- Email: [email protected]
Reduced haloperidol and haloperidol: Effects on homovanillic acid in caudate and prefrontal cortex
BIOL PSYCHIATRY 1987:22:1369-1374
I369
Reduced Haloperidol and Haloperidol: Effects on Homovanillic Acid in Caudate and Prefrontal Cortex Wen-Ho Chang, Ho-Sheng Wu, and Yung-Te Tseng
The effects of acute administration of reduced haloperidol (RHAL) on homovanillic acid (HVA) in the caudate and prefrontal cortex were examined in rats. Haloperidol (HAL) was used as a reference compound. Concentrations of HVA and HAL were measured by HPLCIECD. The maximal HVA response time was 3 hr after the injection, in both caudate and prefrontal cortex, for both RHAL and HAL. The potency of RHAL in the elevations of HVA in the caudate and prefrontal cortex was only about one-third to one-fifth that of HAL. The concentrations of HAL in the prefrontal cortex and caudate after RHAL administration were just about one-third to one-fifth those after HAL administration. These results suggest that less antidopaminergic activity of RHAL in this neuroleptic test might be explained by the lesser conversion of RHAL to HAL.
Introduction Haloperidol (HAL) is a widely used potent butyrophenone neuroleptic drug. In humans, the benzylic ketone of the hydrocarbon chain of the HAL molecule is converted to an alcohol to form a reduced metabolite (Forsman and Larsson 1978). Reduced HAL (RHAL) has a lipid solubility similar to HAL (Korpi et al. 1983) and has been shown to accumulate in the brain of schizophrenic patients treated with HAL (Korpi et al. 1984). RHAL Itself is not an active neuroleptic drug (Korpi and Wyatt 1984; Kirch et al. 1985). However, it was effective in neuroleptic tests in which RHAL was given parenterally in the rat, as it was rapidly oxidized to HAL (Korpi and Wyatt 1984). Nevertheless, the potency of this substance was much weaker than the parent compound (Forsman and Ohman 1979; Korpi et al. 198.5). In a previous study, we suggested that the prefrontal cortex might be a preferential target for HAL, or at least a more sensitive and specific target than the striatal or the mesolimbic systems (Chang et al. 1986b). We have now studied the effects of RHAL on the concentrations of homovanillic acid (HVA), the main metabolite of dopamine, in the prefrontal cortex and caudate in the rat, as dopamine metabolism in these two brain areas is believed to be important to the antipsychotic action and the extrapyramidal side effects of neuroleptics (Laduron et al. 1977; Bacopoulos et al. 1979; Matsumoto et al. 1983; Chang et al. 1986b). HAL was used as a reference compound in this study.
From Taipei City Psychiatric Center, Taiwan, Republic Supported in part by Grants NSC 74-0606-B 109-02 and Address reprint requests to Dr. Wen-Ho Chang, Chief, 54, Alley 200, Lane 151. Section 5. Shin-Yi Road, Recaved August 25, 1986; revised February 27, 1987.
0 1987 Society of Bmlogical Psychiatry
of China. NSC 75-0606.B109-02 from the National Science Council. Laboratory of Biological Psychiatry, Taipei City Psychiatric Center. 10510 Taipei, Taiwan, R.O.C.
ooo6-3223/87/%03.50
1370
W.-H. Chang et al.
BIOL PSYCHIATRY 1987:22:1369-1374
Concentrations of HAL in these brain structures, as well as in plasma, were measured in parallel with HVA, attempting to correlate HVA responses with HAL levels following RHAL and HAL administration.
Methods Male Wistar rats, weighing 150-2.50 g, were used in all experiments.
All animals were fasted, with water available ad lib, for 24 hr before death. HAL (Haldol injectable) and RHAL were obtained from Janssen Pharmaceutics (Beerse, Belgium). HAL was diluted with water. RHAL was dissolved in dilute hydrochloric acid and returned to approximately ph 4 by using sodium hydroxide prior to injection. To determine the time-response curves of HVA and drug kinetics, groups of 6 rats each were injected ip either with saline, 0.5 mg/kg HAL, or 0.5 mg/kg RHAL. The animals were decapitated either 10, 30, 60, 120, 180, or 240 min after the injection. The brains were quickly removed, and the prefrontal cortex and caudate dissected: the right structures were used for HVA measurements and the left for drug analyses. All specimens were stored at -60°C. To study the dose-response curves of HVA, groups of 4-5 rats each were injected ip either with saline, 0.1, 0.2, 0.5, 1, 2, 5, 10, or 20 mg/kg HAL or RHAL. The animals were killed after 180 min (the maximal HVA response was reached at this time), and the prefrontal cortex and caudate specimens were stored for HVA measurements. In addition, groups of 5 rats each were injected ip with various doses of HAL or RHAL as described above. The rats were decapitated after 30 or 60 min (HAL levels in brain specimens peaked at this time following HAL or RHAL administration). Trunk blood was collected in heparinized tubes and plasma separated by a cool centrifuge. The plasma, prefrontal cortex, and caudate samples were stored for drug analyses. HVA (Chang et al. 1983, 1986a) and HAL (Korpi et al. 1983, 1984; Korpi and Wyatt 1984) were measured by high-performance liquid chromatography with electrochemical detection (HPLUECD). Statistical analysis was carried out by means of an unpaired t-test.
Results Time-Response
Curves of HVA for RHAL and HAL
As shown in Figure 1, the maximal responses of HVA levels to both RHAL and HAL in both the caudate and prefrontal cortex were attained at the same time, i.e., 3 hr after the injection, although the elevations in HVA induced by RHAL began somewhat later than those by HAL, and the HAL levels following RHAL administration peaked later than those following HAL administration (60 min versus 30 min). The maximal levels of HVA in the caudate and prefrontal cortex after RHAL injection were much lower than those after HAL injection (309% ? 30% versus 465% + 62%, p < 0.001; 247% + 31% versus 405% ? 46%, p < O.OOl), which is consistent with the maximal HAL concentrations in these brain structures (129 -+ 33 rig/g versus 350 * 35 rig/g,, p < 0.001; 143 ? 14 rig/g versus 479 -+ 69 rig/g,, p < 0.001). Dose-Response
Curves of HVA for RHAL and HAL
As can be seen in Figure 2, HVA responses in the prefrontal cortex and caudate to increasing doses of HAL followed the same pattern as reported previously by Chang et
L
I
r
120
60
0
TIME
I
I
I
(min)
180
I
240
I
0
Figure 1. Mean concentrations (n = 5-6 for each group) and standard errors of HVA in caudate (shaded points) and prefrontal cortex (open points) at different times after ip points) at the dose of 0.5 mg/kg. The absolute HVA values of control groups (n = 59 t 6 rig/g (RHAL) for the prefrontal cortex and 1080 -t 83 rig/g (HAL) and 1145
100
500
60
I
TIME(min)
120
I
I
180
I
240
(% of controls) (left) and HAL (rig/g tissue) (right) injection of HAL (circle points) and RHAL (square 5 for each group) were 56 ? 3 rig/g (HAL) and 2 37 rig/g (RHAL) for the caudate.
0
I
1372
W.-H. Chang et al.
BIOL PSYCHIATRY 1987;22:1369-1374
600 -
I
500
-
400
-
300
-
0 L
ZW Ok 22 Ea Oz
aa f/
2 200
-
100 -
f Iy 0
I
0.1
0.2
O----O
HAL
-
RHAL
‘***
I
I
1
1
I
0.5
1
2
5
10
1
20
T
.
, 0.1
I
0.2
0.5
I
I
I
1
,
1
2
5
10
20
l
DOSE (mg/kg) Figure 2. Dose-response curves for the increase (% of control) of HVA in the caudate and prefrontal cortex after HAL and RHAL administration. Data points are means t SEM of 4-5 determinations. The absolute values of the control groups were 33 2 2 and 43 ? 2 rig/g tissue for the prefrontal cortex and 958 t 40 and 1054 5 46 rig/g tissue for the caudate. *HVA dropped off from the maximal point of 0.5 mg/kg, p < 0.05 or less. **HVA dropped off from the maximal point of 5 mg/kg, p < 0.05. ***HVA dropped off from the maximal point of 2 mglkg, p < 0.01.
al. (1986b). In addition, at the highest dose used (20 mg/kg), HAL also blunted the elevation of HVA in the caudate. Similar responses of HVA to RHAL were observed in both prefrontal cortex and caudate. However, the RHAL dose that caused the maximal responses of HVA in the caudate and prefrontal cortex was 5 mg/kg, at least 5 times that of HAL. Furthermore, the EDs0 values of HAL for the elevations of HVA in the caudate and prefrontal cortex were 0.09 and 0.05 mg/kg, respectively, whereas the EDso values of RHAL were 0.26 and 0.26 mg/kg, respectively. These values of RHAL are about 3 (in the caudate) and 5 (in the prefrontal cortex) times greater than those of the parent compound. Figure 3 shows the HAL levels in brain structures and plasma after RHAL and HAL injections. Concentrations of HAL following HAL administration were about 3-5 times higher than those following RHAL administration, which is consistent with the HVA response
results.
RHAL and HAL: Effect on HVA in Caudate and Cortex
.
1373
BIOL PSYCHIATRY 1987:22:1369-1374
REDUCED HALOPERIDOL INJECTION
o PREFRONTAL 8 CAUDATE q PLASMA
CORTEX
HALOPERIDOL INJECTION
0 PREFRONTAL l CAUDATE a PLASMA
CORTEX
1
I
I
I
I
I
I
I
I
0
0.1
0.2
0.5
1
2
5
10
20
DOSE(mg/kg) Figure 3. Mean concentrations (n = 5 for each point) of HAL in prefrontal cortex, caudate, and plasma after ip injection of HAL (30 min) and RHAL (60 min) at doses from 0. I mg/kg to 20 mg/kg
Discussion The present experiments demonstrated that RHAL mimicked the time and dose effects of HAL on HVA in both the caudate and prefrontal cortex. The maximal responses of HVA to RHAL and HAL were attained at the same time, which may be explained by the fact that RHAL quickly (within 10 min) oxidized in part to HAL (Figure 1). We obtained evidence that the maximal effects of the butyrophenones on the elevations of HVA in both caudate and prefrontal cortex were attained at the same time (3 hr). This evidence is contrary to the results obtained by Matsumoto et al. (1983), who found that HVA increased more slowly in the prefrontal cortex (3 hr) than in the caudate (2 hr) after HAL administration. In another study, we found that the maximal effects on the elevations of HVA were reached at the same time in both caudate and prefrontal cortex for each of 14 antipsychotic drugs at a dose equivalent to 0.2 mg/kg of HAL, although the maximal effect times were different (from 1 to 6 hr) for different drugs (Chang et al. unpublished manuscript 1987).
I374
W.-H. Chang et al.
BIOL PSYCHIATRY 1987:22:1369-1374
In both time-response (Figure 1) and dose-response (Figure 2) experiments, the potency of RHAL in the elevations of HVA was much less than that of HAL. This result was consistent with the conversion rate of RHAL to HAL (Figure 3). As HAL is not easily reduced to RHAL in the rat (Korpi et al. 1984), this evidence suggests that less neuroleptic activity after RHAL administration might be explained by the lesser conversion of RHAL to HAL. HVA levels in the prefrontal cortex peaked (for HAL only) and dropped off (for both HAL and RHAL) at lower doses of the butyrophenones than they did in the caudate. These results demonstrate that dopamine metabolism in the mesocortical system is more sensitive to butyrophenone (and probably other antipsychotics) administration than that in the nigrostriatal system. The present data suggest that the prefrontal cortex may be a possible site of antipsychotic action of some antipsychotic drugs, as we and other investigators have previously suggested (Laduron et al. 1977; Bacopoulos et al. 1979; Matsumoto et al. 1983; Chang et al. 1986b). The authors wish to thank Y.-L. Yeh for statistical
analysis,
S.-J. Lin for typing the manuscript, and H.-F.
Chang and S.-S. Chao for technical assistance.
References Bacopoulos NG, Spokes EG, Bird ED, Roth RH (1979): Antipsychotic drug action in schizophrenic patients: Effect on cortical dopamine metabolism after long-term treatment. Science 204: 1405. Chang WH, Scheinin M, Bums RS, Linnoila M (1983): Rapid and simple determination of homovanillic acid in plasma using high performance liquid chromatography with electrochemical detection. Acta Pharmacol Toxic01 53:275. Chang WH, Yeh, EK, Hu WH. Tseng YT, Chung MC, Chang HF (1986a): Acute and chronic effects of haloperidol on plasma and brain homovanillic acid in the rat. Biol Psychiatry 2 1:374. Chang WH, Yeh EK, Hu WH, Tseng YT, Chung MC, Chang HF (1986b): Prefrontal Possible site of antipsychotic action of haloperidol. Biol Psychiatry 21:422. Forsman A, Larsson M (1978): Metabolism
of haloperidol.
cortex:
Curr Ther Res 24567.
Forsman A, Ohman R (1979): Interindividual variation of clinical response to haloperidol. In Obiols J, Ballus C, Gonzalez Monclus E, Pujol J (eds), Biological Psychiatry Today, vol B. Amsterdam: Elsevier/North-Holland Biomedical Press, pp 949-954. Kirch DC. Palmer MR, Egan M, Fredman R (1985): Electrophysiological interactions between haloperidol and reduced haloperidol, and dopamine, norepinephrine and phencyclidine in rat brain. Neuropharmacology 24~375. Korpi ER, Wyatt RJ (1984): Reduced haloperidol: Effects on striatal dopamine conversion to haloperidol in the rat. Psychopharmacology 83:34.
metabolism
and
Korpi ER, Phelps B, Granger H, Change Wh, Linnoila M, Meek IL, Wyatt RJ (1983): Simultaneous determination of haloperidol and its reduced metabolite in serum and plasma by isocratic liquid chromatography with electrochemical detection. Clin Chem 29:624. Korpi ER, Kleinman JE, Costakos DT, Linnoila M, Wyatt RJ (1984): Reduced haloperidol in the post-mortem brains of haloperidol-treated patients. Psychiatry Res 11:259. Korpi ER, Costakos DT, Wyatt RJ (1985): Rapid formation of reduced haloperidol in guinea pigs following haloperidol administration. Acta Phurmacol Toxicol56:94. Laduron P, DeBie K, Leysen J (1977): Specific effect of haloperidol on dopamine turnover in the frontal cortex. Naunyn-Schmiedeberg Arch Pharmacol 296: 183. Matsumoto T, Uchimura H, Hirano M, Kern JS, Yokoo H, Shimomuro M, Nakahara T, Inoue K, Oomagari K (1983): Differential effects of acute and chronic administration of haloperidol on homovanillic acid levels in discrete dopaminergic areas of rat brain. Eur J Pharmacol 89:27.
I369
Reduced Haloperidol and Haloperidol: Effects on Homovanillic Acid in Caudate and Prefrontal Cortex Wen-Ho Chang, Ho-Sheng Wu, and Yung-Te Tseng
The effects of acute administration of reduced haloperidol (RHAL) on homovanillic acid (HVA) in the caudate and prefrontal cortex were examined in rats. Haloperidol (HAL) was used as a reference compound. Concentrations of HVA and HAL were measured by HPLCIECD. The maximal HVA response time was 3 hr after the injection, in both caudate and prefrontal cortex, for both RHAL and HAL. The potency of RHAL in the elevations of HVA in the caudate and prefrontal cortex was only about one-third to one-fifth that of HAL. The concentrations of HAL in the prefrontal cortex and caudate after RHAL administration were just about one-third to one-fifth those after HAL administration. These results suggest that less antidopaminergic activity of RHAL in this neuroleptic test might be explained by the lesser conversion of RHAL to HAL.
Introduction Haloperidol (HAL) is a widely used potent butyrophenone neuroleptic drug. In humans, the benzylic ketone of the hydrocarbon chain of the HAL molecule is converted to an alcohol to form a reduced metabolite (Forsman and Larsson 1978). Reduced HAL (RHAL) has a lipid solubility similar to HAL (Korpi et al. 1983) and has been shown to accumulate in the brain of schizophrenic patients treated with HAL (Korpi et al. 1984). RHAL Itself is not an active neuroleptic drug (Korpi and Wyatt 1984; Kirch et al. 1985). However, it was effective in neuroleptic tests in which RHAL was given parenterally in the rat, as it was rapidly oxidized to HAL (Korpi and Wyatt 1984). Nevertheless, the potency of this substance was much weaker than the parent compound (Forsman and Ohman 1979; Korpi et al. 198.5). In a previous study, we suggested that the prefrontal cortex might be a preferential target for HAL, or at least a more sensitive and specific target than the striatal or the mesolimbic systems (Chang et al. 1986b). We have now studied the effects of RHAL on the concentrations of homovanillic acid (HVA), the main metabolite of dopamine, in the prefrontal cortex and caudate in the rat, as dopamine metabolism in these two brain areas is believed to be important to the antipsychotic action and the extrapyramidal side effects of neuroleptics (Laduron et al. 1977; Bacopoulos et al. 1979; Matsumoto et al. 1983; Chang et al. 1986b). HAL was used as a reference compound in this study.
From Taipei City Psychiatric Center, Taiwan, Republic Supported in part by Grants NSC 74-0606-B 109-02 and Address reprint requests to Dr. Wen-Ho Chang, Chief, 54, Alley 200, Lane 151. Section 5. Shin-Yi Road, Recaved August 25, 1986; revised February 27, 1987.
0 1987 Society of Bmlogical Psychiatry
of China. NSC 75-0606.B109-02 from the National Science Council. Laboratory of Biological Psychiatry, Taipei City Psychiatric Center. 10510 Taipei, Taiwan, R.O.C.
ooo6-3223/87/%03.50
1370
W.-H. Chang et al.
BIOL PSYCHIATRY 1987:22:1369-1374
Concentrations of HAL in these brain structures, as well as in plasma, were measured in parallel with HVA, attempting to correlate HVA responses with HAL levels following RHAL and HAL administration.
Methods Male Wistar rats, weighing 150-2.50 g, were used in all experiments.
All animals were fasted, with water available ad lib, for 24 hr before death. HAL (Haldol injectable) and RHAL were obtained from Janssen Pharmaceutics (Beerse, Belgium). HAL was diluted with water. RHAL was dissolved in dilute hydrochloric acid and returned to approximately ph 4 by using sodium hydroxide prior to injection. To determine the time-response curves of HVA and drug kinetics, groups of 6 rats each were injected ip either with saline, 0.5 mg/kg HAL, or 0.5 mg/kg RHAL. The animals were decapitated either 10, 30, 60, 120, 180, or 240 min after the injection. The brains were quickly removed, and the prefrontal cortex and caudate dissected: the right structures were used for HVA measurements and the left for drug analyses. All specimens were stored at -60°C. To study the dose-response curves of HVA, groups of 4-5 rats each were injected ip either with saline, 0.1, 0.2, 0.5, 1, 2, 5, 10, or 20 mg/kg HAL or RHAL. The animals were killed after 180 min (the maximal HVA response was reached at this time), and the prefrontal cortex and caudate specimens were stored for HVA measurements. In addition, groups of 5 rats each were injected ip with various doses of HAL or RHAL as described above. The rats were decapitated after 30 or 60 min (HAL levels in brain specimens peaked at this time following HAL or RHAL administration). Trunk blood was collected in heparinized tubes and plasma separated by a cool centrifuge. The plasma, prefrontal cortex, and caudate samples were stored for drug analyses. HVA (Chang et al. 1983, 1986a) and HAL (Korpi et al. 1983, 1984; Korpi and Wyatt 1984) were measured by high-performance liquid chromatography with electrochemical detection (HPLUECD). Statistical analysis was carried out by means of an unpaired t-test.
Results Time-Response
Curves of HVA for RHAL and HAL
As shown in Figure 1, the maximal responses of HVA levels to both RHAL and HAL in both the caudate and prefrontal cortex were attained at the same time, i.e., 3 hr after the injection, although the elevations in HVA induced by RHAL began somewhat later than those by HAL, and the HAL levels following RHAL administration peaked later than those following HAL administration (60 min versus 30 min). The maximal levels of HVA in the caudate and prefrontal cortex after RHAL injection were much lower than those after HAL injection (309% ? 30% versus 465% + 62%, p < 0.001; 247% + 31% versus 405% ? 46%, p < O.OOl), which is consistent with the maximal HAL concentrations in these brain structures (129 -+ 33 rig/g versus 350 * 35 rig/g,, p < 0.001; 143 ? 14 rig/g versus 479 -+ 69 rig/g,, p < 0.001). Dose-Response
Curves of HVA for RHAL and HAL
As can be seen in Figure 2, HVA responses in the prefrontal cortex and caudate to increasing doses of HAL followed the same pattern as reported previously by Chang et
L
I
r
120
60
0
TIME
I
I
I
(min)
180
I
240
I
0
Figure 1. Mean concentrations (n = 5-6 for each group) and standard errors of HVA in caudate (shaded points) and prefrontal cortex (open points) at different times after ip points) at the dose of 0.5 mg/kg. The absolute HVA values of control groups (n = 59 t 6 rig/g (RHAL) for the prefrontal cortex and 1080 -t 83 rig/g (HAL) and 1145
100
500
60
I
TIME(min)
120
I
I
180
I
240
(% of controls) (left) and HAL (rig/g tissue) (right) injection of HAL (circle points) and RHAL (square 5 for each group) were 56 ? 3 rig/g (HAL) and 2 37 rig/g (RHAL) for the caudate.
0
I
1372
W.-H. Chang et al.
BIOL PSYCHIATRY 1987;22:1369-1374
600 -
I
500
-
400
-
300
-
0 L
ZW Ok 22 Ea Oz
aa f/
2 200
-
100 -
f Iy 0
I
0.1
0.2
O----O
HAL
-
RHAL
‘***
I
I
1
1
I
0.5
1
2
5
10
1
20
T
.
, 0.1
I
0.2
0.5
I
I
I
1
,
1
2
5
10
20
l
DOSE (mg/kg) Figure 2. Dose-response curves for the increase (% of control) of HVA in the caudate and prefrontal cortex after HAL and RHAL administration. Data points are means t SEM of 4-5 determinations. The absolute values of the control groups were 33 2 2 and 43 ? 2 rig/g tissue for the prefrontal cortex and 958 t 40 and 1054 5 46 rig/g tissue for the caudate. *HVA dropped off from the maximal point of 0.5 mg/kg, p < 0.05 or less. **HVA dropped off from the maximal point of 5 mg/kg, p < 0.05. ***HVA dropped off from the maximal point of 2 mglkg, p < 0.01.
al. (1986b). In addition, at the highest dose used (20 mg/kg), HAL also blunted the elevation of HVA in the caudate. Similar responses of HVA to RHAL were observed in both prefrontal cortex and caudate. However, the RHAL dose that caused the maximal responses of HVA in the caudate and prefrontal cortex was 5 mg/kg, at least 5 times that of HAL. Furthermore, the EDs0 values of HAL for the elevations of HVA in the caudate and prefrontal cortex were 0.09 and 0.05 mg/kg, respectively, whereas the EDso values of RHAL were 0.26 and 0.26 mg/kg, respectively. These values of RHAL are about 3 (in the caudate) and 5 (in the prefrontal cortex) times greater than those of the parent compound. Figure 3 shows the HAL levels in brain structures and plasma after RHAL and HAL injections. Concentrations of HAL following HAL administration were about 3-5 times higher than those following RHAL administration, which is consistent with the HVA response
results.
RHAL and HAL: Effect on HVA in Caudate and Cortex
.
1373
BIOL PSYCHIATRY 1987:22:1369-1374
REDUCED HALOPERIDOL INJECTION
o PREFRONTAL 8 CAUDATE q PLASMA
CORTEX
HALOPERIDOL INJECTION
0 PREFRONTAL l CAUDATE a PLASMA
CORTEX
1
I
I
I
I
I
I
I
I
0
0.1
0.2
0.5
1
2
5
10
20
DOSE(mg/kg) Figure 3. Mean concentrations (n = 5 for each point) of HAL in prefrontal cortex, caudate, and plasma after ip injection of HAL (30 min) and RHAL (60 min) at doses from 0. I mg/kg to 20 mg/kg
Discussion The present experiments demonstrated that RHAL mimicked the time and dose effects of HAL on HVA in both the caudate and prefrontal cortex. The maximal responses of HVA to RHAL and HAL were attained at the same time, which may be explained by the fact that RHAL quickly (within 10 min) oxidized in part to HAL (Figure 1). We obtained evidence that the maximal effects of the butyrophenones on the elevations of HVA in both caudate and prefrontal cortex were attained at the same time (3 hr). This evidence is contrary to the results obtained by Matsumoto et al. (1983), who found that HVA increased more slowly in the prefrontal cortex (3 hr) than in the caudate (2 hr) after HAL administration. In another study, we found that the maximal effects on the elevations of HVA were reached at the same time in both caudate and prefrontal cortex for each of 14 antipsychotic drugs at a dose equivalent to 0.2 mg/kg of HAL, although the maximal effect times were different (from 1 to 6 hr) for different drugs (Chang et al. unpublished manuscript 1987).
I374
W.-H. Chang et al.
BIOL PSYCHIATRY 1987:22:1369-1374
In both time-response (Figure 1) and dose-response (Figure 2) experiments, the potency of RHAL in the elevations of HVA was much less than that of HAL. This result was consistent with the conversion rate of RHAL to HAL (Figure 3). As HAL is not easily reduced to RHAL in the rat (Korpi et al. 1984), this evidence suggests that less neuroleptic activity after RHAL administration might be explained by the lesser conversion of RHAL to HAL. HVA levels in the prefrontal cortex peaked (for HAL only) and dropped off (for both HAL and RHAL) at lower doses of the butyrophenones than they did in the caudate. These results demonstrate that dopamine metabolism in the mesocortical system is more sensitive to butyrophenone (and probably other antipsychotics) administration than that in the nigrostriatal system. The present data suggest that the prefrontal cortex may be a possible site of antipsychotic action of some antipsychotic drugs, as we and other investigators have previously suggested (Laduron et al. 1977; Bacopoulos et al. 1979; Matsumoto et al. 1983; Chang et al. 1986b). The authors wish to thank Y.-L. Yeh for statistical
analysis,
S.-J. Lin for typing the manuscript, and H.-F.
Chang and S.-S. Chao for technical assistance.
References Bacopoulos NG, Spokes EG, Bird ED, Roth RH (1979): Antipsychotic drug action in schizophrenic patients: Effect on cortical dopamine metabolism after long-term treatment. Science 204: 1405. Chang WH, Scheinin M, Bums RS, Linnoila M (1983): Rapid and simple determination of homovanillic acid in plasma using high performance liquid chromatography with electrochemical detection. Acta Pharmacol Toxic01 53:275. Chang WH, Yeh, EK, Hu WH. Tseng YT, Chung MC, Chang HF (1986a): Acute and chronic effects of haloperidol on plasma and brain homovanillic acid in the rat. Biol Psychiatry 2 1:374. Chang WH, Yeh EK, Hu WH, Tseng YT, Chung MC, Chang HF (1986b): Prefrontal Possible site of antipsychotic action of haloperidol. Biol Psychiatry 21:422. Forsman A, Larsson M (1978): Metabolism
of haloperidol.
cortex:
Curr Ther Res 24567.
Forsman A, Ohman R (1979): Interindividual variation of clinical response to haloperidol. In Obiols J, Ballus C, Gonzalez Monclus E, Pujol J (eds), Biological Psychiatry Today, vol B. Amsterdam: Elsevier/North-Holland Biomedical Press, pp 949-954. Kirch DC. Palmer MR, Egan M, Fredman R (1985): Electrophysiological interactions between haloperidol and reduced haloperidol, and dopamine, norepinephrine and phencyclidine in rat brain. Neuropharmacology 24~375. Korpi ER, Wyatt RJ (1984): Reduced haloperidol: Effects on striatal dopamine conversion to haloperidol in the rat. Psychopharmacology 83:34.
metabolism
and
Korpi ER, Phelps B, Granger H, Change Wh, Linnoila M, Meek IL, Wyatt RJ (1983): Simultaneous determination of haloperidol and its reduced metabolite in serum and plasma by isocratic liquid chromatography with electrochemical detection. Clin Chem 29:624. Korpi ER, Kleinman JE, Costakos DT, Linnoila M, Wyatt RJ (1984): Reduced haloperidol in the post-mortem brains of haloperidol-treated patients. Psychiatry Res 11:259. Korpi ER, Costakos DT, Wyatt RJ (1985): Rapid formation of reduced haloperidol in guinea pigs following haloperidol administration. Acta Phurmacol Toxicol56:94. Laduron P, DeBie K, Leysen J (1977): Specific effect of haloperidol on dopamine turnover in the frontal cortex. Naunyn-Schmiedeberg Arch Pharmacol 296: 183. Matsumoto T, Uchimura H, Hirano M, Kern JS, Yokoo H, Shimomuro M, Nakahara T, Inoue K, Oomagari K (1983): Differential effects of acute and chronic administration of haloperidol on homovanillic acid levels in discrete dopaminergic areas of rat brain. Eur J Pharmacol 89:27.