A diencephalic circuit in rats for opioid analgesia but not positive reinforcement.

Mu opioid receptor (MOR) agonists are potent analgesics, but also cause sedation, respiratory depression, and addiction risk. The epithalamic lateral habenula (LHb) signals aversive states including pain, and here we found that it is a potent site for MOR-agonist analgesia-like responses in rats. Importantly, LHb MOR activation is not reinforcing in the absence of noxious input. The LHb receives excitatory inputs from multiple sites including the ventral tegmental area, lateral hypothalamus, entopeduncular nucleus, and the lateral preoptic area of the hypothalamus (LPO). Here we report that LHb-projecting glutamatergic LPO neurons are excited by noxious stimulation and are preferentially inhibited by MOR selective agonists. Critically, optogenetic stimulation of LHb-projecting LPO neurons produces an aversive state that is relieved by LHb MOR activation, and optogenetic inhibition of LHb-projecting LPO neurons relieves the aversiveness of ongoing pain.

Pregabalin as adjunctive therapy in adult and pediatric patients with generalized tonic-clonic seizures: A randomized, placebo-controlled trial.

OBJECTIVE: Generalized tonic-clonic (GTC) seizures are the most common type of generalized seizure and more common in children than adults. This phase 3 study evaluated the efficacy and safety of pregabalin for GTC seizures in adults and children with epilepsy. METHODS: This randomized, double-blind, multicenter study evaluated pregabalin (5 mg/kg/day or 10 mg/kg/day) vs placebo as adjunctive therapy for 10 weeks (following a 2-week dose escalation), in pediatric and adult patients (aged 5-65 years) with GTC seizures. Primary endpoint was change in log-transformed 28-day seizure rate during active treatment. Secondary endpoints included responder rates, defined as proportion of patients with ≥50% reduction in 28-day GTC seizure rate from baseline. Safety was monitored throughout. RESULTS: Of 219 patients, 75, 72, and 72 were randomized to adjunctive pregabalin 5 mg/kg/day, 10 mg/kg/day, and placebo, respectively. Fifteen, 11, and 6 patients discontinued from the 5 mg/kg/day, 10 mg/kg/day, and placebo arms, respectively, most commonly due to adverse events (AEs; 10.7%, 6.9%, and 5.6%, respectively). A nonsignificant change in log-transformed mean 28-day seizure rate was seen with pregabalin 10 mg/kg/day vs placebo (least-squares [LS] mean difference -0.01 [95% confidence interval (CI) -0.19 to 0.16]; P = .8889) and with pregabalin 5 mg/kg/day vs placebo (LS mean difference 0.02 [CI -0.15 to 0.19]; P = .8121). Similar observations were noted for adults and children. No significant differences were seen for secondary endpoints with pregabalin vs placebo, including responder rate. The most common AEs (≥10%) were dizziness, headache, and somnolence. Most were of mild/moderate intensity. Seven patients had serious AEs, with one death in the placebo arm (sudden unexpected death in epilepsy). SIGNIFICANCE: Adjunctive pregabalin treatment did not change GTC seizure rate in adults or children. The safety profile of pregabalin was similar to that known; treatment was well tolerated with few discontinuations due to AEs.

Differential Modulation of Ventral Tegmental Area Circuits by the Nociceptin/Orphanin FQ System.

The neuropeptide nociceptin/orphanin FQ (N/OFQ) can be released by stressors and is associated with disorders of emotion regulation and reward processing. N/OFQ and its receptor, NOP, are enriched in dopaminergic pathways, and intra-ventricular agonist delivery decreases dopamine levels in the dorsal striatum, nucleus accumbens (NAc), and ventral tegmental area (VTA). We used whole-cell electrophysiology in acute rat midbrain slices to investigate synaptic actions of N/OFQ. N/OFQ was primarily inhibitory, causing outward currents in both immunocytochemically identified dopaminergic (tyrosine hydroxylase positive (TH(+))) and non-dopaminergic (TH(-)) VTA neurons; effect at 1 µm: 20 ± 4 pA. Surprisingly, this effect was mediated by augmentation of postsynaptic GABAAR currents, unlike the substantia nigra pars compacta (SNc), where the N/OFQ-induced outward currents were K+ channel dependent. A smaller population, 17% of all VTA neurons, responded to low concentrations of N/OFQ with inward currents (10 nm: -11 ± 2 pA). Following 100 nm N/OFQ, the response to a second N/OFQ application was markedly diminished in VTA neurons (14 ± 10% of first response) but not in SNc neurons (90 ± 20% of first response). N/OFQ generated outward currents in medial prefrontal cortex (mPFC)-projecting VTA neurons, but inward currents in a subset of posterior anterior cingulate cortex (pACC)-projecting VTA neurons. While N/OFQ inhibited NAc-projecting VTA cell bodies, it had little effect on electrically or optogenetically evoked terminal dopamine release in the NAc measured ex vivo with fast scan cyclic voltammetry (FSCV). These results extend our understanding of the N/OFQ system in brainstem circuits implicated in many neurobehavioral disorders.

Efficacy and Safety of Once-Daily Controlled-Release Pregabalin for the Treatment of Patients With Postherpetic Neuralgia: A Double-Blind, Enriched Enrollment Randomized Withdrawal, Placebo-Controlled Trial.

OBJECTIVES: To assess efficacy and safety of once-daily controlled-release (CR) formulation of pregabalin in patients with postherpetic neuralgia. METHODS: An enriched enrollment, randomized withdrawal trial, with 6-week single-blind pregabalin treatment phase and 13-week double-blind phase, where patients with ≥50% decrease in mean pain score at single-blind end point from baseline were randomized (1:1) to pregabalin CR (82.5 to 660 mg/d) or placebo. Primary efficacy outcome was time to loss of therapeutic response (LTR) (<30% decrease in weekly mean pain score from single-blind baseline or discontinuation due to adverse event or lack of efficacy). Secondary efficacy outcomes included change in weekly mean pain score (1-wk recall period) at double-blind end point. RESULTS: In total, 801 patients were randomized and treated in the single-blind phase, and 413 in the double-blind phase (208, pregabalin CR; 205, placebo). Pregabalin CR significantly increased time to LTR versus placebo (Kaplan-Meier analysis) with significantly fewer LTR events with pregabalin CR than with placebo (29 [13.9%] vs. 63 [30.7%]; P<0.0001). Median time to LTR was not estimable. Pregabalin CR significantly improved weekly mean pain score versus placebo: LS mean difference (95% CI) of -1.11 (-1.47, -0.75) and -1.00 (-1.34, -0.65) (P<0.0001) from single-blind baseline and double-blind baseline, respectively. Most commonly reported adverse events in the single-blind phase were dizziness, somnolence, and peripheral edema. Pregabalin CR was well tolerated. DISCUSSION: Time to LTR was significantly longer with pregabalin CR than with placebo. Safety profile of pregabalin CR was comparable to that reported for the immediate-release formulation in patients with postherpetic neuralgia.

Efficacy and Safety of Pregabalin in Patients with Fibromyalgia and Comorbid Depression Taking Concurrent Antidepressant Medication: A Randomized, Placebo-controlled Study.

OBJECTIVE: To assess pregabalin efficacy and safety in patients with fibromyalgia (FM) with comorbid depression taking concurrent antidepressant medication. METHODS: This randomized, placebo-controlled, double-blind, 2-period, 2-way crossover study was composed of two 6-week treatment periods separated by a 2-week taper/washout phase. Patients with FM (aged ≥ 18 yrs) taking a stable dose of a selective serotonin reuptake inhibitor (SSRI) or a serotonin/norepinephrine reuptake inhibitor (SNRI) for depression were randomized 1:1 to receive pregabalin/placebo or placebo/pregabalin (optimized to 300 or 450 mg/day). Antidepressant medication was continued throughout the study. The primary efficacy outcome was the mean pain score on an 11-point numerical rating scale. Secondary efficacy outcomes included measures of anxiety, depression, patient function, and sleep. RESULTS: Of 197 patients randomized to treatment, 181 and 177 received ≥ 1 dose of pregabalin and placebo, respectively. At baseline, 52.3% of patients were taking an SSRI and 47.7% an SNRI, and mean pain score was 6.7. Mean pain scores at endpoint were statistically significantly reduced with pregabalin (least squares mean difference from placebo -0.61, 95% CI -0.91 - -0.31, p = 0.0001). Pregabalin significantly improved Hospital Anxiety and Depression Scale-Anxiety (difference -0.95, p < 0.0001) and -Depression (difference -0.88, p = 0.0005) scores, Fibromyalgia Impact Questionnaire total score (difference -6.60, p < 0.0001), and sleep quality (difference 0.57, p < 0.0001), but not EuroQol 5-Dimensions score (difference 0.02, p = 0.3854). Pregabalin safety was consistent with previous studies and current product labeling. CONCLUSION: Compared with placebo, pregabalin statistically significantly improved FM pain and other symptoms in patients taking antidepressant medication for comorbid depression. ClinicalTrials.gov identifier: NCT01432236.

A time to remember: the role of circadian clocks in learning and memory.

The circadian system has pronounced influence on learning and memory, manifesting as marked changes in memory acquisition and recall across the day. From a mechanistic perspective, the majority of studies have investigated mammalian hippocampal-dependent learning and memory, as this system is highly tractable. The hippocampus plays a major role in learning and memory, and has the potential to integrate circadian information in many ways, including information from local, independent oscillators, and through circadian modulation of neurogenesis, synaptic remodeling, intracellular cascades, and epigenetic regulation of gene expression. These local processes are combined with input from other oscillatory systems to synergistically augment hippocampal rhythmic function. This overview presents an account of the current state of knowledge on circadian interactions with learning and memory circuitry and provides a framework for those interested in further exploring these interactions.

Dorsomedial hypothalamic lesions block Syrian hamster testicular regression in short day lengths without diminishing increased testosterone negative-feedback sensitivity.

The dorsomedial nucleus (DMN) of the hypothalamus, the only site within the mediobasal hypothalamus of Syrian hamsters that both binds melatonin and has abundant concentrations of androgen receptors, has been proposed as a target tissue for induction of seasonal changes in brain sensitivity to steroid negative feedback. We tested whether DMN ablation, which does not interfere with pineal gland secretion of melatonin in short day lengths, prevents testicular regression by altering sensitivity to steroid negative feedback. Hamsters with DMN lesions, unlike control hamsters, failed to undergo testicular regression after transfer from a long (14 h light/day) to a short day length (8 h light/day); however, increased negative-feedback inhibition of follicle-stimulating hormone by testosterone was not compromised by ablation of the DMN, indicating that this tissue is not an essential mediator of seasonal changes in feedback sensitivity. We propose a redundant neural network comprised of multiple structures, each of which contributes to neuroendocrine mechanisms, that determines the effect of short days on gonadal function.

Time-dependent density functional study of field emission from nanotubes composed of C, BN, SiC, Si, and GaN.

Field emission from various types of nanotubes is studied by propagating the electronic density in real space and time using time-dependent density functional theory. Capped (5, 5) C, BN, SiC, Si, and GaN nanotubes are considered. The GaN, SiC, and Si nanotubes were found to be significantly better field emitters than C and BN nanotubes, both in terms of current magnitude and sharpness of peaks in the energy spectra. By analyzing the electronic structure of the various systems it is seen that the nanotubes with the highest currents have electron densities that extend significantly from the nanotube in the emission direction.

Nucleus accumbens medium spiny neurons target non-dopaminergic neurons in the ventral tegmental area.

The midbrain ventral tegmental area (VTA) projection to the nucleus accumbens (NAc) is implicated in motivation and reinforcement. A significant number of NAc medium spiny neurons (MSNs) project back to the VTA, although the nature of this projection is essentially unknown. For example, do NAc MSNs directly target accumbens-projecting dopamine neurons and do they act via the GABA(A) or GABA(B) receptor? To address these issues, we expressed the light-sensitive channel rhodopsin-2 in the rat NAc and made electrophysiological recordings from VTA neurons ex vivo. We found that the NAc directly targets non-dopaminergic VTA neurons, including some that project back to the NAc. These MSN GABAergic terminals are opioid sensitive and act via GABA(A) receptors.

Reliability in the identification of midbrain dopamine neurons.

Brain regions typically contain intermixed subpopulations of neurons with different connectivity and neurotransmitters. This complicates identification of neuronal phenotypes in electrophysiological experiments without using direct detection of unique molecular markers. A prime example of this difficulty is the identification of dopamine (DA) neurons in the midbrain ventral tegmental area (VTA). Although immunocytochemistry (ICC) against tyrosine hydroxylase (TH) is widely used to identify DA neurons, a high false negative rate for TH ICC following ex vivo electrophysiology experiments was recently reported, calling into question the validity of comparing DA and non-DA VTA neurons based on post-hoc ICC. However, in whole cell recordings from randomly selected rat VTA neurons we have found that TH labeling is consistently detected in ∼55% of neurons even after long recording durations (range: 2.5-150 min). This is consistent with our prior anatomical finding that 55% of VTA neurons are TH(+). To directly estimate a false negative rate for our ICC method we recorded VTA neurons from mice in which EGFP production is driven by the TH promoter. All 12 EGFP(+) neurons recorded with a K-gluconate internal solution (as used in our rat recordings) were strongly labeled by TH ICC (recording duration 16.6±1.8 min). However, using recording electrodes with an internal solution with high Cl(-) concentration reduced the intensity of TH co-labeling, in some cases to background (recording duration 16.7±0.9 min; n = 10). Thus TH is a highly reliable molecular marker for DA neurons in VTA patch clamp recordings provided compatible microelectrode solutions are used.

Infrequent low dose testosterone treatment maintains male sexual behavior in Syrian hamsters.

Testosterone (T) secreted in short pulses several times each day is essential for the maintenance of male sex behavior (MSB) in mammals. Blood T concentrations are relatively low during inter-pulse intervals. Assessment of androgenic influences on MSB of rodents has, with very few exceptions, involved either injections of pure or esterified hormones dissolved in oil or implantation of constant release capsules that generate supraphysiological and/or constantly elevated T concentrations. The minimum daily concentration of T necessary to maintain and restore MSB when T is delivered as a discrete short pulse remains unspecified; nor is it known whether infrequent T pulses in the physiological range sustain MSB. To address these questions, we varied T injection concentrations and frequencies in castrated, sexually-experienced Syrian hamsters. All males injected daily with an aqueous vehicle failed to display the ejaculatory reflex 5 weeks after castration. Once daily 15 microg subcutaneous T injections both maintained and restored MSB, whereas once daily 5 microg T injections resulted in fewer males ejaculating and longer ejaculation latencies. Substantially higher T doses were required to restore MSB in previous studies when T was administered in an oil vehicle. 50 microg T maintained MSB in most hamsters injected once every 4 or 7 days, despite long intervals between injections during which circulating T was undetectable or well below physiological concentrations. Some T regimens that maintained MSB were associated with subnormal seminal vesicle and ventral prostate weights. The demonstration that relatively brief, infrequent elevations of T are sufficient to support MSB provides a useful model to assess the neuroendocrine basis of MSB and raises the possibility that infrequent low dose androgen replacement protocols may restore sex behavior to hypogonadal men without inducing some of the negative side-effects associated with more frequent, higher dose treatments.

Circadian rhythms of photorefractory siberian hamsters remain responsive to melatonin.

Short day lengths increase the duration of nocturnal melatonin (Mel) secretion, which induces the winter phenotype in Siberian hamsters. After several months of continued exposure to short days, hamsters spontaneously revert to the spring-summer phenotype. This transition has been attributed to the development of refractoriness of Mel-binding tissues, including the suprachiasmatic nucleus (SCN), to long-duration Mel signals. The SCN of Siberian hamsters is required for the seasonal response to winter-like Mel signals, and becomes refractory to previously effective long-duration Mel signals restricted to this area. Acute Mel treatment phase shifts circadian locomotor rhythms of photosensitive Siberian hamsters, presumably by affecting circadian oscillators in the SCN. We tested whether seasonal refractoriness of the SCN to long-duration Mel signals also renders the circadian system of Siberian hamsters unresponsive to Mel. Males manifesting free-running circadian rhythms in constant dim red light were injected with Mel or vehicle for 5 days on a 23.5-h T-cycle beginning at circadian time 10. Mel injections caused significantly larger phase advances in activity onset than did the saline vehicle, but the magnitude of phase shifts to Mel did not differ between photorefractory and photosensitive hamsters. Similarly, when entrained to a 16-h light/8-h dark photocycle, photorefractory and photosensitive hamsters did not differ in their response to Mel injected 4 h before the onset of the dark phase. Activity onset in Mel-injected hamsters was masked by light but was revealed to be significantly earlier than in vehicle-injected hamsters upon transfer to constant dim red light. The acute effects of melatonin on circadian behavioral rhythms are preserved in photorefractory hamsters.

Monosodium glutamate-induced arcuate nucleus damage affects both natural torpor and 2DG-induced torpor-like hypothermia in Siberian hamsters.

Siberian hamsters (Phodopus sungorus) have the ability to express daily torpor and decrease their body temperature to approximately 15 degrees C, providing a significant savings in energy expenditure. Daily torpor in hamsters is cued by winterlike photoperiods and occurs coincident with the annual nadirs in body fat reserves and chronic leptin concentrations. To better understand the neural mechanisms underlying torpor, Siberian hamster pups were postnatally treated with saline or MSG to ablate arcuate nucleus neurons that likely possess leptin receptors. Body temperature was studied telemetrically in cold-acclimated (10 degrees C) male and female hamsters moved to a winterlike photoperiod (10:14-h light-dark cycle) (experiments 1 and 2) or that remained in a summerlike photoperiod (14:10-h light-dark cycle) (experiment 3). In experiment 1, even though other photoperiodic responses persisted, MSG-induced arcuate nucleus ablations prevented the photoperiod-dependent torpor observed in saline-treated Siberian hamsters. MSG-treated hamsters tended to possess greater fat reserves. To determine whether reductions in body fat would increase frequency of photoperiod-induced torpor after MSG treatment, hamsters underwent 2 wk of food restriction (70% of ad libitum) in experiment 2. Although food restriction did increase the frequency of torpor in both MSG- and saline-treated hamsters, it failed to normalize the proportion of MSG-treated hamsters undergoing photoperiod-dependent torpor. In experiment 3, postnatal MSG treatments reduced the proportion of hamsters entering 2DG-induced torpor-like hypothermia by approximately 50% compared with saline-treated hamsters (38 vs. 72%). In those MSG-treated hamsters that did become hypothermic, their minimum temperature during hypothermia was significantly greater than comparable saline-treated hamsters. We conclude that 1) arcuate nucleus mechanisms mediate photoperiod-induced torpor, 2) food-restriction-induced torpor may also be reduced by MSG treatments, and 3) arcuate nucleus neurons make an important, albeit partial, contribution to 2DG-induced torpor-like hypothermia.