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Response of mesolimbic substance P systems to methamphetamine treatment
European Journal of Pharmacology, 128 (1986) 265-268
265
Elsevier EJP 416SC Short communication
Response of mesolimbic substance P systems to methamphetamine treatment G l e n R. H a n s o n *, J o s e p h K. Ritter, C h r i s t o p h e r J. S c h m i d t a n d James W. G i b b Department of Biochemical Pharmacology and Toxicology, Universityof Utah, Salt Lake City, UT 84112, U.S.A.
Received 8 July 1986, accepted 15 July 1986
Administration of methamphetamine (METH) has been shown to increase substance P (SP) concentrations in striatonigral structures. Data described herein demonstrate that SP pathways associated with the mesolimbic systems also are influenced by METH treatment. Specifically, multiple doses of METH significantly decreased SP concentrations in the ventral tegmental area and the medial habenular nucleus; whereas, a single METH injection increased the levels of this neuropeptide in the ventral tegmental area. The possible significance of these observations is discussed. Substance P; Methamphetamine; Basal ganglia; Mesolimbic system; Dopamine
1. Introduction M a n y of the behavioral effects of the amphetamines are due to the actions of these stimulants on CNS dopaminergic pathways. Specifically, the dopamine (DA)-containing neuronal circuits of the basal ganglia and mesolimbic systems are postulated to mediate the amphetamine-induced increases in locomotion and stereotypy (Kelly et al., 1975). Although the exact mechanisms for these effects are not known, several studies demonstrate that profound neurochemical changes in the nigrostriatal DA system of the basal ganglia occur in response to multiple toxic doses of the amphetamine analogue, methamphetamine (METH) (Schmidt et al., 1985). Interestingly, the impact of M E T H treatment on the DA system associated with mesolimbic structures, is quite different; the same M E T H treatment which profoundly alters the neurochemistry of the nigrostriatal DA pathways, has little or no detectable effect on the dopaminergic system which * To whom all correspondenceshould be addressed: Room 113 Skaggs Hall, College of Pharmacy, Universityof Utah, Salt Lake City, UT 84112, U.S.A. 0014-2999/86/$03.50 © 1986 ElsevierSciencePublishers B.V.
projects from the ventral tegmental area (VTA) to the nucleus accumbens (Morgan and Gibb, 1980). Neuropeptide transmitter systems have been postulated to serve an important regulatory function to the DA circuitry of both basal ganglia and mesolimbic structures. Of interest in the present study in the undecapeptide, substance P (SP), and its response to the METH-induced changes in the DA systems. Linked to the basal ganglia is a striatonigral SP pathway which is thought to exert an excitatory feedback influence on ascending nigrostriatal DA neurons (Davies and Dray, 1976). Our laboratory has demonstrated that multiple administrations of M E T H result in substantial increases in the concentrations of substance P-like immunoreactivity (SPLI) in the substantia nigra and the striatum (Ritter et al., 1984). One explanation proposed for these changes is that the effects of M E T H on related DA activity cause decreased release of SP and its accumulation within neuronal structures. A SP pathway, comparable to that located in the basal ganglia, is associated with mesolimbic DA neurons. SP-containing cell bodies are found in the medial habenular nucleus which project to the VTA and terminate near neurons which form
266 the mesolimbic D A system (Lindvall et al., 1977). Biochemical and electrophysiological evidence suggests that this D A system is modulated by SP activity. Behaviorally, SP injected into the rat VTA, induces a DA-dependent increase in spontaneous locomotor activity (Kelly et al., 1979). In addition, the behavioral arousal resulting from peripheral administration of amphetamine is intensified by prior infusion of SP into the VTA (Stinus et al., 1978). Although the above-mentioned studies elucidate the role of mesolimbic SP systems in regulation of associated DA pathways, there is little or no information available as to the influence of dopaminergic activity on mesolimbic SP pathways. In the present study we examined the effects of the indirect D A agonist, M E T H , on concentrations of SPLI in mesolimbic structures. These findings suggest that METH-induced changes in the mesolimbic D A system influence the activities of associated SP pathways.
2. Materials and methods
2.1. Treatment, dissection and S P L I determination Male Sprague-Dawley rats (200-250 g) were maintained 1 week prior to experimentation under a standard 12 h light-dark cycle and given free access to water and rat feed. The animals were treated by administering 1 or 5 (at 6 h intervals) doses of either M E T H (15 m g / k g s.c.) or saline vehicle. Animals were killed by decapitation 3, 12, 18 or 24 h following treatment. The whole brain was rapidly removed and the desired tissue areas (substantia nigra reticulata, neostriatum, medial habenular nucleus and VTA) were dissected out from 0.5 m m thick frozen coronal slices using an extra fine dissecting scalpel and were subsequently stored at - 8 0 ° C until assayed for SPLI. The ventral tegmental area examined in these studies corresponded to that brain region designated as the A10 area by Palkovits and Jacobowitz (1974). SPLI concentrations were measured by a radioimmunoassay technique previously described (Ritter et al., 1984).
2.2. Statistics The results are expressed as means + S.E.M. of the percent of control. Differences between means were analyzed by a two-tailed Student's t-test and considered significant when the probability that they were zero was less than 5 %.
3. Results
3.1. Effects of single and multiple doses of M E T H on S P L ! concentrations in VTA In order to determine if M E T H treatment influences the SP system associated with the VTA, rats were administered either 1 or 5 (every 6 h) doses of M E T H (15 m g / k g per administration). Groups of animals were killed either 3, 12 or 24 h following both treatments and the VTA structures were analyzed for SPLI and compared to control groups (fig. 1). There were no significant changes in the SPLI concentration of the VTA in animals killed 3 h following either the single or multiple M E T H administrations. However, 12 h following the acute treatment, there was a 38% increase in
A o. (n
200"
¢,
150 -
~ I--
,
I-.Z W 0
50
Tll
J~
vehicle 3 hr METH
12 hr METH 24 hr METH
O. 0
dose
5 doses
Fig. 1. The effects of 1 and 5 (6 h intervals) doses of METH (15 mg/kg per dose) on SPLI concentrations in ventral tegmental area. Animals were killed 3, 12 or 24'h following treatment. In previous experiments, vehicle injections were not found to have a significant effect on the SPLI levels in the VTA, regardless of the recovery time; thus, for these experiments, a single control group (24 h recovery) was used for comparison for all of the recovery times in each dosing protocol. The averageSPLI concentration for the control groups was 1.61 ng/mg protein. The results represent the means-t-S.E.M. (n = 5 rats/group) and are expressed as percent of control. * P < 0.05, ** P < 0.025 versus control.
267
SPLI concentration in the VTA compared to controis. The data suggest that this elevation was still present 24 h following the METH injection (up 32%), although the increase was not significantly different from controls due to the variability within the group. In contrast, the SPLI concentrations associated with the VTA of rats receiving multiple doses of METH were unchanged 12 h following treatment but by 24 h decreased significantly to 58% of control. Because the original work on SP systems in the basal ganglia was performed in rats killed 18 h following treatment, the remaining experiments described in this study, were carried out under similar circumstances in order to allow comparisons. 3.2. METH-induced changes in S P L I concentrations in VTA, habenula, substantia nigra and neostriatum
The majority of SPLI activity within the VTA is associated with neurons which project from the medial habenular nucleus. Consequently, the effects of multiple doses of METH on SPLI levels in the medial habenular nucleus were examined and compared to the response seen in the VTA. As shown in fig. 2, METH treatment lowered the SPLI concentration to 61% of controls in the habenula compared to 51% of control in the VTA. 300" A D.
r,I'Z
200'
o (J
u.
o IZ uJ O re uJ n
100'
VTA
habenula sub. nlgra
striatum
Fig. 2. Effects of multiple doses of METH on SPLI concentrations in the VTA, medial habenular nucleus, substantia nigra and striatum. Animals were administered 5 doses (6 h intervals) of METH or saline and killed 18 h following treatment. The average control SPLI concentrations (rig/rag protein) for these structures were 1.55, 1.77, 14.10 and 1.45, respectively. The results represent the means+S.E.M. (n = 4 or 5 r a t s / group) and are expressed as percent of control. * P < 0.05, • * P < 0.025, t p < 0.005 versus respective controls.
This is in contrast to an elevation of nigral and striatal SPLI levels (134 and 217% of their respective controls) found in the same animals.
4. Discussion
Convincing evidence has been reported previously which demonstrates that SP pathways play an important role in modulating dopaminergic activity associated with the mesolimbic system. The findings described herein suggest that changes in DA activity, induced by treatment with METH, also influence the SP activity within mesolimbic structures, thus, supporting the hypothesis that an important relationship exists between DA and SP systems which contributes to the regulation of mesolimbic functions. The results demonstrate that treatments with high doses of METH cause significant changes in the concentrations of SPLI in the VTA (fig. 1). Although the data are not shown, we have found that the effects of multiple METH administrations on SPLI levels in VTA are completely blocked by the coadministration of the dopamine antagonist, haloperidol (2 mg/kg per dose), suggesting that these METH effects are mediated by the DA system. It is interesting that the nature of the change in SPLI levels is determined by the length of drug treatment. Consequently, 12 h following a single dose of METH, an increase of 39% in the SPLI concentration of the VTA was observed, whereas, 24 h following multiple doses there was a 42% decrease (fig. 1). Although the reasons for the variations in SPLI concentrations are not yet known, one possible explanation is that they represent changes in the SP release by this VTA neuropeptide system. This explanation is consistent with the observations that METH administration increases dopaminergic activity in mesolimbic structures (Kelly et al., 1975); thus, the activity of an excitatory feedback system, such as the SP projections from the habenula to the ventral tegmental area, would be expected to diminish causing less transmitter release and resulting in peptide buildup. By 12 h following METH treatment, the SP levels in VTA are significantly elevated (up 38% compared to control). There
268
results suggest that the response of the SP system to acute METH treatment occurs quickly. Because the turnover for SP is relatively slow (usually several days) (Keen et al., 1982) it is unlikely that the METH-induced elevated SPLI levels are due to changes in the peptide synthesis rate. It is more difficult to explain the mechanism(s) responsible for the decrease in VTA concentrations of SP following multiple METH administrations. If it is assumed that METH-induced activation of mesolimbic DA systems results in decreased activity of SP projections to the VTA, perhaps conditions eventually lead to a decrease in SP synthesis which, if allowed enough time, results in diminished SPLI levels. An argument against an alteration of synthesis rate as the cause of these changes in SPLI is that the decreases are not apparent 12 h after treatment, but can be observed after 18 h (fig. 2) and 24 h (fig. 1). This suggests that the changes develop quickly (between 12 and 18 h) which, as mentioned above, is usually not a feature of peptide changes due to variations in synthesis rates. Perhaps these SP changes are not due to a direct action of METH but are part of a compensatory response which occurs after the METH has been cleared from the animal. There is a noteworthy similarity in the responses to multiple administrations of METH by SP pathways whose neuronal terminals are associated with the substantia nigra and the VTA. The METH treatment caused changes in SPLI concentrations in both structures containing the neuronal cell bodies similar to those of their corresponding projection sites. Consequently, habenular SPLI concentration decreased (like that of the VTA) and striatal SPLI concentration increased (like that of the substantia nigra) following multiple doses of METH (fig. 2). It is unclear why changes in the concentration of nigral SPLI, in response to multiple METH dosing, are opposite to those observed for SPLI levels in the VTA. However, as discussed in the Introduction, it is known that the mesolimbic and basal ganglia DA projections do not respond identically to METH treatment; consequently, finding that the SP pathways associated
with these two dopaminergic systems also are affected differentially is not inconsistent with these observations. Additional study is necessary to identify the precise mechanisms responsible for these differences.
Acknowledgement This work was supported by U.S. Public Health Service Grants MH 40175 and DA 00869.
References Davies, J. and A. Dray, 1976, Substance P in the substantia nigra, Brain Res. 107, 623. Keen, P., A.J. Harmar, F. Spears and E. Winter, 1982, The striatonigral substance P pathway and dopaminergic mechanisms, in: Substance P and the Nervous System, eds. R. Porter and M. O'Connor (Pitman, London) p. 145. Kelly, P.H., P.W. Seviour and S.D. Iversen, 1975, Amphetamine and apomorphine responses in the rat following 6OHDA lesions of the nucleus accumbens septi and corpus striatum, Brain Res. 94, 507. Kelly, A.E., L. Stinus and S.D. Iversen, 1979, Behavioural activation induced in the rat by substance P infusion into the ventral tegrnental area: Implication of dopaminergic A10 neurones, Neurosci. Lett. 11,335. Lindvall, O., A. Bj~rklund and I. Divac, 1977, Organization of mesencephalic dopamine neurones projecting to neocortex and septum, in: Non-striatal Dopaminergic Neurones, eds. E. Costa and G. Gessa (Raven Press, New York) p. 39. Morgan, M.E. and J.W. Gibb, 1980, Short-term and long-term effects of methamphetamine on biogenic amine metabolism in extra-striatal dopaminergic nuclei, Neuropharmacology 19, 989. Palkovits, M. and D.M. Jacobowitz, 1974, Topographic atlas of catecholamine and acetylchohnesterase-containing neurons in the rat brain, Comp. Neurol. 157, 29. Ritter, J.K., C.J. Sehmidt, J.W. Gibb and G.R. Hanson, 1984, Increase of substance P-like immunoreactivity within striatai-nigral structures following subacute methamphetamine treatment, J. Pharmacol. Exp. Ther. 229, 487. Schmidt, C., J. Ritter, P. Sonsalla, G.R. Hanson and J.W. Gibb, 1985, Role of dopamine in the neurotoxic effects of methamphetamine, J. Pharmacol. Exp~ Ther. 233, 539. Stinus, L., A.E. Kelley and S.D. Iversen, 1978, Increased spontaneous activity following substance P infusion into A10 dopaminergic area, Nature (London) 276, 616.
265
Elsevier EJP 416SC Short communication
Response of mesolimbic substance P systems to methamphetamine treatment G l e n R. H a n s o n *, J o s e p h K. Ritter, C h r i s t o p h e r J. S c h m i d t a n d James W. G i b b Department of Biochemical Pharmacology and Toxicology, Universityof Utah, Salt Lake City, UT 84112, U.S.A.
Received 8 July 1986, accepted 15 July 1986
Administration of methamphetamine (METH) has been shown to increase substance P (SP) concentrations in striatonigral structures. Data described herein demonstrate that SP pathways associated with the mesolimbic systems also are influenced by METH treatment. Specifically, multiple doses of METH significantly decreased SP concentrations in the ventral tegmental area and the medial habenular nucleus; whereas, a single METH injection increased the levels of this neuropeptide in the ventral tegmental area. The possible significance of these observations is discussed. Substance P; Methamphetamine; Basal ganglia; Mesolimbic system; Dopamine
1. Introduction M a n y of the behavioral effects of the amphetamines are due to the actions of these stimulants on CNS dopaminergic pathways. Specifically, the dopamine (DA)-containing neuronal circuits of the basal ganglia and mesolimbic systems are postulated to mediate the amphetamine-induced increases in locomotion and stereotypy (Kelly et al., 1975). Although the exact mechanisms for these effects are not known, several studies demonstrate that profound neurochemical changes in the nigrostriatal DA system of the basal ganglia occur in response to multiple toxic doses of the amphetamine analogue, methamphetamine (METH) (Schmidt et al., 1985). Interestingly, the impact of M E T H treatment on the DA system associated with mesolimbic structures, is quite different; the same M E T H treatment which profoundly alters the neurochemistry of the nigrostriatal DA pathways, has little or no detectable effect on the dopaminergic system which * To whom all correspondenceshould be addressed: Room 113 Skaggs Hall, College of Pharmacy, Universityof Utah, Salt Lake City, UT 84112, U.S.A. 0014-2999/86/$03.50 © 1986 ElsevierSciencePublishers B.V.
projects from the ventral tegmental area (VTA) to the nucleus accumbens (Morgan and Gibb, 1980). Neuropeptide transmitter systems have been postulated to serve an important regulatory function to the DA circuitry of both basal ganglia and mesolimbic structures. Of interest in the present study in the undecapeptide, substance P (SP), and its response to the METH-induced changes in the DA systems. Linked to the basal ganglia is a striatonigral SP pathway which is thought to exert an excitatory feedback influence on ascending nigrostriatal DA neurons (Davies and Dray, 1976). Our laboratory has demonstrated that multiple administrations of M E T H result in substantial increases in the concentrations of substance P-like immunoreactivity (SPLI) in the substantia nigra and the striatum (Ritter et al., 1984). One explanation proposed for these changes is that the effects of M E T H on related DA activity cause decreased release of SP and its accumulation within neuronal structures. A SP pathway, comparable to that located in the basal ganglia, is associated with mesolimbic DA neurons. SP-containing cell bodies are found in the medial habenular nucleus which project to the VTA and terminate near neurons which form
266 the mesolimbic D A system (Lindvall et al., 1977). Biochemical and electrophysiological evidence suggests that this D A system is modulated by SP activity. Behaviorally, SP injected into the rat VTA, induces a DA-dependent increase in spontaneous locomotor activity (Kelly et al., 1979). In addition, the behavioral arousal resulting from peripheral administration of amphetamine is intensified by prior infusion of SP into the VTA (Stinus et al., 1978). Although the above-mentioned studies elucidate the role of mesolimbic SP systems in regulation of associated DA pathways, there is little or no information available as to the influence of dopaminergic activity on mesolimbic SP pathways. In the present study we examined the effects of the indirect D A agonist, M E T H , on concentrations of SPLI in mesolimbic structures. These findings suggest that METH-induced changes in the mesolimbic D A system influence the activities of associated SP pathways.
2. Materials and methods
2.1. Treatment, dissection and S P L I determination Male Sprague-Dawley rats (200-250 g) were maintained 1 week prior to experimentation under a standard 12 h light-dark cycle and given free access to water and rat feed. The animals were treated by administering 1 or 5 (at 6 h intervals) doses of either M E T H (15 m g / k g s.c.) or saline vehicle. Animals were killed by decapitation 3, 12, 18 or 24 h following treatment. The whole brain was rapidly removed and the desired tissue areas (substantia nigra reticulata, neostriatum, medial habenular nucleus and VTA) were dissected out from 0.5 m m thick frozen coronal slices using an extra fine dissecting scalpel and were subsequently stored at - 8 0 ° C until assayed for SPLI. The ventral tegmental area examined in these studies corresponded to that brain region designated as the A10 area by Palkovits and Jacobowitz (1974). SPLI concentrations were measured by a radioimmunoassay technique previously described (Ritter et al., 1984).
2.2. Statistics The results are expressed as means + S.E.M. of the percent of control. Differences between means were analyzed by a two-tailed Student's t-test and considered significant when the probability that they were zero was less than 5 %.
3. Results
3.1. Effects of single and multiple doses of M E T H on S P L ! concentrations in VTA In order to determine if M E T H treatment influences the SP system associated with the VTA, rats were administered either 1 or 5 (every 6 h) doses of M E T H (15 m g / k g per administration). Groups of animals were killed either 3, 12 or 24 h following both treatments and the VTA structures were analyzed for SPLI and compared to control groups (fig. 1). There were no significant changes in the SPLI concentration of the VTA in animals killed 3 h following either the single or multiple M E T H administrations. However, 12 h following the acute treatment, there was a 38% increase in
A o. (n
200"
¢,
150 -
~ I--
,
I-.Z W 0
50
Tll
J~
vehicle 3 hr METH
12 hr METH 24 hr METH
O. 0
dose
5 doses
Fig. 1. The effects of 1 and 5 (6 h intervals) doses of METH (15 mg/kg per dose) on SPLI concentrations in ventral tegmental area. Animals were killed 3, 12 or 24'h following treatment. In previous experiments, vehicle injections were not found to have a significant effect on the SPLI levels in the VTA, regardless of the recovery time; thus, for these experiments, a single control group (24 h recovery) was used for comparison for all of the recovery times in each dosing protocol. The averageSPLI concentration for the control groups was 1.61 ng/mg protein. The results represent the means-t-S.E.M. (n = 5 rats/group) and are expressed as percent of control. * P < 0.05, ** P < 0.025 versus control.
267
SPLI concentration in the VTA compared to controis. The data suggest that this elevation was still present 24 h following the METH injection (up 32%), although the increase was not significantly different from controls due to the variability within the group. In contrast, the SPLI concentrations associated with the VTA of rats receiving multiple doses of METH were unchanged 12 h following treatment but by 24 h decreased significantly to 58% of control. Because the original work on SP systems in the basal ganglia was performed in rats killed 18 h following treatment, the remaining experiments described in this study, were carried out under similar circumstances in order to allow comparisons. 3.2. METH-induced changes in S P L I concentrations in VTA, habenula, substantia nigra and neostriatum
The majority of SPLI activity within the VTA is associated with neurons which project from the medial habenular nucleus. Consequently, the effects of multiple doses of METH on SPLI levels in the medial habenular nucleus were examined and compared to the response seen in the VTA. As shown in fig. 2, METH treatment lowered the SPLI concentration to 61% of controls in the habenula compared to 51% of control in the VTA. 300" A D.
r,I'Z
200'
o (J
u.
o IZ uJ O re uJ n
100'
VTA
habenula sub. nlgra
striatum
Fig. 2. Effects of multiple doses of METH on SPLI concentrations in the VTA, medial habenular nucleus, substantia nigra and striatum. Animals were administered 5 doses (6 h intervals) of METH or saline and killed 18 h following treatment. The average control SPLI concentrations (rig/rag protein) for these structures were 1.55, 1.77, 14.10 and 1.45, respectively. The results represent the means+S.E.M. (n = 4 or 5 r a t s / group) and are expressed as percent of control. * P < 0.05, • * P < 0.025, t p < 0.005 versus respective controls.
This is in contrast to an elevation of nigral and striatal SPLI levels (134 and 217% of their respective controls) found in the same animals.
4. Discussion
Convincing evidence has been reported previously which demonstrates that SP pathways play an important role in modulating dopaminergic activity associated with the mesolimbic system. The findings described herein suggest that changes in DA activity, induced by treatment with METH, also influence the SP activity within mesolimbic structures, thus, supporting the hypothesis that an important relationship exists between DA and SP systems which contributes to the regulation of mesolimbic functions. The results demonstrate that treatments with high doses of METH cause significant changes in the concentrations of SPLI in the VTA (fig. 1). Although the data are not shown, we have found that the effects of multiple METH administrations on SPLI levels in VTA are completely blocked by the coadministration of the dopamine antagonist, haloperidol (2 mg/kg per dose), suggesting that these METH effects are mediated by the DA system. It is interesting that the nature of the change in SPLI levels is determined by the length of drug treatment. Consequently, 12 h following a single dose of METH, an increase of 39% in the SPLI concentration of the VTA was observed, whereas, 24 h following multiple doses there was a 42% decrease (fig. 1). Although the reasons for the variations in SPLI concentrations are not yet known, one possible explanation is that they represent changes in the SP release by this VTA neuropeptide system. This explanation is consistent with the observations that METH administration increases dopaminergic activity in mesolimbic structures (Kelly et al., 1975); thus, the activity of an excitatory feedback system, such as the SP projections from the habenula to the ventral tegmental area, would be expected to diminish causing less transmitter release and resulting in peptide buildup. By 12 h following METH treatment, the SP levels in VTA are significantly elevated (up 38% compared to control). There
268
results suggest that the response of the SP system to acute METH treatment occurs quickly. Because the turnover for SP is relatively slow (usually several days) (Keen et al., 1982) it is unlikely that the METH-induced elevated SPLI levels are due to changes in the peptide synthesis rate. It is more difficult to explain the mechanism(s) responsible for the decrease in VTA concentrations of SP following multiple METH administrations. If it is assumed that METH-induced activation of mesolimbic DA systems results in decreased activity of SP projections to the VTA, perhaps conditions eventually lead to a decrease in SP synthesis which, if allowed enough time, results in diminished SPLI levels. An argument against an alteration of synthesis rate as the cause of these changes in SPLI is that the decreases are not apparent 12 h after treatment, but can be observed after 18 h (fig. 2) and 24 h (fig. 1). This suggests that the changes develop quickly (between 12 and 18 h) which, as mentioned above, is usually not a feature of peptide changes due to variations in synthesis rates. Perhaps these SP changes are not due to a direct action of METH but are part of a compensatory response which occurs after the METH has been cleared from the animal. There is a noteworthy similarity in the responses to multiple administrations of METH by SP pathways whose neuronal terminals are associated with the substantia nigra and the VTA. The METH treatment caused changes in SPLI concentrations in both structures containing the neuronal cell bodies similar to those of their corresponding projection sites. Consequently, habenular SPLI concentration decreased (like that of the VTA) and striatal SPLI concentration increased (like that of the substantia nigra) following multiple doses of METH (fig. 2). It is unclear why changes in the concentration of nigral SPLI, in response to multiple METH dosing, are opposite to those observed for SPLI levels in the VTA. However, as discussed in the Introduction, it is known that the mesolimbic and basal ganglia DA projections do not respond identically to METH treatment; consequently, finding that the SP pathways associated
with these two dopaminergic systems also are affected differentially is not inconsistent with these observations. Additional study is necessary to identify the precise mechanisms responsible for these differences.
Acknowledgement This work was supported by U.S. Public Health Service Grants MH 40175 and DA 00869.
References Davies, J. and A. Dray, 1976, Substance P in the substantia nigra, Brain Res. 107, 623. Keen, P., A.J. Harmar, F. Spears and E. Winter, 1982, The striatonigral substance P pathway and dopaminergic mechanisms, in: Substance P and the Nervous System, eds. R. Porter and M. O'Connor (Pitman, London) p. 145. Kelly, P.H., P.W. Seviour and S.D. Iversen, 1975, Amphetamine and apomorphine responses in the rat following 6OHDA lesions of the nucleus accumbens septi and corpus striatum, Brain Res. 94, 507. Kelly, A.E., L. Stinus and S.D. Iversen, 1979, Behavioural activation induced in the rat by substance P infusion into the ventral tegrnental area: Implication of dopaminergic A10 neurones, Neurosci. Lett. 11,335. Lindvall, O., A. Bj~rklund and I. Divac, 1977, Organization of mesencephalic dopamine neurones projecting to neocortex and septum, in: Non-striatal Dopaminergic Neurones, eds. E. Costa and G. Gessa (Raven Press, New York) p. 39. Morgan, M.E. and J.W. Gibb, 1980, Short-term and long-term effects of methamphetamine on biogenic amine metabolism in extra-striatal dopaminergic nuclei, Neuropharmacology 19, 989. Palkovits, M. and D.M. Jacobowitz, 1974, Topographic atlas of catecholamine and acetylchohnesterase-containing neurons in the rat brain, Comp. Neurol. 157, 29. Ritter, J.K., C.J. Sehmidt, J.W. Gibb and G.R. Hanson, 1984, Increase of substance P-like immunoreactivity within striatai-nigral structures following subacute methamphetamine treatment, J. Pharmacol. Exp. Ther. 229, 487. Schmidt, C., J. Ritter, P. Sonsalla, G.R. Hanson and J.W. Gibb, 1985, Role of dopamine in the neurotoxic effects of methamphetamine, J. Pharmacol. Exp~ Ther. 233, 539. Stinus, L., A.E. Kelley and S.D. Iversen, 1978, Increased spontaneous activity following substance P infusion into A10 dopaminergic area, Nature (London) 276, 616.