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This report investigates the effect of the negative enantiomer of 1-hydroxy-3-aminopyrrolidone-2 (HA-966) on behavioral and biochemical changes elicited by pharmacological or experimental paradigms which activate mesocorticolimbic dopaminergic neurotransmission. Several paradigms were used, including cocaine sensitization and two stressors: restraint for 30 min and an aversive conditioning model. (S)-(-)-HA-966 (3 and 5 mg/kg i.p.) prevented restraint stress-induced dopamine utilization in both the medial prefrontal cortex and nucleus accumbens, in contrast to the positive enantiomer. Conditioned fear increased dopamine metabolism in both the core and shell subdivisions of the nucleus accumbens, an effect blocked by (S)-(-)-HA-966. The conditioned stress-induced increase in dopamine metabolism in the medial prefrontal cortex was also blocked by (S)-(-)-HA-966. In addition, (S)-(-)-HA-966 suppressed fear-induced behaviors: immobility and defecation. In other studies, (S)-(-)-HA-966 (3 mg/kg i.p.) prevented locomotor sensitization without altering the acute motoric response elicited by cocaine. The highest dose of (S)-(-)-HA-966 (5 mg/kg i.p.) blocked acute cocaine-induced locomotion but resulted in sedation. In addition, the highest dose of (S)-(-)-HA-966 tested suppressed weight gain in control rats, unlike its enantiomer, (R)-(+)-HA-966. Because (S)-(-)-HA-966 has been proposed to act at the gamma-aminobutyric acid (GABA)B receptor, we examined the ability of (S)-(-) and (R)-(+)-HA-966 to displace [3H]-(-)-baclofen from cortical membranes to assess GABAB receptor binding. Neither enantiomer significantly altered [3H]-(-)-baclofen binding at relevant concentrations, indicating the actions of (S)-(-)-HA-966 reported here are the results of a mechanism apparently independent of the baclofen binding site on the GABAB receptor.

Previous work has shown that c-Fos and several Fos-like proteins or Fras (Fos-related antigens) are induced acutely in brain in response to a wide variety of stimuli. In contrast, several stimuli induce apparently distinct Fos-like proteins, termed chronic Fras, after chronic administration. We show that delta FosB, a truncated splice variant of FosB, responds like the other acute Fras: it is induced rapidly and transiently in cerebral cortex after acute electroconvulsive seizure (ECS) and in striatum after acute cocaine but does not accumulate after chronic ECS or cocaine treatment. Although the chronic Fras are immunochemically related to delta FosB, they can be distinguished from delta FosB based on their temporal properties in that they are induced after chronic ECS and cocaine treatments only. Moreover, the chronic Fras and delta FosB can be distinguished by their migration patterns on one- and two-dimensional gel electrophoresis. The chronic Fras, therefore, appear to be novel FosB-related proteins. We also provide evidence that the chronic Fras heterodimerize primarily with Jun-D and Jun-B, as opposed to c-Jun. The possibility that AP-1 complexes containing the chronic Fras function as negative regulators of AP-1 mediated transcription is discussed.

Previous studies have shown that repeated exposure to cocaine or to several other stimuli induces novel 35-37 kDa Fos-related antigens (chronic Fras) in specific brain regions. Induction of these proteins is associated with prolonged increases in AP-1 DNA binding activity that parallel the long half-life of the chronic Fras in brain. In the current study, we characterized regulation of the chronic Fras in response to prolonged exposure to morphine. After 5 days of morphine treatment, we observed increased levels of the chronic Fras and of AP-1 binding activity in rat striatum and nucleus accumbens, effects that were not seen in most other brain regions that we studied. Concomitant administration of naltrexone, an opioid receptor antagonist, prevented the induction of these proteins. Two-dimensional gel analysis showed that the chronic Fras induced by chronic morphine administration are identical to those induced after chronic cocaine and other treatments. A time course study indicated that chronic Fra induction was first apparent after 3 days of morphine treatment and peaked between 5 and 7 days of treatment in both the striatum and nucleus accumbens. Withdrawal studies demonstrated robust induction of several known acute Fras, including c-Fos, FosB, Fra-1, Fra-2, and delta FosB, at 6 hr after naltrexone precipitation of withdrawal in the striatum, nucleus accumbens, and several other brain regions. Levels of these proteins returned to basal values by 72 hr. In contrast, no further induction of the chronic Fras was evident after 6 hr of withdrawal in the striatum and nucleus accumbens, but levels of the proteins increased beyond their already elevated chronic morphine values after longer periods (72 hr) of withdrawal, even though physical withdrawal symptoms had resolved at this time point. Chronic Fras were also induced after these prolonged withdrawal periods in several other brain regions, where the proteins were not induced by chronic morphine alone. We discuss the possible roles played by the chronic Fras in the adaptive responses of the brain to chronic opiate exposure and opiate withdrawal.

Previous work has demonstrated that chronic administration of cocaine induces apparently novel Fos-like transcription factors, termed chronic Fras (Fos-related antigens), in the rat striatum and nucleus accumbens. Induction of these proteins is associated with prolonged increases in AP-1 DNA binding activity that parallel the long half-life of the chronic Fras in brain. The goal of the present study was to characterize pharmacologically the regulation of chronic Fra induction by cocaine. Chronic Fra induction was examined with respect to the cocaine dose, time course and administration intervals used. Cocaine was found to induce the chronic Fras over widely differing treatment regimens in the striatum and nucleus accumbens, although clear differences between the two brain regions were observed. In general, maximal induction occurred with moderate treatment conditions, with more or less intensive treatments resulting in lower levels of chronic Fras. The pharmacological mechanisms underlying cocaine induction of the chronic Fras were also investigated. Pretreatment with a D1 receptor antagonist, which did not affect chronic Fra levels by itself, attenuated cocaine induction of the chronic Fras in striatum and nucleus accumbens. In contrast, treatment with a D2 receptor antagonist alone greatly induced chronic Fra levels, with no further increase seen in response to combined treatment with cocaine. Combined treatment with D1 and D2 receptor agonists, or with amphetamine, led to a strong induction of chronic Fras. Similarly, repeated treatment with a specific dopamine transporter inhibitor increased chronic Fra levels, whereas treatment with a specific serotonin or norepinephrine transporter inhibitor failed to produce this effect. These results support an important role for dopaminergic neurotransmission in the induction of chronic Fras by cocaine. Taken together, the results of the present study provide a more complete understanding of the pharmacological properties underlying cocaine regulation of the chronic Fras, which will assist in identifying the functional role played by these proteins in cocaine action.

Developmental exposure to cocaine is associated with cardiovascular abnormalities as well as neurobehavioral disturbances. Because of the profound influence of cocaine on noradrenergic neurotransmission, we examined its acute effects on norepinephrine release from cardiac nerve terminals in the neonatal rat, as assessed by turnover measurements. Cocaine reduced norepinephrine turnover at all ages studied, but with an apparent transition in the mechanism of action related to the development of central control of sympathetic tone. At 1 day of age, before the establishment of functional connections between the central nervous system and sympathetic neurons, cocaine acted primarily through blockade of norepinephrine reuptake and consequent activation of alpha-2 adrenergic autoreceptors that inhibit transmitter release. Accordingly, its effects were shared by the uptake inhibitor, desmethylimipramine and the alpha-2 agonist, clonidine, but not by drugs whose actions depend upon sympathetic activity or high tonic release of transmitter (yohimbine, pargyline or chlorisondamine). By 21 days, when neuronal activity is under dynamic control by the central nervous system, cocaine was still effective in shutting off norepinephrine release, but the effect was no longer dependent upon blockade of reuptake; desmethylimipramine did not reduce turnover at this age, but clonidine, pargyline and chlorisondamine did. Yohimbine evoked a profound increase in turnover by 21 days.(ABSTRACT TRUNCATED AT 250 WORDS)

This paper outlines yield improvements in the integration of damascene copper in low-k SiCOH intermetal dielectric at 65 nm dimensions. Large defect reductions were seen by RIE, wet cleans and CMP process optimization. RIE improvements led to reductions of thirty three percent for missing pattern defects while wet clean optimization resulted in more than a fifty percent reduction in metal voids. CMP carrier head changes provided a more corrosion resistant process and higher throughput. Additionally, a high performance M1 module that maintained process window for all sectors was developed.