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Spin transfer torque (STT) switching realized using a magnetic tunnel junction (MTJ) device has shown great potential for low power and non-volatile storage. A prime application of MTJs is in building non-volatile look up tables (LUT) used in reconfigurable logic. Such LUTs use a hybrid integration of CMOS transistors and MTJ devices. This paper discusses the reliability of STT based LUTs under transistor and MTJ variations in nano-scale. The sources of process variations include both the CMOS device related variations and the MTJ variations. A key part of the STT based LUTs is the sense amplifier needed for reading out the MTJ state. We compare the voltage and current based sensing schemes in terms of the power, performance, and reliability metrics. Based on our simulation results in a 16 nm bulk CMOS, for the same total device area, the voltage sensing scheme offers 17% to 28% lower failure rates under combined intra-die transistor and MTJ variations, comparable delay, and 56% lower active power compared to the current sensing scheme. Moreover, we compare the reliability of the two sensing schemes under negative bias temperature instability (NBTI) of PMOS transistors. Our results indicate that the failures rates increase over time by transistor aging for both designs, and the voltage sensing scheme maintains its improved failure rate over to the current sensing scheme. [ABSTRACT FROM AUTHOR]

Abstract: Leakage power has grown significantly and is a major challenge in SoC design. Among SoC''s components, clock distribution network power accounts for a large portion of chip power. This paper proposes to deploy sleep transistor insertion (STI) in the clock tree of datapaths in ASICs or in general-purpose processors in order to reduce leakage power. It characterizes the effect of sleep transistor sharing and sizing on clock tree wakeup time, leakage power, and propagation delay. It then uses these characteristics during leakage power optimization. It describes a post synthesis sleep transistor insertion (PSSTI), a heuristic clustering algorithm for sleep transistor insertion with the objective of total power minimization in a given clock tree. Sleep transistor sharing and sizing are deployed in order to meet the clock skew and wakeup delay constraints. The potential benefits of STI in ASIC design are evaluated using a standard industrial VLSI-CAD flow including sleep-transistor insertion and routing after the clock synthesis and place-and-route of the benchmark circuits. The results show that the clock tree leakage power is reduced by 19–32% depending on the topology of the synthesized clock tree. We also apply PSSTI in the clock tree of the datapaths in general-purpose processors using architectural control of the sleep mode. This achieves a reduction in the leakage power and the dynamic power of the clock tree within different datapath components (adder, multiplier, etc.) of as much as 80%. This approach is also applicable to other on-chip structure where inverters are large in size and commonly used, e.g. SRAMs or networks-on-a-chip, which combined with the clock tree savings will significantly reduce processor or ASIC overall power consumption. [Copyright &y& Elsevier]

Background: Several lines of evidence suggest that N-methyl-d-aspartate (NMDA) receptor hypofunction may be associated with schizophrenia. Activation of metabotropic glutamate 5 (mGlu5) receptors enhances NMDA receptor mediated currents in vitro, implying that allosteric modulation of mGlu5 receptors may have therapeutic efficacy for schizophrenia. The aim of this study was to determine if positive allosteric modulators of mGlu5 receptors are effective in reversing two cellular effects of NMDA receptor antagonists that are relevant to schizophrenia: increases in corticolimbic dopamine neurotransmission and disruption of neuronal activity in the prefrontal cortex (PFC). Methods: In freely moving rats, we measured the effects of the positive modulator of mGlu5 receptor 3-cyano-N-(1,3-diphenyl-1H-pyrazol-5-yl)benzamide (CDPPB) alone or in combination with the NMDA antagonist MK801 on 1) spontaneous firing and bursting of medial PFC (mPFC) neurons, and 2) dopamine release as measured by microdialysis in the mPFC and nucleus accumbens (NAc). Results: The predominant effect of CDPPB on mPFC neurons was excitatory, leading to an overall excitatory population response. Pretreatment with CDPPB prevented MK801-induced excessive firing and reduced spontaneous bursting. In contrast, CDPPB had no significant effect on basal dopamine release as compared with control rats and did not alter MK801-induced activation of dopamine release in the mPFC and NAc. Conclusions: These results show that positive modulation of mGlu5 receptors reverses the effects of noncompetitive NMDA antagonists on cortical neuronal firing without affecting dopamine neurotransmission. Thus, these compounds may be effective in ameliorating PFC mediated behavioral abnormalities that results from NMDA receptor hypofunction. [Copyright &y& Elsevier]

Background: Mechanisms underlying clozapine’s better clinical efficacy in schizophrenia remain poorly understood. The prefrontal cortex (PFC) has been implicated as a primary site for the therapeutic effects of clozapine; however, evidence for how clozapine influences the activity of PFC neurons in behaviorally relevant contexts is lacking. Methods: Ensemble single unit recording in awake rats was used to measure the activity of PFC neurons in response to clozapine, its main metabolite N-desmethylclozapine (DMClz), and the typical antipsychotic drug haloperidol during baseline conditions and after treatment with the N-methyl-D-aspartate antagonist MK801. Behavioral stereotypy was scored during recording. Results: Clozapine and DMClz but not haloperidol had an activity-dependent influence on spontaneous firing rate of PFC cells: they increased the activity of neurons with low baseline firing rates and decreased the activity of neurons with higher firing rates. Clozapine and DMClz but not haloperidol also reversed the effect of MK801 on PFC neuronal firing. This reversal was strongly correlated with blockade of MK801-induced behavioral stereotypy. Conclusions: These findings indicate that clozapine has the capacity to fine-tune spontaneous and disrupted activity of PFC neurons. This effect might contribute, in part, to the therapeutic efficacy of clozapine in schizophrenia. [Copyright &y& Elsevier]

Recent evidence suggest that endogenous cholecystokinin (CCK) has important roles in central responses to stress. CCK receptors are known as functional modulators of opioidergic system with a tonic antiopioid effect in nociceptive pathways. In contrast, CCK receptor ligands are known to induce anticonvulsant effects similar to endogenous opioids. It is not clear whether endogenous CCK may play a role in the anticonvulsant effects of stress, especially in those stressful paradigms that are associated with strong activation of opioid pathways. The present study examined the role of endogenous CCK receptors in acute stress-induced modulation of seizure (clonic seizures induced by pentylenetetrazole) and nociception (tail-flick) thresholds. Acute restraint stress (for 2 h) and prolonged intermittent footshock stress (30 min) both induced opioid-dependent anticonvulsant and antinociceptive effects. While CCK receptor antagonist proglumide (10, 20, or 40 mg/kg) had no effect on seizure or nociception threshold by itself, it inhibited the anticonvulsant effects of both these types of stress while potentiating their antinociceptive effects. Moreover, proglumide exerted a similar inhibition of the anticonvulsant effect and potentiation of the antinociceptive effect of acute morphine at 1 mg/kg. In contrast, brief and continuos footshock stress (3 min) that induced a nonopioid type of antinociception did not increase the seizure threshold. Proglumide pretreatment did not alter any of these effects of brief footshock stress paradigm. The present data suggest that CCK receptors specifically and differentially modulate the opioid-mediated anticonvulsant and antinociceptive effects of acute stress. [Copyright &y& Elsevier]

The effect of agmatine, an endogenous polyamine metabolite, on seizure susceptibility was investigated in mice. Acute intraperitoneal administration of agmatine (5, 10, 20, 40 mg/kg) had a significant and dose-dependent inhibitory effect on pentylenetetrazole (PTZ)-induced seizures. The peak of this anticonvulsant effect was 45 min after agmatine administration. We further investigated the possible involvement of the α2-adrenoceptors and l-arginine/NO pathway in this effect of agmatine. The α2-adrenoceptor antagonist, yohimbine (0.5–2 mg/kg), induced a dose-dependent blockade of the anticonvulsant effect of agmatine. The nitric oxide synthase (NOS) substrate, l-arginine (60 mg/kg), inhibited the anticonvulsant property of agmatine and this effect was significantly reversed by NOS inhibitor NG-nitro-l-arginine (l-NAME, 30 mg/kg), implying an NO-dependent mechanism for l-arginine effect. We further examined a possible additive effect between agmatine (1 or 5 mg/kg) and l-NAME (10 mg/kg). The combination of l-NAME (10 mg/kg) with agmatine (5 but not 1 mg/kg) induced a significantly higher level of seizure protection as compared with each drug alone. Moreover, a combination of lower doses of yohimbine (0.5 mg/kg) and l-arginine (30 mg/kg) also significantly decreased the anticonvulsant effect of agmatine. In conclusion, the present data suggest that agmatine may be of potential use in seizure treatment. [Copyright &y& Elsevier]

Different kinds of stress induce distinct antinociceptive properties that may be related or unrelated to the endogenous opioid system. Nitric oxide (NO) has been implicated in stress-activated mechanisms. NO also plays an important role in the modulation of nociceptive responses and has many functional interactions with opioidergic pathways. The present study examined the role of NO in two distinct opioid-mediated and nonopioid types of antinociception induced by footshock stress and assessed by the tail flick latency in mice. Brief and continuous footshock (3 min) induced a naloxone-insensitive antinociception that was not altered by either l-NAME (10 mg/kg), aminoguanidine (100 mg/kg) or l-arginine (60 mg/kg). In contrast, prolonged and intermittent footshock (30 min) induced a naloxone-reversible antinociceptive effect that was blocked by l-NAME (2–10 mg/kg) but not by aminoguanidine (100 mg/kg). l-Arginine (20 and 60 mg/kg) also did not alter this type of antinociception. Morphine (1 mg/kg) induced a mild antinociceptive effect in nonstressed animals that was potentiated by l-NAME (2 mg/kg) but not affected by aminoguanidine (100 mg/kg). The same dose of morphine increased the antinociceptive effect of prolonged and intermittent footshock but this increase was inhibited by l-NAME (2 mg/kg) but not by aminoguanidine. In conclusion, NO of constitutive origin is selectively involved in an opioid-mediated type of footshock stress antinociception in mice. [Copyright &y& Elsevier]

Nitric oxide (NO) and morphine have been coupled in many physiological as well as pathological processes. The present study examined the involvement of the l-arginine/NO pathway in the anticonvulsant properties of systemic morphine (2–30 mg/kg) against electroshock seizures (ECS) in mice. Morphine decreased the intensity of maximal electroshock seizures (MES) and increased the threshold for ECS. Neither the NOS substrate l-arginine (30, 60, and 100 mg/kg), the reversible nonspecific NOS inhibitor NG-nitro-l-arginine methyl ester (l-NAME; 3, 10, and 30 mg/kg), the irreversible specific inducible NOS inhibitor aminoguanidine (20, 50, and 100 mg/kg), nor the opioid receptor antagonist naloxone (0.1, 0.3, and 1 mg/kg) did alter per se the ECS threshold or the intensity of MES at doses used. However, both naloxone and l-NAME, but not aminoguanidine, inhibited the anticonvulsant effects of morphine (30 mg/kg) against ECS, while l-arginine potentiated the anticonvulsant effects of lower doses of morphine (2 or 10 mg/kg). Low doses of naloxone (0.1 or 0.3 mg/kg) or l-NAME (3 mg/kg), which did not alter morphine effect per se, showed additive anticonvulsant effects against MES. Thus, the l-arginine/NO pathway seems to play a role in the anticonvulsant properties of morphine against ECS and this mediation involves the constitutive, but not the inducible, form of nitric oxide synthase. [Copyright &y& Elsevier]

Cyclosporin A is known to decrease nitric oxide (NO) production in nervous tissues. The effects of systemic cyclosporine A on the induction and expression of morphine tolerance and dependence, acute morphine-induced antinociception, and the probable involvement of the l-arginine/nitric oxide pathway in these effects were assessed in mice. Cyclosporin A (20 mg/kg), NG-nitro-l-arginine methyl ester (l-NAME) (10 mg/kg) and a combination of the two at lower and per se non-effective doses (5 and 3 mg/kg, respectively) showed a similar pattern of action, inhibiting the induction of tolerance to morphine-induced antinociception and increasing the antinociception threshold in the expression phase of morphine tolerance. These agents also inhibited the expression of morphine dependence as assessed by naloxone-precipitated withdrawal signs, while having no effect on the induction of morphine dependence. l-Arginine, at a per se non-effective dose (60 mg/kg), inhibited the effects of Cyclosporin A. Moreover, acute administration of Cyclosporin A (20 mg/kg) or l-NAME (10 mg/kg) enhanced the antinociception induced by acute administration of morphine (5 mg/kg), while chronic pretreatment with Cyclosporin A (20 mg/kg) or l-NAME (10 mg/kg) for 2 days (twice daily) did not affect morphine-induced antinociception. The inducible nitric oxide synthase inhibitor, aminoguanidine (100 mg/kg), did not alter morphine antinociception, tolerance or dependence. In conclusion, decreasing NO production through constitutive nitric oxide synthase may be a mechanism through which cyclosporin A differentially modulates mophine tolerance, dependence and antinociception. [Copyright &y& Elsevier]

Cyclosporin A (CsA) is known to decrease nitric oxide (NO) release in the nervous system. The present study was aimed at investigating the effects of acute administration of CsA on pentylenetetrazole (PTZ)-induced seizure threshold and latency and probable modulation of these effects by NO synthesis substrate l-arginine, and NO synthesis inhibitors NG-nitro-l-arginine methyl ester (l-NAME) or aminoguanidine. Moreover, the effect of CsA per se or concomitant with l-arginine on the development of PTZ-induced kindling was assessed. CsA (0.05, 1, 5, 10 and 20 mg/kg, s.c.) dose-dependently increased PTZ-induced clonic seizure threshold and the latency for onset of myoclonic jerks, clonic seizures and clonic–tonic generalized seizures following PTZ administration. l-NAME (10 and 30 mg/kg, i.p.) but not aminoguanidine (50 and 100 mg/kg, i.p.) potentiated the anticonvulsant effects of CsA (1 and 10 mg/kg). l-arginine (60, 100 and 200 mg/kg, i.p.) inhibited the anticonvulsant effects of CsA (20 mg/kg) in a dose-related manner. The inhibitory effect of l-arginine on CsA-induced alterations of seizure threshold and latency was blocked by l-NAME but not with aminoguanidine. CsA (20 mg/kg) significantly inhibited the development of PTZ kindling and decreased the seizure intensity as tested by a challenge dose of PTZ. Pretreatment with l-arginine (60 mg/kg) reversed the inhibitory effects of CsA on kindling development. It was concluded that CsA exerts some anticonvulsant properties that may be due to its inhibition of nitric oxide synthesis. [Copyright &y& Elsevier]

Cyclosporin A (CsA) and other immunophilin-binding agents are known to inactivate neuronal nitric oxide synthase (nNOS). Nitric oxide (NO) is involved in the nociception at the spinal level. We evaluated the effect of acute intraperitoneal (ip) administration of CsA on the tail-flick response in mice and the involvement of NO and opioid receptors in this effect. CsA (5, 10, 20 and 50 mg/kg ip) induced a significant increase in tail-flick response. Nitric oxide synthase (NOS) inhibitor NG-nitro-l-arginine (LNNA; 10, 40 and 80 mg/kg ip) significantly potentiated the CsA-induced (5 mg/kg) increase in tail-flick latency (TFL). While NOS substrate l-arginine (100, 200, 400 mg/kg ip) inhibited the CsA-induced (20 mg/kg) antinociception completely and in a dose-dependent manner. Concomitant administration of l-NNA and l-arginine blocked the inhibition exerted by the latter on the CsA-induced antinociception. The opioid receptor antagonist naloxone (4 mg/kg ip) did not alter the CsA effect. These results indicate that acute administration of CsA induces an antinociceptive effect that involves the l-arginine–NO pathway but is not mediated by opioid receptors. [Copyright &y& Elsevier]

The involvement of nitric oxide (NO) in modulation of seizure susceptibility by δ-opioid agonist (+)-4-((alpha R)-alpha-((2S, 5R)-4-allyl-2, 5-dimethyl-1-piperazinyl)-3-methoxybenzyl)-N, N-diethyl-benzamide (SNC80) was examined in mice. Systemic administration of SNC80 (0.1–5 mg/kg, intraperitoneally (i.p.)) decreased the threshold for clonic seizures induced by pentylenetetrazole. The non-specific NO synthase (NOS) inhibitor, NG-nitro-l-arginine methyl ester (3–20 mg/kg, i.p.), but not the specific inducible NOS inhibitor, aminoguanidine (50 and 100 mg/kg, i.p.) inhibited the proconvulsant effect of SNC80. On the other hand, NO substrate, l-arginine (30 and 60 mg/kg, i.p.) potentiated the proconvulsant effect of a lower dose of SNC80 (0.5 mg/kg). These results support the involvement of NO, produced by constitutive NOS, in the proconvulsant effect of the δ-opioid agonist. [Copyright &y& Elsevier]

Lithium has been reported to inhibit opioid-induced properties. The present study examined the effect of acute and chronic administration of lithium chloride (LiCl) on morphine''s biphasic modulation of susceptibility to pentylenetetrazole (PTZ)-induced clonic seizure in mice. We also examined the possible involvement of nitric oxide (NO) pathway in lithium effect. Both acute (0.1 and 1 mg/kg) and chronic (same doses, 21 consecutive days) administration of LiCl completely inhibited the anticonvulsant and proconvulsant effects of morphine (at doses 1 and 30 mg/kg, respectively). A very low and per se noneffective dose of LiCl (0.05 mg/kg) significantly inhibited both phases of morphine effect when administered concomitant with a noneffective low dose of naloxone (0.1 mg/kg). The NO synthase inhibitor NG-nitro-l-arginine methyl ester (L-NAME) at a per se noneffective dose of 0.3 mg/kg potentiated the inhibitory effects of low doses of LiCl (0.01 and 0.05 mg/kg) on both phases of morphine effect. l-arginine, a NO synthase substrate, at a per se noneffective dose of 30 mg/kg reversed the inhibitory effects of lithium (1 mg/kg). Lithium is capable of antagonizing both modulatory effects of morphine on seizure susceptibility even at relatively low doses. These inhibitory effects of lithium may also involve NO synthesis. [Copyright &y& Elsevier]

Cannabinoid and opioid receptor agonists show functional interactions in a number of their physiological effects. Regarding the seizure-modulating properties of both classes of receptors, the present study examined the possibility of a functional interaction between these receptors. We used acute systemic administration of cannabinoid selective CB1 receptor agonist (ACPA) and antagonist (AM251) and opioid receptor agonist (morphine) and antagonists (naltrexone and norbinaltorphimine) in a model of clonic seizure induced by pentylenetetrazole (PTZ). Acute administration of ACPA (1.5–2 mg/kg) increased the PTZ-induced seizure threshold. In contrast, AM251 (0.5–2 mg/kg) dose-dependently decreased the seizure threshold. Low dose of AM251 (0.5 mg/kg), which did not alter seizure threshold by itself, reversed the anticonvulsant effect of ACPA (2 mg/kg), showing a CB1 receptor-mediated mechanism. Naltrexone (1 or 10 mg/kg) but not specific κ-opioid receptor antagonist norbinaltorphimine (5 mg/kg) completely reversed the anticonvulsant effect of ACPA (2 mg/kg). Moreover, the combination of the lower doses of AM251 (0.5 mg/kg) and naltrexone (0.3 mg/kg) had an additive effect in blocking the anticonvulsant effect of ACPA. In accordance with previous reports, morphine exerted biphasic effects on clonic seizure threshold with anticonvulsant effect at lower (0.5–1 mg/kg) and proconvulsant effect at a higher (30 mg/kg) doses. The pretreatment with AM251 blocked the anticonvulsant effect of morphine at 1 mg/kg, while pretreatment with ACPA (1 mg/kg) potentiated the anticonvulsant effect of morphine at 0.5 mg/kg. The proconvulsant effect of morphine at 30 mg/kg was also inhibited by AM251 (2 mg/kg). A similar interaction between cannabinoids and opioids was also detected on their anticonvulsant effects against the generalized tonic–clonic model of seizure. In conclusion, cannabinoids and opioids show functional interactions on modulation of seizure susceptibility. [Copyright &y& Elsevier]

Immunophilin ligands, cyclosporine A and FK506 (tacrolimus), besides their immunosuppressive action, have several effects on different neural functions, such as modulation of the release of many neurotransmitters, the reduction of nitric oxide (NO) production by the inhibition of dephosphorylation of neuronal nitric oxide synthase (nNOS) and the alteration of the expression of certain genes. Many of these actions apparently occur through the inhibition of calcineurin, a calcium-calmodulin-dependent phosphatase. On the other hand, several studies have shown that NO has a critical role in opioid-induced tolerance and dependence in both in vivo and in vitro models. In the present study, the effect of cyclosporine A and FK506 on the development of tolerance to and dependence on morphine in the guinea pig ileum was assessed. Morphine inhibited electrically stimulated twitch of ileum in a concentration-dependent manner (pD2=7.45±0.07). Tolerance to this effect was induced by incubation of ileum with 2×IC50 or 4×IC50 of morphine for 2 h that induced a degree of tolerance of 6.81 and 18.10, respectively. The co-incubation of ileum with morphine along with either cyclosporine A or FK506 reduced the degree of tolerance significantly (P<0.05) and restored the sensitivity of ileum to the morphine inhibitory effect. Dependence was induced by incubation with 4×IC50 of morphine for 2 h and was assessed based on naloxone-induced contractions (10−5 M). Cyclosporine A (10−9 M) and FK506 (10−9 M) can attenuate the development of dependence to morphine as shown by the significant decrease in naloxone-induced contractions (P<0.05). These results suggest that immunophilin ligands at very low concentrations (nanomolar) can reduce the induction of acute tolerance to and dependence on morphine in the myenteric plexus of guinea pig ileum. [Copyright &y& Elsevier]