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Ibotenic acid lesions of prefrontal cortex do not prevent expression of behavioral sensitization to amphetamine
BEHAVIOURAL BRAIN RESEARCH ELSEVIER
BehaviouralBrainResearch84 (1997) 285-289
Research report
Ibotenic acid lesions of prefrontal cortex do not prevent expression of behavioral sensitization to amphetamine Yong Li, Marina E. Wolf * Department of Neuroscience, Finch Universityof Health Sciences~The Chicago Medical School 3333 Green Bay Road, North Chicago, 1L 60064-3095 USA Received 14 May 1996; revised 17 July 1996; accepted 17 July 1996
Abstract
We have shown previously that ibotenic acid lesions of the prefrontal cortex, performed prior to repeated amphetamine administration, do not affect sensitization of stereotyped behaviors but do prevent sensitization of post-stereotypy locomotor hyperactivity [Wolf et al., Neuroscience, 69 (1995) 417-439]. This could reflect an effect of the lesion on either development or expression of locomotor sensitization. To test the latter possibility, rats were treated with repeated amphetamine injections and tested to establish behavioral sensitization. Then, half received ibotenic acid lesions of prefrontal cortex and half received sham lesions. A second amphetamine challenge, 7 days later, demonstrated that the lesion failed to prevent expression of sensitization. Together with previous results, this suggests that intrinsic neurons of prefrontal cortex, most likely those sending excitatory amino acid-containing projections to the ventral tegrnental area, are required for the development but not the expression of behavioral sensitization to amphetamine. Keywords: Amphetamine;Behavioralsensitization;Excitatoryaminoacids; Ibotenicacid; Prefrontalcortex;Ventraltegmentalarea
Behavioral sensitization refers to the progressive enhancement of the locomotor stimulatory properties of psychomotor stimulants such as amphetamine during their repeated administration, and may provide a model for both drug craving and psychosis [23,24]. Sensitization is associated with functional alterations in dopamine (DA) transmission, particularly in the mesoaccumbens DA pathway. Alterations in the ventral tegmental area (VTA), where this pathway originates, are necessary for initiation of sensitization, while alterations within the nucleus accumbens (NAc), where it terminates, are necessary for its expression [1,7,19,21,35,36]. Excitatory amino acid neurotransmitters (EAAs) also play a critical role in sensitization, since antagonists of N-methyl-D-aspartate (NMDA) receptors prevent the development of sensitization when coadministered repeatedly with amphetamine or cocaine [4,5,8,1013,25,29,31,39,40,43], as well as with methamphetamine [18] or morphine [6,40]. MK-801 also blocks cellular changes in the mesoaccumbens DA system that * Correspondingauthor. Fax:(1) (847) 578-3428.
normally accompany the development of behavioral sensitization [42]. AMPA receptors are also involved in the development and expression of behavioral sensitization, although there are differences between stimulants and perhaps between mice and rats ([12,13]; Y. Li, A.J. Vartanian, F.J. White, C.-J. Xue and M.E. Wolf, unpublished observations). Although it is possible that EAAs play only a permissive role in sensitization, some studies suggest that moderate doses of psychomotor stimulants may increase glutamate efflux in VTA, NAc and dorsal striatum [9,16,22,45]. Moreover, sensitization is accompanied by alterations in: (1) glutamate efflux in prefrontal cortex (PFC) [30], (2) EAA receptor expression in VTA, NAc and PFC [2,44], and (3) electrophysiological sensitivity of VTA and NAc neurons to the excitatory effects of glutamate [38]. Repeated amphetamine administration elicits sensitization of both stereotypy and post-stereotypy locomotor hyperactivity. We have shown previously that ibotenic acid lesions of PFC, performed prior to repeated amphetamine treatment, prevent sensitization of poststereotypy locomotor hyperactivity but do not affect sensitization of stereotypy [43]. The idea that sensitiza-
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Y. LL M.E. Wolf/Behavioural Brain Research 84 (1997) 285-289
tion of stereotypy and post-stereotypy locomotor hyperactivity are dissociable events is supported by previous work [ 15]. A question left unanswered by our previous study is whether PFC lesions prevent the development of locomotor sensitization, or whether they permit its development but interfere with its expression. This is an important question, because initiation and expression of sensitization occur in different brain regions (see above) and are associated with different alterations in DA systems (see [41,42]). Thus, depending on whether PFC lesions affect development or expression, different hypotheses will be suggested regarding the role of PFC in the circuitry of sensitization. To address this question, we determined if ibotenic acid lesions of PFC performed after the establishment of amphetamine sensitization prevented subsequent expression of sensitization. Protocols for amphetamine sensitization and ibotenic acid lesions were identical to those used in our previous study [43]. Male Sprague-Dawley rats (Harlan, Indianapolis, IN) weighing 250-300 g were used. All procedures were in strict accordance with the NIH Guide for the Care and Use of Laboratory Animals and were approved by the Institutional Animal Care and Use Committee of Finch University of Health Sciences/The Chicago Medical School. Naive rats were handled for 3-4 days before experiments began. Behavioral testing was performed using photobeam frames (San Diego Instruments, San Diego, CA) located in a separate testing room within the colony. Each frame was 50 x 30cm, with three photocells (separated by 10.5cm) located lengthwise, 3.5 cm above the floor. Standard polyethylene rat cages were set inside each frame. Activity was measured as ambulation counts, which are registered upon breaking of consecutive photobeams and therefore distinguish horizontal locomotion from repetitive interruptions of the same beam produced by stereotyped movements. On day 0, rats were placed in photobeam cages, habituated for 30 min, and injected with water. Activity was monitored for 2 h. This water pretest provided a measure of basal activity. On the following day (day 1), after 30 min of habituation, all rats were injected (s.c.) with 2.5 mg/kg (+)-amphetamine (dose refers to free base). Activity was monitored for 4 h. Stereotyped behaviors were scored by an observer during the first hour. Each rat was scored for 1 min during each 20 min interval for the amount of time spent in: (1) in-place rearing (both front paws off the ground) and (2) in-place, nose-down stereotyped sniffing. Each rat was considered to have spent an interval in continuous rearing if rearing was observed during 58 s or more of the 60-s interval. Each rat was considered to have spent an interval in continuous nose-down sniffing if sniffing was observed during 50 s or more of the 60-s interval. Criteria were more stringent for rearing than sniffing to
distinguish between rats truly engaged in continuous rearing (characteristic of sensitized rats) and rats exhibiting a pattern of rapid up-and-down rearing (characteristic of day 1 rats). Rats exhibiting the latter pattern could often score 40-55 s with both front paws off the ground, despite frequent but brief periods with all paws down. Continuous performance of either behavior (as defined above) has been shown to provide an excellent indicator of sensitized behavioral responding to amphetamine [43]. On days 2-6, amphetamine injections were continued in home cages. No injections were given on day 7. On day 8, all rats were again placed in photobeam cages, habituated for 30 min, and then challenged with 2.5 mg/kg amphetamine to test for sensitization (based on comparison to day 1 responses). Activity was monitored as ambulation counts and by observation. On day 9, half of the rats received ibotenic acid lesions of PFC and half received sham lesions. Rats were assigned to lesion or sham groups so as to create two groups with approximately equivalent day 8 responses (see Fig. 1). Ibotenic acid or an equal volume of vehicle (0.1 M phosphate buffered saline, pH 7.4) was infused (5 #g/0.5 pl/2.5 min) bilaterally using a 1 #1 Hamilton syringe at: A +3.2, L +0.7, V -3.4. Coordinates are expressed relative to Bregrna [20] and to the skull surface. Syringes remained in place for 5 min after the infusion. One week later (day 16), all rats were placed in photobeam cages, habituated for 30 min, and challenged with 2.5 mg/kg amphetamine to test for post-lesion expression of behavioral sensitization. Lesion boundaries, confirmed by examination of 40 #m sections stained with Cresyl Violet, were extremely similar to those we have illustrated previously [43]. Briefly, the average lesion extended from Bregma 4.7 to 2.2 [20]. In all rats, an area of central cavitation was surrounded by an area of neuronal cell loss and gliosis. Within the PFC, cingulate cortex area 3 and infralimbic cortex were virtually destroyed in all rats. Portions of the medial and ventral orbital cortices, cingulate cortex areas 1 and 2, and small portions of frontal cortex area 2 were also affected by most lesions. Based on a previous study of the topographical organization of the efferent projections of the rat PFC [27], the present lesions should have been sufficient to eliminate the majority of projections to the NAc, medial striatum, VTA, and substantia nigra. Fig. 1 compares the response of rats to their first amphetamine injection (day 1) and their pre-lesion response to amphetamine challenge (day 8). As described above, rats were assigned to lesion or sham groups after the day 8 test was run so as to create two groups with approximately equivalent day 8 responses. Day 8 responses of each group are presented separately in Fig. 1 to demonstrate the equivalance of these groups prior to ibotenic acid or sham lesions on day 9. During the first hour of the 4 h test on day 8, rats showed a more rapid and pronounced decrease in ambulation
Y. LL M.E. Wolf/Behavioural Brain Research 84 (1997)285-289
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- O - Day 1 (all rats) --I1-- Day 8 (PFC lesion group - before lesion) Day 8 (sham lesion group - before lesion)
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Fig. 1. Repeated administration of amphetamine elicits sensitization of stereotypy and post-stereotypy locomotor hyperactivity. Fourteen rats were treated on days 1-6 with 2.5 mg/kg amphetamine and challenged with the same dose of amphetamine on day 8. Horizontal locomotor activity was measured on days 1 and 8 and expressed as ambulation counts. Rats were subsequently divided into two groups, one to receive sham lesions of PFC on day 9 and the other to receive ibotenic acid lesions, so as to create two groups with approximately equivalent day 8 responses. A between group comparison of the day 8 responses of rats assigned to sham and lesion groups confirmed that they were not significantly different [ANOVA with time as the repeated measure, group x time effect: F(23,276)=0.86, P=0.65]. However, rats in both groups exhibited sensitization of stereotyped behaviors and post-stereotypy locomotor hyperactivity on day 8. Thus, day 8 responses of both groups were significantly different from their respective day 1 responses, as determined by within group comparison [ANOVA with time as the repeated measure, group x time effect: sham group (n=7), F(23.230)=4.22, P<0.00001; lesion group (n=7), F(23.230)=6.07, P<0.00001]. Group means at each time point were compared using t-tests with Bonferroni corrections (P<0.05). *: Day 1 and day 8 responses differed significantly for both sham and lesion groups. +: Day 1 and day 8 responses differed significantly only for the lesion group. #: Day 1 and day 8 responses differed significantly only for the sham group.
counts than on day 1, due to more rapid entry into stereotyped behavior and exhibition of more focused stereotypies. During the second and third hours of the day 8 test, rats exhibited significant enhancement of post-stereotypy locomotor hyperactivity as measured by ambulation counts. Sensitization of stereotyped behaviors was confirmed by observation. Following the first exposure to amphetamine, rats typically exhibit exploratory locomotor activity with bursts of up-and-down rearing and nose-up sniffing. Thus, of the 42 possible intervals scored for all rats on day 1 (14 rats, 3 intervals/rat in the 60 min observation period), only 1/42 was scored positive for continuous rearing and 0/42 for continuous nose-down sniffing. In contrast, on day 8, 17/21 intervals were scored positive for either continuous rearing or nose-down sniffing for those rats
287
assigned to the lesion group (n=7), while 14/21 were scored positive for the same measures for rats assigned to the sham group (n = 7). Both groups were significantly different from day 1 (P<0.05, Fisher exact probability test). After these groups received either ibotenic acid or sham lesions of PFC on day 9, they were challenged again with amphetamine on day 16. Fig. 2 compares the day 1 response of all rats to the day 16 responses of sham and ibotenic acid lesioned groups. Neither ibotenic nor sham lesions of PFC interfered with expression of amphetamine sensitization. Sensitization of stereotypy in both groups is evident from decreased ambulation counts during the first 90 min of the test on day 16 relative to day 1, as well as from observational data (15/21 intervals scored positive for either continuous rearing or nose-down sniffing for lesioned rats on day 16, and 18/21 for shams; both significantly different from day 1, P<0.05, Fisher exact probability test). --<3-- Day 1 (all rats) - - I - - Day 16 (PFC lesion group - after lesion) Day 16 (sham lesion group - after lesion) 8O
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Time (rain) Fig. 2. Bilateral ibotenic acid lesions of PFC do not prevent the expression of behavioral sensitization to amphetamine. After repeated amphetamine treatment (2.5 mg/kg, days 1-6) and amphetamine challenge on day 8 to test for sensitization, rats received either ibotenic acid ( n = 7 ) or sham lesions ( n = 7 ) of PFC on day 9. On day 16, rats were again challenged with amphetamine (2.5 mg/kg). A between group comparison showed that sham and lesioned groups did not differ significantly in their response to amphetamine challenge on day 16 [ANOVA with time as the repeated measure, group x time effect: F(23.276)= 1.07; P=0.38]. A within group comparison confirmed that both sham and lesioned groups remained sensitized on day 16 as compared to their respective responses on day 1 [ANOVA with time as the repeated measure, group x time effect: sham group (n=7), F(23.23o)=3.67, P<0.00001; lesion group (n=7), F(23,230)=8.71, P<0.00001]. Group means at each time point were compared using t-tests with Bonferroni corrections (P<0.05). *: Day 1 and day 8 responses differed significantly for both sham and lesion groups. +: Day 1 and day 8 responses differed significantly only for the lesion group. #: Day 1 and day 8 responses differed significantly only for the sham group.
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Y. Li, M.E. Wolf/Behavioural Brain Research 84 (1997)285-289
Sensitization of post-stereotypy locomotor hyperactivity is evident during the subsequent 2 h for both sham and lesioned groups. Interestingly, both sham and lesioned groups exhibited more intense sensitization on day 16 than day 8, evident as a longer-lasting decrease in ambulation counts during the period of stereotypy (compare Figs. 1 and 2). ANOVA with time as the repeated measure indicated a highly significant difference between the pooled responses of sham and lesioned groups on day 8 and their pooled responses on day 16 [group x time effect; F(23,598) = 7.4, P < 0.00001 ]. Previous studies have similarly reported intensification of amphetamine sensitization with increasing time of withdrawal [14,15,23]. Together with previous results, the present findings suggest that intrinsic neurons of PFC are required for the development but not the expression of behavioral sensitization to amphetamine. Given that amphetamine sensitization is initiated in the VTA (above) and is prevented by intra-VTA administration of N M D A antagonists [8], the involvement of PFC in sensitization probably reflects the fact that PFC sends monosynaptic EAA inputs to VTA DA neurons [28] that are important in regulating their firing rate and firing pattern [3,17, 32, 34]. At physiological concentrations, glutamate excites VTA DA neurons via a preferential effect on N M D A receptors [37]. Thus, ibotenic acid lesions of PFC [43] and systemic or intra-VTA administration of N M D A antagonists (see above), both of which prevent development of locomotor sensitization, are probably working in the same way, that is, by depriving DA neurons of their major source of excitatory drive. The present findings indicate another similarity between PFC lesions and N M D A antagonists, that is, neither the lesions (present results) nor N M D A antagonists [11,12,43] are capable of preventing the expression of behavioral sensitization. It is possible that normal levels of tonic activity in PFC-VTA projections are sufficient to allow sensitization to develop. In other words, these projections may play only a permissive role. Alternatively, development of sensitization may require psychostimulant-induced alterations in the activity of EAA-containing projections from PFC to VTA, and/or in the responsiveness of VTA DA neurons to their input. Supporting this possibility are studies demonstrating the ability of electrical kindling of PFC to produce behavioral sensitization to cocaine [26], increased levels of GIuR1 mRNA in PFC of amphetamine-pretreated rats [44], increased levels of GIuR1 and NR1 subunits in VTA of cocaine-pretreated rats [2], and enhanced reactivity of VTA DA neurons in amphetamine-pretreated rats to electrical stimulation of PFC [33]. These studies support the hypothesis that increased excitation of VTA DA neurons by PFC, perhaps as a result of compensatory changes in EAA
receptor expression in VTA and PFC, are important in the development of sensitization.
Acknowledgement This work was supported by USPHS grant DA07735 from the National Institute on Drug Abuse. We thank Chang-Jiang Xue for his contributions to this study.
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BehaviouralBrainResearch84 (1997) 285-289
Research report
Ibotenic acid lesions of prefrontal cortex do not prevent expression of behavioral sensitization to amphetamine Yong Li, Marina E. Wolf * Department of Neuroscience, Finch Universityof Health Sciences~The Chicago Medical School 3333 Green Bay Road, North Chicago, 1L 60064-3095 USA Received 14 May 1996; revised 17 July 1996; accepted 17 July 1996
Abstract
We have shown previously that ibotenic acid lesions of the prefrontal cortex, performed prior to repeated amphetamine administration, do not affect sensitization of stereotyped behaviors but do prevent sensitization of post-stereotypy locomotor hyperactivity [Wolf et al., Neuroscience, 69 (1995) 417-439]. This could reflect an effect of the lesion on either development or expression of locomotor sensitization. To test the latter possibility, rats were treated with repeated amphetamine injections and tested to establish behavioral sensitization. Then, half received ibotenic acid lesions of prefrontal cortex and half received sham lesions. A second amphetamine challenge, 7 days later, demonstrated that the lesion failed to prevent expression of sensitization. Together with previous results, this suggests that intrinsic neurons of prefrontal cortex, most likely those sending excitatory amino acid-containing projections to the ventral tegrnental area, are required for the development but not the expression of behavioral sensitization to amphetamine. Keywords: Amphetamine;Behavioralsensitization;Excitatoryaminoacids; Ibotenicacid; Prefrontalcortex;Ventraltegmentalarea
Behavioral sensitization refers to the progressive enhancement of the locomotor stimulatory properties of psychomotor stimulants such as amphetamine during their repeated administration, and may provide a model for both drug craving and psychosis [23,24]. Sensitization is associated with functional alterations in dopamine (DA) transmission, particularly in the mesoaccumbens DA pathway. Alterations in the ventral tegmental area (VTA), where this pathway originates, are necessary for initiation of sensitization, while alterations within the nucleus accumbens (NAc), where it terminates, are necessary for its expression [1,7,19,21,35,36]. Excitatory amino acid neurotransmitters (EAAs) also play a critical role in sensitization, since antagonists of N-methyl-D-aspartate (NMDA) receptors prevent the development of sensitization when coadministered repeatedly with amphetamine or cocaine [4,5,8,1013,25,29,31,39,40,43], as well as with methamphetamine [18] or morphine [6,40]. MK-801 also blocks cellular changes in the mesoaccumbens DA system that * Correspondingauthor. Fax:(1) (847) 578-3428.
normally accompany the development of behavioral sensitization [42]. AMPA receptors are also involved in the development and expression of behavioral sensitization, although there are differences between stimulants and perhaps between mice and rats ([12,13]; Y. Li, A.J. Vartanian, F.J. White, C.-J. Xue and M.E. Wolf, unpublished observations). Although it is possible that EAAs play only a permissive role in sensitization, some studies suggest that moderate doses of psychomotor stimulants may increase glutamate efflux in VTA, NAc and dorsal striatum [9,16,22,45]. Moreover, sensitization is accompanied by alterations in: (1) glutamate efflux in prefrontal cortex (PFC) [30], (2) EAA receptor expression in VTA, NAc and PFC [2,44], and (3) electrophysiological sensitivity of VTA and NAc neurons to the excitatory effects of glutamate [38]. Repeated amphetamine administration elicits sensitization of both stereotypy and post-stereotypy locomotor hyperactivity. We have shown previously that ibotenic acid lesions of PFC, performed prior to repeated amphetamine treatment, prevent sensitization of poststereotypy locomotor hyperactivity but do not affect sensitization of stereotypy [43]. The idea that sensitiza-
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tion of stereotypy and post-stereotypy locomotor hyperactivity are dissociable events is supported by previous work [ 15]. A question left unanswered by our previous study is whether PFC lesions prevent the development of locomotor sensitization, or whether they permit its development but interfere with its expression. This is an important question, because initiation and expression of sensitization occur in different brain regions (see above) and are associated with different alterations in DA systems (see [41,42]). Thus, depending on whether PFC lesions affect development or expression, different hypotheses will be suggested regarding the role of PFC in the circuitry of sensitization. To address this question, we determined if ibotenic acid lesions of PFC performed after the establishment of amphetamine sensitization prevented subsequent expression of sensitization. Protocols for amphetamine sensitization and ibotenic acid lesions were identical to those used in our previous study [43]. Male Sprague-Dawley rats (Harlan, Indianapolis, IN) weighing 250-300 g were used. All procedures were in strict accordance with the NIH Guide for the Care and Use of Laboratory Animals and were approved by the Institutional Animal Care and Use Committee of Finch University of Health Sciences/The Chicago Medical School. Naive rats were handled for 3-4 days before experiments began. Behavioral testing was performed using photobeam frames (San Diego Instruments, San Diego, CA) located in a separate testing room within the colony. Each frame was 50 x 30cm, with three photocells (separated by 10.5cm) located lengthwise, 3.5 cm above the floor. Standard polyethylene rat cages were set inside each frame. Activity was measured as ambulation counts, which are registered upon breaking of consecutive photobeams and therefore distinguish horizontal locomotion from repetitive interruptions of the same beam produced by stereotyped movements. On day 0, rats were placed in photobeam cages, habituated for 30 min, and injected with water. Activity was monitored for 2 h. This water pretest provided a measure of basal activity. On the following day (day 1), after 30 min of habituation, all rats were injected (s.c.) with 2.5 mg/kg (+)-amphetamine (dose refers to free base). Activity was monitored for 4 h. Stereotyped behaviors were scored by an observer during the first hour. Each rat was scored for 1 min during each 20 min interval for the amount of time spent in: (1) in-place rearing (both front paws off the ground) and (2) in-place, nose-down stereotyped sniffing. Each rat was considered to have spent an interval in continuous rearing if rearing was observed during 58 s or more of the 60-s interval. Each rat was considered to have spent an interval in continuous nose-down sniffing if sniffing was observed during 50 s or more of the 60-s interval. Criteria were more stringent for rearing than sniffing to
distinguish between rats truly engaged in continuous rearing (characteristic of sensitized rats) and rats exhibiting a pattern of rapid up-and-down rearing (characteristic of day 1 rats). Rats exhibiting the latter pattern could often score 40-55 s with both front paws off the ground, despite frequent but brief periods with all paws down. Continuous performance of either behavior (as defined above) has been shown to provide an excellent indicator of sensitized behavioral responding to amphetamine [43]. On days 2-6, amphetamine injections were continued in home cages. No injections were given on day 7. On day 8, all rats were again placed in photobeam cages, habituated for 30 min, and then challenged with 2.5 mg/kg amphetamine to test for sensitization (based on comparison to day 1 responses). Activity was monitored as ambulation counts and by observation. On day 9, half of the rats received ibotenic acid lesions of PFC and half received sham lesions. Rats were assigned to lesion or sham groups so as to create two groups with approximately equivalent day 8 responses (see Fig. 1). Ibotenic acid or an equal volume of vehicle (0.1 M phosphate buffered saline, pH 7.4) was infused (5 #g/0.5 pl/2.5 min) bilaterally using a 1 #1 Hamilton syringe at: A +3.2, L +0.7, V -3.4. Coordinates are expressed relative to Bregrna [20] and to the skull surface. Syringes remained in place for 5 min after the infusion. One week later (day 16), all rats were placed in photobeam cages, habituated for 30 min, and challenged with 2.5 mg/kg amphetamine to test for post-lesion expression of behavioral sensitization. Lesion boundaries, confirmed by examination of 40 #m sections stained with Cresyl Violet, were extremely similar to those we have illustrated previously [43]. Briefly, the average lesion extended from Bregma 4.7 to 2.2 [20]. In all rats, an area of central cavitation was surrounded by an area of neuronal cell loss and gliosis. Within the PFC, cingulate cortex area 3 and infralimbic cortex were virtually destroyed in all rats. Portions of the medial and ventral orbital cortices, cingulate cortex areas 1 and 2, and small portions of frontal cortex area 2 were also affected by most lesions. Based on a previous study of the topographical organization of the efferent projections of the rat PFC [27], the present lesions should have been sufficient to eliminate the majority of projections to the NAc, medial striatum, VTA, and substantia nigra. Fig. 1 compares the response of rats to their first amphetamine injection (day 1) and their pre-lesion response to amphetamine challenge (day 8). As described above, rats were assigned to lesion or sham groups after the day 8 test was run so as to create two groups with approximately equivalent day 8 responses. Day 8 responses of each group are presented separately in Fig. 1 to demonstrate the equivalance of these groups prior to ibotenic acid or sham lesions on day 9. During the first hour of the 4 h test on day 8, rats showed a more rapid and pronounced decrease in ambulation
Y. LL M.E. Wolf/Behavioural Brain Research 84 (1997)285-289
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- O - Day 1 (all rats) --I1-- Day 8 (PFC lesion group - before lesion) Day 8 (sham lesion group - before lesion)
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Fig. 1. Repeated administration of amphetamine elicits sensitization of stereotypy and post-stereotypy locomotor hyperactivity. Fourteen rats were treated on days 1-6 with 2.5 mg/kg amphetamine and challenged with the same dose of amphetamine on day 8. Horizontal locomotor activity was measured on days 1 and 8 and expressed as ambulation counts. Rats were subsequently divided into two groups, one to receive sham lesions of PFC on day 9 and the other to receive ibotenic acid lesions, so as to create two groups with approximately equivalent day 8 responses. A between group comparison of the day 8 responses of rats assigned to sham and lesion groups confirmed that they were not significantly different [ANOVA with time as the repeated measure, group x time effect: F(23,276)=0.86, P=0.65]. However, rats in both groups exhibited sensitization of stereotyped behaviors and post-stereotypy locomotor hyperactivity on day 8. Thus, day 8 responses of both groups were significantly different from their respective day 1 responses, as determined by within group comparison [ANOVA with time as the repeated measure, group x time effect: sham group (n=7), F(23.230)=4.22, P<0.00001; lesion group (n=7), F(23.230)=6.07, P<0.00001]. Group means at each time point were compared using t-tests with Bonferroni corrections (P<0.05). *: Day 1 and day 8 responses differed significantly for both sham and lesion groups. +: Day 1 and day 8 responses differed significantly only for the lesion group. #: Day 1 and day 8 responses differed significantly only for the sham group.
counts than on day 1, due to more rapid entry into stereotyped behavior and exhibition of more focused stereotypies. During the second and third hours of the day 8 test, rats exhibited significant enhancement of post-stereotypy locomotor hyperactivity as measured by ambulation counts. Sensitization of stereotyped behaviors was confirmed by observation. Following the first exposure to amphetamine, rats typically exhibit exploratory locomotor activity with bursts of up-and-down rearing and nose-up sniffing. Thus, of the 42 possible intervals scored for all rats on day 1 (14 rats, 3 intervals/rat in the 60 min observation period), only 1/42 was scored positive for continuous rearing and 0/42 for continuous nose-down sniffing. In contrast, on day 8, 17/21 intervals were scored positive for either continuous rearing or nose-down sniffing for those rats
287
assigned to the lesion group (n=7), while 14/21 were scored positive for the same measures for rats assigned to the sham group (n = 7). Both groups were significantly different from day 1 (P<0.05, Fisher exact probability test). After these groups received either ibotenic acid or sham lesions of PFC on day 9, they were challenged again with amphetamine on day 16. Fig. 2 compares the day 1 response of all rats to the day 16 responses of sham and ibotenic acid lesioned groups. Neither ibotenic nor sham lesions of PFC interfered with expression of amphetamine sensitization. Sensitization of stereotypy in both groups is evident from decreased ambulation counts during the first 90 min of the test on day 16 relative to day 1, as well as from observational data (15/21 intervals scored positive for either continuous rearing or nose-down sniffing for lesioned rats on day 16, and 18/21 for shams; both significantly different from day 1, P<0.05, Fisher exact probability test). --<3-- Day 1 (all rats) - - I - - Day 16 (PFC lesion group - after lesion) Day 16 (sham lesion group - after lesion) 8O
#
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Time (rain) Fig. 2. Bilateral ibotenic acid lesions of PFC do not prevent the expression of behavioral sensitization to amphetamine. After repeated amphetamine treatment (2.5 mg/kg, days 1-6) and amphetamine challenge on day 8 to test for sensitization, rats received either ibotenic acid ( n = 7 ) or sham lesions ( n = 7 ) of PFC on day 9. On day 16, rats were again challenged with amphetamine (2.5 mg/kg). A between group comparison showed that sham and lesioned groups did not differ significantly in their response to amphetamine challenge on day 16 [ANOVA with time as the repeated measure, group x time effect: F(23.276)= 1.07; P=0.38]. A within group comparison confirmed that both sham and lesioned groups remained sensitized on day 16 as compared to their respective responses on day 1 [ANOVA with time as the repeated measure, group x time effect: sham group (n=7), F(23.23o)=3.67, P<0.00001; lesion group (n=7), F(23,230)=8.71, P<0.00001]. Group means at each time point were compared using t-tests with Bonferroni corrections (P<0.05). *: Day 1 and day 8 responses differed significantly for both sham and lesion groups. +: Day 1 and day 8 responses differed significantly only for the lesion group. #: Day 1 and day 8 responses differed significantly only for the sham group.
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Y. Li, M.E. Wolf/Behavioural Brain Research 84 (1997)285-289
Sensitization of post-stereotypy locomotor hyperactivity is evident during the subsequent 2 h for both sham and lesioned groups. Interestingly, both sham and lesioned groups exhibited more intense sensitization on day 16 than day 8, evident as a longer-lasting decrease in ambulation counts during the period of stereotypy (compare Figs. 1 and 2). ANOVA with time as the repeated measure indicated a highly significant difference between the pooled responses of sham and lesioned groups on day 8 and their pooled responses on day 16 [group x time effect; F(23,598) = 7.4, P < 0.00001 ]. Previous studies have similarly reported intensification of amphetamine sensitization with increasing time of withdrawal [14,15,23]. Together with previous results, the present findings suggest that intrinsic neurons of PFC are required for the development but not the expression of behavioral sensitization to amphetamine. Given that amphetamine sensitization is initiated in the VTA (above) and is prevented by intra-VTA administration of N M D A antagonists [8], the involvement of PFC in sensitization probably reflects the fact that PFC sends monosynaptic EAA inputs to VTA DA neurons [28] that are important in regulating their firing rate and firing pattern [3,17, 32, 34]. At physiological concentrations, glutamate excites VTA DA neurons via a preferential effect on N M D A receptors [37]. Thus, ibotenic acid lesions of PFC [43] and systemic or intra-VTA administration of N M D A antagonists (see above), both of which prevent development of locomotor sensitization, are probably working in the same way, that is, by depriving DA neurons of their major source of excitatory drive. The present findings indicate another similarity between PFC lesions and N M D A antagonists, that is, neither the lesions (present results) nor N M D A antagonists [11,12,43] are capable of preventing the expression of behavioral sensitization. It is possible that normal levels of tonic activity in PFC-VTA projections are sufficient to allow sensitization to develop. In other words, these projections may play only a permissive role. Alternatively, development of sensitization may require psychostimulant-induced alterations in the activity of EAA-containing projections from PFC to VTA, and/or in the responsiveness of VTA DA neurons to their input. Supporting this possibility are studies demonstrating the ability of electrical kindling of PFC to produce behavioral sensitization to cocaine [26], increased levels of GIuR1 mRNA in PFC of amphetamine-pretreated rats [44], increased levels of GIuR1 and NR1 subunits in VTA of cocaine-pretreated rats [2], and enhanced reactivity of VTA DA neurons in amphetamine-pretreated rats to electrical stimulation of PFC [33]. These studies support the hypothesis that increased excitation of VTA DA neurons by PFC, perhaps as a result of compensatory changes in EAA
receptor expression in VTA and PFC, are important in the development of sensitization.
Acknowledgement This work was supported by USPHS grant DA07735 from the National Institute on Drug Abuse. We thank Chang-Jiang Xue for his contributions to this study.
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