Yunjing Bai

Roles of BDNF, dopamine D(3) receptors, and their interactions in the expression of morphine-induced context-specific locomotor sensitization.

Drug seeking, craving, and relapse can be triggered by environmental stimuli that acquire motivational salience through repeated associations with the drugs effects. Previous studies indicated that the dopamine D(3) receptor (Drd3) might be involved in the expression of drug-conditioned responses in rats, and brain-derived neurotrophic factor (BDNF) could modulate Drd3 expression in the nucleus accumbens (NAc). However, the involvement of neural regions with Drd3 activation and the underlying interaction between BDNF and Drd3 in the expression of behavioral responses controlled by a drug-associated environment have remained poorly understood. The present study used a conditioning procedure to assess the roles of BDNF, Drd3, and their interactions in the NAc in the expression of morphine-induced context-specific locomotor sensitization. We showed that the expression of locomotor sensitization in the morphine-paired environment was accompanied by significantly increased expression of Drd3 mRNA and BDNF mRNA and protein levels. Both sensitized locomotion in morphine-paired rats and enhanced Drd3 mRNA were suppressed by intra-NAc infusion of anti-tyrosine kinase receptor B (TrkB) IgG. Furthermore, intra-NAc infusion of the Drd3-selective antagonist SB-277011A significantly decreased the expression of context-specific locomotor sensitization and upregulated BDNF mRNA. Altogether, these results suggest that BDNF/TrkB signaling and activation of Drd3 in the NAc are required for the expression of morphine-induced context-specific locomotor sensitization.

Orexin A attenuates unconditioned sexual motivation in male rats

Orexins are neuropeptides involved in multiple neurophysiological functions such as reward and motivation. However, it is not clear whether orexins are implicated in sexual motivation. This study aims to evaluate the effects of orexin A and the OX(1)R antagonist SB334867 on unconditioned sexual motivation. Forty-five male Wistar rats are divided into four groups. The four groups are respectively administered intracerebroventricularly with saline, orexin A (1, 10 microg), 10% DMSO (cyclodextrin) and SB334867 (5, 15 microg) 10-15 min before sexual motivation tests. The preference for a receptive female to a male in an open arena with two tethered animals is designated as unconditioned sexual motivation. The results show that orexin A reduces the female preference (reducing time in the female zone and/or increasing time in the male zone), the number of visits for the female zone and the total distance traveled in sexually high-motivated males. SB334867 has no effect on the female preference, the number of visits and the distance traveled in either sexually high-motivated or low-motivated males. Our experiments reveal that centrally administered orexin A attenuates sexual motivation in high-motivated males although endogenous orexin A might not play an important role in the expression of unconditioned sexual motivation.

Altered phosphorylation of GluA1 in the striatum is associated with locomotor sensitization induced by exposure to increasing doses of morphine

Escalation of drug consumption is involved in the transition from drug use to addiction. Our previous study demonstrated that neuronal activation in ventral tegmental area (VTA) and substantia nigra (SN) was associated with behavioral sensitization induced by increasing doses of morphine. Here we sought to characterize the molecular mechanism underlying this behavioral sensitization. We compared mitogen-activated protein kinase (MAPK) signaling following pretreatment with either increasing doses or fixed doses of morphine before and after behavioral sensitization. We found phospho-MAPK markedly increased in ventral striatum and decreased in dorsal striatum after either pretreatment group, but no further change after sensitization induced by 10mg/kg morphine challenge. Furthermore, we also evaluated the level of phospho-glutamate receptor 1 at serine 845 (pSer845-GluA1) and 831 (pSer831-GluA1) sites in ventral striatum and dorsal striatum. The results showed a significant increase in pSer845-GluA1/GluA1 ratio in ventral striatum but not dorsal striatum after pretreatment with increasing doses of morphine but not after fixed-dose or saline pretreatment. Importantly, pSer845-GluA1/GluA1 ratio was increased exclusively in dorsal striatum and not ventral striatum following acute morphine challenge specifically paired with increasing-dose pretreatment and not fixed-dose or saline. These findings indicate that behavioral sensitization-induced by chronic pretreatment with increasing doses of morphine might be more closely associated with the dynamic GluA1 activity in the striatum rather than the modulation of MAPK signaling. These findings also indicate that GluA1 phosphorylation may occur independent of MAPK activation.

Differential patterns of neuronal activation in rostral versus caudal ventral tegmental area involved in behavioral sensitization induced by an escalating-dose morphine administration paradigm

The transition to addiction often involves a gradual process of escalated drug intake. The purpose of the present study was to characterize neuronal activation in the ventral tegmental area (VTA) and substantia nigra (SN) following chronic escalating-dose morphine exposure (days 1-7, 2 mg/kg/d; days 8-21, beginning at 10 mg/kg/d, increasing by 2 mg/kg/d), with steady-dose morphine (2 mg/kg/d, i.p., for 21 days) as the comparison. Using immunohistochemical double-staining for tyrosine hydroxylase (TH) and Fos, we found that the number of Fos(+)TH(+) neurons in the rostral VTA and number of Fos(+)TH(-) neurons in the lateral SNr were significantly increased in escalating-dose morphine-treated rats compared with steady-dose morphine-treated rats and acute morphine-treated rats. Meanwhile, this increase was associated with robust expression of behavioral sensitization after a challenge with 10 mg/kg morphine. The number of Fos(+)TH(+) neurons was significantly increased by acute morphine in the caudal VTA and SNc, but this number did not increase further with morphine pretreatment. These results demonstrate that behavioral sensitization was associated with elevated activation of dopaminergic neurons in the rostral VTA and nondopaminergic neurons in the lateral SNr, which could only be induced by chronic escalating-dose morphine rather than chronic steady-dose morphine pretreatment.

High-dose corticosterone after fear conditioning selectively suppresses fear renewal by reducing anxiety-like response.

Exposure therapy is widely used to treat anxiety disorders, including posttraumatic stress disorder (PTSD). However, preventing the return of fear is still a major challenge after this behavioral treatment. An increasing number of studies suggest that high-dose glucocorticoid treatment immediately after trauma can alleviate the symptoms of PTSD in humans. Unknown is whether high-dose glucocorticoid treatment following fear conditioning suppresses the return of fear. In the present study, a typical fear renewal paradigm (AAB) was used, in which the fear response to an auditory cue can be restored in a novel context (context B) when both training and extinction occur in the same context (context A). We trained rats for auditory fear conditioning and administered corticosterone (CORT; 5 and 25mg/kg, i.p.) or vehicle with different delays (1 and 24h). Forty-eight hours after drug injection, extinction was conducted with no drug in the training context, followed by a test of tone-induced freezing behavior in the same (AAA) or a shifted (AAB) context. Both immediate and delayed administration of high-dose CORT after fear conditioning reduced fear renewal. To examine the anxiolytic effect of CORT, independent rats were trained for cued or contextual fear conditioning, followed by an injection of CORT (5 and 25mg/kg, i.p.) or vehicle at a 1 or 24h delay. One week later, anxiety-like behavior was assessed in the elevated plus maze (EPM) before and after fear expression. We found that high-dose CORT decreased anxiety-like behavior without changing tone- or context-induced freezing. These findings indicate that a single high-dose CORT administration given after fear conditioning may selectively suppress fear renewal by reducing anxiety-like behavior and not by altering the consolidation, retrieval, or extinction of fear memory.

Corticosterone combined with intramedial prefrontal cortex infusion of SCH 23390 impairs the strong fear response in high-fear-reactivity rats.

Accumulating evidence suggests that stress-dose corticosteroids impair fear memory in animals and humans. Corticosteroid treatment after critical illness is seen as a potential psychotropic medication by which to prevent posttraumatic stress disorder. However, individual difference in the responsiveness to stress (i.e., stress reactivity) is a factor that modulates the efficacy of corticosteroids. To understand the contribution of fear reactivity to the effect of post-stress corticosterone, male Sprague-Dawley rats were subjected to classical tone-cued fear conditioning and separated into high and low reactivity (HR and LR, respectively) responder groups based on their levels of freezing during conditioning. The HR rats showed significantly higher fear responses than the LR rats during conditioning as assessed by freezing behavior. At two intervals, 30 min and 48 hr later, the HR rats still displayed more pronounced conditioned responses to cued stimuli compared with the LR rats. Moreover, in contrast to the LR rats, the enhanced fear response in the HR rats was difficult to attenuate by post-training high-dose corticosterone. These results suggest that fear reactivity results in stronger fear memory, and that it is difficult to disrupt this strong fear memory in the HR phenotype using monotherapy. However, the strong fear memory in the HR rats was impaired by concurrent intramedial prefrontal cortex infusion of a high dose of the dopamine D1 receptor antagonist SCH 23390 and systemic administration of corticosterone. SCH 23390 and corticosterone alone did not decrease freezing levels in the HR rats. The fear impairment induced by SCH 23390 combined with corticosterone was not attributable to the effect of these drugs on locomotor activity. This effect was not found with administration of the D2 antagonist eticlopride combined with corticosterone. Our findings demonstrate that the conditioned fear memory in individuals with high stress reactivity is difficult to disrupt using monotherapy, but that combined pharmacotherapy may be useful for treating intervention-resistant fear.

Post-training corticosterone inhibits the return of fear evoked by platform stress and a subthreshold conditioning procedure in Sprague-Dawley rats

The return of fear is an important issue in anxiety disorder research. Each time a fear memory is reactivated, it may further strengthen overactivation of the fear circuit, which may contribute to long-term maintenance of the fear memory. Recent evidence indicates that glucocorticoids may help attenuate pathological fear, but its role in the return of fear is unclear. In the present study, systemic corticosterone (CORT; 25mg/kg) administration 1h after fear conditioning did not impair the consolidation process but significantly suppressed the return of fear evoked by a subthreshold conditioning (SC) procedure and elevated platform (EP) stress. Compared with the SC-induced return of fear, acute stress-induced return was state-dependent. In addition, post-training CORT treatment increased the adrenocorticotropic response after EP stress, which indicates that the drug-induced suppression of the return of fear may possibly derive from its regulation effect of the hypothalamic-pituitary-adrenal axis reactivity to stress. These results suggest that post-training CORT administration may help inhibit the return of fear evoked by EP or SC stress. The possible mechanisms involved in the high-dose CORT-induced suppression of the SC- and EP-induced return of fear are discussed.

Mineralocorticoid receptors in the ventral hippocampus are involved in extinction memory in rats.

Fear extinction decreases conditioned fear responses that normally occur when a conditioned stimulus (CS) is repeatedly presented in the absence of an aversive unconditioned stimulus (US), which is the behavioral basis of exposure therapy for posttraumatic stress disorder (PTSD). However, knowledge about the neurobiology of extinction is insufficient. The present study investigated changes in the protein expression of mineralocorticoid receptors (MRs) and glucocorticoid receptors (GRs) in the dorsal hippocampus (DH)and ventral hippocampus (VH), induced by extinction and return of conditioned fear responses to an auditory signal. Western blot analysis indicated that shock stress enhanced the expression of MRs in only the DH, whereas extinction selectively increased the expression of MRs in the VH. The infusion of MRs antagonist spironolactone in the VH indicated that MRs in the VH did not affect the retrieval of fear and extinction memories, but facilitated the formation of extinction memory. However, no changes in GRs in either the DH or VH were observed in each phase of auditory fear conditioning. These results suggest that MRs in the DH and VH have differential functions in the extinction of auditory fear conditioning. MRs in the DH appear to be related to only stressful experiences, whereas MRs in the VH are involved in extinction formation. The enhancement of MRs in the VH might be necessary to improve PTSD.