Markku Linnoila

Profile of Acute Tolerance to Three Sedative Anxiolytics

Acute tolerance, defined as a decreasing drug effect relative to drug-plasma levels (DPL) over a period of minutes to a few hours, is pronounced following single doses of diazepam or pentobarbital. Both of these lipid-soluble drugs produce an early peak behavioral impairment and subsequent rapid recovery component that is followed by a much slower blood-drug rise time. These pronounced early peak effects were not shared by alcohol, and contribute significantly to the lack of correlation between impairment and DPL.

Effects of oral contraceptives on diazepam‐induced psychomotor impairment

Eight young women taking oral contraceptives and 10 young men each received three different doses of diazepam, 0.07, 0.14, and 0.28 mg/kg. The women also received each dose both on days 10 and 28 of an oral contraceptive cycle. Performance based on both a psychomotor and cognitive‐encoding task was significantly impaired after a 0.28‐mg/kg dose of diazepam in women taking oral contraceptives and in men. In general, however, impairment in performance was less on day 10 than on day 28 of the oral contraceptive cycle. The onset of behavioral impairment was also slower on cycle day 10 than on day 28; peak impairment was reached at 20 min after dosing for men and women on day 28, but at 60 min for women on day 10. The cycle phase effects are potentially dangerous because of their unexpected nature. Individuals may obtain an expectation of intoxication based on the 21‐day OC period yet experience capriciously greater acute impairment during their 7‐day menstrual pause.

Plasma steady‐state concentrations of hydroxylated metabolites of clomipramine

Plasma clomipramine, desmethylclomipramine, 8‐hydroxyclomipramine, and 8‐hydroxydesmethylclomipramine concentrations were measured in nine obsessive‐compulsive outpatients. The mean dose of clomipramine at steady state was 237.5 ± 51.8 (SD) mg/24 hr. The mean concentrations at steady state were: clomipramine, 147.5 ± 57.5; de smethylclomipramine, 313.0 ± 170.0; 8‐hydroxyclomipramine, 56.1 ± 20.9; and 8‐hydroxydesmethylclomipramine, 152.7 ± 83.2 ng/ml. In vitro, the hydroxymetabolites of clomipramine and de smethylclomipramine exhibited serotonin reuptake potency of the same order as that of the parent compounds.

Induced Ovulation in Aged Female Rats by L-dopa Implants into the Medial Preoptic Area

Direct placement of L-dopa into the medial preoptic area (MPOA) of aged pseudopregnant or constant vaginal estrous female rats resulted in a reinitiation of vaginal cycles and ovulation. Similar treatment with L-dopa in the dorsomedial septum or cortex was ineffective. Direct placement of leucine into any of the three brain regions did not have an effect on ovarian function. Intermittent treatment with L-dopa to MPOA was found to reinstate and maintain vaginal cycles in constant estrous females only when administered on the day of vaginal estrus of successive cycles. These findings support the hypothesis that age-dependent disturbances in ovarian function may be initiated by changes in neurotransmitter metabolism within the central nervous system.

Sexual behavior in aged, noncycling female rats

Abstract Sexual behavior of 19 month old, noncycling, female rats was evaluated for a period of 8 days. The sexual behavior of 11 aged females revealing constant vaginal cornification (CVC) for 30 days prior to, and during the observation period was variable. Eight of the CVC females showed consistently high lordosis quotients (LQ), whereas 3 showed no lordosis. A significant negative correlation was found between food intake and LQ over the 8 day period. In 8 other aged females, the vaginal smear was characterized by a mixture of both leucocytes and cornified cells, each day, for a period of 30 days prior to, and during the observation period. Lordosis behavior was absent in all females revealing this mixed type (MX) smear when they were tested. At random times after the test period, 3 CVC and 2 MX females showed a vaginal cycle. As the vaginal cycle was observed each female was again tested for sexual behavior. All 5 females were highly receptive when placed with the male during the evening of vaginal proestrus, but not at other times. It is concluded that despite disruptions of regular ovarian cyclicity, aged female rats are still capable of showing a lordosis response.

Diazepam and N‐desmethyldiazepam redistribution after heparin

The effects of heparin, 1,000 U intravenously, on the blood, plasma, and free concentrations of diazepam and its metabolite, N‐desmethyldiazepam, have been investigated 3 hr after oral administration of 10 mg diazepam to 5 normal subjects. The percent free diazepam and N‐desmethyldiazepam increased 15 min after heparin from 1.66 ± 0.35 to 3.99 ± 1.88 (mean ± SD; p < 0.05) in the case of diazepam and from 2.50 ± 0.65 to 5.00 ± 1.96 (p < 0.05) in the case of its metabolite. The actual free concentration of diazepam rose from 3.6 ± 1.04 to 6.9 ± 1.33 ng/ml (p < 0.05) 15 min after heparin while total blood concentration was unchanged (144 ± 54 vs 130 ± 57 ng/ml). Free concentrations of N‐desmethyldiazepam rose from 0.62 ± 0.17 to 1.01 ± 0.34 but the effect, though consistent, was not statistically significant. Blood concentrations did not change (15 ± 3.2 vs 14 ± 3.9 ng/ml). That free drug level rose without a change in blood or total plasma levels suggests that factors other than simple plasma binding displacement are involved in this drug interaction.

Effects of ethanol and psychomotor tests on state anxiety: interaction with menstrual cycle in women.

10 non-alcoholic women (ages 20 to 25 yr.) were administered drinks containing ethanol 0.0, 0.5, 0.8, and 1.2 g/kg. They then performed four complex psychomotor tasks. Immediately prior to drinking and after completing the tasks they were given the Spielberger State-Anxiety Inventory. Women were tested both during follicular and the luteal phases of their menstrual cycle. A significant positive correlation was found between increments in anxiety scores and blood ethanol levels in the luteal but not in the follicular phase.

Use of simple tasks to test for impairment of complex skills by a sedative

Examination of the effect of three doses of pentobarbital on the comparative performance of a complex psychomotor taks with two simple neuromotor tasks, i.e., standing steady and pendulum eye tracking, revealed a high correlation. These simple tasks could be used as measures of intoxication since they do not require extensive training. Examination of the complex task impairment blood level ratio revealed that impairment relative to blood level was much greater in the absorption phase. This changing ratio underscores the point that blood levels alone are not an adequate estimate of intoxication.

Catecholaminergic-serotonergic balance in the CNS and reproductive cycling in aging rats

Treatment with the serotonin (5-HT) reuptake inhibitor zimelidine, 20 mg/kg/24 hr, SC, for 14 days increased the duration of vaginal cycles in 3 month-old Long Evans hooded rats. It induced persistent vaginal estrus in 12 of 16 ten-month-old animals, and blocked reinitiation of vaginal cycles by L-dopa in 10 of 10 twenty-month-old rats. A single injection of zimelidine at 1400 hr did not alter the vaginal smear pattern of young or middle-aged cycling females or old constant estrus females. Also, a single dose of zimelidine at 1400 hr on the day of vaginal proestrus had no effect on serum LH values in young females. The serotonergic neurotoxin 5,7-dihydroxytryptamine, 4 micrograms, injected into the ventral and dorsal raphe areas (after desipramine, 25 mg/kg IP) reinitiated vaginal cycling in 8 of 13 twenty-month-old rats. These results suggest that age-dependent changes in serotonin metabolism may contribute to the age-dependent changes in luteinizing hormone secretion which eventually lead to the cessation of ovarian function in the rat and that alterations in serotonin function are an important component of the mechanism by which treatments with catecholamine precursors reinstate ovarian function in the old female rat.

Effect of luteinizing hormone-releasing hormone antiserum on sexual behavior in the female rat

Various components of sexual receptivity were measured in ovariectomized, estrone-primed female rats following direct placement of luteinizing hormone releasing hormone (LH-RH) or a LH-RH antiserum into the medial preoptic area. Two hours after treatment with LH-RH antiserum, rats showed a significant increase in lordosis behavior indicative of increased sexual receptivity. When tested 3 and 7 hours after treatment, both LH-RH antiserum and LH-RH-treated rats displayed increased lordosis behavior. Similar treatment with a specific peripheral LH-RH agonist and antagonist had no effect on sexual behavior. Proceptive behavior was absent or minimal in all groups and therefore was not affected by the different treatments. Similarly, there was no difference in the rejection quotients of the females representing the various treatment groups. These results demonstrate that the same behavioral response can be observed in animals treated centrally with LH-RH and a highly specific LH-RH antiserum. Similar treatments with a specific peripheral LH-RH agonist or antagonist were without effect. These results suggest that the characteristics of LH-RH recognition sites in the brain are different from those in the pituitary.