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. Author manuscript; available in PMC: 2021 Mar 15.
Published in final edited form as: Neuropharmacology. 2019 Dec 24;165:107924. doi: 10.1016/j.neuropharm.2019.107924

Corticosterone in the ventral hippocampus differentially alters accumbal dopamine output in drug-naïve and amphetamine-withdrawn rats

Brenna Bray a, Kaci A Clement a, Dana Bachmeier a, Matthew A Weber a,4, Gina L Forster a,b,*
PMCID: PMC7103421  NIHMSID: NIHMS1574147  PMID: 31881169

Abstract

Dysregulation in glucocorticoid stress and accumbal dopamine reward systems can alter reward salience to increase motivational drive in control conditions while contributing to relapse during drug withdrawal. Amphetamine withdrawal is associated with dysphoria and stress hypersensitivity that may be mediated, in part, by enhanced stress-induced corticosterone observed in the ventral hippocampus. Electrical stimulation of the ventral hippocampus enhances accumbal shell dopamine release, establishing a functional connection between these two regions. However, the effects of ventral hippocampal corticosterone on this system are unknown. To address this, a stress-relevant concentration of corticosterone (0.24ng/0.5μL) or vehicle were infused into the ventral hippocampus of urethane-anesthetized adult male rats in control and amphetamine withdrawn conditions. Accumbal dopamine output was assessed with in vivo chronoamperometry. Corticosterone infused into the ventral hippocampus rapidly enhanced accumbal dopamine output in control conditions, but produced a biphasic reduction of accumbal dopamine output in amphetamine withdrawal. Selectively blocking glucocorticoid-, mineralocorticoid-, or cytosolic receptors prevented the effects of corticosterone. Overall, these results suggest that the ability of corticosterone to alter accumbal dopamine output requires cooperative activation of mineralocorticoid and glucocorticoid receptors in the cytosol, which is dysregulated during amphetamine withdrawal. These findings implicate ventral hippocampal corticosterone in playing an important role in driving neural systems involved in positive stress coping mechanisms in healthy conditions, whereas dysregulation of this system may contribute to relapse during withdrawal.

Keywords: Psychostimulant Withdrawal, Ventral Hippocampus, Corticosterone, Nucleus Accumbens Shell, Dopamine, Glucocorticoid Receptors

1. Introduction

Amphetamine dependence is a global health problem with high relapse potential and few effective interventions (Gossop, 2009; Sun et al., 2014). Amphetamine withdrawal is characterized by enhanced physiological and behavioral responses to stress (Bray et al., 2016; Li et al., 2014) as well as craving, anxiety, and dysphoria in humans (Gossop, 2009; Kosten, 2012; Shoptaw et al., 2009) and rodents (Bray et al., 2016; Cryan et al., 2003; Li et al., 2014; Russig et al., 2006; Tu et al., 2014). These negative affective states can induce relapse and maintain addiction (Gossop, 2009; Koob et al., 2014; Paliwal et al., 2008) and are mediated by alterations in dopamine reward- and corticosterone stress responses (Barr et al., 2017; Bray et al., 2016; Koob et al., 2014; Koob and Volkow, 2010).

At a neurobiological level, stress increases dopamine output in the nucleus accumbens shell (Enrico et al., 2013; Kalivas and Duffy, 1995), which can enhance incentive salience (“wanting”) and cue-triggered levels of motivation to pursue sucrose rewards (in rats) (Berridge and Robinson, 2016; Floresco, 2014; Hollon et al., 2015; Pecina and Berridge, 2013). However, stress can also reduce accumbal shell dopamine levels in psychostimulant withdrawal, and can prompt negative affect and dysphoria that drive drug-taking behaviors and predict relapse (Cleck and Blendy, 2008; Koob et al., 2014; Kwako and Koob, 2017; Paliwal et al., 2008; Sinha, 2007; Twining et al., 2014; Wheeler et al., 2008). Therefore, a greater understanding of the mechanisms that enable stress to alter accumbal dopamine output may help identify novel treatment targets for amphetamine withdrawal syndrome.

In addition to its effects on accumbal dopamine output, stress also increases free extracellular corticosterone levels in the dorsal- and ventral hippocampus in rodents (Bray et al., 2016; Droste et al., 2008; Droste et al., 2009), which are augmented in the ventral hippocampus during amphetamine withdrawal (Bray et al., 2016). Corticosterone is thought to be excitatory in the ventral hippocampus and can induce glutamate release in vitro (Karst et al., 2005; Wang and Wang, 2009). In vivo, the ventral hippocampus sends glutamatergic projections to the ventral tegmental area and nucleus accumbens shell (Barr et al., 2017; Sesack and Pickel, 1990; Strange et al., 2014), and electrical stimulation of the ventral hippocampus or N-Methyl-D-aspartic acid (NMDA) infusions into this region enhance accumbal shell dopamine output (Barr et al., 2014; Blaha et al., 1997; Britt et al., 2012; Floresco et al., 2001; Legault et al., 2000; Taepavarapruk et al., 2014; Valenti et al., 2011). Thus, we hypothesized that the local effects of corticosterone in the ventral hippocampus would enhance accumbal shell dopamine output in drug naïve conditions, enabling stress to enhance reward salience and motivate goal-oriented behavior. Here, we directly tested whether corticosterone in the ventral hippocampus regulates dopamine levels in the nucleus accumbens shell.

At the cellular level, corticosterone induces its effects primarily by activating mineralocorticoid and glucocorticoid receptors, both of which are highly expressed in the ventral hippocampus (Herman et al., 1989; Reul and de Kloet, 1986). These receptors can be cytosolic or membrane-bound, genomic or non-genomic, and differ in their affinity for corticosterone, downstream signaling mechanisms, and temporal signatures in a regionally-dependent manner (Barr et al., 2017; Groeneweg et al., 2012; Joels and de Kloet, 2017). In the ventral hippocampus, non-genomic membrane mineralocorticoid receptors can be excitatory or disinhibitory, rapidly enhancing excitatory postsynaptic potential and glutamatergic transmission (Karst et al., 2005; Maggio and Segal, 2007) and reducing inhibitory postsynaptic currents (Maggio and Segal, 2009) in vitro. Non-genomic glucocorticoid receptors can be membrane-bound or cytosolic and are thought to act through retrograde signaling mechanisms to regulate interneuron inhibition and excitatory/inhibitory tone in vitro and ex vivo (Hu et al., 2010; Maggio and Segal, 2009; Zeise et al., 1992), and induce rapid serotonin release in vivo (Barr and Forster, 2011). In sum, corticosterone has rapid effects on local neurotransmission in the ventral hippocampus that have potential to influence activity of limbic structures targeted by this region of the hippocampus. Therefore, we also explored the receptor mechanisms that mediate the ability of corticosterone in the ventral hippocampus to alter accumbal dopamine output.

Glucocorticoid (but not mineralocorticoid) receptor expression and activity in the ventral hippocampus are reduced following 2 weeks of amphetamine treatment in male rats (Barr and Forster, 2011; Li et al., 2014). Furthermore, repeated cocaine exposure enhances the ability of NMDA infusions in the ventral hippocampus to stimulate accumbal dopamine release (Barr et al., 2014). These alterations may disrupt the ability of glucocorticoid receptors to regulate excitatory/inhibitory tone in the ventral hippocampus during withdrawal (Barr et al., 2017; Maggio and Segal, 2009), which in turn, would disrupt the ability of corticosterone in the ventral hippocampus to modulate accumbal dopamine release. Therefore, we also tested whether repeated amphetamine exposure disrupts the effects of glucocorticoid and mineralocorticoid receptor activation on accumbal dopamine output in rats undergoing 2 weeks of amphetamine withdrawal.

2. Materials and Methods

2.1. Animals

All experimental procedures were carried out in accordance with the National Institute of Health Guide for the Care and Use of Laboratory Animals (National Research Council Committee for the Update of the Guide for the and Use of Laboratory, 2011) and were approved by the Institutional Animal Care and Use Committee of the University of South Dakota. All efforts were made to minimize animal suffering and reduce the number of subjects used.

A total of 124 adult male Sprague-Dawley rats were used in this experiment (367 g ± 35 g). Rats were obtained from the University of South Dakota Animal Resource Center at 3 weeks of age and pair-housed in polysulfone cages (Tecniplast, Buguggiate, Varese, Italy; 16.73 × 10.47 × 7.28 in, floor area: 800 cm2/124 in2; corn husk bedding) held at a constant room temperature of 22° C (60% relative humidity) on a reverse 12-h light/dark cycle with lights off from 10:00 – 22:00. To eliminate a possible confound of enrichment-induced hippocampal neurogenesis and enrichment-induced alterations of stress responsiveness (Levone et al., 2015; Tanti et al., 2012), cages contained no enrichment but ad lib access to water and standard rat chow.

2.2. Rat model of amphetamine pretreatment and withdrawal

At 8 – 10 weeks of age, rats were randomly assigned to receive daily injections of physiological saline (n = 74) or d-amphetamine sulfate (n = 50) (2.5 mg/kg, ip.) for 14 days (Barr and Forster, 2011; Bray et al., 2016; Li et al., 2014) followed by a 14-day withdrawal period (Bray et al., 2016; Li et al., 2014; Solanki et al., 2016; Tu et al., 2014). To account for diurnal corticosterone levels (Tye et al., 2009; van Haarst et al., 1997), all injections were administered during the dark phase of the reverse photoperiod, between 11:00 and 14:00. This amphetamine protocol has been shown to enhance stress responses, including anxiety (Reinbold et al., 2014; Tu et al., 2014; Vuong et al., 2010), stress-induced behavioral arousal (Li et al., 2014), and corticosterone stress responses (Bray et al., 2016; Li et al., 2014), as well as reducing glucocorticoid receptor expression in the ventral hippocampus (Barr and Forster, 2013).

2.3. Stereotactic surgery

After the second week of withdrawal from amphetamine or saline pre-treatment, rats were anesthetized with urethane (1.8 g/kg, ip.). Urethane is a long-acting anesthetic that does not affect endogenous dopamine clearance (Barr and Forster, 2011; Blaha et al., 1997; Novick et al., 2015; Sabeti et al., 2003). Rats were placed into a stereotaxic frame (Kopf, Tujunga, CA, USA) with incisor bar set at −3.5 mm and body temperature held at 37 ° C ± 0.5 ° C by a temperature-controlled heating pad (Harvard Apparatus, Holliston, MA, USA). Two 22-gauge stainless-steel guide cannulae were implanted side-by-side into the right or left ventral hippocampus (−5.2 mm AP from bregma; ± 4.5 mm ML; −4.5 mm DV from dura) (Paxinos and Watson, 1998; Tu et al., 2014) and a silica infusion cannula (2 mm > guide) was inserted through each guide cannula.

2.4. In vivo electrochemistry

A custom-made stearate-treated carbon paste recording electrode with 200 μm recording surface diameter (Blaha and Jung, 1991; Miller et al., 2005; Novick et al., 2015; Tye et al., 2009) was implanted into the ipsilateral medial nucleus accumbens shell (1.6 mm AP from bregma; ± 0.7mm ML; −7.0 mm DV from dura) (Miller et al., 2005; Paxinos and Watson, 1998) to measure dopamine oxidation current without interference from other oxidizing species (Blaha, 1996; Blaha and Lane, 1983; Miller et al., 2005; Novick et al., 2015; Tye et al., 2009). A custom-made reference electrode with AgCl-coated tip was placed touching the contralateral cortical tissue and a stainless-steel auxiliary electrode was fixed to the skull with a stainless steel surgical screw (Miller et al., 2005; Novick et al., 2015). Prior in vitro electrode recordings were conducted to confirm a distinct and measurable dopamine oxidation signal after systemic addition of exogenous dopamine, norepinephrine, and ascorbic acid (Novick et al., 2015; Weber et al., 2018).

Following a thirty-minute recovery period, voltammetry sweeps were conducted using an electrometer (Echempro, GMA Technologies, Inc., Vancouver, Canada) to confirm dopamine detection and identify the range of potentials to be applied to the electrode during chronoamperometry (Miller et al., 2005; Novick et al., 2015). This was done by applying an incrementally increasing range of electrical potentials to the working electrode (−150 mV to +450 mV vs. Ag/AgCl, ramp rate 10 mV/second; (Novick et al., 2015)). A 300 mV voltammetric range encompassing the distinct dopamine signal was then selected and the electrometer was set to repetitively apply that range of potential (typically −150 mV to +150 mV vs. Ag/AgCl reference electrode) to the working electrode in brief (1 s) pulses at 30 s intervals, with changes in dopamine oxidation current recorded in ampere at the end of each pulse and converted to nA for analysis (Borland and Michael, 2007; Novick et al., 2015).

After 30 min of stable chronoamperometric baseline recordings, agents were infused into the ventral hippocampus as described below (Section 2.5). Dopamine oxidation current recordings were subsequently collected until they returned to basal levels (~2 hours post-infusion). Rats were then euthanized with a lethal dose of FatalPlus (Vortech, Dearborn, MI, USA; 0.5 mL, ip.) and brains were removed and fixed for confirmation of cannulae and electrode placements.

2.5. Microinfusions

All infusions were administered through a silica infusion cannula using a microinfusion pump (Stoelting, Wood Dale, IL, USA), with 0.5 μL total volume infused over one minute. Infusions were administered during the dark phase of the reverse photoperiod, between 13:00 and 18:00 (average infusion time was 15:30 ± 1:18). Corticosterone (Sigma-Aldrich) was dissolved in 2-hydroxypropyl-β-cyclodextrin [HBC] (Tocris) (0.05%) then diluted with artificial cerebrospinal fluid (aCSF) to produce a 0.48ng/μL concentration (0.24 ng total delivered, equal to 6.927 × 10−13 M of corticosterone). This concentration mimics stress-induced corticosterone levels previously observed in the hippocampus (Bray et al., 2016; Droste et al., 2008). When more than one infusion was made into the ventral hippocampus (e.g. receptor antagonist or vehicle pretreatment prior to corticosterone infusion; Table 1), 10 minutes was allowed between infusions.

Table 1.

Treatment Groups

Group Pre-treatment Region Infusion 1 Infusion 2 N
1 Saline Ventral vHipp Vehicle HBC Vehicle 9
2 Saline Ventral vHipp Vehicle Corticosterone 13*
3 Saline Ventral vHipp Mifepristone HBC Vehicle 6
4 Saline Ventral vHipp Mifepristone Corticosterone 6
5 Saline Ventral vHipp Spironolactone HBC Vehicle 7
6 Saline Ventral vHipp Spironolactone Corticosterone 8*
7 Amphetamine Ventral vHipp Vehicle HBC Vehicle 10
8 Amphetamine Ventral vHipp Vehicle Corticosterone 11*
9 Amphetamine Ventral vHipp Mifepristone HBC Vehicle 7*
10 Amphetamine Ventral vHipp Mifepristone Corticosterone 7
11 Amphetamine Ventral vHipp Spironolactone HBC Vehicle 7
12 Amphetamine Ventral vHipp Spironolactone Corticosterone 8*
13 Saline Ventral vHipp - BSA-HBC 9*
14 Saline Ventral vHipp - BSA-Corticosterone 7
15 Saline Dorsal vHipp Vehicle Corticosterone 5
16 Saline Posterior Amygdala Vehicle Corticosterone 4
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BSA: bovine serum albumin; HBC: 2-hydroxypropyl-β-cyclodextrin; vHipp: ventral hippocampus.

*

One subject’s data was excluded from use in this treatment group, based on its data being identified as a Grubbs outlier at two non-adjacent points farthest from zero in the treatment group’s average datum. Therefore, the number of subjects whose data were used in this treatment group equals N-1.

The effects of corticosterone infusion on accumbal dopamine levels, and which receptor types were responsible for these effects, were assessed in both saline and amphetamine pre-treated rats with the drug infusion combinations outlined for groups 1–12 of Table 1. Mifepristone and spironolactone (Sigma-Aldrich) were dissolved in vehicle [1:1 solution of 100% ethanol (Fisher Scientific) and 5% Kolliphor EL (Sigma-Aldrich)], and then diluted in aCSF to a concentration of 2.91 nM mifepristone or 2.99 nM spironolactone (1.25 μg total delivery). Vehicle infusions were thus 5% ethanol in aCSF. Concentrations of mifepristone and spironolactone were based on those used previously to inhibit glucocorticoid and mineralocorticoid receptors, respectively (Barr and Forster, 2011; Garthwaite and McMahon, 2004). Mifepristone is also a progesterone receptor antagonist with a higher affinity for progesterone vs. glucocorticoid receptors (Heikinheimo, 1997; Heikinheimo and Kekkonen, 1993; Mahajan and London, 1997). Thus, progesterone receptor inhibition also occurred with these infusions, and we cannot exclude the possibility that the effect of mifepristone on accumbal dopamine output was observed in response to its antagonism of progesterone receptors, as has been suggested by others (Perez et al., 2014).

To determine whether the observed effects of ventral hippocampal corticosterone infusions on accumbal dopamine output in saline-pretreated rats were mediated by cytosolic receptors, corticosterone 3-carboxymethyloxime : bovine serum albumin, (Corticosterone 3-CMO : BSA, Steraloids, Inc.) was used (Table 1 groups 13–14), in which corticosterone was commercially conjugated to bovine serum albumin (BSA). BSA is hydrophobic and thus prevents corticosterone from crossing the plasma membrane to act on cytosolic receptors (Groeneweg et al., 2011; Morozov et al., 1988). The corticosterone 3-CMO : BSA conjugate was dissolved in 0.05% HBC then diluted with aCSF to produce a 5.95 ng/μL concentration (2.97 ng total delivered, for a total of 0.24 ng of corticosterone delivered per 0.5 μL infusion to match corticosterone concentrations described above).

2.6. Histology

Following euthanasia, rat brains were removed and fixed in 10% buffered formalin (Fisher Scientific) for ≥ 72 hours, sectioned on a sliding microtome (60 μm at −12° C maintained with dry ice), and analyzed under a light microscope by two individuals blind to treatment, to confirm cannulae and electrode placement and identify anatomical controls (Barr and Forster, 2011; Novick et al., 2015).

2.7. Data analysis and statistics

All statistical analyses were performed using IBM® SPSS® Statistics v25- (SPSS Inc., Armonk, NY) and SigmaPlot 13.0 (Systat Software, Inc., San Jose, CA) software with alpha level set at 0.05 throughout.

To analyze chronoamperometry results, pre- and post-infusion recordings for each individual subject were separately normalized to zero current values, with changes after microinfusions reported as absolute changes in dopamine oxidation current, as previously published (Novick et al., 2015; Weber et al., 2018). Data points were collected every 30 s, but were collapsed into 90 s time bins to facilitate repeated measure of time analysis. Grubbs outlier tests (Grubbs, 1969) were run at the two independent (non-adjacent) points farthest from zero in each treatment group. All data from rats whose dopamine oxidation current values were identified to be Grubbs outliers at both of the two non-adjacent points were excluded as outliers, for a total of six rats. These six rats were evenly spread across the treatment groups and included saline pre-treated rats receiving infusions of: vehicle + corticosterone (n = 1), spironolactone + corticosterone (n = 1), and BSA-HBC (n = 1); and amphetamine pre-treated rats receiving infusions of: corticosterone (n = 1), mifepristone + HBC (n = 1), and spironolactone + corticosterone (n = 1).

An initial three-way analysis of variance (ANOVA) with one repeated measure (pre-treatment × drug infusions into the ventral hippocampus × repeated measure of time) was used to compare dopamine responses across time between pre-treatment and drug infusions into the ventral hippocampus (groups 1–12 of Table 1). Missing values at a single time point in two saline- and two amphetamine pre-treated rats precluded the inclusion of these subjects’ datum from use in this ANOVA. Significant interactions were further analyzed by two-way ANOVAs (one repeated measure of time) or one-way ANOVA performed separately in saline- and amphetamine pre-treatment groups or across drug infusion groups. Main effects of time were followed by separate post hoc Holm-Sidak tests to identify significant changes across time within each pre-treatment group (−2 to −0.5 min time bin set as the baseline control), or between drug infusion groups.

A separate two-way ANOVA with one repeated measure (drug infusion × repeated measure of time) was used to determine whether changes in dopamine output differed over time as a function of Corticosterone 3-CMO : BSA infusion (compared to BSA-HBC infusion) in saline pre-treated rats (groups 13–14 of Table 1).

One-way ANOVA with a repeated measure of time were also separately performed in saline pre-treated rats receiving drug infusions into the dorsoventral hippocampus and amygdala (posterior medial cortical regions) as anatomical controls (groups 15–16 of Table 1), to identify whether infusions of corticosterone outside of the ventral portion of the ventral hippocampus had effects on accumbal dopamine output in saline pre-treated controls.

3. Results

3.1. Electrode and infusion cannula placements

Electrode and infusion cannula placements were similarly distributed in saline- and amphetamine pre-treated rats across all experiments and all infusion conditions (Figs. 1, 3B – C, and 4B – C). Data from rats in which the electrode placements missed the nucleus accumbens shell were excluded from subsequent analyses. However, drug cannulae that missed the ventral hippocampus target region were analyzed separately as anatomical control groups. These drug infusion cannulae were found to be placed in the dorsal aspect of the ventral hippocampus or below the ventral hippocampus in the amygdala (posterior medial cortical regions, Fig. 4C).

Figure 1. Representative diagrams of carbon paste electrode placements in the medial nucleus accumbens shell (left panel) and infusion cannula placements in the ventral subiculum and ventral dentate gyrus regions of the hippocampus (right panel).

Figure 1.

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A) Electrode/cannulae placements corresponding with results shown in Fig. 2A for saline and amphetamine pre-treated rats infused with corticosterone or vehicle, as outlined in Table 1. B and C) Electrode/cannulae placements corresponding with Figs. 2B and 2C respectively, conducted in saline- (B) and amphetamine (C) pre-treated rats receiving mifepristone or spironolactone infusions, as outlined in Table 1. Figures adapted from Paxinos and Watson (1998). AMP: Amphetamine pre-treatment; CORT: Corticosterone; HBC: hydroxypropyl-β-cyclodextrin; MIF: Mifepristone; SAL: Saline pre-treatment; SPIR: Spironolactone; VEH: Vehicle for antagonists.

Figure 3. Stress-relevant concentrations of membrane-impermeable corticosterone infused into the ventral hippocampus of saline pre-treated rats fail to alter accumbal dopamine output relative to vehicle infusions.

Figure 3.

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A) Saline pre-treated rats receiving ventral hippocampus infusions of BSA-corticosterone conjugate or vehicle (BSA-HBC), with tracing for vehicle + corticosterone infusions from Fig. 2A shown as dotted lines for comparison. Data represent mean ± SEM nA. B) Representative diagrams of carbon paste electrode placements in the medial nucleus accumbens shell and infusion cannula placements in the ventral hippocampus. Figures adapted from Paxinos and Watson (1998). BSA: bovine serum albumin; CORT: Corticosterone; HBC: hydroxypropyl-β-cyclodextrin; VEH: Vehicle.

Figure 4. Location of corticosterone infusion differentially affects accumbal dopamine output in saline pre-treated controls.

Figure 4.

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A) Saline pre-treated rats receiving infusions of vehicle + corticosterone into the dorsoventral hippocampus (dvHipp) or posterior medial cortical regions of the amygdala, with tracing for accumbal dopamine output following vehicle + corticosterone infusions (VEH+CORT) into the ventral hippocampus (vHipp) from Fig. 2A shown as dotted line for reference. Data represent mean ± SEM nA *significant effect of time (P < 0.05) but no specific time points identified as significantly different from pre-infusion levels (P > 0.05, Holm Sidak). B) Representative diagrams of carbon paste electrode placements in the medial nucleus accumbens shell and corresponding infusion cannula placements in the dorsoventral hippocampus and posterior medial cortical amygdala. Figures adapted from Paxinos and Watson (1998).

3.2. The effects of corticosterone on accumbal dopamine output differ in drug-naïve- and amphetamine withdrawn rats

An initial three-way ANOVA with one repeated measure (pre-treatment × drug infusion × repeated measure of time) revealed a significant interaction between pre-treatment, time, and infusion(s) (F(18,257) = 3.187, P < 0.0001; Fig. 2). This was followed up with Holm-Sidak post hoc two- and one way ANOVA and repeated measures ANOVAs, as reported below.

Figure 2. Corticosterone infusions into the ventral hippocampus differentially alter accumbal dopamine output in (A) saline- and amphetamine pre-treated rats, and (B-C) antagonism of either glucocorticoid- or mineralocorticoid receptors in the ventral hippocampus blocks the effects of corticosterone.

Figure 2.

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Data corresponds to mean ± SEM nA. A) Saline- and amphetamine pre-treated rats receiving corticosterone and vehicle infusions into the ventral hippocampus (Table 1). B) saline- or C) amphetamine pre-treated rats receiving ventral hippocampus infusions of mifepristone or spironolactone in combination with corticosterone or vehicle (Table 1), with tracings for vehicle + corticosterone infusions from Fig. 2A shown as dotted lines for comparison. *P < 0.05 vs −2 to −0.5 min (within pre-treatment). #P < 0.05 vs VEH + HBC (within pre-treatment). §P < 0.05 vs pre-treatment. AMP: Amphetamine pre-treatment; CORT: Corticosterone; HBC: hydroxypropyl-β-cyclodextrin; MIF: Mifepristone; SAL: Saline pre-treatment; SPIR: Spironolactone; VEH: Vehicle for antagonists.

3.2.1. Stress-relevant concentrations of corticosterone infused into the ventral hippocampus of saline pre-treated rats enhance accumbal dopamine output

In saline pre-treated rats, infusing vehicle + corticosterone into the ventral hippocampus significantly increased accumbal dopamine output relative to pre-infusion levels and to vehicle + HBC infusions, peaking at 57.5 min post-infusion (Fig. 2A). A two-way ANOVA (drug infusion × repeated measure of time) revealed a significant interaction between drug infusion and time (F(2,37) = 3.137, P = 0.049), with vehicle + corticosterone infusions resulting in greater accumbal dopamine output at 28 – 75.5 min post-infusion as compared to vehicle + HBC control levels (Holm-Sidak P < 0.05). A one-way repeated measures ANOVA performed in vehicle + corticosterone infused rats revealed a significant effect of time (F(2,21) = 4.534, P = 0.021), with vehicle + corticosterone infusions resulting in a significantly greater accumbal dopamine output at 36 – 67.5 min post-infusion relative to baseline levels (−2 to −0.5 min time bin) (Holm-Sidak, p < 0.05). In contrast, vehicle + HBC infusions into the ventral hippocampus did not significantly alter accumbal dopamine output over time in saline pre-treated rats (F(4,21) = 1.025, P = 0.410).

3.2.2. Stress-relevant concentrations of corticosterone infused into the ventral hippocampus reduce accumbal dopamine output in amphetamine withdrawal

In rats undergoing two weeks of withdrawal from amphetamine pre-treatment, vehicle + corticosterone infusions into the ventral hippocampus significantly reduced accumbal dopamine output relative to pre-infusion levels and to vehicle + HBC infusions, peaking at 34.5 and 67.5 min post-infusion (Fig. 2A), with a significant interaction between drug infusion and time (F(4,68) = 3.770, P = 0.007). Here, vehicle + corticosterone infusions resulted in a reduction of accumbal dopamine output compared to vehicle + HBC infusions at 16 – 39.5 and 48 – 99.5 min post-infusion (Holm-Sidak, P < 0.05). Further, in vehicle + corticosterone infused rats, a one-way repeated measures ANOVA revealed a significant effect of time (F(3,29) = 5.454, P = 0.004), with reduced accumbal dopamine output at 56 – 85.5 min time points as compared to baseline levels (Holm-Sidak, P < 0.05). Infusing vehicle + HBC into the ventral hippocampus was not found to alter accumbal dopamine output over time (F(3,19) = 0.846, P = 0.474).

3.2.3. Stress-relevant concentrations of corticosterone infused into the ventral hippocampus differentially alter accumbal dopamine output in saline- and amphetamine pre-treated rats

To assess whether corticosterone in the ventral hippocampus alters accumbal dopamine output differently in amphetamine withdrawal (relative to saline pre-treated controls), a two-way ANOVA (pre-treatment × repeated measure of time) was performed in saline- and amphetamine pre-treated rats receiving infusions of vehicle + corticosterone into the ventral hippocampus (Fig. 2A). This revealed a significant interaction between pre-treatment and time (F(3,49) = 6.877, P = 0.001), with accumbal dopamine output differing significantly between the two pre-treatment groups at 18 – 87.5- and 94 – 101.5 min post-infusion (Holm-Sidak, P < 0.05). When comparing the effects of vehicle + HBC infusions in saline- vs amphetamine pre-treated rats over time, there were no main effects of time (F(4,54) = 0.954, P = 0.443) or pre-treatment (F(1,13) = 0.114, P = 0.741) and no significant interactions between pre-treatment and time (F(4,54) = 0.904, P = 0.471).

3.2.4. Blocking either glucocorticoid- or mineralocorticoid receptors in the ventral hippocampus prevents ventral hippocampal corticosterone from altering accumbal dopamine output

Both glucocorticoid- and mineralocorticoid receptor antagonism independently blocked the effects of corticosterone in the ventral hippocampus on accumbal dopamine output in saline pre-treated rats (Fig. 2B). A two-way ANOVA with one repeated measure of time, comparing the effects of mifepristone + corticosterone infusions to those observed following mifepristone + HBC infusions in saline pre-treated rats, revealed no main effects of drug infusion (F(1,10) = 3.853, P = 0.078) or time (F(3,34) = 1.257, P = 0.306) and no significant interactions between drug infusion and time (F(3,34) = 1.379, P = 0.265; Fig. 2B). Similarly, when comparing the accumbal dopamine responses to ventral hippocampus infusions of spironolactone + corticosterone vs spironolactone + HBC infusions (over time), there were no main effects of drug infusion (F(1,11) = 1.400, P = 0.262) or time (F(5,51) = 0.864, P = 0.504) and no significant interactions between drug infusion and time (F(5,51) = 1.298, P = 0.281; Fig. 2B).

Likewise, in rats undergoing two weeks of withdrawal from amphetamine pre-treatment, accumbal dopamine responses to corticosterone in the ventral hippocampus were blocked by either glucocorticoid or mineralocorticoid receptor antagonism (Fig. 2C). A two-way repeated measures ANOVA revealed no main effects of drug infusion (F(1,10) = 0.850, P = 0.378) or time (F(4,35) = 0.881, P = 0.474), and there was no significant interaction between drug infusion and time (F(4,35) = 0.863, P = 0.484; Fig. 2C). When comparing the accumbal dopamine responses to ventral hippocampus infusions of spironolactone + corticosterone vs spironolactone + HBC infusions (over time) there were also no main effects of drug infusion (F(1,10) = 3.229, P = 0.103) or time (F(4,42) = 1.748, P = 0.154) and no significant interaction between drug infusion and time (F(4,42) = 0.410, P = 0.811; Fig. 2C).

3.3. Stress-relevant concentrations of membrane-impermeable corticosterone infused into the ventral hippocampus of saline pre-treated rats fail to alter accumbal dopamine output relative to vehicle infusions

Within saline pre-treated rats receiving infusions of membrane impermeable corticosterone 3-CMO : BSA or its vehicle (BSA-HBC) into the ventral hippocampus, drug infusion was not found to have a significant effect on accumbal dopamine output (F(1,12) = 0.00555, P = 0.942), and there was no main effect of time (F(68,816) = 1.098, P = 0.280) nor a significant interaction between time and infusion (F(68,816) = 0.951, P = 0.590) (Fig. 3).

3.4. Effect of location of corticosterone infusion on accumbal dopamine output in saline pretreated controls

To determine the specificity of corticosterone infusions in the ventral portion of the ventral hippocampus, we also tested whether vehicle + corticosterone infusions made into the dorsoventral hippocampus (n = 5) or below the ventral hippocampus into the posterior medial cortical regions of the amygdala (n = 4) (including the amygdalohippocampal area (AHiPM, n = 1), posteriomedial cortical area (PMCO, n = 2), and amygdalaopiriform atransitional area (APir, n = 1)) produced alterations in accumbal dopamine output (Fig. 4). A one-way repeated measures ANOVA revealed that vehicle + corticosterone infusions into the dorsoventral hippocampus did produce a significant increase in accumbal dopamine output over time (F(65, 260) = 1.974, P < 0.001). However, no specific time period was greater over time when multiple comparisons were assessed vs. pre-infusion controls (Holm Sidak, P > 0.05). Similar to the effects of dorsoventral hippocampal infusions, infusions into the posterior medial cortical regions of the amygdala produced a significant increase in accumbal dopamine output over time (F(60,180) = 1.860, P < 0.001), but no specific time period was greater over time when multiple comparisons were assessed vs. pre-infusion controls (Holm Sidak, P > 0.05).

4. Discussion

4.1. Ventral hippocampal corticosterone enhances accumbal dopamine output in controls

Corticosterone is thought to be excitatory in the ventral hippocampus and can induce rapid glutamate release in vitro (Bekkers and Stevens, 1989; Karst et al., 2005). Electrical or NMDA activation of the ventral hippocampus enhances accumbal dopamine output (Barr et al., 2014; Blaha et al., 1997; Karst et al., 2005; Taepavarapruk et al., 2014). As predicted by these previous observations, infusing corticosterone into the ventral hippocampus of saline pre-treated control rats rapidly enhanced accumbal dopamine release. This effect was most prominent in the ventral portion of the ventral hippocampus where subicular output to the nucleus accumbens in known to arise (Britt et al., 2012; Brog et al., 1993; Goto and Grace, 2005; Groenewegen et al., 1987; O’Donnell and Grace, 1995; Strange et al., 2014). The dorsal aspect of the ventral hippocampus has high expression of glucocorticoid- and mineralocorticoid receptors (Reul and de Kloet, 1985, 1986), but projects to the nucleus accumbens core rather than to the shell (Strange et al., 2014). As such, we observed that infusions of corticosterone into this more dorsal aspect of the ventral hippocampus were less effective at increasing dopamine in the accumbens shell. A more transient effect of corticosterone was also observed when infusions were made deeper than the ventral hippocampus, into the posterior medial cortical regions of the amygdala. These regions of the amygdala have functional connectivity with the ventral hippocampus and other regions of the amygdala, but not to the nucleus accumbens shell (Belujon et al., 2016; Groeneweg et al., 2012; Sah et al., 2003; Salgado and Kaplitt, 2015; Schmitt et al., 2012; Zorrilla and Koob, 2013). Therefore, the effect of corticosterone infusions on accumbal dopamine output observed in posterior medial cortical regions of the amygdala most likely occurred through connectivity with the ventral hippocampus and/or from some corticosterone diffusion into the ventral sub-regions of the hippocampus. However, this conclusion warrants further investigation with larger sample sizes.

The finding that corticosterone infused into the ventral hippocampus stimulates accumbal dopamine has several implications for the ability of stress to alter motivated behaviors. For example, stress-enhanced corticosterone in the ventral hippocampus (Bray et al., 2016; Droste et al., 2008) may contribute to the ability of stressors to enhance reward salience and motivate goal-oriented behavior in control conditions (Berridge and Robinson, 2016; Floresco, 2014; Hollon et al., 2015). Furthermore, acute psychostimulant exposure enhances corticosterone secretion (Bayer et al., 1995; Knych and Eisenberg, 1979; Swerdlow et al., 1993; Zuloaga et al., 2014). Therefore, our findings also suggest that accumbal dopamine responses to corticosterone in the ventral hippocampus may contribute to positive reinforcement of initial psychostimulant use (Robinson and Berridge, 2000).

4.2. Receptor mechanisms in the ventral hippocampus mediating corticosterone stimulation of accumbal dopamine.

The effects of corticosterone were abolished when the steroid was prevented from crossing cellular membranes (conjugated to BSA), suggesting that the rapid stimulatory effects of ventral hippocampal corticosterone on accumbal dopamine release are dependent upon binding of cytosolic receptors. Typically, steroid effects within 30 minutes of onset are associated with non-genomic mechanisms (Barr et al., 2017; de Kloet et al., 2008; Groeneweg et al., 2012; Haller et al., 2008; Makara and Haller, 2001; Prager and Johnson, 2009; Stahn and Buttgereit, 2008; Stahn et al., 2007). Furthermore, the non-genomic effects of corticosterone are most often attributed to membrane-associated mechanisms (Barr et al., 2017; Groeneweg et al., 2012; Joels and de Kloet, 2017; Tasker et al., 2006). However, cytosolic mineralocorticoid and glucocorticoid receptors and receptor complexes can also induce non-genomic effects (Croxtall et al., 2002; Horvath and Wanner, 2006; Liu et al., 2010; Tumlin et al., 1997), supporting the idea that non-genomic cytosolic receptors are involved in mediating the rapid ability of ventral hippocampal corticosterone to alter accumbal dopamine release. Alternatively, the approach used here does not rule out the possibility that concomitant activation of both membrane-bound and cytosolic mechanisms are required for ventral hippocampal corticosterone to alter accumbal dopamine release. This possibility warrants future investigation, when molecular tools advance to differentiate membrane-associated and cytosolic receptor activity and associated signaling cascades.

Furthermore, we have only used one isoform of BSA-conjugated corticosterone, at one dose. It is possible that the carboxymethyloxime-ketone conjugation of BSA to corticosterone’s terminal ketone group (employed in the synthesis of the Corticosterone 3-CMO : BSA isoform used in these studies) blocks corticosterone receptor binding. We believe this is unlikely as prior research has shown similar increases in glutamate transmission induced by both BSA-conjugated corticosterone and corticosterone alone (Karst et al., 2005). Further, intrahippocampal infusions of BSA-conjugated corticosterone and acute stress elicit similar changes in behavioral performance on a spatial discrimination task (Chauveau et al., 2010). However, this possibility still warrants future investigation through the use of other commercially available isoforms of BSA-conjugated corticosterone and a dose-response study.

We anticipated that blocking mineralocorticoid receptors would isolate corticosterone’s effects to glucocorticoid receptors and vice versa, thus revealing the role of each receptor in the ventral hippocampus in mediating accumbal dopamine output in vivo. Surprisingly, selectively blocking either glucocorticoid- or mineralocorticoid receptors in the ventral hippocampus prevented ventral hippocampal corticosterone from altering accumbal dopamine output. This suggests that neither glucocorticoid- nor mineralocorticoid receptors in the ventral hippocampus can sufficiently enable ventral hippocampal corticosterone to alter accumbal dopamine output independently of one another. At the genomic level, a variety of literature suggests specific glucocorticoid target genes may require concomitant activation of mineralocorticoid- and glucocorticoid receptors (Mifsud and Reul, 2018; Mifsud and Reul, 2016). This is thought to occur through heterodimerization of mineralocorticoid and glucocorticoid receptor complexes (Liu et al., 1995; Mifsud and Reul, 2018; Mifsud and Reul, 2016; Ou et al., 2001; Trapp and Holsboer, 1996). This cooperative ability has been demonstrated in ventral hippocampal tissue, and can increase the functional diversity of corticosterone’s genomic actions (Trapp and Holsboer, 1996). Our data raises the intriguing possibility that cooperative activity of the two corticosterone receptor types in the ventral hippocampus is also required to induce distinct non-genomic effects.

4.3. An overall model for how ventral hippocampal corticosterone modulates accumbal dopamine

The ventral hippocampus has an extensive interneuronal network responsible for regulating local excitation (Fig. 5) (Chamberland and Topolnik, 2012; Freund and Buzsaki, 1996; Leranth and Hajszan, 2007). We propose the glutamatergic efferents from the ventral hippocampus responsible for stimulating accumbal dopamine release are under tonic inhibition in basal conditions (Fig. 5). Non-genomic glucocorticoid receptors can regulate interneuron inhibition (Zeise et al., 1992). This may occur in part through their recruitment of serotonin- and membrane-permeable retrograde signaling mechanisms such as nitric oxide (NO, a gas) and the endocannabinoid 2-arachidonoylglycerol (2-AG, an ester/lipid), which activate excitatory and inhibitory serotonin receptors, NO-sensitive guanylyl cyclase (NO-GC), and inhibitory Type I cannabinoid receptors (CB1) (respectively; Fig. 5). These signal transducers are expressed on excitatory glutamatergic terminals and inhibitory GABAergic terminals (Figure 5), including specific subpopulations of GABAergic interneurons and interneuron-inhibiting interneurons (IS-Is), and augment, inhibit, or disinhibit presynaptic interneuron activity (Barr and Forster, 2011; Di et al., 2016; Di et al., 2003; Hu et al., 2010; Li et al., 2014).

Figure 5. Cellular and molecular mechanisms proposed to mediate corticosterone excitation within the ventral hippocampus.

Figure 5.

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The ventral hippocampus is known to have an extensive interneuronal network (shown in red) responsible for regulating local excitation (Chamberland and Topolnik, 2012; Freund and Buzsaki, 1996; Leranth and Hajszan, 2007). Therefore, we propose the ventral hippocampus’ glutamatergic efferents responsible for stimulating accumbal dopamine release (shown in green) may be under tonic inhibition by GABAergic interneuron- and interneuron-inhibiting interneurons (called interneuron-specific interneurons, IS-Is) under basal conditions. We conclude that corticosterone activation of presynaptic membrane mineralocorticoid receptors (MR, purple circles) potentiates local glutamate release onto the ventral hippocampus’ glutamatergic efferents (Bekkers and Stevens, 1989; Karst et al., 2005). Membrane mineralocorticoid receptors also exist postsynaptically and can rapidly and reversibly potentiate glutamate release in the hippocampus; these have not been shown in the figure for the sake of simplicity. However, we propose activation of postsynaptic cytosolic glucocorticoid receptors (GR, blue circles) is also required to induce top-down disinhibition of the glutamatergic efferents whose terminal actions regulate accumbal dopamine output (Liu et al., 2010; Maggio and Segal, 2009; Zeise et al., 1992). The disinhibiting effects of GR activation are thought to occur through its induction of the retrograde signaling (RN: retrograde neurotransmitter) components 2-Arachidonoylglycerol (2-AG; an ester/lipid endocannabinoid), nitric oxide (NO; a gas), and/or serotonin (5-HT; an amino acid), which have been shown to act on inhibitory Gi/o-coupled Type I cannabinoid (CB1) receptors, NO-sensitive guanylyl cyclase, and inhibitory 5-HT1A- and excitatory 5-HT3 receptors (respectively) on the presynaptic terminals of presynaptic GABAergic interneurons (Barr and Forster, 2011; Di et al., 2016; Di et al., 2003; Hu et al., 2010; Li et al., 2014). Overall, we propose GR activation disinhibits GABAergic suppression of the ventral hippocampus’ principal glutamatergic efferents that project to the mesolimbic dopamine system, enabling MR-induced depolarizing events to regulate accumbal excitation/inhibition and dopamine release.

The presence of local interneurons, interneuron-inhibiting interneurons (IS-Is) and long-range GABAergic projections in the hippocampus (Fig. 5) (Chamberland and Topolnik, 2012; Freund and Buzsaki, 1996; Jinno, 2009) make it difficult to discern whether glucocorticoid-receptor-mediated effects on interneuron and IS-I transmission (Liu et al., 2010; Maggio and Segal, 2009) would translate to inhibitory or disinhibitory effects locally and/or in the nucleus accumbens shell in vivo. This is because it is not known whether these glucocorticoid-receptor effects impact interneurons or interneuron inhibiting neurons (IS-Is), or both. Furthermore, we previously found that corticosterone acting on glucocorticoid receptors rapidly increases serotonin levels in the ventral hippocampus (Barr and Forster, 2011). The hippocampus is enriched with all subtypes of excitatory and inhibitory 5-HT receptors, localized to 5-HT presynaptic terminals, GABAergic interneurons, and glutamatergic neurons (Berumen et al., 2012). The combined effects of these 5-HT actions in the hippocampus are complex, however serotonin’s inhibitory 5-HT1A receptors are localized to GABAergic interneurons in this region (Aznar et al., 2003) and 5-HT1A receptors in the hippocampus are thought to provide inhibitory regulation of GABAergic interneurons (Matsuyama et al., 1997). Additionally, serotonin’s excitatory 5-HT3 receptors are preferentially expressed on IS-Is in the ventral hippocampus, reinforcing a disinhibiting effect of serotonin in this region (Berumen et al., 2012; Chamberland and Topolnik, 2012; Freund and Buzsaki, 1996; Pelkey et al., 2017). Thus, it is possible that cytosolic non-genomic glucocorticoid receptor activation results in disinhibition of glutamatergic efferents from the ventral hippocampus to the mesolimbic dopamine system via serotonergic (and retrograde NO or 2-AG) signals acting on local GABAergic neurons (Fig. 5).

Based on our current findings, glucocorticoid receptor-mediated disinhibition of the glutamate efferents from the ventral hippocampus may be insufficient to stimulate accumbal dopamine release without concomitant excitation. Electrophysiology studies suggest pre- and postsynaptic membrane mineralocorticoid receptors can rapidly and reversibly potentiate glutamate release in the hippocampus (Bekkers and Stevens, 1989; Karst et al., 2005). Therefore, we propose concomitant activation of non-genomic mineralocorticoid receptors (Fig. 5) is also required to potentiate glutamate release from the glutamatergic efferents that project from the ventral hippocampus to stimulate accumbal dopamine release when these neurons are disinhibited by glucocorticoid receptor activation. Overall, the model and interactions proposed by Figure 5 require testing in the future to confirm the mechanisms by which corticosterone in the ventral hippocampus modifies accumbal dopamine efflux.

4.4. Ventral hippocampal corticosterone reduces accumbal dopamine output in amphetamine withdrawal

In amphetamine pre-treated rats, corticosterone infusions into the ventral hippocampus produced a biphasic reduction in accumbal dopamine output, highlighting disrupted ventral hippocampal corticosterone modulation of accumbal dopamine in amphetamine withdrawal. This is may be due, in part, to reduced glucocorticoid receptor expression and function in the ventral hippocampus of this amphetamine withdrawal model (Barr and Forster, 2011; Li et al., 2014), which we predict would result in an inability to suppress GABAergic inhibition of glutamatergic efferents from the hippocampus to the nucleus accumbens (Figure 5). Interestingly, mineralocorticoid receptor expression in the ventral hippocampus does not change during amphetamine withdrawal (Barr and Forster, 2011). Our current findings suggest that synergistic activation of glucocorticoid and mineralocorticoid receptors in the ventral hippocampus are required to observe increased dopamine efflux in the nucleus accumbens. Thus, the prominent reduction in glucocorticoid receptor function in the ventral hippocampus during amphetamine withdrawal (Barr and Forster, 2011; Li et al., 2014) is likely to negate any stimulatory effect of corticosterone’s actions on mineralocorticoid receptors (Figure 5) in withdrawn rats. However, our model would predict that corticosterone in the ventral hippocampus would be ineffective in altering accumbal dopamine efflux in the absence of glucocorticoid receptor signaling. The observed decrease in dopamine signal within the nucleus accumbens is thus likely due to other molecular changes induced by amphetamine exposure (Barr et al., 2017) that are revealed when corticosterone is infused into the ventral hippocampus. A likely candidate are corticosterone-sensitive organic cation transporters (OCTs) which play an important role in transport monoamine neurotransmitters within the brain (Gasser, 2019). The expression and function of OCT-3 are increased in the ventral hippocampus of our amphetamine withdrawal rat model (Barr et al., 2013; Solanki et al., 2016) and whether these changes can result in altered glutamatergic neuronal activity in the ventral hippocampus should be explored in the future.

Our findings lead to the implication that disrupted ventral hippocampal corticosterone responses may promote dysphoric states during amphetamine withdrawal by contributing to accumbal dopamine deficiency, which in turn, contributes to stress-related drug-taking behavior and relapse (Brischoux et al., 2009; Haake et al., 2018; Hurley et al., 2017; Paliwal et al., 2008; Robinson et al., 2014; Roitman et al., 2008; Sinha, 2007; Twining et al., 2014; Ungless et al., 2004; Weise-Kelly and Siegel, 2001; Wheeler et al., 2011; Wheeler and Carelli, 2009; Wheeler et al., 2008). The opponent-process theory of addiction suggests that blunted dopamine reward responses and glucocorticoid stress responses contribute to negative reinforcement of drug-taking (Koob and Le Moal, 2008a, b). Previous research has focused on the role of corticotrophin releasing factor (CRF) in the amygdala as contributing to the disruption of reward processes thought to prompt addiction (Koob, 2009; Koob and Le Moal, 2008a, b; Koob and Zorrilla, 2010; Zorrilla et al., 2014). Our findings implicate corticosterone in the ventral hippocampus as a key contributor to the dysregulated opponent processes thought to negatively reinforce drug dependence (Barr et al., 2017).

5. Conclusions

Here we demonstrate for the first time that a stress-relevant concentration of corticosterone in the ventral hippocampus significantly enhances accumbal dopamine output in control conditions, and reduces accumbal dopamine output in protracted amphetamine withdrawal. Our findings suggest that the ability of corticosterone in the ventral hippocampus to alter accumbal dopamine output requires cytosolic access as well as activation of both mineralocorticoid and glucocorticoid receptors that are likely to be at least partly mediated by non-genomic mechanisms. Thus, we propose the ability of corticosterone in the ventral hippocampus to alter accumbal dopamine output requires cooperative activation of excitatory mineralocorticoid receptors and glucocorticoid-receptor-mediated disinhibition to produce excitatory output onto the mesolimbic dopamine circuit. Disruption to this balance within the ventral hippocampus thus appears to reduce accumbal dopamine output during amphetamine withdrawal.

Overall, our findings suggest the ventral hippocampal corticosterone stress response as a potential mechanism that enables stress to enhance incentive salience and promote goal-oriented behavior. This response may also contribute to positive reinforcement of initial drug exposure, and when altered by chronic psychostimulant exposure, contributes to the dysphoric states thought to negatively reinforce drug dependence and relapse during withdrawal.

Bray et al Highlights.

  • Corticosterone in ventral hippocampus increases accumbal dopamine release.

  • Mineralocorticoid and glucocorticoid receptors both mediate this response.

  • Amphetamine withdrawal attenuates corticosterone-induced accumbal dopamine release.

  • Dysregulated hippocampal corticosterone may promote dysphoria during drug withdrawal.

Acknowledgments

We would like to thank: Michael Watt, PhD and Jamie Scholl, MA for the help and training they provided throughout this study; Charles Blaha, PhD for his help in chronoamperometric techniques; Paul Clarke, PhD for providing equipment for these studies; Trevor Arends, Senior Chemist at Steraloids Inc., for his help in use of the corticosterone 3-CMO : BSA conjugate; Wenyu Tu, Elise Hadley, Nathan J. Vinzant, Raisul Rubel, Riley Paulsen, and Eric Graack for their help with histology and administering amphetamine injections. Funding: This work was supported by the National Institutes of Health [grant numbers R01 DA019921 and R25 DA033674] and by the University of South Dakota Graduate School. All authors report no conflicts of interest.

Abbreviations

2-AG

2-arachidonoylglycerol

aCSF

artificial cerebrospinal fluid

AHiPM

amygdalohippocampal area of the amygdala

AMP

amphetamine pre-treatment and withdrawal

ANOVA

analysis of variance

APir

amygdalaopiriform atransitional area of the amygdala

BSA

bovine serum albumin

BSA

Corticosterone, infusions of corticosterone

3-CMO

BSA (corticosterone conjugated to membrane-impermeable BSA)

CB1

Inhibitory Gi/o-coupled type I cannabinoid receptor

CORT

corticosterone

CRF

corticotrophin releasing factor

BSA-HBC

infusion of bovine serum albumin in 0.05% 2-hydroxypropyl-β-cyclodextrin

Corticosterone 3-CMO : BSA

corticosterone 3-corticosterone methyl oxidase conjugated to bovine serum albumin (4-pregnen-11b, 21-diol-3, 20-dione 3-carboxymethyloxime : bovine serum albumin), a membrane-impermeable corticosterone conjugate

GABA

gamma-aminobutyric acid

HBC

2-hydroxypropyl-β-cyclodextrin

IS-I

interneuron specific interneuron

MIF

mifepristone infusion

NMDA

N-Methyl-D-aspartic acid

NO

nitrous oxide

NO-GC

nitrous oxide-sensitive guanylyl cyclase

PMCO

posteriomedial cortical area of the amygdala

SAL

saline pre-treatment

SPIR

spironolactone infusion

Vehicle

vehicle infusion

vHipp

ventral hippocampus.

Footnotes

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