Xiang Yang Zhang

Antioxidant enzymes and lipid peroxidation in different forms of schizophrenia treated with typical and atypical antipsychotics

There is accumulating evidence of altered antioxidant enzyme activities and increased levels of lipid peroxidation in schizophrenia. Free radical-mediated abnormalities may contribute to specific aspects of schizophrenic symptomatology and complications of its treatment. However, few studies have evaluated both antioxidant enzymes and lipid peroxidation in the same schizophrenic patient groups treated with typical or atypical antipsychotics. Plasma malondialdehyde (MDA) levels and superoxide dismutase (SOD), glutathione peroxidase (GSH-Px) and catalase (CAT) activities were analyzed using established procedures in 92 medicated schizophrenia including paranoid (n=34), disorganized (n=18) and residual subtypes (n=40), as well as in control subjects (n=50). The results showed that activities of SOD and GSH-Px were decreased but levels of MDA were elevated in patients with a chronic form of schizophrenia as compared with normal controls. SOD and GSH-Px activities were found to be significantly lower in paranoid and residual subtypes compared to both disorganized subtype and the control group. MDA levels were significantly higher in all subtypes compared to the control group. There were no significant differences in any parameters measured among all three subgroups treated with clozapine (n=44), risperidone (n=20) and typical antipsychotics (n=28). Additionally, a significantly higher MDA levels, but a significantly lower CAT activity was noted in female than male patients. These results suggest that oxidative stress may be implicated in the pathophysiology of all subtypes of schizophrenia, which may contribute to the increased membrane lipid peroxidation. Long-term treatments with typical and atypical antipsychotics may produce the similar effects on the antioxidant enzymes and lipid peroxidation.

Cortisol and cytokines in chronic and treatment-resistant patients with schizophrenia: Association with psychopathology and response to antipsychotics

The bilateral communication between the immune and neuroendocrine systems plays an essential role in modulating the adequate response of the hypothalamic–pituitary–adrenal (HPA) axis to the stimulatory influence of cytokines and stress-related mediators. Growing evidence suggests that neuro-immune-endocrine crosstalk may be impaired in schizophrenia. We determined the relationship between cortisol, cytokines interleukin-2 (IL-2) and interleukin-6 (IL-6), and symptoms in schizophrenia during treatment with typical and atypical antipsychotic drugs. Subjects included 30 healthy controls (HC) and 78 schizophrenic (SCH) in-patients. SCH were randomly assigned to 12-week treatment with 6 mg/day of risperidone or 20 mg/day of haloperidol using a double-blind design. Clinical efficacy was determined using the Positive and Negative Syndrome Scale (PANSS). Serum cortisol and IL-2 levels were assayed by radioimmunometric assay, and serum IL-6 levels by quantitative enzyme-linked immunosorbent assay. Following a 2-week washout period, serum levels of cortisol, IL-2, and IL-6 were increased in patients with schizophrenia compared to HC. Elevations in cortisol were associated with increase in both IL-2 and IL-6 in SCH. Moreover, elevations in cortisol were associated with negative symptoms and IL-2 with positive symptoms. In all, 12 weeks of risperidone treatment significantly decreased elevated cortisol and improved negative symptoms, but produced similar effects on IL-2 and IL-6 as well as on positive symptoms compared to haloperidol. The improvement of negative symptoms was related to the change in cortisol. Our results suggest that the imbalance in the HPA axis and cytokine system in patients with SCH is implicated in clinical symptoms, and is improved with atypical antipsychotic treatment.

Prazosin, an α-1 Adrenergic Antagonist, Reduces Cocaine-Induced Reinstatement of Drug-Seeking

Background Norepinephrine is implicated in cocaine’s behavioral effects. In this study, we tested the effect of prazosin, an α1-adrenergic receptor antagonist, on cocaine-induced reinstatement of drug-seeking behavior. Methods Rats were trained to self-administer cocaine intravenously under a fixed-ratio 3 schedule of reinforcement. After behavior was established, cocaine was replaced with saline and behavior extinguished. The ability of cocaine (0, 5–20 mg/kg) alone or combined with prazosin (.3 mg/kg) to reinstate lever press responding was tested. The effects of prazosin on lever press responding for food was examined in another set of rats. Results Cocaine induced a dose-dependent reinstatement of drug-seeking behavior that was significantly attenuated by prazosin. This dose of prazosin did not alter lever press response rates for food. Conclusions The attenuation in drug-induced reinstatement is likely not due to prazosin-induced suppression of activity. These results suggest α1-adrenergic mechanisms contribute to reinstatement in rats and perhaps, to relapse in addicts.

Neonatal isolation enhances acquisition of cocaine self-administration and food responding in female rats

We showed previously that neonatal isolation (ISO) enhances acquisition of cocaine self-administration in adult male rats without altering acquisition of food responding. Female rats show poorer performance in learning tasks and are differentially affected by stress compared to male rats. Thus, we investigated whether ISO alters acquisition of operant responding for cocaine and food in female rats with comparison to male rats. Litters were subjected to ISO or were non-handled (NH). Activity levels were assessed in adult rats. Then, rats were implanted with jugular catheters and allowed to self-administer cocaine under a fixed-ratio 1 (FR1) schedule of reinforcement using an escalating dose presentation procedure. Cocaine intake, discrimination of active versus inactive levers, and ineffective active lever responses were tabulated. Effects of non-contingent cocaine infusions (primes) and increasing FR on responding were then assessed. Other rats were allowed to lever press for food under an FR1 schedule (10 s time-out). ISO enhanced acquisition of operant responding for food and cocaine in female rats. The latter was demonstrated by better lever discrimination, emission of fewer ineffective responses, and superior performance in response to primes. Yet, NH females ingested more cocaine than ISO females during the initial acquisition phase. In male rats, ISO enhanced acquisition of cocaine self-administration but not food responding. Activity levels were unaffected by ISO or gender. These data confirm and extend our previous findings demonstrating the enduring effects of ISO on adult self-administration behavior and emphasize the importance of measuring behavioral patterns versus intake in acquisition studies.

Chronic neonatal isolation stress enhances cocaine-induced increases in ventral striatal dopamine levels in rat pups.

Cocaine-induced increases in ventral striatal dopamine levels are enhanced in adult rats previously exposed to chronic stress. In neonatal rats, isolation from dam, nest, and siblings is stressful as evidenced by elevated corticosterone levels, an effect that increases with chronic isolation. Whether chronic neonatal isolation cross-sensitizes to cocaine leading to greater increases in ventral striatal dopamine levels was assessed in this study. Litters were assigned to isolate or non-handled conditions. After culling on postnatal Day 1 (PN1), pups in the neonatal isolation condition were isolated individually for 1 h/day on PN days 2-9 while pups in the non-handled condition were left undisturbed. On PN10, pups were implanted with probes aimed at the ventral striatum. Baseline measures of dopamine and its metabolite, DOPAC, were obtained. Separate groups of male and female pups were then administered 0, 2.5, 5.0, or 10 mg/kg cocaine and samples were collected for 2-h. Isolate pups showed greater cocaine-induced increases in ventral striatal dopamine levels than non-handled pups. However, DOPAC levels did not differ by isolation condition or gender. Neonatal isolation-induced increases in the effects of cocaine on ventral striatal dopamine levels are consistent with our previous study using amphetamine in 10-day-old pups and show that chronic stress sensitizes the dopamine response to psychostimulants in infant rats.

Heightened cocaine and food self-administration in female rats with neonatal isolation experience.

Previously, we demonstrated that the early life stress of neonatal isolation facilitates acquisition of cocaine and food self-administration in adult female rats. We now test whether it enhances responding for these reinforcers after operant performance is established. Adult female rats were derived from litters that were either subjected to neonatal isolation (1 h/day isolation; postnatal days 2–9) or were nonhandled and assigned to one of two experiments. In Experiment 1, female rats well trained to self-administer cocaine were tested under a fixed-ratio 3 (FR3) schedule with several cocaine doses (0.0625–1.0 mg/kg/infusion) and under a progressive-ratio (PR) schedule (0, 0.5, and 1.0 mg/kg/infusion cocaine). In Experiment 2, female rats well trained to respond for food reinforcers under an FR15 schedule were tested under two PR schedules. Results show that neonatal isolation enhanced responding for cocaine under both schedules of reinforcement and increased responding for food under a PR schedule of reinforcement. These data extend our previous acquisition study in female rats to show that neonatal isolation enhances responding under maintenance conditions. These enduring behavioral changes may relate to the ability of neonatal isolation to increase striatal dopamine responses to psychostimulants, effects we showed previously in infant and juvenile rats.

Previous exposure to cocaine enhances cocaine self-administration in an alpha 1-adrenergic receptor dependent manner.

Noradrenergic transmission is implicated in the biochemical and behavioral effects of cocaine. Recently, we demonstrated that the alpha 1-adrenergic receptor antagonist prazosin attenuates cocaine-induced reinstatement of drug-seeking behavior. We now assessed whether prazosin could counter the effect of previous exposure to cocaine to enhance subsequent self-administration behavior. Rats were pre-exposed to systemic injections of either saline, prazosin (0.3 mg/kg), saline+cocaine (10 mg/kg), or prazosin+cocaine for 5 days. Starting 15–18 days after the last pre-exposure injection, rats were trained to self-administer cocaine (0.5 mg/kg/infusion) under a fixed ratio 3 (FR3) schedule of reinforcement. Several tests were conducted. First, responding for cocaine under an FR3 schedule was assessed across several doses (0.125–1.0 mg/kg/infusion). Second, responding for cocaine (0.5 mg/kg/infusion) under a progressive-ratio (PR) schedule was examined for 6 consecutive days. Finally, responding for cocaine (0, 0.5, and 1.0 mg/kg/infusion) was determined under the PR schedule of reinforcement. Results showed that cocaine pre-exposed rats self-administer more cocaine compared to saline pre-exposed rats when tested under both the FR and PR schedules. Rats pre-exposed to cocaine plus prazosin did not show enhanced cocaine self-administration. These rats, as well those pre-exposed to prazosin alone, showed levels of cocaine self-administration similar to saline pre-exposed rats. Thus, previous exposure to cocaine enhanced cocaine self-administration, an effect that appears to involve activation of alpha 1-adrenergic receptors. These data, along with several recent studies, show further support for the contribution of noradrenergic transmission in the behavioral effects of cocaine.

Clozapine Blocks D -Amphetamine-Induced Excitation of Dopamine Neurons in the Ventral Tegmental Area

Current antipsychotic drugs are thought to inhibit central dopamine (DA) transmission by blocking DA receptors. Here, we provide evidence that the atypical antipsychotic drug clozapine may produce part of its effect by inhibiting a subset of excitatory inputs to DA neurons. Thus, in chloral hydrate-anesthetized rats, systemic administration of D-amphetamine produced two opposing effects on DA neurons in the ventral tegmental area. Under control conditions, D-amphetamine inhibited the firing of the cell through D2-like receptors. When D2-like receptors were blocked by raclopride, D-amphetamine excited DA neurons, instead of producing no effect. The excitation, expressed as an increase in firing rate and a slow oscillation in firing pattern, was suppressed by the adrenergic α1 receptor antagonist prazosin, suggesting an involvement of α1 receptors. In rats pretreated with the typical antipsychotic drug haloperidol, D-amphetamine also excited DA neurons. However, when given after clozapine, D-amphetamine produced no significant effects. The failure of D-amphetamine to produce an excitation is not due to an incomplete blockade of D2-like receptors by clozapine because co-treatment with clozapine and raclopride also failed to enable the excitatory effect of D-amphetamine. The suggestion that clozapine inhibits the excitatory effect of D-amphetamine is further supported by the finding that clozapine, given after D-amphetamine, reliably reversed D-amphetamine-induced excitation in raclopride-treated rats. Thus, different from raclopride and haloperidol, clozapine may inhibit DA transmission through two additive mechanisms: blockade of DA receptors and inhibition of an amphetamine-sensitive, excitatory pathway that innervates DA neurons.