Brain Research, 534 (1990) 321-323
321
Elsevier BRES 24402
Persistent elevations in dopamine and its metabolites in the nucleus accumbens after mild subchronic stress in rats with ibotenic acid lesions of the medial prefrontal cortex G.E. Jaskiw 1, F.K. K a r o u m 2 and D . R . W e i n b e r g e r 1 Clinical Brain Disorders Branch and 2Neuropsychiatry Branch, Intramural Research Program, National Institute of Mental Health, N1MH Neuroscience Center at St. Elizabeths, Washington, DC 20032 (U.S.A.)
(Accepted 21 August 1990) Key words: Prefrontal cortex; Ibotenic acid; Dihydroxyphenylacetic acid; Stress; Nucleus accumbens
This study assessed the possible influence of the medial prefrontal cortex (MPFC) on the response of subcortical dopamine (DA) systems to subchronic, mild stress. DA and its metabolites as well as noradrenaline were assayed in the nucleus accumbens and corpus striatum, 1 and 7 days after one week of daily intraperitoneal saline injections (Stress) or no handling (No stress), in rats with sham (Sham) or ibotenic acid (IA) lesions of the MPFC. One day after the last saline injection the level of dihydroxyphenylacetic acid (DOPAC) was elevated in the nucleus accumbens of IA/Stress rats in comparison to the Sham/No stress, Sham/Stress, and IA/No Stress groups. Levels of mesolimbic DA, DOPAC and homovanillic acid were still elevated 7 days after the last injection in IA/Stress animals in comparison to all other groups. There were no other significant differences between the groups. The data suggest that in rats with MPFC impairment, mild subchronic stress can induce alterations in mesolimbic DA activity that persist beyond the duration of the stress.
Dopamine ( D A ) terminals within the medial prefrontal cortex (MPFC) possess several unique properties. Mild stressors such as exposure to an unfamiliar environment 26, brief food deprivation 4, conditioned fear and mild footshock s increase neurochemical markers of presynaptic D A activity exclusively in the MPFC. Although more intense or prolonged stress may induce similar alterations in nigrostriatal and mesolimbic D A systems, these generally occur later, are often smaller and may be less consistently detected than those in the MPFC ~°'23. Since the M P F C influences D A transmission in other D A terminal fields 1s'2°, the data suggest an important role for the M P F C in modulating the general stress response of brain D A systems. While partial D A depletion of the M P F C heightens the sensitivity of the mesolimbic D A system to acute footshock stress 7, the effects of mild, subchronic stress following a lesion of the M P F C are not known. In light of this, we have examined how deefferentation of the M P F C affects the response of mesolimbic and nigrostriatal D A systems to a repeated, mild stressor. Male S p r a g u e - D a w l e y rats (Zivic-Miller Labs) weighing 220-250 g were anesthetized with ketamine (70 mg/kg) and xylazine (6 mg/kg) i.m. Ibotenic acid (IA) (Sigma Chemical Co.) (5/~g/0.5 ~1 over 2.5 min) or an
equal volume of vehicle (0.1 M phosphate buffered saline, p H 7.4) was infused bilaterally through 26-gauge stainless steel cannulae at the coordinates16: A P + 3.5 mm, M L + 0.7 m m and V D - 3 . 5 m m relative to dura. Six weeks later, rats either underwent a 7-day course of twice daily normal saline (0.5 ml) injections (i.p.) or remained unhandled. There were thus 4 groups (n = 10-18/group) of animals in each cohort: Sham/No stress, Sham/stress, I A / N o Stress, IA/Stress. Cohorts were decapitated 1 or 7 days after the last injection. The nucleus accumbens and anterior corpus striatum were dissected out and frozen at - 7 0 °C until assay by mass spectroscopy 15. Twelve rats with I A lesions were anesthetized with chloral hydrate (300 mg/kg i.p.) and decapitated. Their brains were quick frozen. Cryostat cut sections were stained with Cresyl violet. Biochemical data from each region were analyzed by a two-factor (lesion and stress) multiple analysis of variance and N e w m a n - K e u l s post hoc tests. Brain regions from the cohorts sacrificed 1 or 7 days after the last saline injection were assayed at different times. Baseline variations preclude comparison between these cohorts. The lesion affected the M P F C without encroaching on the corpus striatum or nucleus accumbens, as described previously 13. No significant main effects of lesion or of
Correspondence: G.E. Jaskiw, WAW Bldg. Rm 500, NIMH Neuroscience Center, 2700 Martin Luther King Jr. Ave. SE, Washington, DC
20032, U.S.A.
322 DAY 1 NAS
•
CS
DA
125
100
8
7S
50 SHAM STRESS
IA NO STRESS
IA STRESS
SHAM
IA
STRESS
NO STRESS
SHAM STRESS
IA NO STRESS
IA
STRESS
DAY 7
uJ
o
8
SHAM STRESS
IA
NO STRESS
IA
STRESS
IA STRESS
Fig. 1. Neurochemical changes in rats with sham (SHAM) or ibotenic acid (IA) lesions of the medial prefrontal cortex, either 1 or 7 days after a 7-day course of no handling (NO STRESS), or twice daily saline injections (STRESS). NA, norepinephrine; DA, dopamine; DOPAC, dihydroxyphenylacetic acid; HVA, homovanillic acid; NAS, nucleus accumbens; CS, corpus striatum. * P < 0.05, IA/STRESS group significantly different from all other groups on Newman-Keuls post hoc tests after MANOVA was significant for the region. (n = 10-18/group).
stress were seen on neurotransmitter levels in either cohort. However, one day after the last injection a significant lesion × stress interaction was evident within the nucleus accumbens (F5,4o = 2.39, P < 0.05) where dihydroxyphenylacetic acid ( D O P A C ) was significantly elevated in the IA/Stress group compared to all other groups (P < 0.05) (Fig. 1). Furthermore, the lesion x stress interaction was still present (F5,43 = 5.15, P
321
Elsevier BRES 24402
Persistent elevations in dopamine and its metabolites in the nucleus accumbens after mild subchronic stress in rats with ibotenic acid lesions of the medial prefrontal cortex G.E. Jaskiw 1, F.K. K a r o u m 2 and D . R . W e i n b e r g e r 1 Clinical Brain Disorders Branch and 2Neuropsychiatry Branch, Intramural Research Program, National Institute of Mental Health, N1MH Neuroscience Center at St. Elizabeths, Washington, DC 20032 (U.S.A.)
(Accepted 21 August 1990) Key words: Prefrontal cortex; Ibotenic acid; Dihydroxyphenylacetic acid; Stress; Nucleus accumbens
This study assessed the possible influence of the medial prefrontal cortex (MPFC) on the response of subcortical dopamine (DA) systems to subchronic, mild stress. DA and its metabolites as well as noradrenaline were assayed in the nucleus accumbens and corpus striatum, 1 and 7 days after one week of daily intraperitoneal saline injections (Stress) or no handling (No stress), in rats with sham (Sham) or ibotenic acid (IA) lesions of the MPFC. One day after the last saline injection the level of dihydroxyphenylacetic acid (DOPAC) was elevated in the nucleus accumbens of IA/Stress rats in comparison to the Sham/No stress, Sham/Stress, and IA/No Stress groups. Levels of mesolimbic DA, DOPAC and homovanillic acid were still elevated 7 days after the last injection in IA/Stress animals in comparison to all other groups. There were no other significant differences between the groups. The data suggest that in rats with MPFC impairment, mild subchronic stress can induce alterations in mesolimbic DA activity that persist beyond the duration of the stress.
Dopamine ( D A ) terminals within the medial prefrontal cortex (MPFC) possess several unique properties. Mild stressors such as exposure to an unfamiliar environment 26, brief food deprivation 4, conditioned fear and mild footshock s increase neurochemical markers of presynaptic D A activity exclusively in the MPFC. Although more intense or prolonged stress may induce similar alterations in nigrostriatal and mesolimbic D A systems, these generally occur later, are often smaller and may be less consistently detected than those in the MPFC ~°'23. Since the M P F C influences D A transmission in other D A terminal fields 1s'2°, the data suggest an important role for the M P F C in modulating the general stress response of brain D A systems. While partial D A depletion of the M P F C heightens the sensitivity of the mesolimbic D A system to acute footshock stress 7, the effects of mild, subchronic stress following a lesion of the M P F C are not known. In light of this, we have examined how deefferentation of the M P F C affects the response of mesolimbic and nigrostriatal D A systems to a repeated, mild stressor. Male S p r a g u e - D a w l e y rats (Zivic-Miller Labs) weighing 220-250 g were anesthetized with ketamine (70 mg/kg) and xylazine (6 mg/kg) i.m. Ibotenic acid (IA) (Sigma Chemical Co.) (5/~g/0.5 ~1 over 2.5 min) or an
equal volume of vehicle (0.1 M phosphate buffered saline, p H 7.4) was infused bilaterally through 26-gauge stainless steel cannulae at the coordinates16: A P + 3.5 mm, M L + 0.7 m m and V D - 3 . 5 m m relative to dura. Six weeks later, rats either underwent a 7-day course of twice daily normal saline (0.5 ml) injections (i.p.) or remained unhandled. There were thus 4 groups (n = 10-18/group) of animals in each cohort: Sham/No stress, Sham/stress, I A / N o Stress, IA/Stress. Cohorts were decapitated 1 or 7 days after the last injection. The nucleus accumbens and anterior corpus striatum were dissected out and frozen at - 7 0 °C until assay by mass spectroscopy 15. Twelve rats with I A lesions were anesthetized with chloral hydrate (300 mg/kg i.p.) and decapitated. Their brains were quick frozen. Cryostat cut sections were stained with Cresyl violet. Biochemical data from each region were analyzed by a two-factor (lesion and stress) multiple analysis of variance and N e w m a n - K e u l s post hoc tests. Brain regions from the cohorts sacrificed 1 or 7 days after the last saline injection were assayed at different times. Baseline variations preclude comparison between these cohorts. The lesion affected the M P F C without encroaching on the corpus striatum or nucleus accumbens, as described previously 13. No significant main effects of lesion or of
Correspondence: G.E. Jaskiw, WAW Bldg. Rm 500, NIMH Neuroscience Center, 2700 Martin Luther King Jr. Ave. SE, Washington, DC
20032, U.S.A.
322 DAY 1 NAS
•
CS
DA
125
100
8
7S
50 SHAM STRESS
IA NO STRESS
IA STRESS
SHAM
IA
STRESS
NO STRESS
SHAM STRESS
IA NO STRESS
IA
STRESS
DAY 7
uJ
o
8
SHAM STRESS
IA
NO STRESS
IA
STRESS
IA STRESS
Fig. 1. Neurochemical changes in rats with sham (SHAM) or ibotenic acid (IA) lesions of the medial prefrontal cortex, either 1 or 7 days after a 7-day course of no handling (NO STRESS), or twice daily saline injections (STRESS). NA, norepinephrine; DA, dopamine; DOPAC, dihydroxyphenylacetic acid; HVA, homovanillic acid; NAS, nucleus accumbens; CS, corpus striatum. * P < 0.05, IA/STRESS group significantly different from all other groups on Newman-Keuls post hoc tests after MANOVA was significant for the region. (n = 10-18/group).
stress were seen on neurotransmitter levels in either cohort. However, one day after the last injection a significant lesion × stress interaction was evident within the nucleus accumbens (F5,4o = 2.39, P < 0.05) where dihydroxyphenylacetic acid ( D O P A C ) was significantly elevated in the IA/Stress group compared to all other groups (P < 0.05) (Fig. 1). Furthermore, the lesion x stress interaction was still present (F5,43 = 5.15, P
