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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/0.5 μL) 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vehicle were infused into the ventral hippocampus of urethane-anesthetized adult male rats in control and amphetamine withdrawn conditions.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.

Being bullied during adolescence is associated with later mental illnesses characterized by deficits in cognitive tasks mediated by prefrontal cortex (PFC) dopamine (DA). Social defeat of adolescent male rats, as a model of teenage bullying victimization, results in medial PFC (mPFC) dopamine (DA) hypofunction in adulthood that is associated with increased drug seeking and working memory deficits. Increased expression of the DA transporter (DAT) is also seen in the adult infralimbic mPFC following adolescent defeat. We propose the functional consequence of this increased DAT expression is enhanced DA clearance and subsequently decreased infralimbic mPFC DA availability. To test this, in vivo chronoamperometry was used to measure changes in accumulation of the DA signal following DAT blockade, with increased DAT-mediated clearance being reflected by lower DA signal accumulation. Previously defeated rats and controls were pre-treated with the norepinephrine transporter (NET) inhibitor desipramine (20 mg/kg, ip.) to isolate infralimbic mPFC DA clearance to DAT, then administered the selective DAT inhibitor GBR-12909 (20 or 40 mg/kg, sc.). Sole NET inhibition with desipramine produced no differences in DA signal accumulation between defeated rats and controls. However, rats exposed to adolescent social defeat demonstrated decreased DA signal accumulation compared to controls in response to both doses of GBR-12909, indicating greater DAT-mediated clearance of infralimbic mPFC DA. These results suggest that protracted increases in infralimbic mPFC DAT function represent a mechanism by which adolescent social defeat stress produces deficits in adult mPFC DA activity and corresponding behavioral and cognitive dysfunction.

The receptors that couple to the G protein Gz in vivo are still relatively unknown. In this study, we investigated the effects of various dopamine receptor agonists in a mouse deficient in the alpha subunit of Gz. The dopamine D1-like receptor agonist SKF38393 stimulated comparable locomotor activity in both wildtype mice and mice lacking Galphaz. In contrast, the dopamine D2-like receptor agonist quinpirole suppressed locomotor activity in both groups of mice, but this suppression was significantly smaller in Galphaz knockout mice. Consistent with these behavioural observations, quinpirole inhibition of dopamine release in the forebrain nucleus accumbens evoked by electrical stimulation of dopamine axons was significantly attenuated in mice lacking Galphaz. In addition, hypothermia and adrenocorticotropic hormone release resulting from activation of dopamine D2-like receptors were also significantly reduced in Galphaz knockout mice. However, adrenocorticotropic hormone secretion induced by corticotrophin releasing hormone and the serotonin 1A receptor agonist 8-hydroxy-dipropylamino-tetralin were similar between wildtype and Galphaz knockout mice. Western blot analysis showed that the expression levels of Galphai, Galphao, Galphas, Galphaq and Gbeta were the same in the brains of mice of both genotypes. Overall, our data suggest that Gz proteins are functionally coupled to dopamine D2-like receptors in vivo.

Acute amphetamine administration activates monoaminergic pathways and increases systemic corticosterone, both of which influence anxiety states and adult dentate gyrus neurogenesis. Chronic amphetamine increases anxiety states in rats when measured at 24 hours and at 2 weeks of withdrawal. However, the effects of chronic amphetamine exposure and withdrawal on long term anxiety-like behavior and adult neurogenesis in the dentate gyrus are unknown. Adult male rats were administered amphetamine (2.5 mg/kg, ip.) daily for two weeks. Anxiety-like behaviors were increased markedly in amphetamine-treated rats following four weeks of withdrawal from amphetamine. Plasma corticosterone level was unaltered by amphetamine treatment or withdrawal. However, norepinephrine and serotonin concentrations were selectively reduced in the dentate gyrus 20 hours following amphetamine treatment. This effect did not persist through the four-week withdrawal period. In separate experiments, rats received bromodeoxyuridine to label cells in S-phase, prior to or immediately following amphetamine treatment. Newly generated cells were quantified to measure extent of progenitor cell proliferation and neurogenesis following treatment or withdrawal. Progenitor cell proliferation and neurogenesis were not significantly affected by amphetamine exposure when measured 20 hours following the last amphetamine treatment. However, neurogenesis in the dentate gyrus was reduced after four weeks of withdrawal when compared to saline-pretreated rats. Overall, our findings indicate that withdrawal from chronic amphetamine leads to persistent anxiety-like behavior which may be maintained by reduced neurogenesis in the dentate gyrus at this protracted withdrawal time point. However, neurogenesis is unaffected at earlier withdrawal time points where anxiety states emerge, suggesting different mechanisms may underlie the emergence of anxiety states during amphetamine withdrawal.