expert technical assistance.
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References Buchanan RW, Kirkpatrick B, Heinrichs DW, Carpenter WT (1990): Clinical correlates of the deficit syndrome of schizophrenia. Am J Psychiatry 147:290 –294. Carpenter WT, Heinrichs DW, Wagman AMI (1988): Deficit and nondeficit forms of schizophrenia: The concept. Am J Psychiatry 145:578 –583. Castner SA, Al-tikriti M, Baldwin RM, Seibyl JP, Innis RB, Goldman-Rakic PS (2000): Behavioral changes and [123I]IBZM equilibrium measurement of AMPH-induced dopamine release in rhesus monkeys. Neuropsychopharm 22:4 – 13. Castner SA, Goldman-Rakic PS (1999a): Long-lasting psychotomimetic consequences of repeated low dose amphetamine exposure in rhesus monkeys. Neuropsychopharm 20:10 –28. Castner SA, Goldman-Rakic PS (1999b): Profound cognitive impairments in nonhuman primates exposed to amphetamine. Soc Neurosci Abstr 25:1563. Castner SA, Vosler PS, Goldman-Rakic PS (2001): Lowered dopamine turnover in amphetamine-sensitized monkeys: Development of a primate model of schizophrenia. Biol Psychiatry Abstr 49(suppl 8):124S. Clarke PBS, Jakubovic A, Fibiger HC (1988): Anatomical analysis of the involvement of mesolimbocortical dopamine in the locomotor stimulant actions of d-amphetamine and apomorphine. Psychopharmacol 96:511–520. Crow TJ (1985): The two-syndrome concept: Origins and current status. Schizophr Bull 11:471–485. Ellinwood, EH Jr (1967): Amphetamine psychosis. I. Description of the individuals and process. J Nerv Ment Dis 144:273–283. Ellinwood EH Jr, Sudilovsky A, Nelson LM (1973): Evolving behavior in the clinical and experimental amphetamine (model) psychosis. Am J Psychiatry 130:1088 –1093. Ellison G, Eison MS (1983): Continuous amphetamine intoxication: An animal model of the acute psychotic episode. Psychol Med 13:751–761. Ellison G, Nielsen EB, Lyon M (1981): Animal model of psychosis: Hallucinatory behaviors in monkeys during the late stage of continuous amphetamine intoxication. J Psychiatry Res 16:13–22. Haber SN, Kunishio K, Mizobuchi M, Lynd-Balta E (1995): The orbital and medial prefrontal circuit through the primate basal ganglia. J Neurosci 15:4851–4867. Kelly PH, Seviour PW, Iversen SD (1975): Amphetamine and apomorphine responses in the rat following 6-OHDA lesions of the nucleus accumbens septi and corpus striatum. Brain Res 94:507–522. Kirkpatrick B, Buchanan RW (1990): The neural basis of the deficit syndrome of schizophrenia. J Nerv and Ment Disease 178:545–555. Lennox BR, Park SBG, Medley I, Morris PG, Jones PB (2000): The functional anatomy of auditory hallucinations in schizophrenia. Psychiatry Res Neuroimaging Section 100:13–20. Levy R, Goldman-Rakic PS (1999): Association of storage and processing functions in the dorsolateral prefrontal cortex of the nonhuman primate. J Neurosci 19:5149 –5158. Liddle PF, Lane CJ, Ngan ETC (2000): Immediate effects of risperidone on cortico-striato-thalamic loops and the hippocampus. Br J Psychiatry 177:402–407.
110
BIOL PSYCHIATRY 2003;54:105–110
Lieberman JA, Sheitman BB, Kinon BJ (1997): Neurochemical sensitization in the pathophysiology of schizophrenia: Deficits and dysfunction in neuronal regulation and plasticity. Neuropsychopharm 17:205–229. Machiyama Y (1992): Chronic methamphetamine intoxication model of schizophrenia in animals. Schizophr Bull 18:107– 113. Malhotra AK, Pinals DA, Adler CM, Elman I, Clifton A, Pickar D, et al (1997): Ketamine-induced exacerbation of psychotic symptoms and cognitive impairment in neuroleptic-free schizophrenics. Neuropsychopharm 17:141–150. McGuire PK, Shah GMS, Murray RM (1993): Increased blood flow in Broca’s area during auditory hallucinations in schizophrenia. Lancet 342:703–706. Miller DD, Andreasen NC, O’Leary DS, Rezai K, Watkins GL, Ponto LL, et al (1997): Effects of antipsychotics on regional cerebral blood flow measured with positron emission tomography. Neuropsychopharmacology 17:230 –240. Miller MH (1976): Behavioral effects of amphetamine in a group of rhesus monkeys with lesions of dorsolateral frontal cortex. Psychopharmacology 47:71–74. Ngan ETC, Lane CJ, Ruth TJ, Liddle PF (2002): Immediate and delayed effects of risperidone on cerebral metabolism in neuroleptic naı¨ve schizophrenic patients: Correlations with symptom change. J Neurol Neurosurg Psychiatry 72:106 – 110. Nielsen EB, Eison MS, Lyon M, Iverson SD (1983a): Hallucinatory behaviors in primates produced by around-the-clock amphetamine treatment for several days via implanted capsules. Prog Clin Biol Res 131:79 –100. Nielsen EB, Lyon M, Ellison G (1983b): Apparent hallucinations in monkeys during around-the-clock amphetamine for seven to fourteen days. Possible relevance to amphetamine psychosis. J Nerv Ment Dis 171:222–233. Ongur D, Price JL (2000): The organization of networks within the orbital and medial prefrontal cortex of rats, monkeys, and humans. Cereb Cortex 10:206 –219. Potkin SG, Buchsbaum MS, Jin Y, Tang C, Telford J, Friedman G, et al (1994): Clozapine effects on glucose metabolic rate in striatum and frontal cortex. J Clin Psychiatry 55(suppl B):63– 66. Ridley RM, Baker HF, Owen F, Cross AJ, Crow TJ (1982): Behavioural and biochemical effects of chronic amphetamine treatment in the vervet monkey. Psychopharm 78:245–251. Sabri O, Erkwoh R, Schreckenberger M, Owega A, Sass H, Buell U (1997): Correlation of positive symptoms exclusively to hyperperfusion or hypoperfusion of cerebral cortex in nevertreated schizophrenics. Lancet 349:1735–1739. Sams-Dodd F, Newman JD (1997): Effects of administration regime on the psychotomimetic properties of d-amphetamine
S.A. Castner and P.S. Goldman-Rakic
in the squirrel monkey (Saimiri sciureus). Pharmacol Biochem Behav 56:471–480. Schlemmer RF, Davis JM (1983): A comparison of three psychotomimetic-induced models of psychosis in nonhuman primate social colonies. In: Ethopharmacology: Primate Models of Neuropsychiatric Disorder. New York: Alan R. Liss, 33–78. Selemon LD, Goldman-Rakic PS (1985): Longitudinal topography and interdigitation of corticostriatal projections in the rhesus monkey. J Neurosci 5:776 –794. Shergill SS, Brammer MJ, Williams SCR, Murray RM, McGuire PK (2000): Mapping auditory hallucinations in schizophrenia using functional magnetic resonance imaging. Arch Gen Psychiatry 57:1033–1038. Silbersweig DA, Stern E, Frith C, Cahill C, Holmes A, Grootoonk S, et al (1995): A functional neuroanatomy of hallucinations in schizophrenia. Nature 378:176 –179. Snyder SH (1972): Catecholamines in the brain as mediators of amphetamine psychosis. Arch Gen Psychiat 27:169 –178. Snyder SH (1973): Amphetamine psychosis: A “model” schizophrenia mediated by catecholamines. Am J Psychiatry 130:61–67. Vita A, Bressi S, Perani D, Invernizzi G, Giobbio GM, Dieci M, et al (1995): High-resolution SPECT study of regional cerebral blood flow in drug-free and drug-naı¨ve schizophrenic patients. Am J Psychiatry 152:876 –882. Vollenweider FX, Leenders KL, Scharfetter C, Antonini A, Maguire P, Missimer J, et al (1997a): Metabolic hyperfrontality and psychopathology in the ketamine model of psychosis using positron emission tomography (PET) and [18F]fluorodeoxyglucose (FDG). Eur Neuropsychopharm 7:9 –24. Vollenweider FX, Leenders KL, Scharfetter C, Maguire P, Stadelmann O, Angst J (1997b): Positron emission tomography and flurodeoxyglucose studies of metabolic hyperfrontality and psychopathology in the psilocybin model of psychosis. Neuropsychopharm 16:357–371. Walker AE (1940): A cytoarchitectural study of the prefrontal area of the macaque monkey. J Comp Neurol 73:59 –86. Whishaw IQ, Fiorino D, Mittleman G, Castaneda E (1992): Do forebrain structures compete for behavioral expression? Evidence from amphetamine-induced behavior, microdialysis, and caudate-accumbens lesions in medial frontal cortex damaged rats. Brain Res 576:1–11. Wolf ME, Dahlin SL, Hu XT, Xue CJ, White K (1995): Effects of lesions of prefrontal cortex, amygdale, or fornix on behavioral sensitization to amphetamine: Comparison with N-methyl-D-aspartate antagonists. Neurosci 69:417–439. Yeterian EH, Pandya DN (1991): Prefrontostriatal connections in relation to cortical architectonic organization in rhesus monkeys. J Comp Neurol 312:43–67.