Methamphetamine Self-Administration: Neurochemical Consequences and Behavioural Effects

<p>It has been suggested that methamphetamine (MA) self-administration is dependent on dopaminergic mechanisms, and that exposure to high doses of methamphetamine is toxic to central dopamine (DA) and serotonin (5-HT) neurons. Most studies, however, have utilised a short duration, high dose, experimenter-administered MA exposure regime, which is not representative of exposure that results from MA use in humans. The present studies sought to investigate the effects of self-administered MA on brain monoamine levels following a short and longer withdrawal period, and to determine the role of D1- and D2-like receptors in the maintenance of MA self-administration and in relapse to MA-seeking. The effects of self-administered MA (0.1 mg/kg/infusion) on tissue monoamine levels were determined in rats either 24 hours or seven days following 20 daily six hour sessions. A yoked-control self-administration protocol was employed to determine the effects of response contingency. The effect of pre-treatment with the D1-like receptor antagonist, SCH 23390 (0.0; 0.01; 0.02 mg/kg; subcutaneous [SC]), or the D2-like receptor antagonist, eticlopride (0.0; 0.0125; 0.025; 0.05 mg/kg; intraperitoneal [IP]) on MA self-administration reinforced according to a fixed ratio (FR) 1, and progressive ratio (PR; 0.2 mg/kg MA) schedule was determined. The effect of these pharmacological manipulations on relapse to MA-seeking was also determined. Additionally, the role of DA in drug-seeking was examined by measuring the effect of priming injections of the direct D1 receptor agonist, SKF 81297 (0.0; 1.0; 2.0; 4.0 mg/kg; IP), the direct D2 receptor agonist, quinpirole (0.0; 1.0 mg/kg; IP), or the DA transporter (DAT) inhibitor, GBR 12909 (0.0; 1.0; 10.0 mg/kg; IP), on MA-seeking behaviour. Self-administered MA produced a transient decrease in tissue levels of DA and an increase in DA turnover. This effect was produced at 24 hours, but not seven days following the final self-administration session. Similar effects were produced in yoked rats that received the same, non-contingent exposure to MA. Pre-treatment with SCH 23390, but not eticlopride, produced a significant alteration in the dose-response curve of MA self-administration reinforced on an FR1 schedule, and reduced MA produced BPs on the PR schedule. MA-seeking was produced by MA, cocaine and GBR 12909. SCH 23390 pre-treatment significantly reduced drug-primed MA-seeking, whereas eticlopride had no significant effect. Finally, neither SKF 81297, nor quinpirole significantly increased MA-seeking. These findings suggest that self-administered MA does not produce the extensive neurotoxicity seen following high-dose experimenter-administered treatment regimes. The finding that pre-treatment with a D1-, but not a D2-like receptor antagonist altered the maintenance of MA self-administration suggests that neuroadaptations take place as a function of MA self-administration, rendering this behaviour more reliant on D1-like receptor mechanisms. This idea is further supported by the finding that a D1-, but not a D2-like antagonist reduced drug-primed MA-seeking, and that priming injections with a D2 agonist failed to increase MA-seeking behaviour. These results are in contrast to the literature on self-administration and reinstatement of drug-seeking following self-administration of other drugs of abuse, and suggest that dependence on different drugs may become mediated by different DA receptor mechanisms.</p>

Methamphetamine Self-Administration: Neurochemical Consequences and Behavioural Effects

<p>It has been suggested that methamphetamine (MA) self-administration is dependent on dopaminergic mechanisms, and that exposure to high doses of methamphetamine is toxic to central dopamine (DA) and serotonin (5-HT) neurons. Most studies, however, have utilised a short duration, high dose, experimenter-administered MA exposure regime, which is not representative of exposure that results from MA use in humans. The present studies sought to investigate the effects of self-administered MA on brain monoamine levels following a short and longer withdrawal period, and to determine the role of D1- and D2-like receptors in the maintenance of MA self-administration and in relapse to MA-seeking. The effects of self-administered MA (0.1 mg/kg/infusion) on tissue monoamine levels were determined in rats either 24 hours or seven days following 20 daily six hour sessions. A yoked-control self-administration protocol was employed to determine the effects of response contingency. The effect of pre-treatment with the D1-like receptor antagonist, SCH 23390 (0.0; 0.01; 0.02 mg/kg; subcutaneous [SC]), or the D2-like receptor antagonist, eticlopride (0.0; 0.0125; 0.025; 0.05 mg/kg; intraperitoneal [IP]) on MA self-administration reinforced according to a fixed ratio (FR) 1, and progressive ratio (PR; 0.2 mg/kg MA) schedule was determined. The effect of these pharmacological manipulations on relapse to MA-seeking was also determined. Additionally, the role of DA in drug-seeking was examined by measuring the effect of priming injections of the direct D1 receptor agonist, SKF 81297 (0.0; 1.0; 2.0; 4.0 mg/kg; IP), the direct D2 receptor agonist, quinpirole (0.0; 1.0 mg/kg; IP), or the DA transporter (DAT) inhibitor, GBR 12909 (0.0; 1.0; 10.0 mg/kg; IP), on MA-seeking behaviour. Self-administered MA produced a transient decrease in tissue levels of DA and an increase in DA turnover. This effect was produced at 24 hours, but not seven days following the final self-administration session. Similar effects were produced in yoked rats that received the same, non-contingent exposure to MA. Pre-treatment with SCH 23390, but not eticlopride, produced a significant alteration in the dose-response curve of MA self-administration reinforced on an FR1 schedule, and reduced MA produced BPs on the PR schedule. MA-seeking was produced by MA, cocaine and GBR 12909. SCH 23390 pre-treatment significantly reduced drug-primed MA-seeking, whereas eticlopride had no significant effect. Finally, neither SKF 81297, nor quinpirole significantly increased MA-seeking. These findings suggest that self-administered MA does not produce the extensive neurotoxicity seen following high-dose experimenter-administered treatment regimes. The finding that pre-treatment with a D1-, but not a D2-like receptor antagonist altered the maintenance of MA self-administration suggests that neuroadaptations take place as a function of MA self-administration, rendering this behaviour more reliant on D1-like receptor mechanisms. This idea is further supported by the finding that a D1-, but not a D2-like antagonist reduced drug-primed MA-seeking, and that priming injections with a D2 agonist failed to increase MA-seeking behaviour. These results are in contrast to the literature on self-administration and reinstatement of drug-seeking following self-administration of other drugs of abuse, and suggest that dependence on different drugs may become mediated by different DA receptor mechanisms.</p>

Glutathione Deficiency during Early Postnatal Development Causes Schizophrenia-Like Symptoms and a Reduction in BDNF Levels in the Cortex and Hippocampus of Adult Sprague–Dawley Rats

Growing body of evidence points to dysregulation of redox status in the brain as an important factor in the pathogenesis of schizophrenia. The aim of our study was to evaluate the effects of l-buthionine-(S,R)-sulfoximine (BSO), a glutathione (GSH) synthesis inhibitor, and 1-[2-Bis(4-fluorophenyl)methoxy]ethyl]-4-(3-phenylpropyl)piperazine dihydrochloride (GBR 12909), a dopamine reuptake inhibitor, given alone or in combination, to Sprague–Dawley pups during early postnatal development (p5–p16), on the time course of the onset of schizophrenia-like behaviors, and on the expression of brain-derived neurotrophic factor (BDNF) mRNA and its protein in the prefrontal cortex (PFC) and hippocampus (HIP) during adulthood. BSO administered alone decreased the levels of BDNF mRNA and its protein both in the PFC and HIP. Treatment with the combination of BSO + GBR 12909 also decreased BDNF mRNA and its protein in the PFC, but in the HIP, only the level of BDNF protein was decreased. Schizophrenia-like behaviors in rats were assessed at three time points of adolescence (p30, p42–p44, p60–p62) and in early adulthood (p90–p92) using the social interaction test, novel object recognition test, and open field test. Social and cognitive deficits first appeared in the middle adolescence stage and continued to occur into adulthood, both in rats treated with BSO alone or with the BSO + GBR 12909 combination. Behavior corresponding to positive symptoms in humans occurred in the middle adolescence period, only in rats treated with BSO + GBR 12909. Only in the latter group, amphetamine exacerbated the existing positive symptoms in adulthood. Our data show that rats receiving the BSO + GBR 12909 combination in the early postnatal life reproduced virtually all symptoms observed in patients with schizophrenia and, therefore, can be considered a valuable neurodevelopmental model of this disease.

Alterations in the Antioxidant Enzyme Activities in the Neurodevelopmental Rat Model of Schizophrenia Induced by Glutathione Deficiency during Early Postnatal Life

The aim of the present study was to assess the effects of l-buthionine-(S,R)-sulfoximine (BSO), a glutathione (GSH) synthesis inhibitor, and GBR 12909, a dopamine reuptake inhibitor, administered alone or in combination to Sprague-Dawley rats during early postnatal development (p5–p16), on the levels of reactive oxygen species (ROS), lipid peroxidation (LP) and the activities of antioxidant enzymes: superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx) and glutathione disulfide reductase (GR) in peripheral tissues (liver, kidney) and selected brain structures (prefrontal cortex, PFC; hippocampus, HIP; and striatum, STR) of 16-day-old rats. The studied parameters were analyzed with reference to the content of GSH and sulfur amino acids, methionine (Met) and cysteine (Cys) described in our previous study. This analysis showed that treatment with a BSO + GBR 12909 combination caused significant decreases in the lipid peroxidation levels in the PFC and HIP, in spite of there being no changes in ROS. The reduction of lipid peroxidation indicates a weakening of the oxidative power of the cells, and a shift in balance in favor of reducing processes. Such changes in cellular redox signaling in the PFC and HIP during early postnatal development may result in functional changes in adulthood.

Glutathione Deficiency and Alterations in the Sulfur Amino Acid Homeostasis during Early Postnatal Development as Potential Triggering Factors for Schizophrenia-Like Behavior in Adult Rats

Impaired glutathione (GSH) synthesis and dopaminergic transmission are important factors in the pathophysiology of schizophrenia. Our research aimed to assess the effects of l-buthionine-(S,R)-sulfoximine (BSO), a GSH synthesis inhibitor, and GBR 12909, a dopamine reuptake inhibitor, administered alone or in combination, to Sprague–Dawley rats during early postnatal development (p5–p16), on the levels of GSH, sulfur amino acids, global DNA methylation, and schizophrenia-like behavior. GSH, methionine (Met), homocysteine (Hcy), and cysteine (Cys) contents were determined in the liver, kidney, and in the prefrontal cortex (PFC) and hippocampus (HIP) of 16-day-old rats. DNA methylation in the PFC and HIP and schizophrenia-like behavior were assessed in adulthood (p90–p93). BSO caused the tissue-dependent decreases in GSH content and alterations in Met, Hcy, and Cys levels in the peripheral tissues and in the PFC and HIP. The changes in these parameters were accompanied by alterations in the global DNA methylation in the studied brain structures. Parallel to changes in the global DNA methylation, deficits in the social behaviors and cognitive functions were observed in adulthood. Only BSO + GBR 12909-treated rats exhibited behavioral alterations resembling positive symptoms in schizophrenia patients. Our results suggest the usefulness of this neurodevelopmental model for research on the pathomechanism of schizophrenia.