binge model of amphetamine-induced psychosis

Regional zif268 mRNA expression

Pergamon PII: S0306-4522(99)00510-2

Neuroscience Vol. 96, No. 1, pp. 83–90, 2000 83 Copyright q 2000 IBRO. Published by Elsevier Science Ltd Printed in Great Britain. All rights reserved 0306-4522/00 $20.00+0.00

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DIFFERENTIAL REGIONAL ZIF268 MESSENGER RNA EXPRESSION IN AN ESCALATING DOSE/BINGE MODEL OF AMPHETAMINE-INDUCED PSYCHOSIS P. D. SHILLING, J. R. KELSOE, R. KUCZENSKI* and D. S. SEGAL Psychiatry Department, School of Medicine, University of California at San Diego, La Jolla, CA 92093, U.S.A.

Abstract—Amphetamine-induced psychosis is most often associated with a high-dose multiple binge pattern of stimulant abuse. To simulate these conditions in rats, we used an escalating dose/binge administration paradigm. Animals were pretreated with escalating doses of amphetamine (1.0–8.0 mg/kg) over four days, then exposed to nine daily binges (8.0 mg/kg every 2 h; four injections/day). Other animals received either multiple injections of saline, saline followed by acute amphetamine (8.0 mg/kg) or single daily injections of amphetamine (8.0 mg/kg) in parallel with the escalating dose/binge treatment. One hour after the last injection, all animals were decapitated and regional brain activation patterns were assessed using in situ hybridization with antisense probes for zif268. Acute amphetamine resulted in a significant elevation of zif268 messenger RNA in both the nucleus accumbens and dorsal striatum. However, whereas after single daily amphetamine treatment this index was no longer elevated above control levels in the dorsal striatum, multiple binge exposures were required for the nucleus accumbens to return to baseline. Agranular insular cortex and medial olfactory tubercle zif268 messenger RNA expression was also markedly increased after acute amphetamine treatment but, unlike the nucleus accumbens and dorsal striatum, this increase was not significantly attenuated by either single daily injection or multiple binge treatment. Zif268 messenger RNA expression in the lateral nucleus of the amygdala also remained elevated above baseline after binge treatment. The possible relationships of these changes in zif268 messenger RNA regional expression patterns to the development of psychosis in high-dose stimulant abusers are discussed. q 2000 IBRO. Published by Elsevier Science Ltd. Key words: amphetamine, dopamine, dorsal striatum, nucleus accumbens, psychosis, zif268 mRNA.

Amphetamine-induced psychosis is frequently associated with a high-dose multiple binge pattern of drug abuse. 2,17 Drug abusers usually precede bingeing with a gradual escalation of drug dose. 1,17 Presumably, the tolerance that develops to the sympathomimetic effects of stimulants enables the drug user to survive the high doses and frequency of administration used in bingeing. 15,16,32,33 To attempt modeling these conditions in rats, we used a recently developed novel injection protocol. 35 The high-dose pattern of stimulant abuse leading to the development of psychosis was simulated by exposing rats to gradually escalating doses of amphetamine followed by daily multiple injections of high doses of this drug (binges). The escalating dose/binge treatment resulted in the progressive emergence of a unique behavioral profile which included both quantitative (sensitization) and qualitative changes in locomotor activity and a decrease in the time spent in stereotypy (tolerance). 35 Kuczenski and Segal 21 have recently reported that, after multiple daily binges, the caudate–putamen (CP) extracellular dopamine (DA) response developed a pronounced tolerance/tachyphylaxis, while the nucleus accumbens (NA) DA response remained unchanged compared to an acute amphetamine challenge. 21 Because the mesostriatal and mesolimbic

DA systems have been shown to be involved in stereotypy and locomotion, respectively, 7,8,37,41 it was suggested that this apparent shift in relative CP and NA DA transmission could be implicated in the unique behavioral profile resulting from binge administration. We hypothesized that this differential presynaptic DA response would also result in a differential postsynaptic activation in the CP (dorsal striatum) vs NA in response to multiple daily amphetamine binges. In this study, we used regional changes in zif268 mRNA expression to test this hypothesis. Immediate early genes (IEGs) such as zif268 (NGFI-A) have been used as measures of neuronal activation. 38 Zif268, a zinc finger transcription factor, has been shown to be induced by membrane depolarization and by changes in various signal transduction (elevation of cyclicAMP or Ca 21) pathways. 12,23,38 Zif268 exhibits low to medium levels of basal expression, presumably regulated by synaptic activity, 48 but is rapidly and transiently induced after neuronal stimulation. In this regard, both acute and chronic amphetamine treatments have been shown to increase zif268 mRNA expression in the CP. 25,44,46 In this study, zif268 mRNA was also measured in other DA-innervated postsynaptic regions to evaluate the generality of its expression profile associated with acute, single daily administration and binge amphetamine treatment.

*To whom correspondence should be addressed. Fax: 1 1-858-534-7653. E-mail address: [email protected] (R. Kuczenski) Abbreviations: ADS, anterior dorsal striatum; AI, agranular insular cortex; CA1/CA2, CA1/CA2 fields of the hippocampus; CC, cingulate cortex; CNA, central amygdaloid nucleus; CP, caudate–putamen; CRF, corticotropin-releasing factor; DA, dopamine; FMI, forceps minor, corpus callosum; IEG, immediate early gene; LNA, lateral amygdaloid nucleus; MDS, middle dorsal striatum; MOT, medial olfactory tubercle; mPFC, medial prefrontal cortex; NA, nucleus accumbens; PC, piriform cortex; SDI, single daily injection.

EXPERIMENTAL PROCEDURES

Animals Four groups of male Sprague–Dawley rats (Simonsen Labs, Gilroy, CA), weighing 300–325 g at the beginning of drug administration, were housed for two weeks prior to experimentation, two or three per cage on a 14-h/10-h light–dark cycle (5.00 a.m. to 7.00 p.m.) with continuous access to food and water. All studies adhered to animal welfare guidelines as promulgated by the “Principles of Laboratory Animal Care” (NIH Publication No. 85-23). 83

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Table 1. Escalating dose/binge injection schedule for amphetamine administration Escalating doses (mg/kg) Day 1 2 3 4

6.00 a.m.

12.00 a.m.

1 3 5 7 mg/kg given at

6.00 p.m.

2 3 4 5 6 7 8.00 a.m. and 8 mg/kg at 2.00 p.m.

Binges (mg/kg) Day

8.00 a.m.

10.00 a.m.

12.00 p.m.

2.00 p.m.

8

8

8

8

6–14 (nine binges)

Drugs d-Amphetamine sulfate (NIDA) was administered subcutaneously (s.c.) in saline (2 ml/kg to avoid local irritation that might result from repeated injections of high concentrations of drug). All doses are expressed as free base.

(MDS), 0.70–0.48 mm from bregma; central nucleus of the amygdala (CNA), lateral nucleus of the amygdala (LNA), hippocampus (CA1/CA2), 2.3–2.8 mm from bregma. 27 In addition, because baseline levels of zif268 mRNA in the CNA were barely detectable, adjacent sections in this region were hybridized with probes to CRF mRNA (described previously), enabling us to locate this nucleus. The previously described regions were analysed in the following manner: a circle 50 pixels in diameter was outlined in the ADS, MDS and mPFC; a circle 40 pixels in diameter was outlined in the AI. In the CC, a 10 × 50 rectangle was outlined. In addition, the shapes used to quantify each region of interest were placed based on structural landmarks which allowed for consistent placement in the same region for each section. For example, the forceps minor of the corpus callosum was used as a landmark to position the 50 × 50 circle in the ADS and MDS. A line was drawn through this region parallel to the midline. The circle was then placed just below the corpus callosum with its right edge next to this line. The NA was quantified by outlining the structure according to Paxinos and Watson. 27 In the hippocampus, the CA1/CA2 pyramidal cell layer was outlined, and for the PC and MOT the layer 2 cell layer was outlined. The LNA was quantified by outlining the structure according to the above atlas using the external capsule as its boundaries. The CNA was quantified by using a circle 25 pixels in diameter which outlined the area of largest zif268 mRNA expression in this region. In addition, for each animal, four adjacent sections containing each region of interest (n ˆ 5 or 6) were analysed bilaterally and the mean value was used in the statistical analysis. Statistical analysis

Escalating dose/binge phase (see Table 1) During the escalating dose phase, animals in one group received three injections per day for four days beginning with 1.0 mg/kg amphetamine on the first day and ending with 8.0 mg/kg on the fourth day. On the fifth day they received two saline injections. Binges began on day 6. During each binge, animals received four injections of 8 mg/kg amphetamine every 2 h beginning at 8.00 a.m. and ending at 2.00 p.m. The binge treatment continued for nine consecutive days. Other animals received either multiple daily injections of saline, saline followed by acute amphetamine (8.0 mg/kg) or nine single daily injections (SDIs) of amphetamine (8.0 mg/kg) in parallel with the escalating dose/binge treatment. All animals received an equivalent number of injections. One hour after the last injection, all animals were decapitated since zif268 mRNA expression, in response to amphetamine challenge, has been reported to be maximal at this time-point. 46 Brains were then quick-frozen in isopentane. In situ hybridization Brains were sectioned coronally (20 mm), thaw mounted on to Fisher SuperFrostPlus slides and stored at 2808C. In situ hybridization was performed as described by Chao and McEwen, 5 with modifications by Shilling et al. 39 Antisense 35S-labeled mRNA probes were transcribed in vitro from a 230-bp cDNA BglII/EcoRI insert from the zif268 cDNA (kindly provided by J. Milbrandt). A 1.1-kb cDNA EcoRI insert (kindly provided by K. Mayo), subcloned into pBS, was used to transcribe probes for corticotropin-releasing factor (CRF). A sense RNA probe was used on control sections. Sections were fixed and acetylated before hybridization. Treated slides were then incubated with hybridation buffer containing 1 × 10 7 c.p.m./ml denatured riboprobe, for 20 h at 538C on a slide warmer. Slides were then treated with RNase A (10 mg/ml) for 20 min, and washed with either 0.5 × standard saline citrate at 558C for 20 min (CRF), or 0.1 × standard saline citrate at 658C for 30 min (zif268) (washes contained 1 M dithiothreitol). Optimal washing conditions were determined empirically for each probe. Slides were apposed to Amersham bMax Hyperfilm along with 14C and/or 35S standards. Regional quantification Quantification of zif268 mRNA was accomplished by computer analysis of digitized images using NIH Image Software (W. Rasband, National Institutes of Health, Bethesda, MD) in the following brain regions (see Fig. 1): medial prefrontal cortex (mPFC), agranular insular cortex (AI), 4.2–3.7 mm from bregma; anterior dorsal striatum (ADS), NA, medial olfactory tubercle (MOT), cingulate cortex (CC), piriform cortex (PC), 1.6 mm from bregma; middle dorsal striatum

Data were analysed by ANOVA and Student–Newman–Keuls post hoc test. RESULTS

Zif268 mRNA expression 1 h after the last treatment in 11 DA projection areas is summarized in Table 2. Acute amphetamine resulted in a significant elevation in zif268 mRNA (Table 2, Figs 2, 3) in both the NA and the dorsal striatum. After SDI, zif268 mRNA expression was no longer elevated above saline controls in the dorsal striatum. In contrast, zif268 mRNA expression was still significantly elevated above baseline in the NA. However, following binge treatment, amphetamine did not elevate zif268 mRNA expression in either region. Our data demonstrate that our methodology can detect significant changes in zif268 mRNA expression below those obtained in the dorsal striatum after SDI (data not shown), suggesting that dorsal striatum values after SDI are not the result of a floor effect. With regard to other areas, a relatively large increase in zif268 mRNA expression occurred in the CNA after acute amphetamine which, as in the NA, was attenuated after SDI and returned to baseline after binges (Table 2, Fig. 4). In contrast, no changes in zif268 mRNA expression were observed in the hippocampus (CA1/CA2) with any of the amphetamine treatments (Table 2). The AI (Table 2, Fig. 5) and MOT exhibited similar zif268 mRNA expression patterns that were unique to these structures. As in most of the other regions analysed, zif268 mRNA significantly increased after acute amphetamine treatment. However, in contrast to its pattern of expression in other regions analysed, the amphetamine-induced increase in zif268 mRNA expression was not attenuated by binge treatment. The LNA also exhibited a unique expression profile. Also, like most of the other regions analysed, this nucleus exhibited a significant increase in zif268 mRNA following acute treatment and SDI attenuated this effect. However, after binges, zif268 mRNA expression remained significantly above baseline (Table 2).

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Fig. 1. Representative sections used for quantification of zif268 mRNA in the AI (1), mPFC (2) (3.70 mm from bregma); NA (3), ADS (4), MOT (5), CC (6), PC (7) (1.60 mm from bregma); MDS (8) (0.48 mm from bregma); CNA (9), LNA (10) and hippocampal, CA1/CA2 fields (11) (22.8 mm from bregma). Diagrams are adapted from Paxinos and Watson. 27

DISCUSSION

Acute amphetamine treatment elevated zif268 mRNA expression in most regions analysed, whereas after SDI and binges this elevation was attenuated. However, a more detailed analysis of these changes revealed that the different amphetamine treatment regimens produced regionally distinct patterns of change in zif268 mRNA expression. Dorsal striatum vs nucleus accumbens Acute amphetamine administration produced a significant up-regulation of zif268 in both the NA and the dorsal striatum, and SDI significantly attenuated this effect. However, whereas zif268 mRNA expression was still significantly elevated in the NA after SDI, expression in the dorsal striatum was not. With binge treatment, zif268 mRNA expression in the NA was further attenuated and was no longer significantly elevated from baseline. Thus, zif268 mRNA expression in both regions was not significantly different from baseline levels after repeated binge exposures.

These results support and extend other reports in the literature regarding the effects of acute and SDI stimulant administration on IEG expression. 25,28,44,46 However, in contrast to our observations, Daunais and McGinty 9 reported that zif268 mRNA in the striatum remained elevated after 10 cocaine binges. These differences may reflect the effects of the escalating dose pretreatment (used only in our study), the different drugs and doses, and/or other methodological variations between the two studies. A more detailed examination of the NA (data not shown) revealed that acute amphetamine treatment increased zif268 mRNA expression most markedly in the medial region. Both Moratalla et al. 25 and Wang et al. 46 observed a similar preferential elevation in zif268 mRNA expression in the NA after acute amphetamine, though their signal was not as intense as we observed. The higher doses of amphetamine (8.0 vs 5.0 mg/kg) we used could account for these differences. Our previous results demonstrated a regionally differential extracellular DA response to amphetamine 21,34,35 after repeated binge exposures, marked by an attenuation of the

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Table 2. The effect of amphetamine on zif268 messenger RNA expression Treatment Region

Acute

SDI

Binges

Striatal/mesolimbic ADS 181 ^ 13** MDS 196 ^ 19** NA 301 ^ 8** MOT 201 ^ 15**

113 ^ 8†† 121 ^ 9†† 178 ^ 12**†† 169 ^ 25*

88 ^ 10†† 109 ^ 10† 85 ^ 9††‡‡ 184 ^ 10*

Cortex mPFC AI CC PC

159 ^ 7* 242 ^ 32** 174 ^ 11** 137 ^ 8**

143 ^ 19 204 ^ 15* 161 ^ 5** 147 ^ 6**

128 ^ 7 237 ^ 16** 114 ^ 14††‡‡ 117 ^ 6‡

Other limbic CNA LNA CA1/CA2

497 ^ 21** 192 ^ 5** 94 ^ 7

336 ^ 38**† 155 ^ 15**† 98 ^ 11

166 ^ 27††‡ 161 ^ 7**† 95 ^ 7

Values are represented as percentage of saline control ^ S.E.M. Significantly different: from saline, **P # 0.01, *P # 0.05; from acute, ††P # 0.01, †P # 0.05; binges vs SDI, ‡‡P # 0.01, ‡P # 0.01 (ANOVA followed by Student–Newman–Keuls post hoc test). Statistical analysis performed on raw optical density values.

CP DA response and no change in the NA DA response. In spite of this differential DA response profile, however, both the CP and NA still responded to amphetamine with substantial increases in extracellular DA. In contrast, both these regions exhibited complete tolerance to the amphetamine-induced elevation of zif268 mRNA expression following this treatment. In this regard, it should be noted that DA D1 activation plays a critical role in

the increased expression of IEGs such as c-fos and zif268 produced by DA agonists in the CP and NA. 6,10,13,18,25 Thus, D1 antagonists block IEG increases in expression in response to DA agonists. 10,25 Furthermore, in D1 receptor knockout mice cocaine failed to elevate striatal cfos or zif268 mRNA expression. 13 Our results suggest, therefore, that exposure to multiple amphetamine binges disrupts the linkage between released DA and D1 DA receptor-mediated activation of zif268 mRNA expression in both the CP and NA. In contrast, after SDI, amphetamine-induced activation of zif268 mRNA expression exhibited complete tolerance only in the dorsal striatum, but not in the NA. Therefore, disruption of the regulation of zif268 mRNA expression by D1 receptors in both the NA and CP, together with the regional shift in extracellular DA release we have observed after escalating dose/binge treatment, may be required for the emergence of the unique behavioral profile associated with multiple binge exposures. Similar changes in the mechanisms regulating the postsynaptic response to DA may be associated with SDI stimulant administration. For example, acute administration of moderate to high doses of amphetamine results in the down-regulation of D1-stimulated adenylate cyclase activity in the CP but not the NA, 4,30 and this effect is enhanced with SDI, 4 perhaps contributing to the differential tolerance of zif268 mRNA expression in these regions. It should also be noted that we have shown that this SDI dosage paradigm results in tolerance to the oral stereotypy associated with high-dose amphetamine administration. 29 Because the mesostriatal DA system has been implicated in this behavior, it is conceivable that the selective (relative to the NA) attenuation of the increase in zif268 mRNA

Fig. 2. The effect of amphetamine treatment on zif268 mRNA expression. Film autoradiographic visualization of 35S-labeled cRNA probes hybridized to the ADS ( p ) and NA ( p p ) of animals treated with saline (A), acute amphetamine (B), SDI of amphetamine (C) or multiple amphetamine binges (D).

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striatum. Of relevance, several studies have shown that amphetamine- and methamphetamine-induced zif268 expression is dependent on activation of N-methyl-daspartate and kainate/a-amino-3-hydroxy-5-methyl-4-isoxazolepropionate receptors. 42,43,45 In addition, dizocilpine, an N-methyl-d-aspartate antagonist, has been shown to prevent both acute amphetamine-induced c-fos expression as well as the down-regulation of c-fos IEG expression usually observed after chronic stimulant administration in this region (NA and CP). 20 Regional differences in glutamate changes produced by the various treatments may also contribute to the apparent dissociation between DA and zif268 response profiles.

Central amygdaloid nucleus Fig. 3. The effect of acute, SDI or binge amphetamine treatment on zif268 mRNA expression in the ADS, MDS and the NA represented as percentage of saline control. Animals were decapitated 1 h after the last treatment. Symbols on histograms indicate significant differences. Compared to saline: *P , 0.05, **P , 0.01; compared to acute: 11P , 0.01; compared to SDI: #P , 0.05 (ANOVA followed by Student–Newman–Keuls post hoc test). ADS: F ˆ 18.149, d.f. ˆ 3,19; MDS: F ˆ 11.558, d.f. ˆ 3,16; NA: F ˆ 100.143, d.f. ˆ 3,19). Data points represent the mean ^ S.E.M. of five to six animals/group.

expression in the CP after SDI contributes to this behavioral change. In addition to DA, glutamate also appears to contribute to the regulation of IEG expression in the

The CNA displayed the largest SDI-induced increase in zif268 mRNA expression of any of the DA projection areas examined. As was observed in the striatal regions, the elevation in CNA zif268 mRNA after acute amphetamine was attenuated by SDI and further attenuated by binge treatment. This nucleus, which receives the largest mesoamygdaloid DA projection, 19 appears to have an important role in the integration of physiological responses to environmental stimuli, 3,24 and therefore it is conceivable that alterations in activation of the CNA could contribute to some of the behavioral changes that emerge with SDI. In fact, there is evidence that the amygdala contributes to stimulant-induced stereotypy 47 and locomotor activity. 40

Fig. 4. The effect of amphetamine treatment on zif268 mRNA expression. Film autoradiographic visualization of 35S-labeled cRNA probes hybridized to the amygdala of animals treated with saline (A), acute amphetamine (B), SDI of amphetamine (C) or multiple amphetamine binges (D).

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Fig. 5. The effect of amphetamine treatment on zif268 mRNA expression. Film autoradiographic visualization of 35S-labeled cRNA probes hybridized to agranular insular cortex of animals treated with saline (A), acute amphetamine (B), SDI of amphetamine (C) or multiple amphetamine binges (D).

Unique zif268 messenger RNA expression profile: agranular insular cortex, medial olfactory tubercle and lateral nucleus of the amygdala

paranoid delusions psychosis.

observed

in

amphetamine-induced

CONCLUSION

The AI and MOT displayed a similar amphetamineinduced zif268 mRNA expression profile, which was different from most of the other regions analysed. In these structures, zif268 mRNA expression was not attenuated by binge treatment. Therefore, a relative disinhibition of these regions could result as a consequence of the tolerance that develops with this treatment in most other areas examined. The resulting increases in activation of selected sensory systems could contribute to the expression of sensory hallucinations typical of amphetamine psychosis. 36 The LNA, which has been shown to be critically involved in fear conditioning, 11,22,26,31 also remained activated after binge administration. In this regard, paranoid delusions, viewed as inappropriate fear responses, 14 are a characteristic feature of amphetamine psychosis. 2 Fibiger 14 has also speculated that DA mechanisms in the amygdala could mediate paranoid delusions. Our results are consistent with a role for the LNA in the development of

In summary, we observed regionally distinct changes in zif268 mRNA expression in the dorsal striatum and NA after SDI and binges that could have relevance to the progressive alterations in stimulant-induced behaviors associated with these treatments. These amphetamine treatments also produced distinguishable patterns of change in zif268 mRNA expression in other DA terminal regions. These findings could have implications for the development of psychosis in high-dose stimulant abusers. Acknowledgements—This work was supported in part by PHS grants DA01568 and DA-04157. D.S.S. is the recipient of NIMH RSA MH-70183. P.D.S. was supported in part by NIH grants 5 T32 MH19934-02 and T32 MH18399-13. We thank Dr Jeffrey Millbrandt and Dr Kelly Mayo for kindly supplying the zif268 and CRF cDNA clones, respectively. We also thank Dr Paul Sawchenko and Dr Raymond Chan for helpful discussions, and express appreciation to Brad Hirakawa, Bahram Khadivi and Lydia Drumright for excellent technical assistance.

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