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Exposure of a ‘witness rat’ to one treated with β-carboline FG 7142 does not increase dopamine turnover in the medial prefrontal cortex of the ‘witness rat’
Neuroscience Letters 302 (2001) 151±153
www.elsevier.com/locate/neulet
Exposure of a `witness rat' to one treated with b-carboline FG 7142 does not increase dopamine turnover in the medial prefrontal cortex of the `witness rat' George E. Jaskiw a,*, Barbara K. Lipska b, Farouk Karoum b, Daniel R. Weinberger b a
Veterans Administration Medical Center and Department of Psychiatry, Case Western Reserve University, Cleveland, 10000 Brecksville Road, Brecksville, OH 44141, USA b Clinical Brain Disorders Branch 2, NIMH, Bethesda, MD, USA Received 1 February 2001; received in revised form 12 February 2001; accepted 12 February 2001
Abstract A method for selectively activating the dopaminergic ®eld of the prefrontal cortex would be highly useful for studies of mesocortical dopamine systems. When a rat (`witness' rat) is exposed to a rat that is undergoing footshock, prefrontocortical dopamine metabolism is selectively increased in the witness rat. Since the anxiogenic b-carboline FG 7142 mimics many of the effects of footshock, we hypothesized that exposure of a witness-rat to a rat treated with FG 7142 would also increase dopamine metabolism in the prefrontal cortex. We found that while as expected, FG 7142 itself increased prefrontal cortex dopamine metabolism, there was no signi®cant change in dopamine metabolism in the witness rat. Thus exposure to a rat treated with FG 7142 does not selectively activate the mesocortical dopamine system. q 2001 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Stress; Dopamine; Prefrontal cortex
Growing interest in the mesocortical dopamine (DA) system has created a need for easily reproducible techniques that selectively increase DA turnover in the medial prefrontal cortex (MPFC) of the rat. Most physical stressors increase dopamine (DA) synthesis in the MPFC [17], but this effect is not regionally con®ned. While activation of the MPFC DA system usually occurs earlier and with a lower stress threshold, as the intensity or duration of the stress increase, other DA terminal ®elds are activated as well [17]. Early reports suggested that the anxiogenic b-carboline FG 7142 increased DA turnover only in the MPFC [3,10,20] but it is now known that DA turnover is increased in the mesolimbic system as well [9,16]. Psychological stress may also selectively activate mesocortical DA systems [8,14]. Exposure of a `witness' rat to another rat undergoing inescapable footshock increases DA turnover selectively in the MPFC of the `witness' rat [14]. However, this paradigm is relatively labor intensive and requires access to calibrated footshock apparatus. We posited that `witnessing' another rat experiencing stressors * Corresponding author. Tel.: 11-440-526-3030 ext. 6846; fax: 11-440-717-2838. E-mail address: [email protected] (G.E. Jaskiw).
similar to footshock would also selectively activate the mesocortical DA system. Administration of FG 7142 mimics most behavioral [4,13,18] and neurochemical effects [2,17,19] of inescapable footshock. Discrimination for FG 7142 generalizes to footshock [15]. Thus, we posited that exposure of a `witness' rat to a rat treated with FG 7142 would selectively increase MPFC DA turnover in the witness-rat, and provide a simple, quick and easily reproducible probe of mesocortical DA systems. Male Zivic±Miller rats (250±300 g) were housed in groups of four/cage on a standard day/night cycle with food and water ad libitum. Within each cage, each rat was randomly assigned to one of four groups (n 8±11/group), vehicle (VEH), VEH-witness, FG 7142 (FG), FG-witness. Each day for 4 days rats were moved from the home cage and placed in pairs in clean Plexiglas containers with sawdust for 2 h. The same rats were paired throughout. On the 5th day, after 1 h in the container, FG rats were injected intraperitoneally (i.p.) with FG 7142 (Schering Aktiengesellschaft, Germany) 15 mg/kg (sonicated suspension) and VEH rats with the vehicle (three drops Tween 80 in 10 ml distilled water). `Witness' rats were picked up in the same fashion as injected rats but were then returned to
0304-3940/01/$ - see front matter q 2001 Elsevier Science Ireland Ltd. All rights reserved. PII: S03 04 - 394 0( 0 1) 01 68 9- 5
152
G.E. Jaskiw et al. / Neuroscience Letters 302 (2001) 151±153
their containers without any further manipulation. Thus the VEH-witness and FG-witness rats had full sensory exposure to the VEH- and FG- injected rats, respectively. All rats were sacri®ced by decapitation 45 min after they or their counterpart received an injection. The order of sacri®ce of rats from within each container was counterbalanced. Brains were rapidly removed and 2-mm thick sections cut in a brain mold on wet ice. The MPFC and the nucleus accumbens were dissected out, frozen and stored until assay by mass spectroscopy [11]. For each brain region, values for a given assay were compared across the four groups by analysis of variance (ANOVA) (see Table 1). If the initial ANOVA was signi®cant, Student±Newman±Keul's comparisons were then carried out. Within the MPFC, there was a signi®cant main effect for the ratio dihydroxyphenylacetic acid (DOPAC)/DA (F 3; 36 3:68; P , 0:02), a trend towards signi®cance for DOPAC (F 3; 36 2:72; P , 0:06) but not for DA F 3; 36 0:43; P , 0:7) or norepinephrine (NE) (F 3; 36 0:75; P , 0:5). The DOPAC/DA ratio was significantly increased by 45% in the FG rats. Within the nucleus accumbens, there were no main effects for any of the neurotransmitters measured (DOPAC/DA (F 3; 36 0:55; P , 0:65, DOPAC F 3; 36 2:2; P , 0:1, DA F 3; 36 1:02; P , 0:40, NE (F 3; 36 0:33; P , 0:8). Contrary to our hypothesis, exposure to a rat treated with FG 7142 did not affect MPFC DA indices in the `witness' rat. There are several considerations. Handling is a stressor per se and increases MPFC DA release [6]; the latter could theoretically obscure effects in FG-witness rats by producing a `ceiling' effect. Indeed our basal MPFC DOPAC/DA ratio was 0.66, higher than that reported by most laboratories [1]. On the other hand, our rats were habituated according to a procedure previously used to demonstrate activation of mesocortical DA [8]. Furthermore, basal DOPAC/DA ratios in the range 0.65±0.71 have certainly been reported [5,19]. Finally, in the current study FG 7142 increased the MPFC DOPAC/DA ratio signi®cantly above basal levels. Another possibility is that repeated handling attenuates the anxiogenic effects of FG 7142. This is unlikely. We used a dose of FG 7142 (15 mg/kg
i.p.) that consistently induces stress-like behaviors [7,11]. Furthermore, the magnitude of the FG 7142-induced changes in the MPFC DOPAC/DA ratio is consistent with other reports [10,20]. Another possibility is that the duration of the witness rats exposure or the time of their sacri®ce prevented detection of a true change. This does not appear likely. Behavioral effects of FG 7142 are evident within 15 min of its administration [12]. The increase in FG 7142-induced MPFC DA release peaks at 20 min and remains elevated for 100 min (after i.p. administration) [3]. Since witness rats must be exposed for at least 30 min to a footshock-stressed rat before an increase in MPFC DOPAC/DA can be detected [14], rats in the current experiment were also exposed for 30 min to a rat during the presumed period of maximal FG 7142induced stress. Of greater concern is whether being `witness' to a rat under the acute in¯uence of FG 7142 constitutes a psychological stress. In an earlier study, footshock-witness rats observed `emotional responses of foot-shocked rats, such as vocalization, jumping, struggling, defecating, urinating', some of which presumably could be perceived across the clear but solid plastic barrier between them [14]. We have not observed these type of behaviors in FG 7142 treated rats across a wide range of FG 7142 doses (5±25 mg/kg i.p.) (G.E.J. unpublished observations). FG 7142 suppresses exploratory activity but does not induce other gross behaviors at the 15 mg/kg dose [7,12]. Whether FG 7142 treated animals display olfactory, vocal or other stress-related cues has not, to our knowledge, been studied in the adult rat. Our FG-witness rats could make visual, olfactory and tactile contact with the FG 7142-treated rats. However, it is quite possible that in contrast to the physical nociceptive experience of footshock, the `emotional' distress induced by FG 7142 may not be re¯ected in a pro®le of sensory cues that communicates distress. FG 7142 did not affect DA indices in the whole nucleus accumbens as reported by others [9,16]. Accumbens changes can be detected only when the accumbens core and shell are separately assayed [9]. In summary, exposing one rat to another, which has been treated with FG 7142,
Table 1 Regional monoamine and metabolite levels a Medial prefrontal cortex VEH (8) VEH-witness (11) FG-witness (11) Nucleus accumbens VEH (8) VEH-witness (11) FG (10) FG-witness (11) a
NE
DA
DOPAC
DOPAC/DA
12.69 ^ 0.40 12.17 ^ 0.58 13.14 ^ 0.48 12.42 ^ 0.42
6.81 ^ 0.73 6.02 ^ 0.38 6.17 ^ 0.58 6.22 ^ 0.37
4.24 ^ 0.45 4.41 ^ 0.36 5.69 ^ 0.53 4.23 ^ 0.37
0.66 ^ 0.09 0.75 ^ 0.07 0.97 ^ 0.09* 0.68 ^ 0.04
10.10 ^ 0.65 11.95 ^ 2.6 10.69 ^ 0.85 13.05 ^ 3.0
509 ^ 30.0 455.4 ^ 41 532.2 ^ 22 513.3 ^ 35
89.4 ^ 4.5 79.0 ^ 6.3 95.8 ^ 4.9 97.4 ^ 6.4
0.18 ^ 0.005 0.18 ^ 0.008 0.18 ^ 0.007 0.21 ^ 0.04
* . all other groups, P , 0:05. VEH, vehicle; NE, norepinephrine; DA, dopamine; DOPAC, dihydroxyphenylacetic acid; FG, FG7142. Values are in pmol/mg protein. Numbers in parentheses refer to number of animals in the group.
G.E. Jaskiw et al. / Neuroscience Letters 302 (2001) 151±153
does not provide a means of selectively activating the mesocortical DA system in the `witness' rat. We thank Schering Aktiengesellschaft (Germany) for their generous gift of FG 7142. [1] Bannon, M.J. and Roth, R.H., Pharmacology of mesocortical dopamine neurons, Pharmacol. Rev., 35 (1983) 53± 68. [2] Barbaccia, M.L., Roscetti, G., Bolacchi, F., Concas, A., Mostallino, M.C., Purdy, R.H. and Biggio, G., Stressinduced increase in brain neuroactive steroids: antagonism by abecarnil, Pharmacol. Biochem. Behav., 54 (1996) 205± 210. [3] Bradberry, C.W., Lory, J.D. and Roth, R.H., The anxiogenic beta-carboline FG 7142 selectively increases dopamine release in rat prefrontal cortex as measured by microdialysis, J. Neurochem., 56 (1991) 748±752. [4] Drugan, R.C., Maier, S.F., Skolnick, P., Paul, S.M. and Crawley, J.N., An anxiogenic benzodiazepine receptor ligand induces learned helplessness, Eur. J. Pharmacol., 113 (1985) 453±457. [5] Dunn, A.J. and File, S.E., Cold restraint alters dopamine metabolism in frontal cortex, nucleus accumbens and neostriatum, Physiol. Behav., 31 (1983) 511±513. [6] Feenstra, M.G., Botterblom, M.H. and van Uum, J.F., Novelty-induced increase in dopamine release in the rat prefrontal cortex in vivo: inhibition by diazepam, Neurosci. Lett., 189 (1995) 81±84. [7] File, S.E., Pellow, S. and Braestrup, C., Effects of the betacarboline FG 7142, in the social interaction test of anxiety and the holeboard: correlations between behaviour and plasma concentrations, Pharmacol. Biochem. Behav., 22 (1985) 941±944. [8] Herman, J.P., Guillonneau, D., Dantzer, R., Scatton, B., Semerdjian-Rouquier, L. and Le Moal, M., Differential effects of inescapable footshocks and of stimuli previously paired with inescapable footshocks on dopamine turnover in cortical and limbic areas of the rat, Life Sci., 30 (1982) 2207±2214. [9] Horger, B.A., Elsworth, J.D. and Roth, R.H., Selective increase in dopamine utilization in the shell subdivision
[10]
[11]
[12]
[13] [14]
[15]
[16]
[17] [18] [19] [20]
153
of the nucleus accumbens by the benzodiazepine inverse agonist FG 7142, J. Neurochem., 65 (1995) 770±774. Ida, Y. and Roth, R.H., The activation of mesoprefrontal dopamine neurons by FG 7142 is absent in rats treated chronically with diazepam, Eur. J. Pharmacol., 137 (1987) 185±190. Jaskiw, G.E., Karoum, F., Freed, W.J., Phillips, I., Kleinman, J.E. and Weinberger, D.R., Effect of ibotenic acid lesions of the medial prefrontal cortex on amphetamine-induced locomotion and regional brain catecholamine concentrations in the rat, Brain Res., 534 (1990) 263±272. Jaskiw, G.E. and Weinberger, D.R., Ibotenic acid lesions of the medial prefrontal cortex potentiate FG-7142-induced attenuation of exploratory activity in the rat, Pharmacol. Biochem. Behav., 36 (1990) 695±697. Kameyama, T. and Nagasaka, M., Effects of apomorphine and diazepam on a quickly learned conditioned suppression in rats, Pharmacol. Biochem. Behav., 17 (1982) 59±63. Kaneyuki, H., Yokoo, H., Tsuda, A., Yoshida, M., Mizuki, Y., Yamada, M. and Tanaka, M., Psychological stress increases dopamine turnover selectively in mesoprefrontal dopamine neurons of rats: reversal by diazepam, Brain Res., 557 (1991) 154±161. Leidenheimer, N.J. and Schechter, M.D., Discriminative stimulus control by the anxiogenic beta-carboline FG 7142: generalization to a physiological stressor, Pharmacol. Biochem. Behav., 30 (1988) 351±355. McCullough, L.D. and Salamone, J.D., Anxiogenic drugs beta-CCE and FG 7142 increase extracellular dopamine levels in nucleus accumbens, Psychopharmacology, 109 (1992) 379±382. Roth, R.H., Tam, S.-Y., Ida, Y., Yang, J.-X. and Deutch, A.Y., Stress and the mesocorticolimbic dopamine systems, Ann. N.Y. Acad. Sci., 537 (1988) 138±147. Short, K.R. and Maier, S.F., Stressor controllability, social interaction, and benzodiazepine systems, Pharmacol. Biochem. Behav., 45 (1993) 827±835. Sudha, S. and Pradhan, N., Stress-induced changes in regional monoamine metabolism and behavior in rats, Physiol. Behav., 57 (1995) 1061±1066. Tam, S.-Y. and Roth, R.H., Selective increase in dopamine metabolism in the prefrontal cortex by the anxiogenic betacarboline FG-7142, Biochem. Pharmacol., 34 (1985) 1595± 1598.
www.elsevier.com/locate/neulet
Exposure of a `witness rat' to one treated with b-carboline FG 7142 does not increase dopamine turnover in the medial prefrontal cortex of the `witness rat' George E. Jaskiw a,*, Barbara K. Lipska b, Farouk Karoum b, Daniel R. Weinberger b a
Veterans Administration Medical Center and Department of Psychiatry, Case Western Reserve University, Cleveland, 10000 Brecksville Road, Brecksville, OH 44141, USA b Clinical Brain Disorders Branch 2, NIMH, Bethesda, MD, USA Received 1 February 2001; received in revised form 12 February 2001; accepted 12 February 2001
Abstract A method for selectively activating the dopaminergic ®eld of the prefrontal cortex would be highly useful for studies of mesocortical dopamine systems. When a rat (`witness' rat) is exposed to a rat that is undergoing footshock, prefrontocortical dopamine metabolism is selectively increased in the witness rat. Since the anxiogenic b-carboline FG 7142 mimics many of the effects of footshock, we hypothesized that exposure of a witness-rat to a rat treated with FG 7142 would also increase dopamine metabolism in the prefrontal cortex. We found that while as expected, FG 7142 itself increased prefrontal cortex dopamine metabolism, there was no signi®cant change in dopamine metabolism in the witness rat. Thus exposure to a rat treated with FG 7142 does not selectively activate the mesocortical dopamine system. q 2001 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Stress; Dopamine; Prefrontal cortex
Growing interest in the mesocortical dopamine (DA) system has created a need for easily reproducible techniques that selectively increase DA turnover in the medial prefrontal cortex (MPFC) of the rat. Most physical stressors increase dopamine (DA) synthesis in the MPFC [17], but this effect is not regionally con®ned. While activation of the MPFC DA system usually occurs earlier and with a lower stress threshold, as the intensity or duration of the stress increase, other DA terminal ®elds are activated as well [17]. Early reports suggested that the anxiogenic b-carboline FG 7142 increased DA turnover only in the MPFC [3,10,20] but it is now known that DA turnover is increased in the mesolimbic system as well [9,16]. Psychological stress may also selectively activate mesocortical DA systems [8,14]. Exposure of a `witness' rat to another rat undergoing inescapable footshock increases DA turnover selectively in the MPFC of the `witness' rat [14]. However, this paradigm is relatively labor intensive and requires access to calibrated footshock apparatus. We posited that `witnessing' another rat experiencing stressors * Corresponding author. Tel.: 11-440-526-3030 ext. 6846; fax: 11-440-717-2838. E-mail address: [email protected] (G.E. Jaskiw).
similar to footshock would also selectively activate the mesocortical DA system. Administration of FG 7142 mimics most behavioral [4,13,18] and neurochemical effects [2,17,19] of inescapable footshock. Discrimination for FG 7142 generalizes to footshock [15]. Thus, we posited that exposure of a `witness' rat to a rat treated with FG 7142 would selectively increase MPFC DA turnover in the witness-rat, and provide a simple, quick and easily reproducible probe of mesocortical DA systems. Male Zivic±Miller rats (250±300 g) were housed in groups of four/cage on a standard day/night cycle with food and water ad libitum. Within each cage, each rat was randomly assigned to one of four groups (n 8±11/group), vehicle (VEH), VEH-witness, FG 7142 (FG), FG-witness. Each day for 4 days rats were moved from the home cage and placed in pairs in clean Plexiglas containers with sawdust for 2 h. The same rats were paired throughout. On the 5th day, after 1 h in the container, FG rats were injected intraperitoneally (i.p.) with FG 7142 (Schering Aktiengesellschaft, Germany) 15 mg/kg (sonicated suspension) and VEH rats with the vehicle (three drops Tween 80 in 10 ml distilled water). `Witness' rats were picked up in the same fashion as injected rats but were then returned to
0304-3940/01/$ - see front matter q 2001 Elsevier Science Ireland Ltd. All rights reserved. PII: S03 04 - 394 0( 0 1) 01 68 9- 5
152
G.E. Jaskiw et al. / Neuroscience Letters 302 (2001) 151±153
their containers without any further manipulation. Thus the VEH-witness and FG-witness rats had full sensory exposure to the VEH- and FG- injected rats, respectively. All rats were sacri®ced by decapitation 45 min after they or their counterpart received an injection. The order of sacri®ce of rats from within each container was counterbalanced. Brains were rapidly removed and 2-mm thick sections cut in a brain mold on wet ice. The MPFC and the nucleus accumbens were dissected out, frozen and stored until assay by mass spectroscopy [11]. For each brain region, values for a given assay were compared across the four groups by analysis of variance (ANOVA) (see Table 1). If the initial ANOVA was signi®cant, Student±Newman±Keul's comparisons were then carried out. Within the MPFC, there was a signi®cant main effect for the ratio dihydroxyphenylacetic acid (DOPAC)/DA (F 3; 36 3:68; P , 0:02), a trend towards signi®cance for DOPAC (F 3; 36 2:72; P , 0:06) but not for DA F 3; 36 0:43; P , 0:7) or norepinephrine (NE) (F 3; 36 0:75; P , 0:5). The DOPAC/DA ratio was significantly increased by 45% in the FG rats. Within the nucleus accumbens, there were no main effects for any of the neurotransmitters measured (DOPAC/DA (F 3; 36 0:55; P , 0:65, DOPAC F 3; 36 2:2; P , 0:1, DA F 3; 36 1:02; P , 0:40, NE (F 3; 36 0:33; P , 0:8). Contrary to our hypothesis, exposure to a rat treated with FG 7142 did not affect MPFC DA indices in the `witness' rat. There are several considerations. Handling is a stressor per se and increases MPFC DA release [6]; the latter could theoretically obscure effects in FG-witness rats by producing a `ceiling' effect. Indeed our basal MPFC DOPAC/DA ratio was 0.66, higher than that reported by most laboratories [1]. On the other hand, our rats were habituated according to a procedure previously used to demonstrate activation of mesocortical DA [8]. Furthermore, basal DOPAC/DA ratios in the range 0.65±0.71 have certainly been reported [5,19]. Finally, in the current study FG 7142 increased the MPFC DOPAC/DA ratio signi®cantly above basal levels. Another possibility is that repeated handling attenuates the anxiogenic effects of FG 7142. This is unlikely. We used a dose of FG 7142 (15 mg/kg
i.p.) that consistently induces stress-like behaviors [7,11]. Furthermore, the magnitude of the FG 7142-induced changes in the MPFC DOPAC/DA ratio is consistent with other reports [10,20]. Another possibility is that the duration of the witness rats exposure or the time of their sacri®ce prevented detection of a true change. This does not appear likely. Behavioral effects of FG 7142 are evident within 15 min of its administration [12]. The increase in FG 7142-induced MPFC DA release peaks at 20 min and remains elevated for 100 min (after i.p. administration) [3]. Since witness rats must be exposed for at least 30 min to a footshock-stressed rat before an increase in MPFC DOPAC/DA can be detected [14], rats in the current experiment were also exposed for 30 min to a rat during the presumed period of maximal FG 7142induced stress. Of greater concern is whether being `witness' to a rat under the acute in¯uence of FG 7142 constitutes a psychological stress. In an earlier study, footshock-witness rats observed `emotional responses of foot-shocked rats, such as vocalization, jumping, struggling, defecating, urinating', some of which presumably could be perceived across the clear but solid plastic barrier between them [14]. We have not observed these type of behaviors in FG 7142 treated rats across a wide range of FG 7142 doses (5±25 mg/kg i.p.) (G.E.J. unpublished observations). FG 7142 suppresses exploratory activity but does not induce other gross behaviors at the 15 mg/kg dose [7,12]. Whether FG 7142 treated animals display olfactory, vocal or other stress-related cues has not, to our knowledge, been studied in the adult rat. Our FG-witness rats could make visual, olfactory and tactile contact with the FG 7142-treated rats. However, it is quite possible that in contrast to the physical nociceptive experience of footshock, the `emotional' distress induced by FG 7142 may not be re¯ected in a pro®le of sensory cues that communicates distress. FG 7142 did not affect DA indices in the whole nucleus accumbens as reported by others [9,16]. Accumbens changes can be detected only when the accumbens core and shell are separately assayed [9]. In summary, exposing one rat to another, which has been treated with FG 7142,
Table 1 Regional monoamine and metabolite levels a Medial prefrontal cortex VEH (8) VEH-witness (11) FG-witness (11) Nucleus accumbens VEH (8) VEH-witness (11) FG (10) FG-witness (11) a
NE
DA
DOPAC
DOPAC/DA
12.69 ^ 0.40 12.17 ^ 0.58 13.14 ^ 0.48 12.42 ^ 0.42
6.81 ^ 0.73 6.02 ^ 0.38 6.17 ^ 0.58 6.22 ^ 0.37
4.24 ^ 0.45 4.41 ^ 0.36 5.69 ^ 0.53 4.23 ^ 0.37
0.66 ^ 0.09 0.75 ^ 0.07 0.97 ^ 0.09* 0.68 ^ 0.04
10.10 ^ 0.65 11.95 ^ 2.6 10.69 ^ 0.85 13.05 ^ 3.0
509 ^ 30.0 455.4 ^ 41 532.2 ^ 22 513.3 ^ 35
89.4 ^ 4.5 79.0 ^ 6.3 95.8 ^ 4.9 97.4 ^ 6.4
0.18 ^ 0.005 0.18 ^ 0.008 0.18 ^ 0.007 0.21 ^ 0.04
* . all other groups, P , 0:05. VEH, vehicle; NE, norepinephrine; DA, dopamine; DOPAC, dihydroxyphenylacetic acid; FG, FG7142. Values are in pmol/mg protein. Numbers in parentheses refer to number of animals in the group.
G.E. Jaskiw et al. / Neuroscience Letters 302 (2001) 151±153
does not provide a means of selectively activating the mesocortical DA system in the `witness' rat. We thank Schering Aktiengesellschaft (Germany) for their generous gift of FG 7142. [1] Bannon, M.J. and Roth, R.H., Pharmacology of mesocortical dopamine neurons, Pharmacol. Rev., 35 (1983) 53± 68. [2] Barbaccia, M.L., Roscetti, G., Bolacchi, F., Concas, A., Mostallino, M.C., Purdy, R.H. and Biggio, G., Stressinduced increase in brain neuroactive steroids: antagonism by abecarnil, Pharmacol. Biochem. Behav., 54 (1996) 205± 210. [3] Bradberry, C.W., Lory, J.D. and Roth, R.H., The anxiogenic beta-carboline FG 7142 selectively increases dopamine release in rat prefrontal cortex as measured by microdialysis, J. Neurochem., 56 (1991) 748±752. [4] Drugan, R.C., Maier, S.F., Skolnick, P., Paul, S.M. and Crawley, J.N., An anxiogenic benzodiazepine receptor ligand induces learned helplessness, Eur. J. Pharmacol., 113 (1985) 453±457. [5] Dunn, A.J. and File, S.E., Cold restraint alters dopamine metabolism in frontal cortex, nucleus accumbens and neostriatum, Physiol. Behav., 31 (1983) 511±513. [6] Feenstra, M.G., Botterblom, M.H. and van Uum, J.F., Novelty-induced increase in dopamine release in the rat prefrontal cortex in vivo: inhibition by diazepam, Neurosci. Lett., 189 (1995) 81±84. [7] File, S.E., Pellow, S. and Braestrup, C., Effects of the betacarboline FG 7142, in the social interaction test of anxiety and the holeboard: correlations between behaviour and plasma concentrations, Pharmacol. Biochem. Behav., 22 (1985) 941±944. [8] Herman, J.P., Guillonneau, D., Dantzer, R., Scatton, B., Semerdjian-Rouquier, L. and Le Moal, M., Differential effects of inescapable footshocks and of stimuli previously paired with inescapable footshocks on dopamine turnover in cortical and limbic areas of the rat, Life Sci., 30 (1982) 2207±2214. [9] Horger, B.A., Elsworth, J.D. and Roth, R.H., Selective increase in dopamine utilization in the shell subdivision
[10]
[11]
[12]
[13] [14]
[15]
[16]
[17] [18] [19] [20]
153
of the nucleus accumbens by the benzodiazepine inverse agonist FG 7142, J. Neurochem., 65 (1995) 770±774. Ida, Y. and Roth, R.H., The activation of mesoprefrontal dopamine neurons by FG 7142 is absent in rats treated chronically with diazepam, Eur. J. Pharmacol., 137 (1987) 185±190. Jaskiw, G.E., Karoum, F., Freed, W.J., Phillips, I., Kleinman, J.E. and Weinberger, D.R., Effect of ibotenic acid lesions of the medial prefrontal cortex on amphetamine-induced locomotion and regional brain catecholamine concentrations in the rat, Brain Res., 534 (1990) 263±272. Jaskiw, G.E. and Weinberger, D.R., Ibotenic acid lesions of the medial prefrontal cortex potentiate FG-7142-induced attenuation of exploratory activity in the rat, Pharmacol. Biochem. Behav., 36 (1990) 695±697. Kameyama, T. and Nagasaka, M., Effects of apomorphine and diazepam on a quickly learned conditioned suppression in rats, Pharmacol. Biochem. Behav., 17 (1982) 59±63. Kaneyuki, H., Yokoo, H., Tsuda, A., Yoshida, M., Mizuki, Y., Yamada, M. and Tanaka, M., Psychological stress increases dopamine turnover selectively in mesoprefrontal dopamine neurons of rats: reversal by diazepam, Brain Res., 557 (1991) 154±161. Leidenheimer, N.J. and Schechter, M.D., Discriminative stimulus control by the anxiogenic beta-carboline FG 7142: generalization to a physiological stressor, Pharmacol. Biochem. Behav., 30 (1988) 351±355. McCullough, L.D. and Salamone, J.D., Anxiogenic drugs beta-CCE and FG 7142 increase extracellular dopamine levels in nucleus accumbens, Psychopharmacology, 109 (1992) 379±382. Roth, R.H., Tam, S.-Y., Ida, Y., Yang, J.-X. and Deutch, A.Y., Stress and the mesocorticolimbic dopamine systems, Ann. N.Y. Acad. Sci., 537 (1988) 138±147. Short, K.R. and Maier, S.F., Stressor controllability, social interaction, and benzodiazepine systems, Pharmacol. Biochem. Behav., 45 (1993) 827±835. Sudha, S. and Pradhan, N., Stress-induced changes in regional monoamine metabolism and behavior in rats, Physiol. Behav., 57 (1995) 1061±1066. Tam, S.-Y. and Roth, R.H., Selective increase in dopamine metabolism in the prefrontal cortex by the anxiogenic betacarboline FG-7142, Biochem. Pharmacol., 34 (1985) 1595± 1598.