The escalation of drug intake observed with extended access is produced at multiple doses of methamphetamine. The rapidity of escalation depends on the dose. Ultimately, all doses in the dose-response study engendered self-administration of the same amount of total drug in a 6-h session in the extended-access group. Results suggest that the rapidity of escalation is dependent on dose and has an upper limit of intake over a period of 21 days.

Aspects of drug withdrawal may become conditioned to previously neutral environmental stimuli via classical conditioning processes. Nevertheless, the significance of conditioned withdrawal effects in motivating drug intake remains largely unexplored. Here, we investigated the effects of conditioned withdrawal in modulating heroin consumption and brain reward sensitivity in rats. Rats intravenously self-administered heroin (20 g/infusion) during 0 h (control), 1 h (nondependent), or 23 h (dependent) sessions and had daily intracranial self-stimulation (ICSS) thresholds assessed. ICSS thresholds remained stable and unaltered in control rats. In nondependent rats, heroin self-administration induced a transient activation of reward systems, reflected in lowering of ICSS thresholds. In dependent rats, heroin intake escalated across sessions and was associated with a gradual decrease in reward sensitivity, reflected in progressively elevated ICSS thresholds. Thus, as dependence develops, heroin may be consumed not only for its acute reward-facilitating effects, but also to counter persistent deficits in reward sensitivity. In nondependent rats, the opioid receptor antagonist naloxone (30 g/kg) increased heroin consumption and reversed heroin-induced lowering of ICSS thresholds, effects resistant to classical conditioning. In contrast, in dependent rats naloxone (30 g/kg) increased heroin consumption and also elevated ICSS thresholds above their already elevated baseline levels (i.e., precipitated withdrawal). Most importantly, stimuli repeatedly paired with naloxone-precipitated withdrawal provoked heroin consumption and elevated ICSS thresholds in dependent rats. Thus, conditioned stimuli predicting the onset of heroin withdrawal, and hence the reward deficits coupled with this state, may play a critical role in provoking craving and relapse in human opiate addicts.

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N-myc downstream-regulated gene 2 (Ndrg2) is a differentiation-and stress-associated molecule predominantly expressed in astrocytes in the central nervous system (CNS). To study the expression and possible role of Ndrg2 in quiescent and activated astrocytes, mice were administrated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropypridine (MPTP), a Parkinson disease (PD)-related neurotoxin which causes both neurodegeneration and glial activation.Immunohistological analysis revealed that Ndrg2 was highly expressed in both types of astrocytes, but less so in astrocytes during the early process of activation. Ndrg2 was also expressed in astrocyte-like cells, but not in neurons, in human brains from PD and

Methamphetamine (METH) has been shown to induce neurotoxicity. In a previous human study using quantitative Western blotting and radioligand binding assay, dopaminergic terminal marker deficits were induced in chronic METH users. In this study, we examined the suitability of the immunohistochemical detection of tyrosine hydroxylase (TH), dopamine transporter (DAT), and vesicular monoamine transporter-2 (VMAT2) levels, and caspase-3 activation in the striatum to diagnose METH abuse. Decreases in TH immunoreactivity in the nucleus accumbens and DAT in the nucleus accumbens and putamen were induced in METH users, whereas a significant difference of VMAT2 was not evident between METH and control groups. However, in the nucleus accumbens of two METH users, levels of VMAT2, a stable marker of striatal dopaminergic terminal integrity, were reduced remarkably. These findings might indicate that dopaminergic terminal degeneration is induced in the striatum of some METH abusers. On the other hand, we observed little caspase-3 activation, indicative of apoptosis, in the striatal neurons of chronic METH users. Overall, the findings of dopaminergic terminal markers were similar to those in the previous human study. Therefore, it is suggested that immunohistochemical techniques could be used to examine dopaminergic terminal marker levels and could also give useful information on chronic and/or lethal METH use in cases of METH-related death, where METH intoxication may not be toxicologically demonstrated.

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A neuropathological study of 41 forensic autopsy cases of hypoxic/ischemic brain damage has been undertaken, using immunohistochemical staining to detect the 70-kDa heat shock protein (hsp70) and the status of the glial cells. In cases surviving 2-5 h after hypoxic/ischemic injury, ischemic cell changes were seen whereas glial reactions were not apparent. In cases of longer survival, neuronal necrosis and a loss of neurons were seen, and these changes were accompanied by proliferation of glial fibrillary acidic protein (GFAP), vimentin-positive astrocytes and microglia which transformed into rod cells or lipid-laden macrophages. In cases with a history of hypoxic attacks, GFAP-positive and vimentin-negative astrocytes had proliferated in the CA3 and CA4 regions of hippocampus. The cases of severe hypoxic injury, such as an asthmatic attack and choking, showed no ischemic changes in the hippocampal neurons. On the other hand, the CA1 pyramidal cells showed neuronal necrosis in a patient suffering from tetralogy of Fallot (TOF), who survived for 2 h after a traffic accident. Therefore, it is suggested that even moderate hypoxic injury induces astrocytosis in the CA3 and CA4 regions and may affect the neuronal proteins and the metabolism, and that in cases with a history of hypoxic attacks neuronal damage may be severe even several hours after ischemic injury. The protein hsp70 expression was found in the CA2, CA3 and CA4 regions in cases of long-term survival after severe hypoxic/ischemic injury and in cases of alcoholic intake or toluene abuse just before acute death.(ABSTRACT TRUNCATED AT 250 WORDS)