Anxiogenic aspects of diazepam withdrawal can be detected in animals

Animals can be trained to discriminate the presence of pentylenetetrazol, and this discrimination has previously been proposed as an animal bioassay for anxiogenicity. In rats made dependent on diazepam, pentylenetetrazol-like stimuli occurred during spontaneous or precipitated (with RO 15-1788) withdrawal; these stimuli were blocked by pentobarbital. These results demonstrate that the pentylenetetrazol-based animal model of anxiety can be used to objectively quantify a subjective aspect of benzodiazepine dependence/withdrawal.     

Nicotine exposure can be detected in cerebrospinal fluid of active and passive smokers

A simple, rapid and sensitive liquid chromatography/mass spectrometry (LC/MS) method has been utilized for the quantitative determination of nicotine and its major metabolite cotinine (COT) in human cerebrospinal fluid (CSF) of active and passive smokers. CSF samples from 18 smokers, 15 non-smokers, 15 children, 15 infants, and 9 neonatal were analyzed for nicotine (NIC) and cotinine content. Cotinine levels in the CSF of smokers ranged from 27.3 to 457.1 ng/ml, whereas nicotine levels were considerably lower (6.0–215.1 ng/ml). Cotinine could be detected in 4 of the 15 CSF samples from non-smokers (3.5–30.4 ng/ml), and a few other passive smokers, including neonates from smoking mothers (15.6–81.1 ng/ml). The concentrations of cotinine in CSF samples suggests that nicotine easily passes into the CSF, which makes it an excellent CSF marker for tobacco-smoke exposure.     

Remyelinating strategies: What can be learned from normal brain development

Multiple sclerosis (MS) is a neuroinflammatory demyelinating and neurodegenerative disease of the central nervous system (CNS). Immunomodulatory therapies are effective in reducing relapses, however, there is no remedy for progressive disease emphasizing the need for regenerative strategies. Chronic demyelination causes axonal injury and loss which is a key component of neurodegeneration and permanent disability in MS. New oligodendrocyte progenitor cells (OPCs) proliferate in response to inflammatory demyelination representing the potential for remyelination to protect axons and preserve neuronal function. The majority of remyelinating therapies have targeted intrinsic signaling processes in oligodendrocytes to promote differentiation or utilized methods for transplantation of oligodendrocytes. Here, we discuss specific roles of microglia in contributing to normal myelin development and the significance of these functions for remyelinating strategies.     

Delta-9-tetrahydrocannabinol (THC) increases brain prostaglandins in the rat

Intraperitoneal administration of 9-trans-delta-tetrahydrocannabinol (THC), the major psychoactive component of cannabis, in doses of 0.5, 1.0 and 2.0 mg/kg, produced a dose-related increase in the brain concentrations of prostaglandin (PG) E₂ and PGF₂ in male rats 4 h after THC administration, as assessed by radioimmunoassay. A time-course investigation indicated that THC (2 mg/kg, IP) induced maximal increases in rat brain concentration of both PGs 2 and 4 h after administration; PG levels declined appreciably by 8 h and were normal by 24 h.A time-course study on the hexobarbitone (100 mg/kg, IP) -induced hypnosis potentiating effect of THC (2.0 mg/kg, IP) in male rats revealed that this pharmacological action of the cannabinoid correlated well with the time-course of the THC-induced increase in rat brain PG concentrations.The present study lends support to earlier reports contending that PGs may mediate some of the central actions of THC.     

5-HT1D binding sites in porcine brain can be sub-divided by GR43175.

We have examined the binding of 5-carboxamidotryptamine (5-CT) and GR43175 (3-(2-dimethylamino)ethyl-N-methyl-1H-indole-5-methane sulphonamide) to 5-HT1D sites labelled with [3H]-5-hydroxytryptamine [( 3H]-5-HT) in neonatal porcine caudate membranes. In competition studies, 5-CT produced shallow inhibition curves (Ki 138 nM, slope 0.31), indicating binding site heterogeneity, while GR43175 interacted with a single population of binding sites (Ki 251 nM, slope 0.98), producing a maximum of only 52% inhibition of [3H]-5-HT binding compared to 100% for 5-HT or 5-CT. In the presence of excess GR43175 (10 microM), 5-CT produced a monophasic inhibition curve with a Ki value of 800 nM for the remaining sites (slope 0.89). These preliminary data suggest that under the conditions employed, GR43175, and to a lesser extent 5-CT, may discriminate between two sub-populations of 5-HT1D binding sites in porcine brain.     

Tacrine-induced seizures and brain damage in LiCl-treated rats can be prevented by N omega-nitro-L-arginine methyl ester.

The effects of tacrine (5 mg/kg i.p.), a potent acetylcholinesterase inhibitor, were studied in rats pretreated (24 h beforehand) with a single dose (12 mEq/kg i.p.) of LiCl. Tacrine and LiCl were ineffective when given individually. Tacrine elicited seizures and brain damage in 90% of the rats treated. The intracerebroventricular microinfusion of N omega-nitro-L-arginine methyl ester (300 micrograms given 24 h after LiCl administration) significantly reduced the seizures and brain damage produced by tacrine (given 15 min later). These experiments suggest that the seizures and brain damage elicited by tacrine may be due, in part, to increased nitric oxide production in the brain.     

Val-Tyr as a natural antihypertensive dipeptide can be absorbed into the human circulatory blood system

1. Intact absorption of the bioactive dipeptide Val-Tyr (VY), with in vivo antihypertensive ability in normotensive human subjects, was investigated. 2. As a result of a single oral administration of VY, the VY absorption curve occurred maximally over the second hour postprandially; a greater than 10-fold higher increment of VY following a dose of 12 mg was observed in the plasma at 2 h compared with the baseline concentration of VY at 0 h (1934 +/- 145 vs 159 +/- 11 fmol/mL plasma, respectively). 3. Plasma VY levels increased with dose administered (3, 6 and 12 mg), suggesting that exogenous VY could be absorbed intact into the human blood depending on the dose. The elimination half time (t1/2) of VY was estimated to be 3.1 h. The area under the curve for the 12 mg VY dose was 9185 +/- 688 fmol small middle doth/mL plasma.     

Pharmacokinetics of THC in brain and testis,male gametotoxicity and premature apoptosis of spermatozoa

An earlier report described the pharmacokinetics of delta-9 THC and the resulting brain function responses. In the present studies the pharmacokinetics of THC in plasma, brain and testis were related to impairment of spermatogenesis. THC- containing preparations, whatever their route of administration, were associated with the induction of gametotoxicity in all species studied including man. The pharmacokinetics and molecular binding of THC is similar in all experimental models. Concentrations of THC in plasma, fat, testis, brain and spleen were measured following administration of tracer amounts of C(14) delta-8 THC labelled at the C(11) position. Rats were administered 2 microCi of the tracer by i.m. injection, and killed at regular intervals after a single or multiple dose of the label. After a single dose, the maximal radioactivity was reached in brain after 2 and 4 h and amounted to 0.06% of the administered dose. In the testis, the concentration did not exceed 0.023% of the administered dose. In epididymal fat, the total radioactivity after 4 h was five times higher than in the brain and after 24 h it was eight times greater. After multiple injections of C(14) THC, concentrations of the drug remained low in the plasma, brain and testis not exceeding 2-7 ng/g, but the epididymal fat tracer concentration was 40-80 times higher. Plasma concentrations of C(14) THC were of the same magnitude as those measured by GCMS in the plasma of men exposed to marihuana smoke or THC, and in whom alterations of spermatogenesis were observed. In these studies, plasma THC ranged from 9.5x10(12) M to 2.4x10(14) M. These data illustrate the efficiency of the blood-brain barrier and blood-testicular barrier in limiting the storage of THC into brain and testis. During chronic exposure to THC the pharmacokinetic molecular mechanisms which limit the storage of THC in the brain and testis are not sufficient to prevent a persistent deregulation of membrane signalling and the induction of functional and morphological changes which reflect a premature apoptosis of spermatogenic cells. Long term, longitudinal epidemiological studies have reported decreased spermatogenesis in healthy, fertile adult males. But no study has been initiated to relate the oligospermia of this population to the consumption of widely used psychoactive drugs.