Racial inequality in the annual risk of Tuberculosis infection in the United States, 1910-1933.

Tuberculosis (TB) mortality rates in the USA fell rapidly from 1910 to 1933. However, during this period, racial disparities in TB mortality in the nation's expanding cities grew. Because of long delays between infection and disease, TB mortality is a poor indicator of short-term changes in transmission. We estimated the annual risk of TB infection (ARTI) in 11 large US cities to understand whether rising inequality in mortality reflected rising inequality in ARTI using city-level TB mortality data compiled by the US Department of Commerce from 1910 to 1933. We estimated ARTI for African-Americans and whites using pediatric extrapulmonary TB mortality data for African-Americans and whites in our panel of cities. We also estimated age-adjusted pulmonary TB mortality rates for these cities. We find that the ratio of ARTI for African-Americans vs. whites increased from 2·1 (95% CI = 1·7, 2·4) in 1910 to 4·2 (95% CI = 3·4, 5·2) in 1933. This change mirrored the increasing inequality in age-adjusted pulmonary TB mortality during this period. These findings may reflect the combined effects of migration, inequality in access to care, increasing population density, and racial residential segregation in northern cities during this period.

Naloxone reverses the inhibitory effect of gamma-hydroxybutyrate on central DA release in vivo in awake animals: a microdialysis study.

gamma-Hydroxybutyrate (GHB) is a 4-carbon anesthetic that acts primarily by inhibiting presynaptic dopamine (DA) release in vivo. A number of studies have reported a reversal of many of the central effects of GHB by the allegedly pure opiate antagonist naloxone (NX) but its mechanism of action is unclear. In vivo microdialysis performed in the present preliminary study disclosed a significant inhibitory effect of GHB (500 mg/kg) on striatal DA release which was completely reversed by a low dose of NX (0.8 mg/kg). The results indicate that NX likely inhibits many of the central effects produced by GHB primarily through its reversal of the GHB induced inhibition of central DA release.

On the synthesis of neurotransmitter receptor agonists with antagonist potential.

The synthesis of a new type of antagonist is described, capable of inactivating neuroreceptors with heretofore unattainable selectivity and permanence. These antagonists are referred to as mazek agonists (i.e. direct, inhibitory agonists) as they have the high receptor affinity and initial receptor-stimulatory effect of direct agonists and are positively coupled to effector systems. However, like direct antagonists, they have a high receptor affinity and the potential to inhibit or prevent receptor stimulation. The synthesis of the present compounds consisted of the covalent attachment of a tethered dye to three different neurotransmitter analogues, resulting in dye-neuropeptide conjugates with a high affinity for the FMRFa receptor. The dye was prepared from azure B (Az), the neurotransmitter was the neuropeptide FMRFamide (FMRFa), and the dye-neuropeptide conjugates synthesized were Az-CFMRFa; Az-CFMRF and Az-CLRFa. In this procedure, the analogues serve as carrier molecules, bound at one end to the receptor and at the other end to the dye, which is thereby brought into close contact with the receptor. The receptor can then be inactivated by singlet oxygen generated by laser irradiation of the photosensitized receptor.

Effect of gamma-hydroxybutyrate on central dopamine release in vivo. A microdialysis study in awake and anesthetized animals.

gamma-Hydroxybutyrate (GHB) is generally considered to be an inhibitor of striatal dopamine (DA) release. However, a number of recent reports and at least one major review suggest that GHB enhances rather than inhibits striatal DA release. To examine this discrepancy, the effect of GHB on striatal DA release was monitored for 2 hr by microdialysis in awake and urethane-anesthetized rats. GHB (500 mg/kg, i.p.) significantly inhibited striatal DA release in conscious animals. However, anesthetic pretreatment completely abolished the inhibitory effect of GHB on DA release. In urethane-anesthetized animals, intraperitoneal injections of GHB resulted in a dialysis DA output that was the same as basal and saline control levels for all but the last three intervals where DA release was elevated slightly. In contrast to the intraperitoneal route, subcutaneous injections of GHB in anesthetized animals produced significant elevations of DA release above baseline levels. The increases ranged from 125 to 133% of basal levels. These results indicate that while GHB enhances striatal DA release in anesthetized animals, it inhibits rather than enhances this release in awake animals. This would explain why GHB induces an inhibition of DA-release-dependent behaviors rather than an enhancement. The results also indicate that the route of GHB administration influences its effects on striatal DA release, at least in anesthetized animals.

Effects of naloxone on amphetamine induced striatal dopamine release in vivo: a microdialysis study.

The opiate antagonist naloxone (NX) alters amphetamine (AMPH) induced behaviors including locomotor activity, rearing and stereotypy. However, the exact nature of the NX induced alteration of AMPH induced behaviors is controversial, with some studies using high (5-40 mg/kg) doses of NX reporting an inhibition, and others using low (< or = 1-2 mg/kg) doses observing a potentiation. As these behaviors are mediated by AMPH induced dopamine (DA) release, the effect of NX on the latter was examined by microdialysis in an effort to resolve the controversy. Saline and NX pretreated groups subsequently administered AMPH were compared in vivo across nine separate 10 min intervals as well as by grouped intervals. NX alone (0.8 mg/kg) and saline exerted statistically equivalent effects on striatal DA release with the exception of the fifth interval, where a small but significant increase was seen after NX. On the other hand, the same dose of NX significantly enhanced AMPH induced striatal DA release relative to saline pretreated animals during each of four separate intervals, from 30 to 70 minutes following AMPH (1.5 mg/kg), and across all nine intervals combined. NX pretreatment (0.8 mg/kg) followed by a higher dose of AMPH (3.0 mg/kg) produced a significantly greater cumulative effect on DA release than saline pretreatment over the last six combined intervals (30-90 min) and over two grouped intervals (30-50 min and 40-60 min inclusive). However, a comparison of single rather than paired or grouped intervals revealed no significant differences. Previous studies have also examined the effect of NX on AMPH induced striatal DA release using in vivo microdialysis. However, the doses used were invariably high (5 mg/kg) and the results on striatal DA release always inhibitory. The present results suggest that NX potentiates AMPH induced striatal DA release when lower doses of NX are used. These results combined with those of previous studies also suggest that NX exerts a biphasic effect on AMPH induced DA release, with lower doses potentiating release and higher doses inhibiting release. This is close agreement with behavioral observations and may be due to the effect of low versus high doses of NX on intraterminal calcium influx.

Does gamma-hydroxybutyrate inhibit or stimulate central DA release?

Gamma-hydroxybutyrate (GHB), a four-carbon fatty acid and anaesthetic, is widely considered to be a relatively specific inhibitor of central dopamine (DA) release. The inhibitory effect of GHB on the latter is thought to occur as a consequence of its diminution of impulse flow in central dopaminergic neurons. However, a number of studies have recently reported that GHB primarily stimulates rather than inhibits central DA release, with any inhibitory effect produced of a modest and transitory nature. GHB has been and continues to be widely used as an important research tool largely because it is one of only a few drugs available that acts primarily on DA release. Consequently, it is important to determine whether GHB inhibits DA release as previously thought, or stimulates DA release, as more recently suggested. Following a critical review of the literature, the present report suggests that GHB does inhibit rather than stimulate presynaptic DA release in consonance with its behavioral and pharmacological activity. Recent in vivo studies indicating that GHB stimulates DA release were done under anaesthesia or in the presence of a high concentration of calcium. Both conditions have been found to spuriously enhance striatal DA release in vivo, which may account for the failure of some studies to observe an inhibitory effect of GHB on DA release in vivo.

Naloxone reverses the inhibitory effect of gamma-hydroxybutyrate on central DA release in vivo in awake animals: a microdialysis study.

gamma-Hydroxybutyrate (GHB) is a 4-carbon anesthetic that acts primarily by inhibiting presynaptic dopamine (DA) release in vivo. A number of studies have reported a reversal of many of the central effects of GHB by the allegedly pure opiate antagonist naloxone (NX) but its mechanism of action is unclear. In vivo microdialysis performed in the present preliminary study disclosed a significant inhibitory effect of GHB (500 mg/kg) on striatal DA release which was completely reversed by a low dose of NX (0.8 mg/kg). The results indicate that NX likely inhibits many of the central effects produced by GHB primarily through its reversal of the GHB induced inhibition of central DA release.

Gamma hydroxybutyrate is not a GABA agonist.

Gamma hydroxybutyrate (GHB) is primarily known and used as a relatively specific inhibitor of central DA release. However, it is also widely assumed to be an agonist or prodrug of gamma-aminobutyric acid (GABA) and its central activity has been attributed to an action exerted at GABA receptors. Nevertheless, there is compelling evidence that: (1) GHB formation may occur independently of GABA; (2) GHB is behaviorally, biochemically and physiologically distinct from GABA in many ways, and does not consistently effect GABAA or GABAB agonist induced responses; (3) GHB has little effect on either GABAA or GABAB receptors at less than millimolar concentrations. Consequently, GHB does not appear to be either a GABA prodrug or a GABA agonist. However, the GHB metabolite gamma butyrolactone (GBL) may possess some limited GABA agonist activity.

Lack of effect of gamma-hydroxybutyrate on mu, delta and kappa opioid receptor binding.

gamma-Hydroxybutyrate (GHB) and morphine induce a number of similar effects. Moreover, the effects they elicit can be reversed by the opiate antagonist naloxone (NX), suggesting that GHB may produce at least some of its central effects by acting as an opiate agonist. The present study considered this possibility by examining the effect of GHB on mu, delta, and kappa-opioid receptor binding in concentrations of 1 nM-0.1 mM. GHB was inactive in each instance, at every dose examined. GHB is consequently not a direct opiate receptor agonist. It is also unlikely to be an indirect (enkephalin or dynorphin release-stimulating) agonist. The mechanism of action involved whereby NX can reverse the effects of GHB must therefore not involve opioid mechanisms; at least not directly.

Receptor inactivation by dye-neuropeptide conjugates. 3. Comparative binding of dye-neuropeptide conjugates to FMRFamide receptors of Helix aspersa and Loligo pealei.

Three neuropeptide analogues of FMRFamide (FMRFa) were covalently attached to a tethered derivative of methylene blue to form dye-neuropeptide conjugates. The comparative binding of the latter to FMRFa receptors was subsequently examined in both Helix aspersa (circumesophageal ganglia) and squid (optic lobe membrane). In Helix, the FMRFa analogue CFMRFamide (CFMRFa) inhibited the specific binding of the FMRFa ligand [125I]daYFnLRFa in a dose-dependent manner. Az-CFMRFa, one of the dye-neuropeptide conjugates, also dose-dependently inhibited the specific binding of [125I]daYFnLRFa. Moreover, their potencies equaled or exceeded that of FMRFamide. In squid, the binding of CFMRFa and FMRFa was similar. However, the dye-neuropeptide conjugate (IC50 of 14 nM) was about 44-fold less potent than FMRFa. The conjugates were synthesized as part of a study seeking to target and inactivate preselected receptors with heretofore unattainable selectivity and permanence.

Receptor inactivation by dye-neuropeptide conjugates: 1. The synthesis of Cys-containing dye-neuropeptide conjugates.

In an attempt to attenuate specifically identified receptors through photolysis, a four-step synthesis is of a useful tethered derivative of Azure-B (Az) was developed After characterization, this derivative was covalently attached to CFMRFamide, CFMRF, and CLRFamide (i.e., three different neuropeptide analogues of the putative neurotransmitter FMRFamide. This resulted in the formation of three dye-neuropeptide conjugates: Az-CFMRFamide, Az-CFMRF, and Az-CLRFamide.

Receptor inactivation by dye-neuropeptide conjugates: 2. Characterization of the quantum yield of singlet oxygen generated by irradiation of dye-neuropeptide conjugates.

Different neuropeptide analogues of the neurotransmitter FMRFamide were covalently attached to a tethered dye, forming dye-neuropeptide conjugates capable of stably binding to the FMRFamide receptors. Singlet oxygen (1 delta O2) generated by laser irradiation of the conjugates bound to this receptor should inactivate it if (a) the distance 1 delta O2 must diffuse to reach the photo-sensitized receptor is less than 1000 A, (b) the conjugate binds the receptor with the same affinity as the indigenous neurotransmitter, and (c) the quantum yield (phi) of 1 delta O2 is sufficient. Previous studies determined that the first two constraints are satisfied. The results of the present study confirm that the third constraint is also satisfied, as the phi of 1 delta O2 resulting from the laser irradiation of the conjugates were uniformly large, exceeding those for the dye itself, ranging from 0.25 at pD 6.0 to 0.93 at pD 9.0.

The effect of naloxone on spontaneous and evoked dopamine release in the central and peripheral nervous systems.

A number of studies have reported that the opiate antagonist naloxone (NX) inhibits behaviors dependent upon central dopamine (DA) release. However, equally compelling evidence from other studies suggests that NX excites a facilitatory effect. The present review was undertaken to resolve the issue by critically evaluating the effects of NX on DA release; the substrate subserving these behaviors. Included are studies reporting an effect of NX on spontaneous as well as drug altered DA release in various central regions. In the preponderant majority of these studies, NX was found to significantly enhance DA release in the virtually every major DA pathway, irrespective of whether DA release was initially stimulated or inhibited by various agents. It is concluded that NX most probably enhances behaviors induced by DA release, especially when administered in low, specific doses. Studies finding an inhibitory effect of NX on such behaviors may inadvertently produce conditions which mask the stimulatory effects of NX on DA release-dependent behaviors.

Suppression of neuropathic pain behavior in rats by a non-psychotropic synthetic cannabinoid with NMDA receptor-blocking properties.

HU211 is a novel synthetic derivative of tetrahydro-cannabinol (THC), the active marijuana ingredient. The stereochemistry of HU211 is enantiomeric to that of THC. In contrast to THC, HU211 is not psychotropic. This agent exhibits other types of biological activities; it is a non-competitive NMDA receptor blocker and has antinociceptive activity when injected with cupric chloride. This study examined its effects in autotomy, a behavioral model of neuropathic pain. Autotomy, a behavior of self-mutilation of denervated areas, was induced in Sabra rats by cutting the sciatic and saphenous nerves. We found that injections of HU211 (2.5 mg/kg) with cupric chloride (0.8 mg/kg) every 2nd day markedly suppressed autotomy during the injection period by delaying its average onset day and reducing the incidence of severe autotomy. Moreover, suppression of autotomy was retained in the postinjection period (for at least 30 days) but only when the drug was injected intraperitoneally. Lesser effects were achieved by subcutaneous injections. Cupric chloride or HU211 alone were ineffective. The general behavior and open field motor activity indicated that the effects of HU211 with Cu++ on autotomy were not due to sedation or ataxia but presumably due to antinociception mediated by NMDA receptor blockade.

Nonpsychotropic cannabinoid acts as a functional N-methyl-D-aspartate receptor blocker.

Binding studies using the enantiomers of the synthetic cannabinoid 7-hydroxy-delta 6-tetrahydrocannabinol 1,1-dimethylheptyl homolog in preparations of rat brain cortical membranes reveal that the (+)-(3S,4S) enantiomer HU-211 blocks N-methyl-D-aspartate (NMDA) receptors in a stereospecific manner and that the interaction occurs at binding sites distinct from those of other noncompetitive NMDA antagonists or of glutamate and glycine. Moreover, HU-211 induces stereotype and locomotor hyperactivity in mice and tachycardia in rat, effects typically caused by NMDA receptor antagonists. HU-211 is also a potent blocker of NMDA-induced tremor, seizures, and lethality in mice. This compound may therefore prove useful as a nonpsychoactive drug that protects against NMDA-receptor-mediated neurotoxicity.

Inhibition of cisplatin-induced emesis in the pigeon by a non-psychotropic synthetic cannabinoid.

The (+) enantiomer of the synthetic cannabinoid, 7-hydroxy-delta-6-tetrahydrocannabinol, dimethylheptyl homolog (HU-211), possesses significant antimetic efficacy in the pigeon. However, unlike all anti-emetic cannabinoids tested in the past, it is devoid of psychotropic (cannabimimetic) activity. The anti-emetic activity of HU-211 was determined in pigeons given 10 mg/kg i.v. cisplatin, a widely used antitumour agent, which is also a potent emetogenic agent at this dose. This activity was compared with that of delta-1-tetrahydrocannabinol (delta-1-THC). HU-211 pretreatment elicited a dose-related inhibition of cisplatin vomiting, with the optimal dose of HU-211 (2.5 mg/kg) inhibiting emesis by nearly 90%. Delta-1-THC in doses up to 5 mg/kg caused only an insignificant reduction in vomiting. The activity was increased in the presence of cupric chloride (0.8 mg/kg). The optimal dose of delta-1-THC (5.0 mg/kg) with CuCl2 very significantly diminished the total amount of vomitus expelled (up to 90%). However, it failed to inhibit emesis in 50% of all animals tested, did not significantly affect the time of onset of emesis and was highly psychotropic. The optimal dose of HU-211 (2.5 mg/kg) with CuCl2 inhibited emesis by 97%, significantly delayed the time on onset of emesis in the very few animals that did vomit and was completely non-psychotropic. The curve for the antiemetic effect of HU-211 was U-shaped over a narrow dose range. The present report demonstrates that complete separation of psychotropic and antiemetic activities is possible in the cannabinoid series.

Enantiomeric cannabinoids: stereospecificity of psychotropic activity.

The 1,1-dimethylheptyl homolog of (-)-(3R,4R)-7-hydroxy-delta-6- tetrahydrocannabinol (compound II) is highly psychotropic in mice, rats and pigeons. The (+)-(3S,4S) enantiomer (III) was found to be psychotropically inactive at doses up to several thousand times those of the ED50 of (II).

Diethylstilbestrol counteracts barbiturate narcosis and hypothermia in male mice.

Treatment with DES one hour prior to pentobarbital injection resulted in diminution of the narcotic sleep and hypothermia usually found after pentobarbital (50 mg/kg 1) injection in male mice. The effect was biphasic: significantly countered relative to saline pretreated controls at low (.001-.10 mg/kg 1) and at high (10-50 mg/kg -1) DES doses only. Giving DES alone did not change core body temperature compared to saline injected controls, at either 25 degrees C or at 33 degrees C. At 33 degrees C, neither PeB narcosis nor body temperature loss was significantly inhibited by DES. Possible cytoplasmic, nonsex differentiated bases for these estrogen effects on barbiturate action in the brain is discussed.

Stereochemical requirements for cannabimimetic activity.

The SAR of cannabimimetic activity in the cannabinoid series are reviewed with emphasis on the stereochemical requirements. Some new results are presented. The most important are that a, in humans, (-)-(1S)-delta-3-THC is much more active than (+)-(1R)-delta-3-THC; and b, with the 7-OH-delta-6-THC DMH enantiomers (32) and (33), the activity in several animal species resides completely in the (-)-(3R, 4R) enantiomer (32), the difference between the two enantiomers being up to several thousand times. The (3R,4R)-enantiomer (32) is much more active than delta-1- or delta-6-THC in animal tests, the exact level of activity depending on the test employed. The cannabimimetically inactive (+)-(3S,4S) enantiomer (33) was shown to be a potent analgetic in several animal tests. Thus, a complete dissociation between the cannabimimetic and the analgetic effects in a cannabinoid has been achieved, apparently for the first time.