Cellular and learned tolerances to chlordiazepoxide hypothermia and ataxia.

Four groups of rats received chlordiazepoxide (CDP): a) intermittently, experiencing hypothermia and rotarod performance (RR) deficit after test doses (contingency); b) chronically, experiencing hypothermia and RR deficit after test doses; c) intermittently, RR preceding test doses and with protection against hypothermia afforded by exposure to heat lamps (nonexperienced, noncontingency); and d) chronically, RR preceding test doses and with protection against hypothermia. After 36 days of chronic CDP (groups 2 and 4) or vehicle (groups 1 and 3), all groups experienced RR and body temperature (BT) drug deficits after test doses of CDP at the postwithdrawal test. Group 1 but not group 3 was tolerant to peak hypothermia of the drug. Both chronic groups (2 and 4) showed marked tolerance to hypothermia. At the postwithdrawal test, after discontinuing chronic CDP or vehicle for 9 days, only groups 2 and 4 lost drug tolerance to hypothermia. After extinction training (daily testing of RR and BT after injecting vehicle over 9 days), group 2 but not group 4 was again less sensitive to CDP-induced hypothermia at the postextinction test. Regarding CDP-induced RR ataxia, group 1 was more tolerant than group 3 at the postchronic test, while group 4 but not group 2 also showed tolerance to ataxia. At the postwithdrawal test, only group 4 lost tolerance to peak RR ataxic effects of CDP. At the postextinction test, only group 1 lost tolerance for ataxia relative to postchronic test results.(ABSTRACT TRUNCATED AT 250 WORDS)

Cellular and learned tolerances for pentobarbital hypothermia.

The development of behavioral tolerance to pentobarbital-induced hypothermia, as separable from cellular and metabolic tolerance, was established. Pentobarbital (PB) was administered to 4 groups of rats, 2 groups of which received intermittent (INT) IP PB treatment. One of these groups, INT/EXP, experienced the hypothermic (measured as rectal body temperature) drug effect after PB injection. The other group, INT/NONEXP, was monitored for body temperature functions (room temperature) before receiving PB (vehicle administration) and then prevented from experiencing PB-induced hypothermia by maintenance of body temperature with a towel wrap restraint and a heating lamp. The INT/EXP group also received equivalent exposure to this towel wrap after vehicle administration. Two other groups received chronic PB treatment (IP and in ground chow), one with experience for hypothermia after injections (CHR/EXP) and one prevented from experiencing the hypothermia (CHR/NONEXP). These groups also received equivalent exposure to the body temperature (at room temperature) testing and towel wrap restraint, EXP rats after vehicle injections and NONEXP after drug injections. A postchronic test of all groups compared the extent of PB hypothermia to prechronic test effects to assess the degree of tolerance. The INT/EXP group demonstrated behavioral tolerance for PB-induced hypothermia, as contrasted with the INT/NONEXP group which demonstrated little or no tolerance. Prominent tolerance was noted in both chronic groups for PB hypothermia, without a significant difference between them. After the postchronic test, chronic treatment was discontinued for 9 days (withdrawal) followed by 9 days of extinction training (vehicle behavioral testing). The two intermittent groups demonstrated no change in the hypothermic drug response during the postwithdrawal and postextinction drug tests.(ABSTRACT TRUNCATED AT 250 WORDS)

Cellular and learned tolerance to pentobarbital ataxia.

Pentobarbital was administered to 4 groups of rats: 1) intermittently before testing on the rotarod (RR) (experienced, EXP), 2) chronically (CHR) before testing on the RR (EXP), 3) intermittently (INT) after being tested on the RR (NONEXP), and 4) chronically (CHR) after being tested on the RR (NONEXP). On postchronic testing, Group 1 (INT/EXP) failed to show tolerance to the RR decrement, related to prechronic scores, while Group 3 (INT/NONEXP) actually showed an enhanced RR decrement. Group 2 (CHR/EXP) and Group 4 (CHR/NONEXP) both exhibited prominent tolerance to RR impairment at the postchronic test, with a nonsignificant trend for greater tolerance in Group 2. The lack of an expressed behavioral tolerance in INT/EXP rats and the enhanced RR decrement in INT/NONEXP subjects at the postchronic test was attributed to repeated use of a towel wrap restraint during the chronic treatment period. When the prechronic tests for INT/EXP animals were separated into the first 3 and last 3 days, pentobarbital impairment of RR during days 4-6 was significantly less than during days 1-3. This tolerance in INT/EXP rats was lost at the postchronic testing, while INT/NONEXP subjects had by then developed an enhanced RR impairment to pentobarbital. Following postchronic testing, chronic pentobarbital (CHR/EXP and CHR/NONEXP groups) and chronic vehicle (INT/EXP and INT/NONEXP groups) were discontinued for 9 days (withdrawal), after which an intermediate dose of the drug was tested on RR performance. Next, 9 days of extinction training involved vehicle injection daily before testing RR performance, after which the intermediate drug dose was again tested. INT/EXP and INT/NONEXP groups showed no change in RR impairment at the postwithdrawal and postextinction tests. However, in CHR/EXP rats pentobarbital tolerance was partly lost at the postwithdrawal test, with a significantly greater loss at the postextinction test.(ABSTRACT TRUNCATED AT 250 WORDS)

Cellular and learned tolerances for ethanol hypothermia.

Four groups of rats received ethanol: 1) intermittently while experiencing hypothermia, 2) chronically while experiencing hypothermia, 3) intermittently while protected from hypothermia, and 4) chronically while being protected from hypothermia. On postchronic testing, Group 1 showed tolerance to 2.0 and 2.3 but not 2.7 g/kg ethanol, Group 2 was tolerant to all 3 doses, Group 3 was tolerant to none, and Group 4 was tolerant only to 2.7 g/kg. On withdrawal of chronic ethanol or vehicle, Groups 1 and 2 showed trends to lose tolerance which became significant after subsequent extinction training. The treatments were repeated in other rats up to the postchronic test for tolerance, after which they were killed at 15-120 min after ethanol to assay serum and brain concentrations. Serum and brain levels of ethanol were higher in Groups 2 and 4 despite less intense hypothermia (i.e., no metabolic tolerance). Analysis of covariance indicated less tolerance in Group 1 vs. Group 2 and Group 3 vs. Group 4 for the same brain levels of ethanol (i.e., cellular tolerance in Groups 2 and 4). Therefore, both learned and cellular tolerances were observed in these subjects and appeared to be separable phenomena according to the various treatments imposed.

Evidence for 5-HT2 receptor mediation in quipazine anorexia.

Doses of d-amphetamine (3.2 mg/kg), fenfluramine (10 mg/kg) and quipazine (8 mg/kg) cause a significant reduction in food intake during a 30-min daily feeding session in food-deprived rats. Pirenperone and ritanserin, 5-HT2 receptor antagonists, significantly blocked the anorectic effect of quipazine, while d-amphetamine and fenfluramine effects were not modified. Metergoline, a non-specific blocker of 5-HT receptors, significantly blocked the anorectic effects of fenfluramine and quipazine, but not the d-amphetamine effect. Pretreatment with alpha- and beta-adrenergic receptor antagonists (prazosin, propranolol and pindolol), dopamine receptor antagonists (haloperidol and pimozide), the catecholamine synthesis inhibitor alpha-methyl-para-tyrosine, and the opioid receptor antagonist naloxone failed to modify the anorectic effects of all three agents, with the exception that quipazine-induced anorexia was significantly reduced by pimozide. These results suggest that the quipazine anorexia is largely mediating through 5-HT2 receptors, although the effect of pimozide remains to be explained. Consistent with previous studies, the fenfluramine effect appears to be mediated through 5-HT1B receptors. Receptors involved in the anorectic effect of higher doses of d-amphetamine are still unidentified by this analysis. Further investigation is required to define the mechanisms by which quipazine and larger doses of d-amphetamine bring about a reduced appetite for food.

Disruption of FR-40 by 5-HT agonists. I. Effects of chronic imipramine or trazodone.

Doses of LSD, quipazine, 8-OHDPAT and TFMPP were established that prominently disrupted FR-40 operant response pattern in two groups of rats. Subsequently, one group received daily intraperitoneal (IP) injections of imipramine, 2.5 mg/kg, for 4 weeks, then 10 mg/kg for 2 additional weeks. The second group received 5 mg/kg/day, IP, of trazodone for the first 4 weeks, then 20 mg/kg/day for the next two weeks. For these periods and the 3 weeks after discontinuing the chronic drug treatments (washout), test doses of the 4 agonists were evaluated twice weekly in random order for their effects to decrease FR-40 reinforcements and increase pauses. No consistent, systematic changes in sensitivity to the agonist effects on FR-40 behavior were observed during chronic drug treatments, although significant effects were at times observed. However, during the washout period in the imipramine group, both LSD and 8-OHDPAT effects on reinforcements were reversed to baseline levels. The effect of 5-OHDPAT on pauses during washout in this group was also attenuated. During washout in the trazodone group, the 8-OHDPAT-induced pausing and loss of reinforcements was reduced so as to be not significantly different from baseline values. Previous studies have demonstrated antagonism of LSD- and quipazine-induced disruption of FR-40 by pretreating with the 5-HT2-selective antagonist pirenperone (28). Since chronic antidepressants down-regulate brain 5-HT2 binding sites, the effects of LSD and quipazine were expected to be attenuated, which was not the case.(ABSTRACT TRUNCATED AT 250 WORDS)

Disruption of FR-40 by 5-HT agonists. II. Effects of chronic phenelzine or isocarboxazid.

Effects of chronic treatment with the monoamine oxidase inhibitors phenelzine and isocarboxazid on disruption of FR-40 operant responses by 5-HT agonists have been studied. Three groups of rats that were trained in the FR-40 operant schedule showed marked disruption by 0.1 mg/kg IP lysergic acid diethylamide (LSD), 2 mg/kg IP quipazine (Q), 0.05 mg/kg SC 8-hydroxy-2-(di-n-propylamino)tetralin (8-OHDPAT), and 1 mg/kg SC (m-trifluoromethyl-phenyl)piperazine (TFMPP), administered twice weekly in random order. Subsequently, one group received daily IP injection of phenelzine (5 and 10 mg/kg), the second group received 5 mg/kg IP of isocarboxazid, and the third group received vehicle (0.5% methyl cellulose) for 24 days (Period 1 and Period 2). For these periods and 12 days after discontinuing the MAOI treatments (Washout Period), test doses of 5-HT agonists were evaluated for their effects to decrease reinforcements (R) and increase pauses (P). No change in sensitivity to the LSD, Q and TFMPP effects on FR-40 behavior was observed in the vehicle-treated group. However, an attenuated effect of 8-OHDPAT was found in this group. In phenelzine- and isocarboxazid-treated rats the disruption of FR-40 responses by LSD and 8-OHDPAT were significantly reduced during Period 1, Period 2 and Washout Period. A significantly less effect on disruption in FR-40 responses by quipazine and TFMPP during Period 2 and the Washout Period was also seen. Since MAO inhibitors appear to down-regulate both 5-HT1 and 5-HT2 binding sites in brain, the attenuated effects of the 5-HT agonists were anticipated.(ABSTRACT TRUNCATED AT 250 WORDS)

Teratogenicity of n-propanol and isopropanol administered at high inhalation concentrations to rats.

As part of a teratological evaluation of several alcohols, 10,000, 7000 and 3500 ppm n-propanol or isopropanol were administered by inhalation to groups of 15 pregnant Sprague-Dawley rats for 7 hr/day on gestation days 1-19. The dams were killed on day 20. Half of the foetuses were examined for skeletal defects and the others for visceral defects using the Wilson technique. The highest concentration of n-propanol produced only minimal maternal toxicity, as indicated by observation and by measurement of weight gain and feed and water intake. In contrast, the same concentration of isopropanol produced narcosis in the dams, retarded body-weight gain and reduced the feed intake. At 7000 ppm isopropanol, body-weight gain was retarded but there were no other observable effects in the dams. Following exposure to 10,000 ppm of either alcohol, there were significant (P less than or equal to 0.05) increases in resorptions and decreases in foetal weights compared with the control groups. Foetal weights were also reduced significantly following exposure to 7000 ppm of either alcohol and to 3500 ppm isopropanol. Significantly more litters had malformations following exposure to 10,000 or 7000 ppm of either alcohol, but these effects were seen only in the presence of maternal toxicity. At 3500 ppm, no detectable teratogenic effects were produced by either solvent.

Neurochemical, but not behavioral, deviations in the offspring of rats following prenatal or paternal inhalation exposure to ethanol.

In addition to its widespread social use, ethanol is used extensively as an industrial solvent. Inhalation exposures to ethanol which produce narcosis in maternal rats are not teratogenic. The present study sought to extend the previous research by including offspring from paternal exposures, and testing for behavioral disorders in the offspring following maternal or paternal exposures. Groups of 18 male (approximately 450 g) and 15 female (200-300 g) Sprague-Dawley rats were exposed 7 hours/day for six weeks or throughout gestation to 16000, 10000, or 0 ppm ethanol by inhalation and then mated with untreated rats. Litters were culled to 4 males and 4 females, and were fostered within 16 hours after birth to untreated dams which had delivered their litters within 48 hours previously. Offspring from paternally or maternally exposed animals performed as well as controls on days 10-90 in tests of neuromotor coordination (ascent on a wire mesh screen, rotorod), activity levels (open field, modified-automated open field, and running wheel), and learning ability (avoidance conditioning and operant conditioning). In addition, brains of 10 21-day-old pups were analyzed for neurochemical differences from controls in concentrations of protein and the neurotransmitters acetylcholine, dopamine, norepinephrine, 5-hydroxytryptamine, substance P, Met-enkephalin, and beta-endorphin. Levels of acetylcholine, dopamine, substance P, and beta-endorphin were essentially unchanged in the offspring of rats exposed to ethanol. Complex, but significant changes in levels of norepinephrine occurred only in paternally exposed offspring. 5-Hydroxytryptamine levels were reduced in the cerebrum, and Met-enkephalin levels were increased in all brain regions of offspring from both maternally and paternally exposed rats.