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Hypofrontality does not occur with 6-hydroxydopamine lesions of the medial prefrontal cortex in rat brain
EUROPEANNEURO. PSYCHOPHARMACOLOGY ELSEVIER
European Neuropsychopharmacology 5 (1995) 63-68
Hypofrontality does not occur with 6-hydroxydopamine lesions of the medial prefrontal cortex in rat brain Masayoshi Kurachi a'*, Shin-Ichi Yasui a, Teru Kurachi a, R y o k o Shibata a, Masahiko M u r a t a a, H i r o h u m i Hagino a, Yasuyuki Tanii a, Kouichi Kurata a, Michio Suzuki a, Yoshio Sakurai b aDepartment of Neuropsychiatry, Faculty of Medicine, Toyama Medical and Pharmaceutical University, 2630 Sugitani, Toyama 930-01, Japan bDepartment of Psychology, Faculty of Medicine, Toyama Medical and Pharmaceutical University, 2630 Sugitani, Toyama 930-01, Japan Received 27 December 1993; revision received 13 September 1994; accepted 26 October 1994
Abstract
This study examined the effect of lesions of dopamine (DA) nerve terminals in the medial prefrontal cortex on local cerebral glucose utilization (LCGU) and dopamine metabolism in the rat brain. Bilateral 6-hydroxydopamine lesions were stereotaxically placed in the medial prefrontal cortex. Twenty-eight days after the lesion, concentrations of DA and its metabolites, 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), were determined in eight brain regions with a high-performance liquid chromatographic assay. LCGU was assessed by [14C]2-deoxy-D-glucose autoradiography. The lesion produced a striking reduction in DA (to 6% of the control value), and a moderate reduction in DOPAC and HVA in the medial prefrontal cortex. The ratio of DOPAC to DA in the medial prefrontal cortex was significantly elevated in the 6-OHDA lesioned animals. In contrast to DA depletion, LCGU in the medial prefrontal cortex of the lesioned rats was unaltered when compared with the control. These findings suggest that decreased energy metabolism in the frontal cortex, i.e., hypofrontality, does not occur with decreased DA innervation of that site.
Keywords: Local cerebral glucose utilisation; Dopamine metabolism; Medial prefrontal cortex; 6-Hydroxydopamine; Rat
1. Introduction
Decreased activity in the frontal lobe, that is, hypoffontality, has been reported in many, though not all, brain imaging studies on regional cerebral blood flow or glucose utilization in schizophrenia (Ingvar and Franzen, 1974; Kurachi et al., 1985; Suzuki et al., 1992; Andreasen et al., 1992). However, the neural mechanism by which hypofrontality occurs in this disease is not yet known. Hypoffontality may represent impairment of frontal activation by subcortical neurons, and/or may be due to the impairment of the frontal neurons themselves. In view of the dopamine (DA) hypothesis of schizophrenia, dysfunction of mesocortical DA neurons may be related to hypofrontality. Weinberger (1987) hypothesized that mesocortical dopamine deficiency, which produces mesolimbic dopamine hyperactivity (Pycock et al., 1980a,b), may be the core neurochemical deficit in * Corresponding author. Fax: 0764-34-5030. 0924-977X/95/$09.50 (~) 1995 Elsevier Science B.V. All rights reserved SSD1 0 9 2 4 - 9 7 7 X ( 9 4 ) 0 0 1 3 6 - 7
schizophrenia. In support of this, lower levels of homovanillic acid in cerebrospinal fluid have been reported to be associated with activation deficit in prefrontal regional cerebral blood flow in patients with schizophrenia (Weinberger et al., 1988). Experimentally, reduced local cerebral glucose utilization (LCGU) in the prefrontal cortex has been observed after unilateral electrolytic lesions of the rat lateral hypothalamic area through which the catecholaminergic pathways ascend (Schwartz, 1978). Kozlowski and Marshall (1980), however, observed no significant change in LCGU in the frontal cortex following unilateral injections of 6-hydroxydopamine (6OHDA) into the rat ventral tegmental area that produced decreased concentrations of DA in the prefrontal cortex. In contrast to these reports, which suggest either reduced or unaltered frontal LCGU in hypodopaminergic state, MK-801, a selective noncompetitive N-methyl-o-aspartate (NMDA) receptor antagonist that increases DA metabolism in the prefrontal cortex (Rao et al., 1990), has been reported to
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reduce LCGU in the frontal cortex (Kurumaji et al., 1989; Nehls et al., 1990). To clarify the role of dopaminergic neurons in L C G U in the medial prefrontal cortex more directly, in the present experiment we examined the effect of bilateral 6-OHDA lesions of the medial prefrontal cortex on LCGU at that site and other brain areas, in comparison with DA metabolism.
2. Materials and methods
Male Wistar rats weighing 220-240 g at the time of surgery were used. They were housed at 24 ___2°C on a daily light/dark schedule of 12/12 h with free access to food and water. 6-OHDA hydrobromide was purchased from Sigma Chem. Co. (St. Louis, USA). [14C]DG, spec. act. 11.1-13.3 GBq/mmol (ARC, l12A) was used.
2.1. Subject lesions The rats were pretreated with 25 mg/kg (i.p.) desipramine (Ciba-Geigy Hyogo Japan) 30 min before being anesthetized with 30 mg/kg (i.p.) pentobarbital, to block the uptake of 6-OHDA into noradrenergic terminals. The animals were then placed in a stereotaxic apparatus with 30 gauge stainless steel tubing directed bilaterally into the medial prefrontal cortex. The coordinates used were: A, bregma + 2.7 mm; L, 0.8 mm; and V, 3.3-3.4 mm from the dura (Paxinos and Watson, 1982). Rats were given one of two injections: vehicle (2 /xl, 0.1% ascorbic acid in Ringer's solution), or 6-OHDA-HBr (4/zg dissolved in 2 /xl vehicle, calculated as the salt). This dose was selected, because the results of preliminary experiments showed that concentrations of norepinephrine were better maintained with 4 ~ g / 2 / z l 6-OHDA-HBr than with 8/~g/2/.d (68% and 39% of control values, respectively). Vehicle or 6-OHDA was infused bilaterally over a 2-min period, and the injection cannulae were left in place for an additional 3 min after the cessation of infusion. Rats were allowed to recover, and neurochemical assays and determinations of L C G U were performed in separate groups of animals 28 days after surgery.
anteromedial and posterolateral caudate-putamen, nucleus accumbens, lateral amygdala, substantia nigra and ventral tegmental area. Tissue punches were homogenized and centrifuged, and aliquots of the supernatant were injected into a high-performance liquid chromatograph (Model LC-6A, Shimazu, Japan) with a coulometric electrochemical detector (Model 5100A, ESA Inc., USA). Concentrations of DA, 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), norepinephrine (NE), 5hydroxytryptamine (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) were determined. The assay method was as described in detail elsewhere (Kurata et al., 1987; Kurachi et al., 1994). The protein content of the tissue pellet was determined using the modified method of Lowry (Markwell et al., 1987).
2.3. Determination of LCGU LCGU was determined after a bolus intravenous injection of a tracer amount of [14C]DG 3.7 MBq (100 /xCi)/kg. Animal preparation and the conduct of the experiment have been described in detail elsewhere (Kurachi et al., 1994). Radioactivity in 11 brain regions was determined by quantitative autoradiography. Anatomical regions were identified by comparing autoradiograms with an atlas of the rat brain (K6nig and Klippel, 1963; Zilles, 1985), and, where necessary, with cresyl violet-stained sections taken adjacent to those used for autoradiography. L C G U was calculated from brain and plasma radioactivity levels and from plasma glucose concentrations using equations and constants provided by Sokoloff et al. (1977).
2.4. Statistics Statistical evaluation was conducted using an unpaired two-tailed Student's t-test. The criterion for significance was set at P < 0 . 0 1 , because multiple measurements were performed in the same subjects. Values of P < 0.05 are reported as indicating trends.
3. Results
2.2. Neurochemical analyses The animals were decapitated, and the brain was removed rapidly, frozen with dry ice and stored at -80°C until analysis. Serial slices approximately 700 /zm thick were made in a cold box at - 15°C. Tissue punches were made from eight brain regions using 0.5 mm or 1.0 mm (i.d.) stainless steel tubing, i.e., from the medial prefrontal cortex, anterior cingulate gyrus,
As shown in Table 1, bilateral injection of 6-OHDA into the medial prefrontal cortex caused a striking reduction of the DA concentration (to 6% of the control value, P < 0.01) and a moderate reduction of DOPAC, HVA and NE at that site (to 67%, 56% and 60% of the control values, respectively; all P < 0.01). Concentrations of DA and DOPAC in the anterior cingulate gyrus were also significantly decreased (to
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Table 1 Changes in the concentration of monoamines and their metabolites following 6-OHDA lesions of the prefrontal cortex in rats Area of brain
DA
DOPAC
Medial prefrontal cortex Control 1.8-+0.1 Lesion 0.1 -+ 0.02 (6)**
0.8-+0.1 0.5 -+ 0.07 (67)**
Anterior cingulate gyrus Control 3.9-+0.3 Lesion 0.6 -+ 0.1 (15)**
1.2-+0.1 0.4 -+ 0.05 (30)**
HVA
NE
0.6-+0.04 0.4 -+ 0.04 (56)**
5-HT
5-HIAA
3.8-+0.1 2.3 -+ 0.4 (60)**
8.3-+0.5 7.4 -+ 0.9 (89)
3.9-+0.3 5.0 -+ 0.5 (130)*
-
7.7-+0.4 6.4 -+ 0.9 (83)
4.9-+0.4 4.8 -+ 0.6 (98)
4.0-+0.1 4.3 -+ 0.3 (109)
Caudate-putamen, anteromedial Control 199.6-+11.2 Lesion 216.9-+16.2(109)
21.5-+0.8 21.8-+1.3(101)
8.8-+0.5 10.2+--0.7(116)
1.3-+0.1 1.2-+0.1(95)
Caudate-putamen, dorsolateral Control 141.6-+3.9 Lesion 155.5-+6.4(110)
11.2-+0.4 12.8-+0.6(114)*
9.5-+0.6 11.4-+0.3(120)*
1.4-+0.1 1.1-+0.2(79)
Nucleus accumbens Control 134.1-+11.2 Lesion 170.9-+10.6(128)*
22.1-+2.0 30.7-+1.5(139)**
6.9-+0.8 10.1-+0.6(147)**
1.2-+0.1 1.2-+0.09(104)
Lateral amygdala Control 8.7-+0.3 Lesion 8.3-+0.4(95)
-
1.3-+0.1 1.6-+0.4(125)
Substantia nigra Control 26.0-+1.1 Lesion 21.7-+1.8(84)*
5.7-+0.2 5.1-+0.3(89)
2.9-+0.1 2.7---0.1(94)
Ventral tegmental area Control 71.3-+4.4 Lesion 60.3-+5.3(85)
13.2-+0.6 12.0-+0.5(91)
9.3-+0.4 10.0-+0.5(107)
10.7-+0.2 10.8-+0.8(100)
7.2-+0.1 6.0-+0.2(83)**
20.1-+1.3 19.2-+1.0(96)
-
4.7-+0.3 5.1-+0.6(110)
5.9-+0.5 7.4_+0.4(125) *
6.6-+0.3 8.1-+0.3(123)**
9.7-+1.1 12.1-+1.1(125)
6.0+0.4 8.7-+0.6(144)**
18.1-+1.0 17.7-+1.3(98)
6.9-+0.2 8.0-+0.4(114)*
13.5-+0.6 14.5-+1.0(107)
7.4-+0.3 8.1-+0.5(110)
17.6-+0.8 17.2-+1.1(98)
9.1-+0.6 10.0-+0.7(110)
Results are expressed as ng/mg protein -+ SEM. Figures in parentheses indicate percentages of control concentrations. Control, n = 8; lesion, n=7. * P < 0.05, **P < 0.01 (Student's t-test, control vs. lesion).
15% and 30% of the control values, respectively, P < 0.01). The ratio of D O P A C to D A in the medial prefrontal cortex of the lesioned animals (5.9-+ 1.3, mean-SEM) was significantly elevated compared with the control value (0.43 - 0.10, P < 0.01), and this was also seen in the anterior cingulate gyrus ( 0 . 6 9 0.07 vs. 0.32 - 0.01, P < 0 . 0 1 ) . In the nucleus accumbens, concentrations of DOPAC, HVA and 5 - H I A A showed a significant increase in the lesioned animals (139%, 147% and 144%, respectively, of control values, P < 0.01 each). The concentration of 5 - H I A A in the dorsolateral caudate-putamen showed a significant increase and those of DOPAC, HVA and 5-HT showed a tendency to increase (P < 0.05) as a result of 6 - O H D A lesions of the prefrontal cortex. The results of L C G U determinations are shown in Table 2. L C G U in the medial prefrontal cortex of the lesioned rats was unaltered and there were no significant differences between the lesioned and control rats in L C G U in either area.
Table 2 Changes in local cerebral glucose utilization following bilateral 6-OHDA lesions of the medial prefrontal cortex in rats Area of brain
Local cerebral glucose utilization Control, n = 8 Lesion, n = 8
Medial prefrontal cortex Frontal area 2 Anterior cingulate gyrus Caudate-putamen, anteromedial Caudate-putamen, dorsolateral Nucleus accumbens Medial thalamus Lateral amygdala Entorhinal cortex Substantia nigra Ventral tegmental area
109,5 -+ 6.8 94.7 -+ 7.9 115.1 -+ 9.8 102.5 -+ 6.2 102.3-+ 5.8 87.7 _+3.4 98.7 -+ 4.0 74.1 -+ 3.5 79.1 -+ 4.3 85.2 -+ 4.7 83.0-+3.1
110.4 -+ 3.1 (101) 98.3 -+ 7.2 (104) 111.5 -+ 3.7 (97) 112.7 -+ 4.1 (110) 101.5 -+ 4.4 (99) 93.9 -+ 3.4 (107) 100.2 -+ 4.7 (102) 81.3 -+ 2.8 (110) 85.5 -+ 4.5 (108) 89.4 -+ 3.2 (105) 83.6-+4.8(101)
Results are expressed as means _+ SEM (~zmol/100 g tissue/min). Figures in parentheses indicate percentages of control values. There was no significant difference between controls and lesion groups (Student's t-test).
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4. Discussion
Bilateral 6-OHDA lesions of the rat medial prefrontal cortex produced profound depletion of DA, and a moderate reduction in DOPAC and HVA in the medial prefrontal cortex. The ratio of DOPAC to DA was significantly elevated at that site. The concentration of NE was decreased to 60% of the control value, although desmethylimipramine had been administered in advance. This value was intermediate between those in other reports, as the range of NE concentrations includes reports of 94% (Leccese and Lyness, 1987), approximately 60% (Pycock et al., 1980a; Haroutunian et al., 1988; Deutsch et al., 1990), and 30% of control values (Hemby et al., 1992) after pretreatment with desmethylimipramine. In contrast to the depletion of DA, LCGU in the medial prefrontal cortex was unaltered. Subsequent studies by Suzuki et al. (submitted) also showed that local cerebral blood flow in the prefrontal cortex is not decreased in the lesioned animals. These findings are consistent with those of Kozlowski and Marshall (1980) who observed no significant change in LCGU in the medial frontal cortex 7-14 days after unilateral injections of 6-OHDA into the ventral tegmental area of rats. Although reduced LCGU in the prefrontal cortex has been reported 2 h after electrolytic lesions of the lateral hypothalamic area, which persist at least 14 days postoperatively (Schwartz, 1978), neural pathways other than those of DA fibers may have been involved. There are several possible reasons why profound DA depletion of the medial prefrontal cortex caused no change in LCGU at that site. First, at the presynaptic site, DA turnover may have been increased, as suggested by the elevated ratio of DOPAC to DA. An elevated ratio of DOPAC to DA at the lesion site has also been reported by Bubster and Schmidt (1990) and Hemby et al. (1992), although this is at variance with the results of Haroutunian et al. (1988). Second, at the postsynaptic site, supersensitivity of postsynaptic DA receptors after dopaminergic denervation, which has been reported in the striatum (Ungerstedt, 1971) and nucleus accumbens (Winn and Rubbins, 1985; Wolterink et al., 1990a,b), may also have occurred in the medial prefrontal cortex, as suggested by the following findings. Systemic administration of 0.5 mg/kg of apomorphine to sham-operated rats increases their locomotor activity, but has no significant effect on or instead decreases locomotor activity of rats which had received 6-OHDA in the medial prefrontal cortex (Haroutunian et al., 1988; Shibata et al., 1990). Furthermore, Shibata et al. (1992a) showed that bilateral microinfusion of apomorphine into the medial prefrontal cortex in normal rats decreased locomotor activity in a dose-
dependent manner. If the mesofrontal DA system holds corticostriatal projection neurons, including those to the nucleus accumbens, under tonic inhibition (Deutsch et al., 1990), apomorphine-induced decreases of motor activity in 6-OHDA lesioned rats may represent supersensitivity of postsynaptic DA receptors in the medial prefrontal cortex. Third, it has been reported that the relationship between DA metabolism and LCGU differs in various brain areas. Following administration of apomorphine (0.5 mg/kg, i.v.), LCGU was reportedly reduced in the anterior cingulate cortex and lateral habenular nucleus, but elevated in the frontal cortex and caudate nucleus (McCulloch et al., 1982). MK-801, a selective noncompetitive NMDA receptor antagonist that increases DA metabolism in the prefrontal cortex, entorhinal cortex, and amygdala (Rao et al., 1990), has been reported to reduce LCGU in neocortical areas, including the frontal cortex, and increase L C G U in limbic areas, such as the hippocampus and entorhinal cortex (Kurumaji et al., 1989; Nehls et al., 1990). Phencyclidine, which is also a noncompetitive N M D A receptor antagonist, seems to have effects similar to MK-801 on DA metabolism and LCGU in the frontal cortex (Nishikawa et al., 1991; Weissman et al., 1987). Thus, in the frontal cortex, decreased LCGU is probably associated with increased DA metabolism. 6-OHDA lesions of the prefrontal cortex have been reported to augment DA metabolism in the striatum and nucleus accumbens (Pycock et al., 1980a,b; Leccese and Lyness, 1987; Haroutunian et al., 1988; Martin-Iverson et al., 1986). The present study also showed a significant increase in concentrations of DA metabolites in the nucleus accumbens in the 6-OHDA lesioned animals. The 5-HIAA concentration also showed a significant increase in this area. Although Rosin et al. (1992) did not observe any increase in basal DA metabolites in these subcortical areas, they did find that the magnitude of the haloperidol-induced increase in enzyme activity in the nucleus accumbens was significantly greater in lesioned subjects than in control animals. Shibata et al. (1992b) observed that rats which had received 6-OHDA in the medial prefrontal cortex showed a gradual increase in locomotor activity over 4 weeks. Thus the increased concentrations of DA metabolites in the accumbens nucleus are likely to represent increased dopaminergic function in this area, which plays a crucial role in locomotor activity (Radhakishun et al., 1988). A possible mechanism for enhanced DA transmission in subcortical areas with a 6-OHDA lesion of the medial prefrontal cortex is removal of tonic dopaminergic inhibition over cortico-fugal projection neurons (Deutsch et al., 1990). Consistent with this, using brain dialysis, Tanii et al. (in preparation)
M. Kurachi et al. / European Neuropsychopharmacology 5 (1995) 63-68
observed that there was no significant difference between the lesioned and control rats in the decrease of D A release in the nucleus accumbens induced by a low dose (0.05 mg/kg, s.c.) of apomorphine, suggesting that the autoreceptor sensitivity of DA neurons innervating this site was unaltered. In addition, Tanii et al. (1992) showed that infusion of the D1 antagonist SCH23390, but not the D2 antagonist sulpiride, into the nucleus accumbens enhanced dopamine release in this area of the rat brain with 6-OHDA lesions of the prefrontal cortex compared with non-lesioned rats. In conclusion, these findings suggest that hypofrontality may not occur as a result of hypoactivity, but rather from hyperactivity of the dopaminergic input to the frontal cortex. Further studies are needed to clarify the pathogenesis of hypofrontality in schizophrenia.
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Hypofrontality does not occur with 6-hydroxydopamine lesions of the medial prefrontal cortex in rat brain Masayoshi Kurachi a'*, Shin-Ichi Yasui a, Teru Kurachi a, R y o k o Shibata a, Masahiko M u r a t a a, H i r o h u m i Hagino a, Yasuyuki Tanii a, Kouichi Kurata a, Michio Suzuki a, Yoshio Sakurai b aDepartment of Neuropsychiatry, Faculty of Medicine, Toyama Medical and Pharmaceutical University, 2630 Sugitani, Toyama 930-01, Japan bDepartment of Psychology, Faculty of Medicine, Toyama Medical and Pharmaceutical University, 2630 Sugitani, Toyama 930-01, Japan Received 27 December 1993; revision received 13 September 1994; accepted 26 October 1994
Abstract
This study examined the effect of lesions of dopamine (DA) nerve terminals in the medial prefrontal cortex on local cerebral glucose utilization (LCGU) and dopamine metabolism in the rat brain. Bilateral 6-hydroxydopamine lesions were stereotaxically placed in the medial prefrontal cortex. Twenty-eight days after the lesion, concentrations of DA and its metabolites, 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), were determined in eight brain regions with a high-performance liquid chromatographic assay. LCGU was assessed by [14C]2-deoxy-D-glucose autoradiography. The lesion produced a striking reduction in DA (to 6% of the control value), and a moderate reduction in DOPAC and HVA in the medial prefrontal cortex. The ratio of DOPAC to DA in the medial prefrontal cortex was significantly elevated in the 6-OHDA lesioned animals. In contrast to DA depletion, LCGU in the medial prefrontal cortex of the lesioned rats was unaltered when compared with the control. These findings suggest that decreased energy metabolism in the frontal cortex, i.e., hypofrontality, does not occur with decreased DA innervation of that site.
Keywords: Local cerebral glucose utilisation; Dopamine metabolism; Medial prefrontal cortex; 6-Hydroxydopamine; Rat
1. Introduction
Decreased activity in the frontal lobe, that is, hypoffontality, has been reported in many, though not all, brain imaging studies on regional cerebral blood flow or glucose utilization in schizophrenia (Ingvar and Franzen, 1974; Kurachi et al., 1985; Suzuki et al., 1992; Andreasen et al., 1992). However, the neural mechanism by which hypofrontality occurs in this disease is not yet known. Hypoffontality may represent impairment of frontal activation by subcortical neurons, and/or may be due to the impairment of the frontal neurons themselves. In view of the dopamine (DA) hypothesis of schizophrenia, dysfunction of mesocortical DA neurons may be related to hypofrontality. Weinberger (1987) hypothesized that mesocortical dopamine deficiency, which produces mesolimbic dopamine hyperactivity (Pycock et al., 1980a,b), may be the core neurochemical deficit in * Corresponding author. Fax: 0764-34-5030. 0924-977X/95/$09.50 (~) 1995 Elsevier Science B.V. All rights reserved SSD1 0 9 2 4 - 9 7 7 X ( 9 4 ) 0 0 1 3 6 - 7
schizophrenia. In support of this, lower levels of homovanillic acid in cerebrospinal fluid have been reported to be associated with activation deficit in prefrontal regional cerebral blood flow in patients with schizophrenia (Weinberger et al., 1988). Experimentally, reduced local cerebral glucose utilization (LCGU) in the prefrontal cortex has been observed after unilateral electrolytic lesions of the rat lateral hypothalamic area through which the catecholaminergic pathways ascend (Schwartz, 1978). Kozlowski and Marshall (1980), however, observed no significant change in LCGU in the frontal cortex following unilateral injections of 6-hydroxydopamine (6OHDA) into the rat ventral tegmental area that produced decreased concentrations of DA in the prefrontal cortex. In contrast to these reports, which suggest either reduced or unaltered frontal LCGU in hypodopaminergic state, MK-801, a selective noncompetitive N-methyl-o-aspartate (NMDA) receptor antagonist that increases DA metabolism in the prefrontal cortex (Rao et al., 1990), has been reported to
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reduce LCGU in the frontal cortex (Kurumaji et al., 1989; Nehls et al., 1990). To clarify the role of dopaminergic neurons in L C G U in the medial prefrontal cortex more directly, in the present experiment we examined the effect of bilateral 6-OHDA lesions of the medial prefrontal cortex on LCGU at that site and other brain areas, in comparison with DA metabolism.
2. Materials and methods
Male Wistar rats weighing 220-240 g at the time of surgery were used. They were housed at 24 ___2°C on a daily light/dark schedule of 12/12 h with free access to food and water. 6-OHDA hydrobromide was purchased from Sigma Chem. Co. (St. Louis, USA). [14C]DG, spec. act. 11.1-13.3 GBq/mmol (ARC, l12A) was used.
2.1. Subject lesions The rats were pretreated with 25 mg/kg (i.p.) desipramine (Ciba-Geigy Hyogo Japan) 30 min before being anesthetized with 30 mg/kg (i.p.) pentobarbital, to block the uptake of 6-OHDA into noradrenergic terminals. The animals were then placed in a stereotaxic apparatus with 30 gauge stainless steel tubing directed bilaterally into the medial prefrontal cortex. The coordinates used were: A, bregma + 2.7 mm; L, 0.8 mm; and V, 3.3-3.4 mm from the dura (Paxinos and Watson, 1982). Rats were given one of two injections: vehicle (2 /xl, 0.1% ascorbic acid in Ringer's solution), or 6-OHDA-HBr (4/zg dissolved in 2 /xl vehicle, calculated as the salt). This dose was selected, because the results of preliminary experiments showed that concentrations of norepinephrine were better maintained with 4 ~ g / 2 / z l 6-OHDA-HBr than with 8/~g/2/.d (68% and 39% of control values, respectively). Vehicle or 6-OHDA was infused bilaterally over a 2-min period, and the injection cannulae were left in place for an additional 3 min after the cessation of infusion. Rats were allowed to recover, and neurochemical assays and determinations of L C G U were performed in separate groups of animals 28 days after surgery.
anteromedial and posterolateral caudate-putamen, nucleus accumbens, lateral amygdala, substantia nigra and ventral tegmental area. Tissue punches were homogenized and centrifuged, and aliquots of the supernatant were injected into a high-performance liquid chromatograph (Model LC-6A, Shimazu, Japan) with a coulometric electrochemical detector (Model 5100A, ESA Inc., USA). Concentrations of DA, 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), norepinephrine (NE), 5hydroxytryptamine (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) were determined. The assay method was as described in detail elsewhere (Kurata et al., 1987; Kurachi et al., 1994). The protein content of the tissue pellet was determined using the modified method of Lowry (Markwell et al., 1987).
2.3. Determination of LCGU LCGU was determined after a bolus intravenous injection of a tracer amount of [14C]DG 3.7 MBq (100 /xCi)/kg. Animal preparation and the conduct of the experiment have been described in detail elsewhere (Kurachi et al., 1994). Radioactivity in 11 brain regions was determined by quantitative autoradiography. Anatomical regions were identified by comparing autoradiograms with an atlas of the rat brain (K6nig and Klippel, 1963; Zilles, 1985), and, where necessary, with cresyl violet-stained sections taken adjacent to those used for autoradiography. L C G U was calculated from brain and plasma radioactivity levels and from plasma glucose concentrations using equations and constants provided by Sokoloff et al. (1977).
2.4. Statistics Statistical evaluation was conducted using an unpaired two-tailed Student's t-test. The criterion for significance was set at P < 0 . 0 1 , because multiple measurements were performed in the same subjects. Values of P < 0.05 are reported as indicating trends.
3. Results
2.2. Neurochemical analyses The animals were decapitated, and the brain was removed rapidly, frozen with dry ice and stored at -80°C until analysis. Serial slices approximately 700 /zm thick were made in a cold box at - 15°C. Tissue punches were made from eight brain regions using 0.5 mm or 1.0 mm (i.d.) stainless steel tubing, i.e., from the medial prefrontal cortex, anterior cingulate gyrus,
As shown in Table 1, bilateral injection of 6-OHDA into the medial prefrontal cortex caused a striking reduction of the DA concentration (to 6% of the control value, P < 0.01) and a moderate reduction of DOPAC, HVA and NE at that site (to 67%, 56% and 60% of the control values, respectively; all P < 0.01). Concentrations of DA and DOPAC in the anterior cingulate gyrus were also significantly decreased (to
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Table 1 Changes in the concentration of monoamines and their metabolites following 6-OHDA lesions of the prefrontal cortex in rats Area of brain
DA
DOPAC
Medial prefrontal cortex Control 1.8-+0.1 Lesion 0.1 -+ 0.02 (6)**
0.8-+0.1 0.5 -+ 0.07 (67)**
Anterior cingulate gyrus Control 3.9-+0.3 Lesion 0.6 -+ 0.1 (15)**
1.2-+0.1 0.4 -+ 0.05 (30)**
HVA
NE
0.6-+0.04 0.4 -+ 0.04 (56)**
5-HT
5-HIAA
3.8-+0.1 2.3 -+ 0.4 (60)**
8.3-+0.5 7.4 -+ 0.9 (89)
3.9-+0.3 5.0 -+ 0.5 (130)*
-
7.7-+0.4 6.4 -+ 0.9 (83)
4.9-+0.4 4.8 -+ 0.6 (98)
4.0-+0.1 4.3 -+ 0.3 (109)
Caudate-putamen, anteromedial Control 199.6-+11.2 Lesion 216.9-+16.2(109)
21.5-+0.8 21.8-+1.3(101)
8.8-+0.5 10.2+--0.7(116)
1.3-+0.1 1.2-+0.1(95)
Caudate-putamen, dorsolateral Control 141.6-+3.9 Lesion 155.5-+6.4(110)
11.2-+0.4 12.8-+0.6(114)*
9.5-+0.6 11.4-+0.3(120)*
1.4-+0.1 1.1-+0.2(79)
Nucleus accumbens Control 134.1-+11.2 Lesion 170.9-+10.6(128)*
22.1-+2.0 30.7-+1.5(139)**
6.9-+0.8 10.1-+0.6(147)**
1.2-+0.1 1.2-+0.09(104)
Lateral amygdala Control 8.7-+0.3 Lesion 8.3-+0.4(95)
-
1.3-+0.1 1.6-+0.4(125)
Substantia nigra Control 26.0-+1.1 Lesion 21.7-+1.8(84)*
5.7-+0.2 5.1-+0.3(89)
2.9-+0.1 2.7---0.1(94)
Ventral tegmental area Control 71.3-+4.4 Lesion 60.3-+5.3(85)
13.2-+0.6 12.0-+0.5(91)
9.3-+0.4 10.0-+0.5(107)
10.7-+0.2 10.8-+0.8(100)
7.2-+0.1 6.0-+0.2(83)**
20.1-+1.3 19.2-+1.0(96)
-
4.7-+0.3 5.1-+0.6(110)
5.9-+0.5 7.4_+0.4(125) *
6.6-+0.3 8.1-+0.3(123)**
9.7-+1.1 12.1-+1.1(125)
6.0+0.4 8.7-+0.6(144)**
18.1-+1.0 17.7-+1.3(98)
6.9-+0.2 8.0-+0.4(114)*
13.5-+0.6 14.5-+1.0(107)
7.4-+0.3 8.1-+0.5(110)
17.6-+0.8 17.2-+1.1(98)
9.1-+0.6 10.0-+0.7(110)
Results are expressed as ng/mg protein -+ SEM. Figures in parentheses indicate percentages of control concentrations. Control, n = 8; lesion, n=7. * P < 0.05, **P < 0.01 (Student's t-test, control vs. lesion).
15% and 30% of the control values, respectively, P < 0.01). The ratio of D O P A C to D A in the medial prefrontal cortex of the lesioned animals (5.9-+ 1.3, mean-SEM) was significantly elevated compared with the control value (0.43 - 0.10, P < 0.01), and this was also seen in the anterior cingulate gyrus ( 0 . 6 9 0.07 vs. 0.32 - 0.01, P < 0 . 0 1 ) . In the nucleus accumbens, concentrations of DOPAC, HVA and 5 - H I A A showed a significant increase in the lesioned animals (139%, 147% and 144%, respectively, of control values, P < 0.01 each). The concentration of 5 - H I A A in the dorsolateral caudate-putamen showed a significant increase and those of DOPAC, HVA and 5-HT showed a tendency to increase (P < 0.05) as a result of 6 - O H D A lesions of the prefrontal cortex. The results of L C G U determinations are shown in Table 2. L C G U in the medial prefrontal cortex of the lesioned rats was unaltered and there were no significant differences between the lesioned and control rats in L C G U in either area.
Table 2 Changes in local cerebral glucose utilization following bilateral 6-OHDA lesions of the medial prefrontal cortex in rats Area of brain
Local cerebral glucose utilization Control, n = 8 Lesion, n = 8
Medial prefrontal cortex Frontal area 2 Anterior cingulate gyrus Caudate-putamen, anteromedial Caudate-putamen, dorsolateral Nucleus accumbens Medial thalamus Lateral amygdala Entorhinal cortex Substantia nigra Ventral tegmental area
109,5 -+ 6.8 94.7 -+ 7.9 115.1 -+ 9.8 102.5 -+ 6.2 102.3-+ 5.8 87.7 _+3.4 98.7 -+ 4.0 74.1 -+ 3.5 79.1 -+ 4.3 85.2 -+ 4.7 83.0-+3.1
110.4 -+ 3.1 (101) 98.3 -+ 7.2 (104) 111.5 -+ 3.7 (97) 112.7 -+ 4.1 (110) 101.5 -+ 4.4 (99) 93.9 -+ 3.4 (107) 100.2 -+ 4.7 (102) 81.3 -+ 2.8 (110) 85.5 -+ 4.5 (108) 89.4 -+ 3.2 (105) 83.6-+4.8(101)
Results are expressed as means _+ SEM (~zmol/100 g tissue/min). Figures in parentheses indicate percentages of control values. There was no significant difference between controls and lesion groups (Student's t-test).
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4. Discussion
Bilateral 6-OHDA lesions of the rat medial prefrontal cortex produced profound depletion of DA, and a moderate reduction in DOPAC and HVA in the medial prefrontal cortex. The ratio of DOPAC to DA was significantly elevated at that site. The concentration of NE was decreased to 60% of the control value, although desmethylimipramine had been administered in advance. This value was intermediate between those in other reports, as the range of NE concentrations includes reports of 94% (Leccese and Lyness, 1987), approximately 60% (Pycock et al., 1980a; Haroutunian et al., 1988; Deutsch et al., 1990), and 30% of control values (Hemby et al., 1992) after pretreatment with desmethylimipramine. In contrast to the depletion of DA, LCGU in the medial prefrontal cortex was unaltered. Subsequent studies by Suzuki et al. (submitted) also showed that local cerebral blood flow in the prefrontal cortex is not decreased in the lesioned animals. These findings are consistent with those of Kozlowski and Marshall (1980) who observed no significant change in LCGU in the medial frontal cortex 7-14 days after unilateral injections of 6-OHDA into the ventral tegmental area of rats. Although reduced LCGU in the prefrontal cortex has been reported 2 h after electrolytic lesions of the lateral hypothalamic area, which persist at least 14 days postoperatively (Schwartz, 1978), neural pathways other than those of DA fibers may have been involved. There are several possible reasons why profound DA depletion of the medial prefrontal cortex caused no change in LCGU at that site. First, at the presynaptic site, DA turnover may have been increased, as suggested by the elevated ratio of DOPAC to DA. An elevated ratio of DOPAC to DA at the lesion site has also been reported by Bubster and Schmidt (1990) and Hemby et al. (1992), although this is at variance with the results of Haroutunian et al. (1988). Second, at the postsynaptic site, supersensitivity of postsynaptic DA receptors after dopaminergic denervation, which has been reported in the striatum (Ungerstedt, 1971) and nucleus accumbens (Winn and Rubbins, 1985; Wolterink et al., 1990a,b), may also have occurred in the medial prefrontal cortex, as suggested by the following findings. Systemic administration of 0.5 mg/kg of apomorphine to sham-operated rats increases their locomotor activity, but has no significant effect on or instead decreases locomotor activity of rats which had received 6-OHDA in the medial prefrontal cortex (Haroutunian et al., 1988; Shibata et al., 1990). Furthermore, Shibata et al. (1992a) showed that bilateral microinfusion of apomorphine into the medial prefrontal cortex in normal rats decreased locomotor activity in a dose-
dependent manner. If the mesofrontal DA system holds corticostriatal projection neurons, including those to the nucleus accumbens, under tonic inhibition (Deutsch et al., 1990), apomorphine-induced decreases of motor activity in 6-OHDA lesioned rats may represent supersensitivity of postsynaptic DA receptors in the medial prefrontal cortex. Third, it has been reported that the relationship between DA metabolism and LCGU differs in various brain areas. Following administration of apomorphine (0.5 mg/kg, i.v.), LCGU was reportedly reduced in the anterior cingulate cortex and lateral habenular nucleus, but elevated in the frontal cortex and caudate nucleus (McCulloch et al., 1982). MK-801, a selective noncompetitive NMDA receptor antagonist that increases DA metabolism in the prefrontal cortex, entorhinal cortex, and amygdala (Rao et al., 1990), has been reported to reduce LCGU in neocortical areas, including the frontal cortex, and increase L C G U in limbic areas, such as the hippocampus and entorhinal cortex (Kurumaji et al., 1989; Nehls et al., 1990). Phencyclidine, which is also a noncompetitive N M D A receptor antagonist, seems to have effects similar to MK-801 on DA metabolism and LCGU in the frontal cortex (Nishikawa et al., 1991; Weissman et al., 1987). Thus, in the frontal cortex, decreased LCGU is probably associated with increased DA metabolism. 6-OHDA lesions of the prefrontal cortex have been reported to augment DA metabolism in the striatum and nucleus accumbens (Pycock et al., 1980a,b; Leccese and Lyness, 1987; Haroutunian et al., 1988; Martin-Iverson et al., 1986). The present study also showed a significant increase in concentrations of DA metabolites in the nucleus accumbens in the 6-OHDA lesioned animals. The 5-HIAA concentration also showed a significant increase in this area. Although Rosin et al. (1992) did not observe any increase in basal DA metabolites in these subcortical areas, they did find that the magnitude of the haloperidol-induced increase in enzyme activity in the nucleus accumbens was significantly greater in lesioned subjects than in control animals. Shibata et al. (1992b) observed that rats which had received 6-OHDA in the medial prefrontal cortex showed a gradual increase in locomotor activity over 4 weeks. Thus the increased concentrations of DA metabolites in the accumbens nucleus are likely to represent increased dopaminergic function in this area, which plays a crucial role in locomotor activity (Radhakishun et al., 1988). A possible mechanism for enhanced DA transmission in subcortical areas with a 6-OHDA lesion of the medial prefrontal cortex is removal of tonic dopaminergic inhibition over cortico-fugal projection neurons (Deutsch et al., 1990). Consistent with this, using brain dialysis, Tanii et al. (in preparation)
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observed that there was no significant difference between the lesioned and control rats in the decrease of D A release in the nucleus accumbens induced by a low dose (0.05 mg/kg, s.c.) of apomorphine, suggesting that the autoreceptor sensitivity of DA neurons innervating this site was unaltered. In addition, Tanii et al. (1992) showed that infusion of the D1 antagonist SCH23390, but not the D2 antagonist sulpiride, into the nucleus accumbens enhanced dopamine release in this area of the rat brain with 6-OHDA lesions of the prefrontal cortex compared with non-lesioned rats. In conclusion, these findings suggest that hypofrontality may not occur as a result of hypoactivity, but rather from hyperactivity of the dopaminergic input to the frontal cortex. Further studies are needed to clarify the pathogenesis of hypofrontality in schizophrenia.
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