Department of Neuropharmacology, Zoological Institute, University of Tübingen, Mohlstrasse 54/1, D-72074 Tübingen, Germany
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Abstract |
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Introduction |
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In the case of the mPFC, excitotoxic lesions of the dorsal but not the ventral mPFC disrupted the expression of cocaine- induced sensitization (Pierce et al., 1998). On the other hand, large excitotoxic lesions of the mPFC did not affect the expression (Li et al., 1999a
) but blocked the development of cocaine sensitization (Li et al., 1999b
). Such lesions also had no effect on the expression and development of sensitization of amphetamine-induced stereotypy but blocked the development of sensitization of post-stereotypy hyperlocomotion (Wolf et al., 1995
; Li and Wolf, 1997
). Thus, dissociations with respect to development and expression of sensitization, with respect to cocaine and amphetamine, and with respect to the involvement of dorsal versus ventral portions of the mPFC appear to exist.
The mPFC is not a homogenous structure but can be subdivided into at least three subareas, the infralimbic (il), the prelimbic (pl) and the anterior cingulate area (cg) (Van Eden and Uylings, 1985; Fuster, 1989
; Groenewegen et al., 1990
), each of which has distinct afferent and efferent connections (see Discussion for details and references). The anatomical distinc- tions suggest that functional differences also exist between these different mPFC subareas. That this is indeed the case and that subregion-specific lesions or drug injections can produce behaviourally specific effects has been demonstrated primarily in the context of spatial and discrimination learning and memory tasks (Morgan and LeDoux, 1995
; Seamans et al., 1995
; Delatour et al., 1996; Ragozzino and Kesner, 1998
). However, a possible functional heterogeneity of the mPFC with respect to the development of behavioural sensitization and possible different effects of mPFC lesions on amphetamine- versus cocaine- induced sensitization has not yet been examined systematically. In a first report addressing this issue (Tzschentke and Schmidt, 1998a
) we have shown that selective quinolinic acid lesions of the pl mPFC disrupt the development of cocaine-induced behavioural sensitization. We have now extended our studies to test lesions of the il and the cg subareas and amphetamine as a sensitizing drugs under identical experimental conditions. Parts of these data have been presented in abstract form (Tzschentke and Schmidt, 1998c
).
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Materials and Methods |
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Male SpragueDawley rats (Charles River, Germany) weighing 250300 g at the time of surgery, served as subjects. They were group-housed with six or seven animals per cage under constant conditions (23 ± 2°C, 12 h light cycle with lights on at 07.00 h). Water was available ad libitum and food (14 g of Altromin standard lab chow per animal) was provided in the late afternoon of each day. All experiments were carried out between 08.00 and 16.00 h.
Drugs
Quinolinic acid (QuinA) (Sigma, St Louis, MO, USA) (45 nmol/0.5 µl) was dissolved in warm 0.1 M phosphate-buffered saline (PBS) and adjusted to pH 7.4 with 1 M NaOH. DL-Amphetamine sulphate (1.5 and 3 mg/kg) and cocaine hydrochloride (10 and 20 mg/kg) (Geyer, Renningen, Germany) were dissolved in saline and injected i.p. at 1 ml/kg body wt. n = 512 for the different lesion and treatment groups, for details see figure legends.
Surgery
Animals were anaesthesized with chloral hydrate (7 %, 5 ml/kg). Each animal received an s.c. injection of atropin sulphate (Serva, Heidelberg, Germany; 0.5 mg/kg) before surgery. Surgery was performed using a Kopf stereotactic apparatus. For intracranial injection of QuinA or PBS the injection cannula was aimed at the following coordinates, with respect to bregma (Paxinos and Watson, 1986): infralimbic mPFC: AP +3.2, L ±0.7, V 5.4; prelimbic mPFC: AP +3.2, L ±0.7, V 4.0; anterior cingulate mPFC: AP +3.2, L ±0.7, V 3.0; whole mPFC: the combination of all three of the aforementioned coordinates. For intracranial injection, the cannula was lowered to the respective coordinate, and 0.5 µl QuinA or PBS was injected over the course of 2.5 min. After injection, the cannula remained in place for another 2.5 min to allow for diffusion. For the whole mPFC lesion the cannula was first lowered to the most ventral coordinate and the injection procedure was repeated three times at the respective coordinates from ventral to dorsal. The same procedure was then repeated in the other hemisphere. Behavioural experiments began 1114 days after surgery.
Behavioural Testing
The behaviour of the animals was examined in two test situations: an open-field and an experimental chamber (sniffing-box). The open-field consisted of a grey plastic floor and walls (70 x 70 x 30 cm). The floor area was divided by white lines into 16 equal-sized squares. In the centre of each of these squares there was a hole (diameter 5 cm, depth 3 cm). The open-field was placed inside a wooden box (75 x 75 x 105 cm) to provide some degree of visual and acoustic isolation. The box was illuminated by four 25 W red light bulbs, and a fan provided ventilation and background noise. A video camera mounted on top of the box recorded the behaviour of the animals for later manual analysis. The following behavioural parameters were analysed: locomotion (in terms of line crossings from one square to another), rearing, grooming and exploration (in terms of head-dips into the holes in the floor of the open-field).
The sniffing-box (30 x 10 x 10 cm) was designed to restrict loco- motion as far as possible without actually restraining the animal (Schmidt, 1986) such that sniffing behaviour can be examined in detail by close-up monitoring. Again, the behaviour was videotaped for subsequent behav- ioural analysis. Sniffing was defined as repetitive nosewall contacts, which can be distinguished very clearly from other movements by an experienced observer. The following behaviours were analysed: total number of sniffing, up-sniffing (i.e. sniffing directed towards the lid of the box), down-sniffing (i.e. sniffing directed towards the floor of the box), number of turns and grooming. Tests in the sniffing-box and in the open-field lasted 10 min each. To restrict behavioural analysis to such a short time window can potentially be problematic, in particular when testing the effects of a drug like amphetamine which can produce markedly different behaviours at different times after injection of higher doses. We have previously shown (Tzschentke and Schmidt, 1996
) that even 5 min tests are sensitive enough to detect sensitization or tolerance effects, and in the present study we tested a dose of amphetamine that did not produce any overt signs of stereotypy but only locomotion, thus eliminating the major potential confounding factor (see below).
Experimental Procedure
On day 0 of the experiment each animal was placed in the sniffing-box and in the open-field for 10 min each without prior injection. There were eight different treatment groups for each of the different types of lesions. For cocaine sensitization: a sham-lesioned and a QuinA-lesioned saline control group, and a sham-lesioned and a QuinA-lesioned group receiving repeated cocaine; for amphetamine sensitization: the same groups, with amphetamine instead of cocaine for the latter two groups. On day 1, each animal of the saline groups received an injection of saline, each animal of the amphetamine groups received an injection of DL-amphetamine (1.5 mg/kg), and each animal of the cocaine groups received an injection of cocaine (10 mg/kg). Cocaine-treated and respective control animals were tested 10 min after drug injection. Testing of the amphetamine-treated and respective control animals commenced 30 min after drug injection. This choice of test times was based on available data about the time course of drug effects and was chosen such that the test periods included the peak drug effects (with respect to locomotor stimulation) (Stewart and Druhan, 1993; Heidbreder et al., 1995
; Kuczenski et al., 1997
; Steketee, 1998a
). On days 2, 4, 6, 8, 10, 12 and 14 each animal received an injection of its respective drug [saline, DL-amphetamine (4 mg/kg) or cocaine (20 mg/kg)] and was placed back to its home cage without testing, while on the intervening days no injections were made. It has been shown repeatedly that treatment regimens with longer than 1 day intervals between drug injections can elicit robust sensitization (McCreary and Marsden, 1993
; Stewart and Druhan, 1993
; Carey et al., 1995
). On day 16 (i.e. after 1 day of withdrawal) and on day 30 (i.e. after 2 weeks of withdrawal) all animals were challenged with either amphetamine (1.5 mg/kg) or cocaine (10 mg/kg). On all test days the order of testing environments was counterbalanced across groups such that of each group half of the animals were tested first in the sniffing-box and the other half was tested first in the open-field. Each test session in each of the test situations lasted 10 min. The doses of the drugs used and the treatment schedule were chosen in order to produce reliable sen- sitization of locomotor activity. On test days lower drug doses were used to avoid the occurrence of stereotypy which would have confounded locomotion measures in the open-field.
Histology
After completion of the experiment, animals were killed with an over- dose of pentobarbital. Their brains were removed and stored in formalin. After incubation in a 30% sucrose solution for at least 36 h, 40 µm sections were cut on a cryostat and cresyl violet-stained for light- microscopical assessment of the lesion size using camera lucida drawings.
Statistics
For the analysis of the data from the day 0 habituation session all animals from all prospective treatment groups were pooled together according to their type of lesion. Individual comparisons between sham- and the respective QuinA-lesioned groups were made using Student's t-test. The development of sensitization was assessed with three-factorial analysis of variance (ANOVA) with repeated measures over days. Thus, the ANOVA had the following design: factor A with four levels: day 0, day 1, day 16, day 30; factor B with two levels: saline versus drug (amphetamine or cocaine); factor C with two levels: sham lesion versus QuinA lesion. Individual comparisons were done with post-hoc Fischer's LSD test where appropriate. In all cases, a P < 0.05 was considered as significant.
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Results |
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On day 0, in the open-field none of the lesions affected the parameters line-crossing, rearing and head-dips. The only effect observed was an increase in grooming induced by il and whole mPFC lesions (t = 2.561, P < 0.05, and t = 2.738, P < 0.01 respectively) (Fig. 1a). In the sniffing-box somewhat more pronounced effects of the lesions were found. Up-sniffing was reduced by il and whole mPFC lesions (t = 2.697, P < 0.01, and t = 3.269, P < 0.01 respectively) (Fig. 1b
). Down-sniffing was also reduced only by il and whole mPFC lesions (il: t = 2.017, P < 0.05; whole: t = 2.867, P < 0.01) (Fig. 1c
). When up-sniffing and down-sniffing were added up, total sniffing was also significantly reduced only by il and whole mPFC lesions (t = 3.835, P < 0.01, and t = 2.255, P < 0.05 respectively) (Fig. 1d
). The number of turns was significantly reduced and grooming was significantly increased only by whole mPFC lesions (t = 4.147, P < 0.01, and t = 3.047, P < 0.01 respectively) (Fig. 1e,f
). In general, the effects of the lesions, even the whole mPFC lesions, on spon- taneous behaviour were relatively weak, even when significantly different from sham-lesioned controls. Lesioned animals did not show any gross behavioural abnormalities, and the lesion effects were only observed during detailed behavioural analysis.
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Amphetamine
Sham-lesioned animals treated with saline on days 114 and receiving amphetamine on day 16 for the first time displayed a level of activity very similar to that of sham-lesioned animals undergoing repeated amphetamine treatment after their first amphetamine injection on day 1, showing that repeated saline injections did not alter the response to a subsequent amphetamine challenge. Sham-lesioned animals treated with amphetamine over 14 days showed sensitization to the psycho- motor-activating effects of the drug. Both the initial response to amphetamine and the subsequent sensitization was evident in several of the behavioural parameters examined, in both the open field and the sniffing box. For the sake of brevity and clarity we will limit our presentation of the results to those parameters for which we found the most reliable and consistent effects, namely line-crossing and rearing in the open-field, and up- sniffing, down-sniffing, and turning in the sniffing-box. The same selection was made for the results of the cocaine-treated groups (see below). Typically, repeated amphetamine treatment resulted in an increased number of line crossings in the open-field, and increased up-sniffing and turning in the sniffing box while rearing in the open-field did not change and down- sniffing in the sniffing-box showed a decrease in response to a challenge injection of amphetamine after 1 day of withdrawal on day 16. The effects observed after 2 weeks of withdrawal on day 30 were generally the same as on day 16. In cases where there was a change from the first to the second challenge, the response to amphetamine on day 30 tended to smaller than on day 16. The most important finding from this part of the study, however, was that none of the lesions significantly affected any of the responses described above. Neither lesions of il, pl nor cg nor lesions of the whole mPFC had effects on the initial responses to amphetamine or the develop- ment of sensitization in any of the behavioural parameters examined. Because of the absence of lesion effects, for the sake of brevity only the data and statistical analyses for the lesions of the whole mPFC are presented (Fig. 2, see figure legend for statistical details).
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Sham-lesioned animals treated with saline on days 114 and receiving cocaine on day 16 for the first time displayed a level of activity very similar to that of sham-lesioned animals undergoing repeated cocaine treatment after their first cocaine injection on day 1, showing that repeated saline injections did not alter the response to a subsequent cocaine challenge. Sham-lesioned animals treated with cocaine over 14 days showed sensitization to the psychomotor-activating effects of the drug. Both the initial response to cocaine and the subsequent sensitization was evid- ent in several of the behavioural parameters examined, in both the open-field and the sniffing-box. Typically, repeated cocaine treatment resulted in an increased number of line-crossings and rearings in the open-field, and increased up-sniffing and turning in the sniffing box, while down-sniffing showed a decrease after a challenge injection of cocaine after 1 day of withdrawal on day 16. The effects observed after 2 weeks of withdrawal on day 30 were generally similar to those observed on day 16. In cases where there was a change from the first to the second challenge, the response to cocaine on day 30 tended to smaller than on day 16. As in the case of amphetamine, il lesions (Fig. 3) and cg lesions (Fig. 5
) had no effects on the initial response to cocaine or on the development of behavioural sensitization (the only exception from this was a significant effect of the cg lesion on down-sniffing on day 30). However, unlike the case of amphetamine, pl lesions (Fig. 4
) and lesions of the whole mPFC (Fig. 6
), while having no effects on the initial response to cocaine, consistantly and significantly blocked or attenuated the development of cocaine-induced sensitization. This disruption of sensitization was evident in all behavioural parameters that showed sensitization in sham-lesioned animals (see figure legends for statistical details).
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All the subarea-specific lesions were largely restricted to the intended target area and only little damage to regions adjacent to the target regions was observed. When quinolinic acid was injected into all three target areas, the resulting lesion extended from the ventral border of the il area up to the dorsal border of the cg area. Lesioned areas were of approximately the same size in both hemispheres. The extent of all types of lesions is shown in Figure 7.
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Discussion |
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mPFC Lesions Affect Cocaine- but not Amphetamine- induced Sensitization
The finding that pl and whole mPFC lesions disrupted the devel- opment of cocaine- but not amphetamine-induced sensitization might appear surprising at first sight. The basic pharmacological differences between both drugs are well established (Carroll et al., 1992; Kuczenski and Segal, 1994
). However, differences in the molecular, neurochemical and behavioural effects of both drugs, in particular after long-term administration, are not characterized to the same extent. Accumulating evidence sug- gests that in particular with respect to the rewarding and sensitization-inducing effects there may be profound differences between both drugs (White et al., 1998
), and many of these differences seem to be at least in part related to a differential involvement of the mPFC in the mediation of the effects of both drugs. For example, it has been shown that repeated cocaine- administration resulted in a sensitization of its DA-elevating effects in the NAS but in a tolerance to its DA-elevating effects in the mPFC (Kalivas and Duffy, 1990
; Sorg et al., 1997
). In contrast, repeated amphetamine-administration produced a sen- sitization to its DA-elevating effects in both structures (Robinson et al., 1988
; Stephans and Yamamoto, 1995
). Acute systemic injection of amphetamine inhibits firing of mesoaccumbal as well as mesocortical DA neurons, whereas acute injection of cocaine also inhibits mesoaccumbal DA neurons but does not affect firing of mesocortical DA neurons (Chiodo et al., 1984
; Einhorn et al., 1988
). Cocaine is self-administered into the mPFC but not into the NAS, whereas the reverse is the case for amphetamine (Goeders and Smith, 1983
; Hoebel et al., 1983
; Goeders et al., 1986
). In addition, cocaine injected into the NAS does not produce a conditioned place preference (CPP), while amphetamine injected into the NAS but not into the mPFC produces CPP (Carr and White, 1986
; Hemby et al., 1990
, 1992
). Also, mPFC electrical self-stimulation is only potentiated by cocaine but not or only to a lesser degree by amphetamine (or morphine) (Hand and Franklin, 1983
; Corbett, 1991
, 1992
). Finally, a recent anatomical study demonstrated that while repeated administration of amphetamine or cocaine both increased dendritic branching and spine density on medium spiny neurons in the NAS shell and on the apical dendrites of layer V pyramidal cells in the prelimbic area of the mPFC, only cocaine but not amphetamine also increased dendritic branches and spine density on the basilar dendrites of these pyramidal cells (Robinson and Kolb, 1999
). All this evidence suggests that the mPFC may play a particularly important role in the mediation of cocaine-induced behavioural effects, whereas the effects produced by amphetamine appear to be less dependent on mPFC function. The reason for this distinction is not clear. One possibility is that the activity of mesocortical DA neurons is regulated differently from that of mesoaccumbal DA neurons, and that the peculiarities of the former render them particu- larly responsive to the pharmacological effects of cocaine. Mesocortical DA neurons appear to lack impulse- and synthesis- regulating autoreceptors (Chiodo et al., 1984
; Wolf and Roth, 1987
) and this may be one reason for the high basal firing rates and high rates of DA release, reuptake and turnover observed in mesocortical DA neurons (relative to the rates seen in meso- accumbal or mesostriatal DA neurons) (Bannon et al., 1981
; Hoffman et al., 1988; Garris and Wightman, 1994
). One basic difference between amphetamine and cocaine with respect to their effect on extracellular DA levels is that the effect of amphetamine is at least partly impulse-independent, while the effect of cocaine is impulse-dependent (Kuczenski and Segal, 1994
; Benwell et al., 1993
). Since mesocortical DA neurons have a higher rate of impulse-flow (higher firing rate and higher rate of DA release) than other DA neurons, cocaine may be particularly potent in excerting its effects in the mPFC relative to subcortical sites, while amphetamine would affect all DA neurons in a similar fashion independent of their activity level. Therefore, the mPFC might play a particularly important, albeit not exclusive, role in the mediation of cocaine-induced behav- ioural effects.
The lack of effect of mPFC lesions on amphetamine sensitiza- tion stands in apparent contrast to another report. Wolf and co-workers found that lesions of the whole mPFC blocked the development of amphetamine-induced sensitization of post- stereotypy locomotion, while at the same time the lesions did not affect sensitization of amphetamine-induced stereotypy (Wolf et al., 1995). However, profoundly different experimental designs were used in the two studies, which may well account for the observed differences. We deliberately chose our amphetamine dose and treatment schedule in order to avoid the occurrence of stereotypy since stereotypic behaviour interferes with the expression of locomotion. Wolf and colleagues used a more aggressive treatment schedule, which produced a biphasic response to amphetamine, i.e. a period of focused stereotypy followed by a period of locomotion. Nevertheless, this does not necessarily mean that our locomotor response corresponds exactly to the post-stereotypy locomotor response examined by Wolf et al. because different mechanisms of sensitization might have been at work in the two studies. It has long been recognized that the different components of the behavioural response to repeated amphetamine are mediated by different neural mechanisms and probably also different anatomical substrates (Leith and Kuczenski, 1982
).
Rats in the Wolf et al. study received seven injections of 2.5 mg/kg D-amphetamine within 8 days, whereas our rats received two injections of 1.5 mg/kg and 7 injections of 3 mg/kg DL-amphetamine over the course of 16 days. Amphetamine has been shown to increase plasma levels of stress-related hormones (Knych and Eisenberg, 1979); thus it is likely that the injection of a moderate to high dose of amphetamine is a stressful event for the animal. It has also been demonstrated that powerful cross-sensitization between stress and psychostimulants can occur (Antelman et al., 1980
), and it may therefore be the case that when a more aggressive sensitization regimen is used, these stress effects contribute to the development of sensitization (Deroche et al., 1992
; Reid et al., 1998
). Since the mesocortical DA system has been shown to be more responsive to moderate stress than other DA projections (Thierry et al., 1976b
; Deutch et al., 1991
; Finlay and Zigmond, 1997
), it may be the case that lesions of this region are effective in blocking those forms of sensitization in the development of which stress has played a certain role, while leaving unaffected those forms of sensitiza- tion that have developed independently of stress effects. In line with this hypothesis is (i) the observation that repeated stress has the same effects as repeated cocaine (as opposed to the effects of repeated amphetamine) on the DA response within the mPFC (Sorg and Kalivas, 1993a
) (see discussion above) and (ii) our finding in the present study that pl and whole mPFC lesions were effective in disrupting cocaine-induced sensitization since, at least in a moderate dose-range, cocaine appears to elicit a relatively stronger neuroendocrine stress response than amphetamine (Carey et al., 1994
; Goeders, 1997
).
Only lesions of the Prelimbic or the Whole mPFC Disrupt Cocaine Sensitization
To our knowledge, this is the first study that systematically examined the contribution of the different mPFC subareas to the effects of large mPFC lesions. We found that lesions of the most ventral (il) and the most dorsal (cg) aspects of the mPFC were without effect on the development of cocaine-induced behav- ioural sensitization. On the other hand, lesions restricted to the medial aspects of the mPFC were able to impair significantly the development of sensitization. This effect was mimicked qualitatively and quantitatively by lesions of the whole mPFC. Thus, the mPFC appears to be functionally hetereogenous with respect to the involvement of its subareas in cocaine sensi- tization. As far as we know, all studies that have examined the role of the mPFC in sensitization so far have not distinguished between the different subareas and have employed rather big lesions (Wolf et al., 1995; Cador et al., 1997
; Li and Wolf, 1997
) or they have made a relatively gross distinction between dorsal and ventral mPFC (Pierce et al., 1998
). We do not know the reason for the particular role of the pl mPFC in cocaine sensi- tization, but we would suggest that it is likely due to its particular anatomical organization.
The anterior cingulate cortex receives afferents from the caudal part of the mediodorsal thalamus (MD) and neocortical areas (Condé et al., 1990, 1995
) and sends efferents prefer- entially to the dorsal striatum and the caudal part of the MD, and to also to a number of neocortical and brainstem areas (Sesack et al., 1989
). The prelimbic cortex receives strong input from the rostral part of the MD, the hippocampus and (along with the infralimbic cortex) the densest dopamine input from the VTA of all mPFC subdivisions (Thierry et al., 1976a
; Lindvall et al., 1978
; Jay et al., 1989
; Condé et al., 1990
, 1995
). It projects prefer- entially to the core part of the NAS and the rostral part of the MD, and also to the VTA, basolateral amygdala and other forebrain structures (Phillipson and Griffiths, 1985
; Phillipson, 1979
; Sesack et al., 1989
; Groenewegen et al., 1990
; Berendse et al., 1992
). The infralimbic cortex is distinguished from other prefrontal cortical areas by its lack of input from the MD. It receives afferents from the hypothalamus, amygdala, hippo- campus and autonomic brainstem nuclei (Azuma and Chiba, 1996
) and projects preferentially to the shell part of the NAS and the rostral part of the MD, and also to the hypothalamus, amygdala and a number of autonomic brainstem structures (Terreberry and Neafsey, 1987
; Sesack et al., 1989
; Hurley et al., 1991
; Laubach and Woodward, 1995
). Apart from the fact that the infralimbic mPFC is thought to be involved in autonomic functions (because of its extensive connections with autonomic brain stem regions) the function of these medial prefrontal cortical areas is not well characterized (Alexander et al., 1986
, 1990
), although it is widely assumed that they are involved in the processing of cognitive and emotional information (Shaw and Aggleton, 1993
; Aggleton et al., 1995
; Granon and Poucet, 1995
; Dias et al., 1996
) (reviewed by Kolb (Kolb, 1984
)]. As mentioned above, the pl mPFC receives dense dopaminergic input from the VTA and projects strongly to the core of the NAS which is considered as the motor part of the ventral striatum (Zahm and Brog, 1992
). Thus, the pl mPFC, in contrast to the other mPFC subareas, may be in a special position to be affected by cocaine and to convey these cocaine effects to the basal ganglia to produce locomotion and the sensitization thereof. This is consistent with the finding by Pierce et al., who showed that in cocaine-sensitized animals a cocaine challenge increases extracellular levels of glutamate in the core but not in the shell of the NAS (Pierce et al., 1996
). Of particular relevance may also be the fact that the pl mPFC has a stronger projection to the VTA than the il or cg mPFC (Beckstead, 1979
; Sesack et al., 1989
; Hurley et al., 1991
). The current prevailing model of the induc- tion of sensitization (Sorg and Kalivas, 1993b
; Kalivas, 1995
) assigns a crucial role in the processes leading to sensitization to the glutamatergic input to the VTA, which is assumed to be originating from the mPFC. If true, then lesioning that part of the mPFC which provides the strongest glutamatergic input to the VTA (pl) would be expected to have the strongest disruptive effect on the developement of sensitization, which is what we observed in the present study.
Only Lesions of the Infralimbic or the Whole mPFC Disrupt Spontaneous Activity
Altogether, the mPFC lesions in our present study had only weak effects on the spontaneous behaviour of the rats during their initial exposure to the sniffing-box and the open-field. Only lesions of the il and the whole mPFC produced a small decrease in motor activity. In the case of the il mPFC lesions this was evident only indirectly in the open-field as an increase in time spent grooming, and in the sniffing-box as a decrease in sniffing. Lesions of the whole mPFC had somewhat stronger effects, especially on the behaviour in the sniffing-box, although groom- ing was still the only parameter affected in the open-field. The effects of large mPFC lesions on spontaneous activity reported in the literature to date are inconsistent, but in most cases increases in spontaneous activity have been reported (Jaskiw et al., 1990; Weissenborn et al., 1997
; Fritts et al., 1998
) although Isaac et al. (Isaac et al., 1989
) reported no effect and we are aware of only very few studies that report on the effects of mPFC subregion-specific lesions on spontaneous locomotion in a novel environment. Two reports (Brito and Brito, 1990
; Fritts et al., 1998
) showed that selective lesions of the pl mPFC increased spontaneous activity, whereas Burns and co-workers found that pl mPFC lesions had no such effect (Burns et al., 1993
, 1996
). Jinks and McGregor reported that infralimbic but not prelimbic lesions reduced spontaneous ambulation in an open-field, a finding which fits our results very nicely (Jinks and McGregor, 1997
). Also, the lack of effect of the pl mPFC lesions in the present study is consistent with our earlier finding that this kind of lesion does not affect spontaneous behaviour in a place- preference conditioning setup (Tzschentke and Schmidt, 1998b
). We do not know the reason for this inconsistency of findings in the above-mentioned studies, and clearly a more systematic approach with respect to type of lesions (electro- lytic, excitotoxic) size and location of lesions, and test conditions will be necessary in the future to characterize the contribution of the different mPFC subregions to spontaneous behaviour.
Jinks and McGregor also report that il and pl mPFC lesions decreased the time spent in the central region of an open-field, indicating increased anxiety (Jinks and McGregor, 1997). In our analysis of open-field behaviour we have also divided our open-field into a peripheral region and a central region but found no effect of any of the lesions on the time spent in each of those regions (data not shown). There is, however, one obvious procedural difference between the two studies which may explain the different findings. In our study we used a square open-field with a side-length of 70 cm; Jinks and McGregor used a much larger circular open-field with a diameter of 1.75 m (Jinks and McGregor, 1997
). It is therefore possible that our open-field was not large enough to induce a relevant degree of anxiety in rats which have left the vicinity of the side-walls. This would have rendered us unable to measure different degrees of anxiety in our particular setup. In fact, when Jinks and McGregor tested their lesioned animals in a smaller, enclosed, presumably non-stressful environment they found no differences in the locomotor activity between lesioned and non-lesioned animals (Jinks and McGregor, 1997
).
In conclusion, we have shown a functional heterogeneity of the mPFC in its role in psychomotor stimulant-induced behav- ioural sensitization, first with respect to its different subregions, second with respect to different drugs. The differential con- tribution of the different mPFC subregions to spontaneous and drug-induced behaviour may account for at least some of the inconsistencies in the data originating from previous studies that have used large, subregion-nonspecific lesions or drug- injections. A better understanding of the function of the mPFC in general and of its subregions in particular may be a step towards a refinement of our knowledge of the processes leading to sensitization, which may in turn have considerable relevance for our understanding of the mechanisms leading to the develop- ment and maintenance of drug addiction.
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Notes |
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Address correspondence to Thomas M. Tzschentke, Grünenthal GmbH, Research and Development, Department of Pharmacology, Postfach 500444, D-52088 Aachen, Germany. Email: thomas.tzschenthe{at}grunenthal.com.
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Footnotes |
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References |
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