Phase-response curve for ethanol: alterations in circadian rhythms of temperature and activity in rats.

Circadian rhythms of core body temperature and general activity in Sprague-Dawley rats were monitored for 21 days using remote radiotelemetry to examine acute and sustained effects of 0 (saline) 1.0, and 2.0 g/kg ethanol injections administered at four different times of day. Ethanol produced dose-dependent and statistically significant hypothermia and hypoactivity when injected at 0100, 0700, 1300, and 1900 h; however, the magnitude of the hypothermic effect was greatest at the 1900-h injection time. Cosinor analyses revealed persistent alterations in both activity and temperature rhythms, which lasted for at least 48 h postinjection. Ethanol significantly shortened the period of activity rhythms when injected in either 1.0 or 2.0 g/kg doses at 0700 and 1300 h, and produced similar period-shortening effects on temperature rhythms at 1300 and 1900 h. The acrophase of the activity rhythm was significantly phase delayed by 1.0 g/kg ethanol at 0700 h, while the acrophase of temperature was significantly phase advanced by 2.0 g/kg ethanol at 0100 h, but significantly phase delayed by the same dose administered at 1300 h. A statistically significant and dose-dependent reduction in the amplitude of the body temperature rhythm was observed at the 1900-h administration time. There were no differences in the MESOR (Midline Estimating Statistic of Rhythm; i.e., rhythm-adjusted mean value) of either temperature or activity circadian rhythms as a function of ethanol treatment at any dose.

State-dependent stimulus control: cuing attributes of acute cocaine rebound in rats.

Sprague-Dawley (Rattus norvegicus) rats were trained in a drug discrimination task using the state-dependent interoceptive stimulus attributes of cocaine's delayed or rebound effects (CDE) versus "normal" basal homeostasis. Rats were injected with either 32 mg/kg cocaine or equivalent volumes of saline (SAL), subcutaneously, 13 hr before the sessions. Rats demonstrated > 90% discriminative accuracy. Test sessions showed a time-dependent acute cocaine isodirectional rebound state that engendered a shift from predominantly SAL- to CDE-appropriate responding approximately 7 hr after the high training dose injection and lasted for approximately 10 hr (17 hr postinjection). The delayed or rebound state was dose dependent and engendered only a biphasic partial generalization with acute cocaine injections. There were no detectable levels of cocaine or any of its behaviorally active metabolites at the 13-hr postinjection interval. Tests conducted with various doses of lidocaine, chlordiazepoxide, N-methyl-d-aspartic acid, ketamine, and buspirone engendered SAL- or default-appropriate responding. The anxiogenic drug, pentylenetetrazole, produced partial generalization to the cocaine rebound cue.

Reinforcing effects of caffeine, ephedrine, and their binary combination in rats.

The reinforcing effects of caffeine, ephedrine, and caffeine + ephedrine combinations were tested in rats maintained to self-administer 0.5 mg/kg/injection of cocaine in daily 4 h limited access periods. The dose-response relationship for cocaine demonstrated a a typical inverted U-shaped function. The dose-dependent administration of cocaine was stable over the 3-day substitution epochs. Similar to earlier reports, neither caffeine nor ephedrine engendered stable patterns of self-injections. Combinations of caffeine + ephedrine produced biphasic patterns of administration only on the first day of substitution. Days 2 and 3 of the caffeine-ephedrine substitution periods engendered variable and inconsistent reinforcer deliveries that did not significantly differ from saline substitution tests. These reduced patterns of self-administered caffeine-ephedrine combinations were not attributed to behavioral toxicity. Progressive-ratio tests demonstrated rank ordered break points of: food > cocaine > caffeine ephedrine combination = caffeine = ephedrine = saline. Caffeine-ephedrine pretreatments failed to show any significant change in the administration of the maintenance dose of cocaine except at the highest combination dose tested. Although previous data from this laboratory demonstrated symmetrical crossgeneralization between the discriminative effects of caffeine-ephedrine combinations and cocaine, the present data suggest limited reinforcing effects of these combinations in rats.

Moderate, long-term, alcohol consumption potentiates normal, age-related spatial memory deficits in rats.

A modified "Samson" sucrose fading procedure was used to establish voluntary consumption of a 20% ethanol (EtOH) solution in male Sprague-Dawley rats for 18 consecutive months. Intakes were stable over the life span, and corresponded to the moderate to high levels of intake typically observed in human "social" drinkers and alcoholics. The Morris Water Maze (WM), Olton Radial Arm Maze (RM), and a "balance beam" test were used to assess the effects of alcohol and aging on spatial memory and motor function. Aged EtOH-consuming rats (AGED/ALC) demonstrated impaired task acquisition, relative to aged controls (AGED), not reaching criterion performance in either spatial memory task even when given four additional days of training. AGED/ALC rats scored significantly lower on percent correct out of the first eight arm entries, and committed more perseverative errors in the RM. There were no significant performance differences between AGED and AGED/ALC rats on a balance beam test of fine motor coordination and equilibrium, suggesting that deficits observed in the RM and WM were not related to differential motor functioning. These results demonstrated that long-term, moderate, oral self-administration of EtOH, within the range typically consumed by humans, had adverse effects on spatial memory in rats, and that such a pattern of EtOH consumption seemed to exacerbate the decline in cognitive functioning associated with normal aging.

The stimulus properties of two common over-the-counter drug mixtures: dextromethorphan + ephedrine and dextromethorphan + diphenhydramine.

Two groups of rats were trained in a two-choice drug discrimination procedure under a fixed-ratio 10 schedule of food reinforcement. One group of rats (n=12) was trained to discriminate the presence and absence of a drug mixture containing 10 mg/kg dextromethorphan + 10 mg/kg diphenhydramine. The other group of rats (n=12) was trained to discriminate the presence and absence of another drug mixture containing 10 mg/kg dextromethorphan + 10 mg/kg ephedrine. Cross-generalization tests conducted with each of the stimulus elements demonstrated that (1) the drug mixtures were not perceived as new entities distinct from their component elements and (2) the stimulus element saliency may be a factor determining the nature of discriminative control by drug mixtures. Cross-generalization tests conducted with the psychomotor stimulants, cocaine and amphetamine, engendered complete generalization to the training cues in both groups, whereas, pentobarbital engendered predominantly saline- or default-lever responding. These data suggest a potential abuse liability for both of these common over-the-counter drug mixtures and cautions against the use of such combinations in pediatric patients.

Genetic selection of alcohol preference can be countered by conditioning processes.

Twenty-four P rats and 24 NP rats were conditioned to consume 10% w/v alcohol in daily 0.5-h limited access periods using a modified version of Samson's sucrose fading procedure. Both P and NP rats demonstrated a strikingly similar day-to-day pattern of alcohol intakes. For the most part, P rats drank more than NP rats, but by the middle of the fourth month of drinking, P and NP rats were drinking equivalent amounts of alcohol. Both P and NP rats consumed alcohol in amounts similar to two outbred strains of rats (Wistar and Sprague-Dawley) previously conditioned to drink alcohol in this laboratory.

Discriminative stimulus characteristics of BMY 14802 in the pigeon.

Pigeons were trained to discriminate intramuscular injections of 5.6 mg/kg BMY 14802, a drug that has relatively high affinity for sigma binding sites, from saline in a two-key operant procedure. Many compounds that displace sigma binding failed to produce BMY 14802-like discriminative stimulus effects; these included (+)-SKF 10,047, (+)3-PPP, DTG and MR 2035; the typical antipsychotic haloperidol; the putative antipsychotics tiospirone, cinuperone and rimcazole; and the uncompetitive NMDA antagonist phencyclidine. In addition, MR 2035 and tiosperone failed to antagonize the discriminative stimulus effects of BMY 14802. The selective D2 antagonist eticlopride and the norepinephrine uptake blocker and antidepressant desmethylimipramine also failed to evoke substantial BMY 14802-appropriate responding. In contrast to sigma ligands and other reference compounds, the 5-HT1A agonists buspirone, 8-OH-DPAT and spiroxatrine dose-dependently produced BMY 14802-like discriminative stimulus effects. The limited-efficacy 5-hydroxytryptamine (HT)1A agonist NAN 190 did not produce BMY 14802-like discriminative effects; however, it did competitively antagonize the stimulus effects of BMY 14802 and the BMY 14802-like stimulus effects of (+/-)-8-hydroxy-2-(di-n-propylamino)tetralin. Other serotonergic compounds failed to produce substantial BMY 14802-appropriate responding; such as 5-HT1 agonist I-5-HTP; 5-HT1A/1B agonist RU24969; 5-HT1B/1C agonist m-CPP; 5-HT1C/2 agonist quipazine; 5-HT1C/2 antagonists, metergoline and the atypical antipsychotic clozapine; and 5-HT3 antagonist ondansetron. Also, metergoline, ondansetron and pirenpirone failed to antagonize the stimulus effects of BMY 14802. These results indicate that the discriminative stimulus effects of BMY 14802 are serotonergically mediated primarily by 5-HT1A receptors rather than by sigma sites.

Effects of time-of-day and photoperiod phase shifts on voluntary ethanol consumption in rats.

Two experiments were conducted to examine the circadian fluctuations in voluntary ethanol (ETOH) consumption in male Sprague-Dawley rats conditioned to consume ETOH in their homecage and exposed to photoperiod phase shifts equivalent to those experienced by humans. Using a maintenance concentration of 20% w/v ETOH, changes in homecage drinking in 42 rats were assessed after photoperiod phase shifts similar to those inducing "jet lag" in humans and after experimenter-induced "hangover." A single 8-hr photoperiod phase advance significantly increased ETOH intake for three consecutive days, and a single photoperiod phase-delay increased intake only on the day of the phase shift. Acute ETOH withdrawal significantly reduced the voluntary consumption of ETOH for two consecutive days. In a second group of 30 rats maintained to consume a lower concentration of 10% w/v ETOH, the long-term effects of "shift lag" initiated by repeated photoperiod phase shifting similar to those experienced by humans working under a rotating work schedule were examined. Significant increases in intake occurred over the 2-month testing period. The significant alterations in voluntary intake initiated by the shift work schedule was related to the significant changes in blood alcohol concentrations.

Pharmacological characterization of an operant discrimination among two doses of morphine and saline in pigeons.

A cumulative dose, multiple-trial test procedure was developed in eight pigeons trained to discriminate among saline, 1.8mg/kg morphine, and 10mg/kg morphine. Initially, single-trial tests were used to evaluate stimulus effects of acute doses of morphine. Next, the test procedure was altered so that cumulative doses were tested within a single session. Results from cumulative-dose tests of morphine were consistent with those from single-trial tests. The cumulative-dose test procedure was then used to characterize the high-dose and low-dose morphine training stimuli. The mu agonists etorphine, fentanyl, methadone and morphine dose-dependently evoked both low-dose and high-dose morphine-like effects, with a similar potency order (etorphine > fentanyl > methadone = morphine). In contrast, nalbuphine evoked only low-dose effects, consistent with low efficacy mu agonist activity. The kappa opiate U50,488H evoked saline-key responses, whereas the non-opiate ketamine evoked saline-key responses in the majority of pigeons, but high-dose and/or low-dose responding in others. Naltrexone dose-dependently antagonized both low-dose and high-dose stimulus effects of morphine, but not its rate-decreasing effects. Apparent pA(2) values for naltrexone were 7.2 for low-dose stimulus effects of morphine, and 7.4 for high-dose effects. These characteristics suggest that stimulus effects of both low and high training doses of morphine are mediated by common, presumably mu opioid, receptor populations.

The discriminative stimulus effects of clozapine in pigeons: involvement of 5-hydroxytryptamine1C and 5-hydroxytryptamine2 receptors.

Pigeons were trained to discriminate i.m. injections of the atypical antipsychotic clozapine (1.0 mg/kg) from saline in a two-key operant procedure. In substitution tests, compounds that shared antagonistic action at 5-hydroxytryptamine (5-HT)1C and 5-HT2 receptors produced discriminative stimulus effects similar to clozapine: cyproheptadine, metergoline, mianserin, pizotifen and fluperlapine. 5-HT antagonists selective for 5-HT2 vs. 5-HT1C receptors (e.g., ketanserin, pirenperone, risperidone and methiothepin) failed to produce substantial clozapine-appropriate responding. Other serotonergic compounds failed to produce substantial clozapine-appropriate responding: the 5-HT3 antagonist, ondansetron; the 5-HT1A agonists, (+-)-8-hydroxy-2-(di-n-propylamino)tetralin and BMY 14802; the 5-HT1A/1B agonist, RU24969; the 5-HT1A partial agonist, NAN190; the 5-HT1C/2 antagonist, mesulergine; the 5-HT1 agonist, I-5-hydroxytryptophane; and the 5-HT1C/2 agonist, quipazine. Other reference compounds such as the typical antipsychotics, chlorpromazine and thioridazine; the selective dopamine D-2 antagonists, droperidol and sulpiride; the dopamine D-1 antagonist, SCH 23390; the antimuscarinics, atropine and scopolamine; the antihistamines, pyrilamine and diphenhydramine; the alpha-1 antagonist, prazosin; and the antidepressants, imipramine and chloromipramine also failed to produce clozapine-appropriate responding. Promethazine, cinanserin and amitriptyline produced only partial generalization to the clozapine cue. The results suggest that blockade of both 5-HT2 and/or 5-HT1C receptors is important in the pharmacological mediation of the discriminative stimulus effects of clozapine. Blockade of 5-HT2 receptors appears not to be sufficient to produce clozapine-like discriminative stimulus effects. The precise role of 5-HT1C receptors in the clozapine discriminative stimulus is unclear due to the lack of compounds selective for this receptor.(ABSTRACT TRUNCATED AT 250 WORDS)

Tripelennamine effects on body and organ weights, water intake, and several behaviors of rats.

The effects of 14 daily injections of tripelennamine on several dependent measures were determined in groups of rats that received 0.0 (vehicle only), 2.0, 4.0, 8,0, or 16.0 mg/kg of the drug.l Tripelennamine did not affect body weights, organ weights (heart, liver, adrenals, kidneys), or blood glucose levels. Daily water intake was, however, directly and significantly related to tripelennamine dose. The drug failed to influence performance in a grasping response assay, or locomotion as measured in running wheels when rats received footshocks immediately before assessment of locomotion. Tripelennamine did significantly reduce locomotion when rats were not shocked before testing. Nociception, as measured via a hot-plate assay, also was altered by the drug. Here, rats exposed to 16 mg/kg evinced paw-lick latencies far greater than those that received lower doses. These results indicate that tripelennamine produced observable behavioral effects at doses which are not obviously toxic.