Neolithic economic autonomy and social distance.

The following hypothesis was tested in the prehistoric Mogollon culture area of the American Southwest: increasing dependence on agriculture leads to increasing social distance between the minimal economic units needed to make agriculture a successful economic base. Both variables covaried positively. As dependence on agriculture increased, villages became more endogamous.

Different kinetics of tolerance to behavioral and electroencephalographic effects of chlordiazepoxide in the rat.

The daily oral administration of chlordiazepoxide (40 mg/kg) over 9 weeks in rats elicited full tolerance to muscle relaxant effects within 7 weeks, as revealed by twice weekly evaluations of abdominal tone myorelaxation and decreased grip strength. No full tolerance was achieved, however, during the 9 weeks of treatment in terms of ataxia. Electroencephalographic (EEG) studies showed that this tolerance to the behavioural effects was accompanied by a progressive decrease in mean power spectra, associated with a progressive decrease in the beta band, but in this case, full tolerance was reached within 4 weeks. Once weekly evaluations of the ability of chlordiazepoxide to protect the animals against pentylenetetrazole seizures revealed a similar pattern. Treatment with flumazenil (50 mg/kg p.o.) 24 h after the last chlordiazepoxide administration induced a clear withdrawal syndrome associated with EEG changes which consisted of an increase in total power spectra associated with an increase in the delta band (in comparison with chlordiazepoxide-dependent rats not given the antagonist). These findings suggest that the different kinetics of the tolerance to anticonvulsant and EEG effects in comparison to myorelaxant effects can be attributed to a different involvement of benzodiazepine receptor subtypes.

Dose-dependent conditioned place preference produced by etonitazene and morphine.

The conditioned place preference (CPP) paradigm was used to study the reinforcing properties of etonitazene in comparison with those of morphine. Increasing doses of etonitazene (2.5-15 micrograms/kg i.p.) and morphine (1-80 mg/kg i.p.) induced a dose-dependent CPP. High doses of etonitazene (25-40 micrograms/kg) did not elicit CPP. In addition, these reinforcing properties were related to behavioral modifications such as analgesia, assessed with the tail-flick method, and increased catalepsy, evaluated by a scoring system. It is concluded that neither the strong behavioral effects induced by etonitazene nor tolerance to such effects account for the results. These findings are discussed with regard to the possibility that etonitazene could interfere with associative learning motivated by reward.

Polydeoxyribonucleotide (defibrotide) protects against post-ischemic behavioral, electroencephalographic and neuronal damage in the gerbil.

The effectiveness of defibrotide, a single-stranded polydeoxyribonucleotide compound, in preventing damage caused by cerebral ischemia was studied. Global ischemia was induced in anesthetized gerbils by bilateral carotid artery occlusion for 10 min. Defibrotide (100 mg/kg) or saline was injected, i.v., immediately after reperfusion. The following parameters were evaluated simultaneously: (1) electroencephalographic (EEG) spectral power, recorded before, during and after the ischemic period; (2) body temperature, monitored with a rectal thermistor probe after reperfusion for 120 min; (3) spontaneous motility, evaluated through a photocell system and quantified in terms of total distance travelled in 30 min, 1 h after recirculation and at periods over 15 days; (4) mnemonic functions assessed by passive avoidance test from 3 to 15 days after ischemia; (5) histological examination, 7 days after reperfusion, counting CA1 hippocampal neuronal cells. The ischemia-induced complete flattening of spectral power was significantly reversed (P < 0.01) by post-ischemic treatment with defibrotide between 30 and 90 min after ischemia. A complete recovery of total EEG spectral power was seen in the defibrotide group at 6 h and the saline ischemic group at 1 day. Seven days after bilateral carotid occlusion, there was a significant decrease in spectral power (-70% +/- 6) together with a loss of the number of CA1 cells in the saline ischemic group (-64%). Treatment with defibrotide significantly protected against the decrease in spectral power (-30% +/- 7) and cell loss (-9%). Finally, the number of animals found to be protected against the ischemia-induced flattening was significantly larger for defibrotide-treated gerbils than for saline-treated animals throughout the experiment except for the third day. Body temperature was significantly decreased only at 30 min after reperfusion in both ischemic and sham-operated groups. Defibrotide reduced ischemia-induced hypermotility but only 6 h after the insult. The ischemia-induced impairment of memory was partially reversed within 3 days in the defibrotide-treated animals and fully reversed within 7 days in the defibrotide group and 15 days in the saline group. Our results demonstrate that defibrotide, even when administered after the post-ischemic period, possesses anti-ischemic properties. The mechanism by which defibrotide protects the ischemic reperfused brain is still largely unknown. However, a neuroprotection via adenosine A1 and A2 subtype receptor interaction can be put forward.

Effect of centrally administered atropine and pirenzepine on radial arm maze performance in the rat.

The effect of two anticholinergic drugs administered intracerebroventricularly on acquisition of an 8-arm radial maze task was examined in the rat. Increasing doses of atropine (1, 4.5, 22.5, 45 micrograms/rat) and pirenzepine (4.5, 15, 60, 90 micrograms/rat) significantly impaired performance in the working-memory components of the task. For both drugs this impairment was linearly related to the log of the administered doses and log-dose-response relationship were parallel. The regression lines calculated for each parameter for both drugs were parallel to each other, thus allowing us to calculate the potency of atropine versus pirenzepine: atropine was 5.4 times more potent than pirenzepine for correct arm entries, 10 times more potent for the number of errors and 4 times more potent for the total time taken to complete the task. The relevance of M1 and M2 subtype central acetylcholine receptors in cognitive processes is discussed.

Chronic morphine affects working memory during treatment and withdrawal in rats: possible residual long-term impairment.

An eight-arm radial maze was used to investigate a possible short-term (during the development of tolerance and dependence) and long-term (6, 9 and 12 months after treatment) effect on working memory, in young rats, which drank morphine (0.5mg/ml) for 1 month, or to which the drug was administered by i.p. injection (at weekly increasing doses of 20, 50, 100, 200mg/kg). Tail flick test and cortically derived electroencephalographic (EEG) recordings were also carried out in the same rats to determine any modifications in analgesia and in total EEG mean power spectra during treatment and withdrawal. Complete tolerance to morphine analgesia developed during the period of drug treatment. Chronic morphine significantly impaired radial maze performance in the working memory components of the task during both treatment and early withdrawal, but only in the i.p. group. Six and 9 months after morphine treatment, both the oral and i.p. group showed a significant impairment of radial maze performance. The mean power spectra were altered during treatment but returned to baseline values during abstinence, except for the first day. These findings suggest the possibility of morphine-induced premature ageing, which is more evident in i.p. treated animals. The mechanism by which morphine treatment produces residual long-term learning impairment requires further elucidation.

Central effect of yohimbine on sexual behavior in the rat.

A large range of doses of yohimbine (Y) was administered intracerebroventricularly (ICV) (5-100 micrograms/rat) or intraperitoneally (IP) (0.35-10 mg/kg) to male rats and the effects on sexual, locomotor and general behavior were evaluated. For both routes there was a clear-cut inverted-U effect (stimulating/depressing), calculable as parabolic regressions on the log of administered doses. The maximal stimulating doses (15 micrograms/rat ICV and 1 mg/kg IP) significantly shortened mount, intromission and ejaculation latencies and the mean interintromission interval. These data indicate the importance of CNS mechanisms in the sexual effect of Y.

Effects of phenoxyacetic acid herbicides on chicken embryo liver drug metabolizing enzymes.

Chick embryos were treated on day 0 of incubation with two phenoxy herbicides, 2-methyl-4-chlorophenoxyacetic acid (MCPA) (0.4, 2 mg/egg) and 2,4-dichlorophenoxyacetic acid (2, 4-D) (1, 2, 4 mg/egg). Both herbicides seemed to exert toxic effects mainly on the liver of 19-day-old embryos. Specific histological analysis indicated biliary stasis. Ethoxycoumarin O-deethylase was depressed by MCPA but raised by 2, 4-D. Other hepatic monooxygenase activities were unaffected by the herbicides and no significant changes were found in cytochromes. The higher dose of MCPA increased NADPH-cytochrome P450 reductase. 2,4-D treatment increased by activity of glutathione-S-transferases in the hepatic post-microsomal fraction while MCPA increased them at the lower dose and significantly reduced them at the higher. The phenoxyacetic herbicides appear thus to have some effects on hepatic drug metabolizing enzymes of the chick embryo which cannot be easily interpreted. Biliary retention, produced in particular by MCPA, could be partly responsible for these effects.

Possibility of spontaneous drug abuse tested in rat.

Given that a number of the techniques used to test drug abuse liability are not free from criticism, a series of oral free-choice experimental procedures was adopted. When simultaneously offered as alternatives to glucose using the classical polydipsic procedure, no preference for buprenorphine (0.025 mg/ml), morphine (0.5 mg/ml) or fentanyl (0.005 mg/ml) solutions was shown by premedicated rats. The same result was obtained when the two-bottle procedure was used for at least one month to offer etonitazene (10 micrograms/ml), buprenorphine (60 micrograms/ml), cocaine (300 micrograms/ml) and haloperidol (25 micrograms/ml) solutions as simultaneous alternatives to aspartame. This absence of preference was maintained even when the rats showed evident pharmacological effects and, in the case of the opiates, tolerance and withdrawal syndrome. However, when a gustatory marker (quinine) was introduced into one of the two solutions, preference was always shown for the other. Finally, in a conditioned taste aversion (CTA) test, etonitazene (5 or 40 micrograms/kg, i.p.) and haloperidol (0.5 or 2 mg/kg, i.p.) did not induce any reduction in saccharin consumption, while morphine (40 mg/kg) did. Pretreatment with naloxone (120 micrograms/kg, i.c.v.) did not antagonize morphine-induced CTA, while it did antagonize morphine-induced analgesia.

EEG power spectra and behavioral correlates in rats given chronic morphine. Lack of residual long-term EEG and neuronal changes.

The short-term (during tolerance to behavioural effects and withdrawal) and long-term (3, 6, 9 and 12 months after treatment) effects of morphine on mean total electroencephalographic spectral power (analysed by means of fast Fourier transform) and band distribution (delta, theta, alpha, beta) were studied in freely moving young rats implanted with chronic cortical bilateral recording electrodes. Morphine was administered i.p. daily for 1 month at weekly increasing doses of 20, 50, 100 and 200 mg kg-1, and the electroencephalogram was evaluated for 2 h at every change of dose. Treatment with 20, 50 and 100 mg kg-1 led to a significant increase in mean total spectral power 30-60 min from treatment. However, the dose of 100 mg kg-1 led to a smaller increase than that obtained with 50 mg kg-1 and no change was shown with the highest dose, suggesting the progressive development of tolerance. The modification observed for 100 mg kg-1 was accompanied by a relative increase in the delta and decrease in the theta and alpha power spectra. Between the last day of morphine and the first 3 days of abstinence, a progressive decrease in mean total spectral power accompanied by a significant increase in delta and beta and a decrease in theta and alpha frequency was observed. Long-term EEG activity and the counting of the pyramidal cells of the hippocampus failed to reveal any pathological findings after 3, 6, 9 and 12 months.