Internet abusers associate with a depressive state but not a depressive trait.

AIM: The present study investigated three issues: (i) whether Internet abusers display a depressive state without a depressive trait; (ii) which symptoms are shared between Internet abuse and depression; and (iii) which personality characteristics were shown in Internet abusers. METHODS: Ninety-nine male and 58 female participants aged 18-24 years were screened with the Chen Internet Addiction Scale. After screening, subjects were separated into the high- (n = 73) and low-risk (n = 84) Internet abuser groups. Participants were respectively administered the Chinese version of the Beck Depression Inventory-II to assess a depressive state and the Minnesota Multiphasic Personality Inventory-2 to assess a depressive trait. RESULTS: The present results showed that high-risk Internet abusers exhibited a stronger depressive state than low-risk Internet abusers in the Beck Depression Inventory-II. However, high-risk Internet abusers didnot show a depressive trait in the Minnesota Multiphasic Personality Inventory-2 compared to low-risk Internet abusers. Therefore, high-risk Internet abuse participants exhibited a depressive state without a depressive trait. CONCLUSIONS: In a comparison of the symptoms of depression and Internet abuse, it was found that high-risk Internet abuse participants shared some common behavioral mechanisms with depression, including the psychiatric symptoms of loss of interest, aggressive behavior, depressive mood, and guilty feelings. High-risk Internet abuse participants may be more susceptible to a temporal depressive state but not a permanent depressive trait. The present findings have clinical implications for the prevention and treatment of Internet abuse.

Neural substrates of amphetamine-induced behavioral sensitization: unconditioned (zero context) and conditioned (switch versus same context) components in c-fos overexpression.

The neural substrates of the unconditioned and conditioned components of amphetamine (AMPH)-induced behavioral sensitization remain unknown. The present study examines the brain activation of rats in response to an AMPH challenge with augmented locomotion in groups receiving chronic AMPH under chloral hydrate anesthetization (i.e., the 'zero context') or when tested in the 'same context' as a chronic treatment, or when tested in a 'different context'. The neural activations of the three groups reveal fairly consistent patterns: (a) The substantia nigra is activated in the same context condition and the pure AMPH effect (i.e., the zero context with the unconditioned component), but not in the switch context condition. (b) The ventral pallidum showed Fos expression in the switch context and the same context, but not in the zero context condition. (c) The other nuclei, including the medial prefrontal cortex, nucleus accumbens, caudate putamen, medial thalamus, hippocampus, amygdala, and ventral tegmental area, are activated in all contextual conditions and the pure AMPH effect (the zero context). The context exerts definable effects on the mesocorticolimbic dopamine system on AMPH-induced behavioral sensitization. (d) The ventral pallidum and the substantia nigra activations dissociate the unconditioned component from the conditioned component in behavioral sensitization. Further studies are needed to determine how these two nuclei mediate the effect in terms of primary and conditioned rewards.

Examination of neuroinflammatory cytokine interleukin-1 beta expression in the medial prefrontal cortex, amygdala, and hippocampus for the paradoxical effects of reward and aversion induced by morphine.

A growing body of evidence has shown that abused drugs could simultaneously induce the paradoxical effect-reward and aversion. Moreover, the medial prefrontal cortex (mPFC), amygdala, and hippocampus were involved in this paradoxical effect by abused drugs. However, no research examined whether neuroinflammatory changes in the mPFC [including cingulate cortex area 1 (Cg1); prelimbic cortex (PrL); infralimbic cortex (IL)], basolateral amygdala, and hippocampus [e.g., CA1, CA2, CA3, and dentate gyrus (DG)] after morphine-induced reward in conditioned place preference (CPP) and aversion in conditioned taste aversion (CTA). The results showed that after morphine administration, the consumption of a 0.1% saccharin solution decreased; the mean time spent in the morphine-paired side compartment of the CPP box increased, indicating that morphine simultaneously induced the paradoxical effects of reward and aversion. The PrL and IL of the mPFC, the BLA of the amygdala, the CA1, CA2, CA3, and DG of the hippocampus but not the Cg1 presented hyperactive IL-1ß expression in response to morphine's aversion and reward. The mPFC, amygdala, and hippocampus may appear neuroinflammation activity following morphine-induced paradoxical effect-reward in CPP and aversion in CTA. The present data may provide a better understanding of the relationship between neuroinflammation and morphine addiction.

Motor function in an animal model with ouabain-induced bipolar disorder and comorbid anxiety behavior.

In a clinical setting, anxiety disorder is highly correlated with bipolar I disorder in humans. However, the comorbidity of anxiety behavior and bipolar disorder still remains unclear in an animal model. This study utilized an ouabain-induced animal mode to examine anxiety and mania in an open field test. In the present study, 5 µl of artificial cerebrospinal fluid (aCSF) or ouabain (10-5, 10-4, and 10-3 M) were administered into the left ventricle. The animals' motor functions and anxiety behaviors were measured for 15 min. The results showed that 10-3 M ouabain significantly increased the animal's total distance traveled, average speed, and maximum speed compared to the control group. The time spent inside (i.e., how much time rats spent in the center of the square) and the inside-outside times of the central square (i.e., how many times rats ran across the center square) of the higher-concentration groups (10-4 M and 10-3 M) were significantly decreased. Therefore, a high concentration of ouabain may induce hyperactivity. The 10-4 M and 10-3 M ouabain groups exhibited more anxiety behaviors. The study is the first model to examine comorbid anxiety behaviors and bipolar disorder in an animal model. The study provides some insights for comorbid anxiety and bipolar disorder in clinics.

Xanthohumol-induced presynaptic reduction of glutamate release in the rat hippocampus.

This study examined whether xanthohumol, a hop-derived prenylated flavonoid present in beer, affects glutamate release in the rat hippocampus. In the rat hippocampal nerve terminals (synaptosomes), xanthohumol inhibited the release of 4-aminopyridine (4-AP)-evoked glutamate and the elevation of cytosolic Ca(2+) concentration, whereas it had no effect on 4-AP-mediated depolarization. The inhibitory effect of xanthohumol on the evoked glutamate release was prevented by removing extracellular Ca(2+), using the Cav2.2 (N-type) and Cav2.1 (P/Q-type) channel blocker ω-CgTX MVIIC, the calmodulin antagonists W7 and calmidazolium, and the protein kinase A inhibitor H89; however, no such effect was observed when the G-protein inhibitor N-ethylmaleimide was used. In addition, immunocytochemical data demonstrated that GABAA receptors are present in the hippocampal synaptosomes and that the xanthohumol effect on evoked glutamate release was antagonized by the GABAA receptor antagonist SR95531. Furthermore, in slice preparations, xanthohumol reduced the frequency of miniature excitatory postsynaptic currents without affecting their amplitude. We conclude that xanthohumol acts at GABAA receptors present in the hippocampal nerve terminals to decrease the Ca(2+) influx through N- and P/Q-type Ca(2+) channels, which subsequently suppresses the Ca(2+)-calmodulin/PKA cascade to decrease the evoked glutamate release.

Hesperidin inhibits glutamate release and exerts neuroprotection against excitotoxicity induced by kainic acid in the hippocampus of rats.

The citrus flavonoid hesperidin exerts neuroprotective effects and could cross the blood-brain barrier. Given the involvement of glutamate neurotoxicity in the pathogenesis of neurodegenerative disorders, this study was conducted to evaluate the potential role of hesperidin in glutamate release and glutamate neurotoxicity in the hippocampus of rats. In rat hippocampal nerve terminals (synaptosomes), hesperidin inhibited the release of glutamate and elevation of cytosolic free Ca(2+) concentration evoked by 4-aminopyridine (4-AP), but did not alter 4-AP-mediated depolarization. The inhibitory effect of hesperidin on evoked glutamate release was prevented by chelating the extracellular Ca(2+) ions and blocking the activity of Cav2.2 (N-type) and Cav2.1 (P/Q-type) channels or protein kinase C. In hippocampal slice preparations, whole-cell patch clamp experiments showed that hesperidin reduced the frequency of spontaneous excitatory postsynaptic currents without affecting their amplitude, indicating the involvement of a presynaptic mechanism. In addition, intraperitoneal (i.p.) injection of kainic acid (KA, 15 mg/kg) elevated the extracellular glutamate levels and caused considerable neuronal loss in the hippocampal CA3 area. These KA-induced alterations were attenuated by pretreatment with hesperidin (10 or 50 mg/kg, i.p.) before administering the KA. These results demonstrate that hesperidin inhibits evoked glutamate release in vitro and attenuates in vivo KA-induced neuronal death in the hippocampus. Our findings indicate that hesperidin may be a promising candidate for preventing or treating glutamate excitotoxicity related brain disorders such as neurodegenerative diseases.

Apigenin, a natural flavonoid, inhibits glutamate release in the rat hippocampus.

The purpose of this study was to examine the effect and mechanism of apigenin, a natural flavonoid, on glutamate release in the rat hippocampus. In rat hippocampal nerve terminals (synaptosomes), apigenin inhibited glutamate release and the elevation of the cytosolic free Ca(2+) concentration evoked by 4-aminopyridine, whereas it had no effect on 4-aminopyridine-mediated depolarization and Na(+) influx. The apigenin-mediated inhibition of evoked glutamate release was prevented by chelating the extracellular Ca(2+) ions and blocking Cav2.2 (N-type) and Cav2.1 (P/Q-type) channel activity. Furthermore, we determined that gamma-aminobutyric acid type A (GABAA) receptors are present in the hippocampal nerve terminals because they are colocalized with the presynaptic marker synaptophysin. However, the effect of apigenin on 4-aminopyridine-evoked glutamate release from synaptosomes was unaffected by the GABAA receptor antagonists SR95531 and bicuculline. Furthermore, in slice preparations, whole-cell patch-clamp experiments showed that apigenin reduced the frequency of spontaneous excitatory postsynaptic currents without affecting their amplitude, suggesting a presynaptic mechanism. On the basis of these results, we suggested that apigenin exerts its presynaptic inhibition probably by reducing Ca(2+) entry mediated by the Cav2.2 (N-type) and Cav2.1 (P/Q-type) channels, thereby inhibiting glutamate release from the rat hippocampal nerve terminals.

Amphetamine sensitization: nonassociative and associative components.

Rats, pretreated with amphetamine (AMPH, 1 mg/kg) or saline for 2 weeks, were challenged with AMPH (0.5 mg/kg) or saline following 1 week of abstinence, and locomotion was measured. In Experiments 1 and 2, the pretreatment occurred in various contexts (home cage, novel box, test box). Sensitization was observed only when pretreatment context and test context were the same; a context switch abolished sensitization. When rats anesthetized with chloral hydrate were pretreated with AMPH, sensitization was completely dependent on the pretreatment, but independent of context. This "zero context" condition isolated the basal level of excitation attributable to unconditioned neural change to determine the role of contextual input to be a modulator that enhances or inhibits sensitization.

Dissociating effects of spatial learning from locomotor activity for ouabain-induced bipolar disorder-like rats.

Whether ouabain, a Na+ - and K+-activated adenosine triphosphatase inhibitor, mimics cognitive impairments that can be dissociated from motor effects in the bipolar disorder-like animal model remains unclear. Ouabain and the vehicle aCSF were microinjected into the left lateral ventricle immediately, after 4h, and after 24h. The results showed that (a) locomotion responses of the Immediate group were significantly decreased compared to those of the aCSF group, particularly the first five minutes. (b) The ouabain-treated rats have longer latency and total distance traveled in the water maze task; however, the velocity was not affected for the ouabain group. (c) The analysis of covariance showed that the latency time (but not the total distance traveled and velocity) of the ouabain group was more impaired than that of the aCSF group, regardless of omitting total distance traveled and cross movement in the open field test. The latency might be more sensitive than the distance traveled and the velocity for assessing spatial learning. Dissociating the spatial learning from the movement may allow testing drug treatments of cognitive deficits independent of locomotor effects associated with bipolar disorder.

Upregulation of presynaptic proteins and protein kinases associated with enhanced glutamate release from axonal terminals (synaptosomes) of the medial prefrontal cortex in rats with neuropathic pain.

Although nerve injury-induced long-term postsynaptic changes have been investigated, less is known regarding the molecular mechanisms within presynaptic axonal terminals. We investigated the molecular changes in presynaptic nerve terminals underlying chronic pain-induced plastic changes in the medial prefrontal cortex (mPFC). After neuropathic pain was induced by spared nerve injury (SNI) in rats, we assessed the release of the excitatory neurotransmitter glutamate by using in vitro synaptosomal preparations from the mPFC. We also measured the levels of synaptic proteins and protein kinases in synaptosomes using Western blotting. The results showed that unilateral long-term SNI augmented depolarization-evoked glutamate release from synaptosomes of the bilateral mPFC. This result was confirmed by a rapid destaining rate of FM1-43 dye in SNI-operated rats. Unilateral long-term nerve injury also significantly increased synaptic proteins (including synaptophysin, synaptotagmin, synaptobrevin, syntaxin, and 25-kDa synaptosome-associated protein) in synaptosomal fractions from the bilateral mPFC, and ultrastructure images demonstrated increased synaptic vesicular profiles in synaptosomes from SNI animals. Chronic pain upregulated the phosphorylation of endogenous protein kinases, including extracellular signal-regulated kinases 1 and 2 (ERK1/2) and Ca(2+)/calmodulin-dependent kinase II (CaMKII), and synapsin I, the primary presynaptic target of ERK1/2 and CaMKII. Both presynaptic proteins and protein kinases were upregulated after SNI in a time-dependent manner. These results indicate that the long-term neuropathic pain-induced enhancement of glutamate release in the mPFC is linked to increased synaptic vesicle proteins and the activation of the ERK1/2- and CaMKII-synapsin signaling cascade in presynaptic axonal terminals.

Effects of lithium and carbamazepine on spatial learning and depressive behavior in a rat model of bipolar disorder induced by ouabain.

Lithium (LiCl) and carbamazepine (CBZ), the common mood stabilizers, are thought to be effective treatments for bipolar disorder. The aim of the present study was to investigate whether LiCl as well as CBZ has similar effects on the bipolar disorder-associated cognitive dysfunctions in rats, particularly the spatial learning and depressive responses. Adult male Wistar rats were administered intracerebroventricularly with 5µl of 10(-3)M ouabain on session 1, and then received an intraperitoneal injection of LiCl or CBZ for 4 sessions (1 session/2days). For the behavioral tests, all rats were subjected to the water maze 15min for spatial learning and the forced swimming test 5min for depression on each session. The present results showed that ouabain resulted in increased latency and longer distance traveled to reach the hidden platform in the water maze, indicating that ouabain impaired the spatial learning. However, ouabain did not affect swimming velocity in the water maze and depressive responses in the forced swimming test. LiCl treatment decreased the ouabain-enhanced latency and the total distance, but not the velocity, swam to reach the hidden platform in the water maze task. Additionally, LiCl did not result in changes of any depressive indices, such as struggling behavior, swimming behavior, and floating behavior. Likewise, CBZ did not affect any behavioral indices of spatial learning and depression. A linear regression analysis suggested that LiCl, but not CBZ, could predict the decreased latency and total distance traveled except the velocity of swimming in the water maze and depressive behaviors. In summary, the present results suggested that lithium provided a better therapeutic effect than CBZ for ouabain-caused dysfunctions of spatial learning in a rat model of bipolar disorder.

Gender differences in the effects of presynaptic and postsynaptic dopamine agonists on latent inhibition in rats.

The present study investigated gender differences in the effects of presynaptic and postsynaptic DA agonists on latent inhibition in the passive avoidance paradigm. During the preexposure phase, 32 male and 32 female Wistar rats were exposed to a passive avoidance box (or a different context) and received drug injections in three trials: the control group received an injection of 10% ascorbic acid in a different context. The experimental groups received injections of 10% ascorbic acid (latent inhibition [LI] group), 1mg/kg of the postsynaptic DA D(1)/D(2) agonist apomorphine (APO group), and 1.5mg/kg of the presynaptic DA agonist methamphetamine (METH group) in a passive avoidance box. All experimental groups were placed in the light compartment of the passive avoidance box and were allowed to enter into the dark compartment to receive a footshock (1mA, 2s) in five trials over 5 days. The latency to enter into the dark compartment was recorded in these five trials. The latent inhibition occurred in the female LI group but not in the male LI group. Regardless of gender, the APO group exhibited an increase in latent inhibition. Male rats in the METH group exhibited a decrease in latent inhibition, but female rats in the METH group exhibited an increase in latent inhibition, indicating that the METH group exhibited sexual dimorphism. The gender factor interacted only with the METH group and not the LI or APO group. The present paper discusses whether gender, the postsynaptic DA D(1)/D(2) agonist APO, and presynaptic DA agonist METH may be related to schizophrenia.

Curcumin inhibits glutamate release in nerve terminals from rat prefrontal cortex: possible relevance to its antidepressant mechanism.

There is abundant evidence suggesting the relevance of glutamate to depression and antidepressant mechanisms. Curcumin, a major active compound of Curcuma longa, has been reported to have the biological function of antidepressant. The aim of the present study was to investigate the effect of curcumin on endogenous glutamate release in nerve terminals of rat prefrontal cortex and the underlying mechanisms. The results showed that curcumin inhibited the release of glutamate that was evoked by exposing synaptosomes to the K(+) channel blocker 4-aminopyridine (4-AP). This phenomenon was blocked by the chelating the extracellular Ca(2+) ions, and by the vesicular transporter inhibitor bafilomycin A1, but was insensitive to the glutamate transporter inhibitor DL-threo-ß-benzyl-oxyaspartate (DL-TBOA). Further experiments demonstrated that curcumin decreased depolarization-induced increase in [Ca(2+)](C), whereas it did not alter the resting membrane potential or 4-AP-mediated depolarization. Furthermore, the inhibitory effect of curcumin on evoked glutamate release was prevented by blocking the Ca(v)2.2 (N-type) and Ca(v)2.1 (P/Q-type) channels, but not by blocking intracellular Ca(2+) release or Na(+)/Ca(2+) exchange. These results suggest that curcumin inhibits evoked glutamate release from rat prefrontocortical synaptosomes by the suppression of presynaptic Ca(v)2.2 and Ca(v)2.1 channels. Additionally, we also found that the inhibitory effect of curcumin on 4-AP-evoked glutamate release was completely abolished by the clinically effective antidepressant fluoxetine. This suggests that curcumin and fluoxetine use a common intracellular mechanism to inhibit glutamate release from rat prefrontal cortex nerve terminals.

Paradoxical simultaneous occurrence of amphetamine-induced conditioned taste aversion and conditioned place preference with the same single drug injection: a new "pre- and post-association" experimental paradigm.

The paradoxical phenomenon of co-existing physically aversive and psychologically rewarding effects of drugs is a crucial issue for drug addiction. The present study employed a new experimental paradigm to test whether the rewarding and aversive properties of amphetamine (AMPH) can exist simultaneously. Rats were given a 15 min period of exposure to saccharin injected with 0.15M NaCl or 1.5mg/kg AMPH and then were confined to one compartment of a test box for 30 min. After three paired and unpaired cycles, the aversive and rewarding effects were assessed. A reduction in consumption of the paired flavored solution provided evidence of avoidance while preference for the AMPH injection context provided evidence of rewarding effects. The present findings demonstrate that the development of AMPH-induced rewarding and aversive effects depends on the particular behavioral conditions and support both the task-dependent drug effects hypothesis and the reward comparison hypothesis. The formation of associations with stimuli that comes before (pre) vs. after (post) the unconditioned stimulus and the role of the dopaminergic system in such associations are discussed.

Effects of single and group housing conditions and alterations in social and physical contexts on amphetamine-induced behavioral sensitization in rats.

Repeated administration of amphetamine (AMPH) can produce behavioral sensitization. However, whether contextual elements and housing conditions influence AMPH-induced behavioral sensitization remains uncertain. This study was designed to examine the effects of housing conditions (single- vs. group-housed) and different contextual changes, including social (with two other co-drug partners) and physical (novel box) context changes, on AMPH-induced behavioral sensitization. During the training phase, all rats were exposed for 7 days to AMPH (1mg/kg, intraperitoneally) in a Locometer chamber, with the exception of animals tested for the effects of physical context changes trained in a novel box. Following a 7-day withdrawal phase, all rats received an AMPH (0.5mg/kg) challenge, and locomotor activity in a Locometer box was recorded before and after AMPH injection during the testing phase. Under group housing conditions, animals exposed to a different physical environment between the training and testing phases or accompanying co-drug partners during the training phase exhibited decreased AMPH-induced locomotor sensitization. In contrast, single housing conditions did not have an inhibitory effect on AMPH-induced behavioral sensitization after manipulations of the physical and social contexts. These results suggest that under group housing conditions, both physical and social context changes can attenuate AMPH-induced behavioral sensitization. The possible neural mechanisms underlying the involvement of different housing conditions in AMPH-induced behavioral sensitization are discussed.

Roles of corticosterone in formalin-induced conditioned place aversion in rats.

Glucocorticoid hormones have been shown to contribute to many cognitive functions, such as depressions, learning and memory, and abnormal glucocorticoid secretion results in functional changes in prefrontal cortex and amygdala. In the present study, we used the conditioned place aversion (CPA) paradigm to investigate the role of corticosterone (CORT) in the negative affective component of chemical somatic pain induced by intraplantar injection of formalin into male adult Long-Evan rats. Five percent of formalin produced acute biphasic nociceptive behaviors, including flinching and licking of hindpaw, and CPA. Intraplantar formalin induced CPA was abolished by bilateral adrenalectomy and the impairment of CPA can be restored by the CORT treatment. However, the adrenalectomy failed to affect the formalin-produced acute nociceptive behaviors. Therefore, data from the present study suggest that CORT secretion by the adrenal cortex may play a role in chemical somatic noxious stimuli-induced avoidance learning and aversive memory, but not sensory discrimination of noxious stimulation.