Gregory Galbicka

Dose-response curves and time-course effects of selected anticholinergics on locomotor activity in rats

Abstract  Rationale: In order to facilitate direct comparisons of anticholinergic drug effects on activity, nine drugs were tested in one laboratory using a standardized procedure. Objective: The present study compared the effects of aprophen hydrochloride, atropine sulfate, azaprophen hydrochloride, benactyzine hydrochloride, biperiden hydrochloride, diazepam, procyclidine hydrochloride, scopolamine hydrobromide, and trihexyphenidyl hydrochloride on activity levels in rats. Methods: Both fine motor activity (reflecting smaller movements) and ambulatory activity (reflecting larger movements) were recorded for 23 h following drug administration in food-restricted rats. All drugs were administered during the light period of the photocycle. Results: Atropine, azaprophen, biperiden, scopolamine, and trihexyphenidyl increased both ambulations and fine motor activity significantly during the first hour post-injection, but the increased activity levels returned to vehicle control levels within 2–6 h post-injection. Benactyzine and procyclidine only increased fine motor activity significantly above vehicle control levels and activity levels returned to vehicle control levels within 2–3 h. Finally, aprophen and diazepam generally did not increase measures of activity significantly above vehicle controls at the dose ranges examined. Conclusions: Based on potencies relative to scopolamine, the potency of the drugs could be ranked as follows: scopolamine > trihexyphenidyl > biperiden > azaprophen > procyclidine > benactyzine > atropine > aprophen. The comparison of drug effects on activity may be useful in selecting anticholinergic drug therapies with a minimal range of side effects. In addition, these data may reduce the number of anticholinergic drugs that need to be tested in comparison studies involving more complex behavioral tests.

Behavioral and immunological effects of exogenous butyrylcholinesterase in rhesus monkeys.

Although conventional therapies prevent organophosphate (OP) lethality, laboratory animals exposed to such treatments typically display behavioral incapacitation. Pretreatment with purified exogenous human or equine serum butyrylcholinesterase (Eq-BuChE), conversely, has effectively prevented OP lethality in rats and rhesus monkeys, without producing the adverse side effects associated with conventional treatments. In monkeys, however, using a commercial preparation of Eq-BuChE has been reported to incapacitate responding. In the present study, repeated administration of commercially prepared Eq-BuChE had no systematic effect on behavior in rhesus monkeys as measured by a six-item serial probe recognition task, despite 7- to 18-fold increases in baseline BuChE levels in blood. Antibody production induced by the enzyme was slight after the first injection and more pronounced following the second injection. The lack of behavioral effects, the relatively long in vivo half-life, and the previously demonstrated efficacy of BuChE as a biological scavenger for highly toxic OPs make BuChE potentially more effective than current treatment regimens for OP toxicity.

Behavioral effects of enantiomers of dizocilpine under two “counting” procedures in rats

Stereoisomers of the N-methyl-D-aspartate antagonist dizocilpine (MK-801) were studied to determine whether behavioral effects on complex operants depend on reinforcement loss accompanying behavioral disruption. Rats earned food pellets if the run of consecutive left-lever presses preceding a trial-terminating right-lever press approximated a target of 12. A percentile schedule reinforced any run closer to the target than two-thirds of the runs on the most recent 24 trials. Once the sequence was learned, half the subjects were shifted to a procedure that yoked reinforcement for each length run to the probability that length generated pellets during asymptototic percentile performance. Although these two procedures generate similar control run and reinforcement distributions, disrupting behavior reduced reinforcement probability far more under the yoked than the percentile procedure. Despite this difference in drug-induced reinforcement loss, both enantiomers produced similar dose-related decreases in run length and response rate under both procedures, with the (-) isomer approximately one log unit less potent than the (+) isomer. The absence of differential effects under these procedures diminishes the likelihood that reinforcement loss contributes to dizocilpines effects, indirectly bolstering claims that dizocilpine directly affects learning.

Tolerance to behavioral effects of physostigmine under interval schedules of positive or negative reinforcement.

The present experiments examined whether the rate and type of events maintaining responding help determine physostigmines behavioral effects. The first two experiments examined the acute and chronic effects of physostigmine, respectively, on lever pressing of rats under variable-interval schedules of food presentation. The third examined the chronic effects of physostigmine on lever pressing under random-interval schedules of shock avoidance. Three different variable intervals (18, 56, and 180 s) and two different random intervals (20 and 60 s) were studied, each associated with a distinctive stimulus. Baseline rates of responding were directly related to the scheduled rate of food delivery or shock avoidance. Acute administration of 0.154–1.233 μmol/kg (0.1–0.8 mg/kg) physostigmine sulfate produced monotonic decreases in overall response rate under all schedules of food presentation. Acute effects (per cent of control response rate) did not differ systematically under the various interval values. Large doses (i.e., 0.4 or 0.8 mg/kg) suppressed the rate of food delivery as well. When initially administered, 0.967 μmol/kg (0.4 mg/kg) physostigmine salicylate also suppressed avoidance response rates and per cent shocks avoided. Tolerance developed to the effects of this dose of physostigmine salicylate on pellet or shock-avoidance frequency more rapidly than to effects on overall response rate. Tolerance to the latter developed only very gradually and could in the case of shock-avoidance response rates be considered partial at best. Tolerance was not affected by the scheduled rate of food or shock presentation. Blood acetylcholinesterase levels showed no recovery during chronic physostigmine. Tolerance is discussed in terms of the reinforcement-loss hypothesis.