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NEUROPHARMACOLOGY
Brain Injury and Repair Group, Howard Florey Institute (C.S.M., T.F., E.K., A.J.L.), and Centre for Neuroscience (C.S.M., T.F., A.J.L.), University of Melbourne, Parkville, Victoria, Australia
Received May 15, 2007; accepted July 11, 2007.
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Abstract |
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). Studies have developed the case for the importance of environment (or context) in the process of sensitization (Uslaner et al., 2003).
Sensitization to intermittent psychostimulant exposure is often used as a de facto indicator for long-lasting neural change following drug use (Turgeon et al., 1997). In rodents, this observation is robust and reproducible (Pierce and Kalivas, 1997). The bulk of studies thus far concerning sensitization have typically focused upon regions involved in the now well established mesotelencephalic dopaminergic projections, terminating on the striatum (Konradi et al., 1994; Berridge and Robinson, 1995; Cole et al., 1995), and more recently, corticotegmental and corticostriatal glutamate projections (Boudreau and Wolf, 2005). Indeed, extensive evidence implicates the ventral striatum (nucleus accumbens; NAcc) in rewarding and reinforcing salience, with the dorsal striatum (caudate putamen; CPu) contributing to associative habitual learning and stereotypies (Berke and Hyman, 2000).
Sensitization has been previously demonstrated to last up to a year or multiple years in rodents (Paulson et al., 1991) and humans, respectively (Sax and Strakowski, 2001); however, it is widely acknowledged (Nestler, 2004) that the molecular substrates mediating these changes are yet to be completely characterized. Among the potential substrates, a leading molecular target is the bZIP family transcription factor cAMP-response element-binding protein; CREB). CREB functions in cells to enhance transcriptional activity of many products crucial to cellular signaling, growth, substrate-trafficking/targeting, and development (Shaywitz and Greenberg, 1999).
An intermittent cocaine-dosing conditioned place preference paradigm displayed no changes in phosphorylated CREB (pCREB) expression within the BNST, NAcc, and VTA 10 days after the last dose, but pCREB expression was increased within the amygdala (Kreibich and Blendy, 2004). Difficulties present themselves when cross-interpreting these results with factors such as the technique (immunoblotting for pCREB protein) and drug and dosing schedule, which often produce potential confounders to interpretation that lie not only with studies of psychostimulants but also extend to those using ethanol, methamphetamine, and morphine (McPherson and Lawrence, 2007). The existing literature assaying for CREB or pCREB subsequent to drug exposure typically focuses upon the striatum (Cole et al., 1995; Miller and Marshall, 2005). Such a constrained treatment is inadequate if we are to better to establish how CREB signaling operates in systems that mediate ongoing cellular change following drug administration. Therefore, in the present study using amphetamine, we have examined acute, contextual, and sensitized patterns of pCREB expression in parallel, assaying across multiple nuclei that have been implicated in drug-seeking.
An involvement of the lateral hypothalamus in the salience of prandial states has been known for some time (Anand and Brobeck, 1951; Fadel et al., 2002), as well as being implicated in arousal and sleep regulation (Sakurai, 2007). It was subsequently discovered that a distinguishing hallmark of these neurons is the expression of orexins (also known as hypocretins). These neurons project widely through the brain, with efferent fibers synapsing throughout the neuraxis (Peyron et al., 1998), making a case for the orexinergic system as a potential modulator of reward systems. Indeed, the selective OX1 receptor antagonist SB-334867 prevents cue-induced reinstatement of alcohol-seeking (Lawrence et al., 2006) and stress-induced reinstatement of cocaine-seeking (Boutrel et al., 2005). Consequently, we examined coexpression of pCREB or c-Fos double labeling within orexin A-immunopositive neurons to assay for concurrent activation of these systems.
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Materials and Methods |
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Drug Administration. The model of amphetamine sensitization has been described previously (McPherson and Lawrence, 2006). Briefly, rats were randomized into three equal groups (n = 16 per group) and allowed to acclimatize to the holding room for 5 days. In a test environment separate from the holding room, rats were injected with either low- or high-dose amphetamine (2.0 or 10.0 mg/kg i.p. d-amphetamine sulfate powder; Sigma, VIC, Australia) dissolved in saline, or saline (1.0 ml/kg i.p. 0.9% NaCl; Delta West P/L, Bentley, WA, Australia) once daily for 10 consecutive days.
After a 4-week period of abstinence, each group was equally divided and challenged with saline (1 ml/kg i.p.) or amphetamine sulfate (1.5 mg/kg i.p.). Ninety minutes following challenge, rats were deeply anesthetized with sodium pentobarbitone (80 mg/kg i.p.). The experimental treatment schedule is demonstrated in Table 1. The final groups (n = 8) are denoted based on their treatment and subsequent challenge: saline treatment-saline challenge (control), saline treatment-amphetamine challenge (acute), low-dose amphetamine (2.0 mg/kg) treatment-saline challenge (low-saline; L-S), low-dose amphetamine treatment-amphetamine challenge (low-challenge; L-C), high-dose amphetamine (10.0 mg/kg) treatment-saline challenge (high-saline; H-S), and high-dose amphetamine treatment-amphetamine challenge (high-challenge; H-C).
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Tissue Preparation. Anesthetized rats were transcardially perfused individually with 100 ml of 0.1 M phosphate-buffered saline (PBS), pH 7.4, followed by fixation with 250 ml of 4% paraformaldehyde (PFA; Sigma) in PBS. The rats were immediately decapitated, and brains were quickly removed and postfixed overnight in fixative containing 10% sucrose. Brains were subsequently sectioned on a freezing microtome at 50 µm in the coronal plane and floated in 48-well tissue culture microplates containing cryoprotectant solution, and stored at –20°C until use (McPherson and Lawrence, 2006). Every fourth section (200-µm interval) was slide-mounted with 0.5% gelatin, counterstained with neutral red (0.5%), and then differentiated, cleared, and coverslipped with Gurr DePex mounting medium (BDH, Poole, Dorset, UK). Sections were kept as a reference map for each rat.
Immunostaining. Immunohistochemical procedures were performed essentially as described previously (McDougall et al., 2004; McPherson and Lawrence, 2006). Brain sections from each treatment group were processed simultaneously for each discrete brain region (n = 4 sections per brain region of interest per rat from n = 6 rats per treatment group). The brain regions examined included the striatum and lateral septum (bregma, 1.7–0.7), amygdala and habenula (bregma, –2.2 to –3.3), bed nucleus of the stria terminal (bregma, –0.3 to –0.8), mesencephalon (bregma, –4.8 to –6.04), and hypothalamus (bregma, –2.56 to –3.6) (Paxinos and Watson, 1986).
This equated to a typical assay of 144 sections from any given anatomic level. Sections were removed from cryoprotectant, washed in 0.1 M PBS (3 x 10 min), and then preblocked with 10% normal horse serum, 0.3% Triton X-100, and 0.1 M PBS for 15 min. After washing (3 x 5 min in PBS), sections were incubated with a rabbit polyclonal pCREB antibody (1:1000; Upstate Biotechnology, Charlottesville, VA) in PBS containing 1% normal horse serum and 0.3% Triton X-100 (PBS-NTx) for 48 h at 4°C, with agitation. The following morning, sections were removed from refrigeration, washed, and then incubated in PBS-NTx containing biotinylated horse anti-rabbit IgG (1:200; Vector Laboratories, Burlingame, CA) solution for 1 h, again rinsed, and then immersed in PBS-NTx containing streptavidin horseradish peroxidase (1:500; Vector Laboratories) for 1 h. After washing, sections were reacted with nickel enhanced 3,3'-diaminobenzidine tetrahydrochloride chromagen (Sigma) solution [0.1 M PBS and 0.004% (w/v) ammonium chloride/ammonium nickel(II) sulfate hexahydrate] for 10 min, and immunoreactivity was then developed by addition of 0.03% hydrogen peroxide. The reaction was terminated by washing in 0.1 M PBS (3 x 10 min). Sections were subsequently slide-mounted and coverslipped.
Sections from the level of the hypothalamus were first immunostained for pCREB or c-Fos (1:1000; Santa Cruz Biotechnology, Inc., Santa Cruz, CA), according to the aforementioned procedure. Subsequently, the sections were assayed for orexin A immunoreactivity using a goat anti-orexin A antibody (1:4000, sc-8070; Santa Cruz Biotechnology, Inc.) overnight at 4°C on a shaker, followed by biotinylated rabbit anti-goat secondary IgG (1:500; Vector Laboratories). Immunoreactivity was developed with 3,3'-diaminobenzidine, in the absence of nickel enhancement and ammonium chloride, generating a brown stain for orexin A-immunopositive cytoplasm, relative to pCREB/c-Fos-expressing nuclei, which were stained black.
Microscopic Analysis. Counting of pCREB-immunoreactive (-IR) nuclei was performed unilaterally in each section, without reference to treatment group. Regions quantified included the caudate putamen, nucleus accumbens, amygdaloid complex, substantia nigra pars compacta, ventral tegmental area, lateral septum, habenula, and the BNST. pCREB-IR quantification was conducted with a stereology L-RGB video capture device analysis system as described previously (McPherson and Lawrence, 2006). Quantification of c-Fos and orexin A immunoreactivity was conducted using a 20x objective using the same stereological apparatus.
Statistics. pCREB-IR was analyzed by a two-way ANOVA within regions, with factors being pretreatment dose and challenge. One-way ANOVAs were used to determine differential c-Fos/orexin A colabeling, with treatment group as a factor through each discrete hypothalamic region. A value of P < 0.05 was regarded as statistically significant in all cases.
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Results |
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). Representative pCREB immunostaining photomicrographs are demonstrated in Fig. 1, whereas examples of pCREB quantitation within a nucleus are presented in Fig. 2.
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Drug-Environment Associations. Upon re-exposure to the drug context environment, in the low-saline group, expression of pCREB was diminished within all quadrants of the CPu (P < 0.05; see Table 2 for detail; see Fig. 2B for dorsomedial quadrant) but unchanged in the high-saline group. In the NAcc, pCREB-IR in the high-saline group was double that of the controls (saline-saline; q = 4.015, P = 0.005) (Fig. 2A), although this was not observed in the low-saline group. This pattern of pCREB-IR was paralleled in the lateral septum (LS) where the high-saline group showed increased pCREB-IR compared with controls (q = 4.028, P = 0.006), whereas the low-saline group was equivalent with controls.
Within the hypothalamus there was a significant interaction between pretreatment and challenge (F2,86 = 5.956, P = 0.004) in the DMH. Notably, in the low-saline group pCREB-IR was reduced compared with controls (q = 3.16, P = 0.028), whereas in the high-saline group pCREB-IR was increased (q = 3.968, P = 0.006) throughout the DMH. A similar outcome was observed in the PFA, where an interaction between pretreatment and challenge (F2,87 = 3.164, P = 0.047) occurred. Post hoc analysis indicated that pCREB-IR in the low-saline group was reduced compared with controls (q = 4.403, P = 0.003), but this was not the case for the high-saline group. The situation in the LH mirrored that in the PFA, where pCREB-IR was reduced in the low-saline group compared with control (q = 3.979, P = 0.006), whereas the high-saline group showed similar pCREB-IR as controls.
Sensitization Effects of Amphetamine. Low-challenge rats demonstrated sensitization effects, with elevated pCREB-IR levels within the CeA (q = 3.653, P = 0.032) (Fig. 2D), MeA (q = 4.995, P = 0.003), and DMH (q = 2.888, P = 0.044), compared with rats acutely challenged with amphetamine (Table 2).
In all dorsal striatal quadrants and the NAcc, high-challenge sensitized rats exhibited greater pCREB expression than low-challenge rats (Table 2). High-challenge sensitized rats exhibited greater pCREB expression than acutely treated rats in the LHab (q = 3.845, P = 0.008), CPu (all quadrants; P < 0.05), and NAcc (q = 5.649, P < 0.001) (Fig. 2A). Similar to the low-challenge rats, amygdaloid CREB activation was not different from controls (but different from acute amphetamine; Table 2), and mesencephalic (SNc) pCREB-IR levels were also similar to basal, but elevated compared with contextual re-exposure (48 ± 9 versus 14 ± 4 high pretreatment alone: q = 3.166, P = 0.028). pCREB expression in the DMH demonstrated a pretreatment x challenge interaction (F2,86 = 5.956, P = 0.004), because all sensitized rats had enhancement of pCREB expression, regardless of pretreatment amphetamine dose. A schematic of the circuitry responsive to acute, contextual, and/or sensitized effects of amphetamine is depicted in Fig. 3.
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Lateral Hypothalamic Orexinergic Neurons: Coexpression with c-Fos, Not pCREB. There was a distinct absence of pCREB and orexin A double staining within the lateral hypothalamus, perifornical area, and dorsomedial hypothalamus. The number of orexin A-expressing neurons, however, did not differ between groups through these regions of the hypothalamus. To verify that the methods used were robust and to fully assay for activation of orexinergic neurons, parallel sections from the high-dose amphetamine pretreatment group were processed for both c-Fos and orexin A coexpression. Representative immunolabeling photomicrographs are presented in Fig. 4. Sensitized rats (high-challenge) demonstrated a significantly greater proportion of c-Fos/orexin A double-labeled cells relative to both control and acutely treated rats within the DMH (q = 4.848 versus control, q = 4.192 versus acute; both P < 0.05), as demonstrated in Fig. 5. A similar scenario occurred in the PFA whereby sensitization to amphetamine increased the proportion of c-Fos/orexin A double-labeled cells (q = 4.905 versus acute, q = 7.121 versus control; both P < 0.01). In the LH, sensitization to amphetamine increased the proportion of c-Fos/orexin A double-labeled cells compared with controls (q = 4.177, P = 0.016) but not compared with acute amphetamine.
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Discussion |
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Acute Effects of Amphetamine. Rats received amphetamine treatment during periadolescence and the behavioral consequences were published previously (McPherson and Lawrence, 2006). Neuronal reorganization during this ontogenetic period may result in elevated basal pCREB levels relative to adulthood within the telencephalon (Crews et al., 2007). The SNc, CeA, and MeA were affected by acute amphetamine, with enhancement (SNc) or reduction (amygdala) of pCREB-IR. These structures are components of a basal ganglia motor circuit and limbic system, with the CeA and SNc sharing reciprocal connectivity. Previous studies using adult rats indicate enhancement of striatal pCREB expression following acute amphetamine (4–6 mg/kg i.p.) (Konradi et al., 1994; Cole et al., 1995; Choe et al., 2002; Choe and Wang, 2002). Although we observed a strong trend for pCREB-IR enhancement within the NAcc, this was not mirrored in the CPu unlike c-Fos-IR (McPherson and Lawrence, 2006). This may in part be explained by differing developmental ages, treatment paradigms, and doses. Fos, a target gene for CREB and involved in downstream transcriptome expression, can exhibit (a)synchronous expression with CREB, as noted previously (Herdegen and Leah, 1998). Collectively, these results suggest that a single exposure to psychostimulants can alter gene expression via CREB signaling.
Drug-Environment Associations. Environmental drug-context effects are acquired subsequent to drug treatment, and they are expressed upon rechallenge (McPherson and Lawrence, 2006). Our data demonstrate a significant reduction in pCREB-IR in the dorsolateral CPu following re-exposure to drug environment, a structure previously implicated in habitual learning (Fuchs et al., 2006; Nelson and Killcross, 2006). Within the hypothalamus, a polarized pCREB response to low or high amphetamine pretreatment occurred. The DMH is implicated in stress responses, and it shares connectivity with the amygdaloid complex either directly, or via the paraventricular nucleus of the hypothalamus (McDougall et al., 2004).
pCREB was depressed in the basal ganglia and hypothalamus in the low-saline group. This may reflect a refractory period or allostasis (although this was not observed following pretreatment with high-dose amphetamine). Regardless, behavioral sensitization (McPherson and Lawrence, 2006) and "recovery" of pCREB activation upon challenge following low amphetamine pretreatment occurred. Examining the temporal profile of pCREB following variable amphetamine pretreatment doses may explain the lability of this cellular mechanism.
Sensitization Effects of Amphetamine. The striatum functions as a primary interface for afferent dopaminergic and glutamatergic coincident detection (Berke and Hyman, 2000; Kelley, 2004), integrated within GABAergic medium-spiny neurons that feedback onto mesencephalic dopamine neurons. Given that striatal CREB activation was only apparent following high-dose amphetamine pretreatment, it would seem that for certain structures, pretreatment dose is critical. Moreover, there was no impact of pretreatment dose upon sensitized behavior (McPherson and Lawrence, 2006). Indeed, these data agree with a mismatch between behavior and c-Fos expression within the basal ganglia (McPherson and Lawrence, 2006). This does not preclude a role for pCREB in drug-induced plasticity within the striatum or other brain structures. Locomotor activity is only one of a number of traits that can indicate drug-induced plasticity. The development of behavioral sensitization takes place over time, alongside fluctuations in transcription factors and protein synthesis. This discrepancy in pCREB-IR between groups may be explained by the notion that expression of sensitization is less contingent upon striatal pCREB levels than the development of sensitization. Alternatively, our data may reflect differential desensitization of CREB phosphorylation, apparently as it occurs with cocaine (Edwards et al., 2007).
When compared with contextual controls, drug-sensitized rats had a recovery of pCREB in the amygdala. The CeA participates in contextual stimulus-response drug associations (See et al., 2003). Although the BLA participates in both stimulus-response association and expression, we failed to observe differences in pCREB expression between groups within this structure, as reported for c-Fos (McPherson and Lawrence, 2006). The LS has been shown to exhibit stimulated glutamatergic signaling following chronic cocaine exposure (Liu et al., 2005) and enhanced extracellular dopamine following systemic or intra-VTA morphine (Sotomayor et al., 2005). We observed enhancement of pCREB-IR in the LS of high-challenge-sensitized rats.
A Dual Neural Network to Describe Sensitization to Psychostimulants. We hypothesize that a dual neural network is activated within our paradigm. These may interdependently regulate contextual drug associations acquired during chronic exposure and adaptations of signaling pathways in discrete nuclei, which seem to respond differently upon representation of drug. Structures encompassing a network of contextual association included the DMH, LS, PFA, and LH. In contrast, an acute and drug-sensitized network selectively involved the amygdala and NAcc. Some structures may be common to both networks (e.g., SNc, CPu, and habenula). Importantly, there may also be additional components to these networks that have not been characterized in this study. For example, cocaine self-administration causes enhancement of pCREB within the prefrontal cortex, CPu, NAcc core, and CeA. Neither acute nor chronic cocaine enhanced phosphorylation of CREB in hippocampal subregions (Edwards et al., 2007).
Orexinergic Neurons in the Hypothalamus Do Not Coexpress pCREB upon Sensitization. We observed a absence of overlap between neurons positive for orexin A and pCREB. Although these results may seem surprising given the implication of orexin-expressing neurons of the LH in the context of addiction (Harris et al., 2005), this can be reconciled. It is possible that orexin A-expressing cells of the LH do not use CREB as a transcription factor but rely upon Fos/Jun activator protein-1 or other immediate early genes (Egr1 and Stat-3) (Blendy and Maldonado, 1998). Chronic morphine and naltrexone-induced withdrawal individually produced a near 10-fold enhancement of CRE-activity in LH orexin-expressing neurons. Although this seems to provide support of CREB-based orexin A activation, the orexin gene has not yet been identified as a target of the cAMP-induced cascade. Moreover, orexin A gene expression was not activated by chronic morphine, but only upon naltrexone-induced withdrawal (Georgescu et al., 2003). Although CREB is present in all cells, functional heterogeneity is afforded through cell-dependent CREB-CRE binding (Cha-Molstad et al., 2004). It is possible that activity-dependent phosphorylation of CREB is not a major regulatory mechanism for transcription in these orexinergic cells and that constitutive levels of endogenous CREB phosphorylation are sufficient for cytosolic response to drug-stimulus activation.
Alternatively, there may be a differential time course of CREB activation in these cells. Possibly, different stimuli are required to activate CREB in these cells, such as motivational/appetitive aspects of reward-related behavior, rather than adaptations/responses to noncontingent schedules. Thus, psychostimulant sensitization may be more selective toward extrahypothalamic circuitry, whereas place preference involves this structure (Harris et al., 2005), via declarative, reward-driven behaviors. The wide distribution of orexin-expressing axons (Peyron et al., 1998) suggests orexinergic neurons may function in afferent coincident response systems.
Orexinergic Neurons of the Hypothalamus Do Coexpress c-Fos upon Sensitization. Sensitization to amphetamine resulted in preferential activation of c-Fos in DMH and PFA orexin A-containing cells. In the LH, sensitized rats showed increased activation of orexin A-containing neurons compared with controls, but not compared with acute amphetamine. In contrast, place preference to drug and natural rewards showed preferential activation of the LH (Harris et al., 2005), whereas chronic morphine exposure alone did not activate LH neurons (Georgescu et al., 2003). Interestingly, the former study showed a high percentage of orexin A-positive neurons, which coexpressed c-Fos, in contrast to the latter and herein. Interestingly, c-Fos activation in orexin A-containing neurons was not increased following acute amphetamine. This contrasts with a report of increased activation in medial hypothalamic Orexin-containing neurons (but not within the LH/PFA) (Fadel et al., 2002). It could be that an acute aprandial aspect of amphetamine inside our time frame (90 min) had partly recovered 2 h following treatment (Fadel et al., 2002). Together, these data suggest that activation of hypothalamic subregions is differentially responsive to discrete stimuli.
A dichotomy of orexin A-containing neurons between the LH (reward processing) and the DMH/PFA (stress/arousal) has been suggested (Harris and Aston-Jones, 2006). Although on the surface the present data may seem to contradict this notion, further consideration of the enhanced locomotor activity upon amphetamine sensitization in these rats (McPherson and Lawrence, 2006) would predict activation of the DMH/PFA. It should be remembered that behavioral sensitization to noncontingently administered drug somewhat differs to reinstatement of reward seeking. Consequently, the present data suggest functional heterogeneity within orexin-containing cells (Harris and Aston-Jones, 2006).
Orexin A is implicated in the development of cocaine-induced plasticity in the VTA (Borgland et al., 2006), suggesting that the subpopulation of orexinergic neurons identified in the current model likely synapse directly onto dopaminergic neurons. The heterogeneous nature of hypothalamic orexinergic neurons (Fadel et al., 2002) indicates a need to ascertain markers unique to these subpopulations. Indeed, our data further support this notion, suggesting subpopulations of orexinergic neurons within and between hypothalamic nuclei that may play discrete roles in various affective states, possibly linked to individual afferent targets.
In conclusion, this study has examined central patterns of pCREB protein expression along the neuraxis, subsequent to behavioral sensitization to amphetamine. The results highlight a role for CREB phosphorylation in drug-induced plasticity. These data also suggest that orexinergic neurons are activated during the expression of behavioral sensitization, although in a heterogenous manner.
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Footnotes |
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
ABBREVIATIONS: NAcc, nucleus accumbens; CPu, caudate putamen; CREB, cAMP-response element-binding protein; p, phosphorylated; IR, immunoreactive; VTA, ventral tegmental area; BNST, bed nucleus of the stria terminal; L-S, low-saline; L-C, low-challenge; H-S, high-saline; H-C, high-challenge; PBS, phosphate-buffered saline; PFA, paraformaldehyde; NTx, 1% normal horse serum and 0.3% Triton X-100; LS, lateral septum; CeA, central nucleus of the amygdala; SNc, substantia nigra pars compacta; MeA, medial amygdala; LHab, lateral habenular; LH, lateral hypothalamus; ANOVA, analysis of variance; CRE, cAMP response element; BLA, basolateral nucleus of the amygdala; Amph, amphetamine; SB-334867, N-(2-methyl-6-benzoxazolyl)-N''-1,5-naphthrydin-4-yl urea hydrochloride.
Address correspondence to: Dr. Andrew J Lawrence, Howard Florey Institute, University of Melbourne, Parkville, VIC 3010, Australia. E-mail: andrew.lawrence{at}florey.edu.au
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, p < 0.05 for acute versus control (acute drug effect); *, p < 0.05 for high-challenge or low-challenge versus acute (sensitization effect); 
, p < 0.05 for high-challenge versus low-challenge (dose effect); #, p < 0.05 for high-saline or low-saline versus control (context effect).
