Imidazenil prevention of alprazolam-induced acquisition deficit in patas monkeys is devoid of tolerance

Abstract

The partial allosteric modulators (PAMs) of gamma-aminobutyric acid-gated Cl(-) current intensities at gamma-aminobutyric acid type A receptors have high affinity but low intrinsic efficacy on benzodiazepine recognition sites. Unlike the full allosteric modulators (FAM), like alprazolam, triazolam, and diazepam, PAMs are virtually devoid of unwanted side effects, including tolerance. Imidazenil (IMD) is a PAM that elicits potent anxiolytic and anticonvulsant actions in rodents and nonhuman primates and retains its anticonvulsant and anxiolytic effects, even in rodents that are tolerant to FAMs. IMD antagonizes the side effects of FAMs in rodents and nonhuman primates. Using patas monkeys and a multiple schedule with repeated acquisition and performance of chain responses, we report that IMD administration for 17 days antagonized without showing tolerance ALP-induced disruption of acquisition.

Figure 1

Cumulative records showing the within-session pattern of responding for monkey A during representative vehicle (V) session and sessions preceded by administration of 1.8 μmol/kg of ALP on days 1, 10, and 17 of a 17-day ALP daily treatment. Each record represents a complete session (reinforcements), except on days 1 and 10 of ALP treatment, which show the first 60 min of the respective treatments during the 2-hr sessions. The response pen stepped with each correct response and was deflected downward each time food was presented. Errors are indicated by the event pen (below each record), which was held down during each timeout. The event pen was deflected and the response pen reset each component of the multiple schedule changed. Each daily session began with a different four-response chain in the acquisition component (A) and then alternated with a performance component (P) after 10 reinforcements or 15 min, whichever occurred first.

Figure 2

Effects of repeated administration of 0.56 or 1 μmol/kg (open bars) and 1 or 1.8 μmol/kg (hatched bars) of ALP alone, on response rate and percent errors in each component of the multiple schedule for three subjects. The bars indicate the mean values for at least 10 vehicle sessions and single determinations during repeated daily administration of ALP. The symbols represent the values for the individual subjects after the treatment with the respective doses of ALP. Monkeys A and G received daily administration of 1 (open bars) and 1.8 (hatched bars) μmol/kg, whereas monkey F received 0.56 (open bars) and 1 (hatched bars) μmol/kg of ALP. Note that monkey F received lower doses of ALP because this subject was more sensitive to the effects of ALP.

Figure 3

Cumulative record showing within-session pattern of responding for monkey G during a representative vehicle (V) session and sessions preceded by the administration of 0.25, 0.5, and 1.25 μmol/kg of IMD or 1 μmol/kg ALP alone, and a combination of this dose of ALP with 1.25 μmol/kg IMD on days 4, 8, and 15 of repeated IMD (1.25 μmol/kg) treatment. The same single dose of ALP was administered alone on day 2 after discontinuation of a 17-day repeated IMD treatment. The response pen stepped with each correct response and was deflected downward each time food was presented. Errors are indicated by the event pen (below each record), which was held down during each timeout. The event pen was deflected and the response pen reset each time the component of the multiple schedule changed. Each session began with an acquisition component (A) and then alternated with a performance component (P) after 10 reinforcements or 15 min, whichever occurred first.

Figure 4

(A) Effects of repeated oral administration of 0.25, 0.5, or 1.25 μmol/kg of IMD or 0.56 and 1 μmol/kg of ALP alone, and a combination of ALP with IMD during repeated administration of 1.25 μmol/kg of IMD on percent errors in each component of the multiple schedule for three subjects. Points and vertical lines at V and ALP indicate the mean and range for at least 10 vehicle (⧫) and two ALP (□) sessions, respectively. The points in the time effect curves without vertical lines indicate single determinations of the effects of IMD alone (▴) or in combination (○, arrows) with a single dose of ALP. Monkeys A and G received 1 μmol/kg and Monkey F received 0.56 μmol/kg of ALP. All monkeys received repeated administration of increasing doses (0.25, 0.5, and 1.25 μmol/kg) of IMD for 4, 4, and 15 days, respectively. (B) Effects of repeated oral administration of 0.25, 0.5, and 1.25 μmol/kg of IMD and a single 0.56 or 1 μmol/kg of ALP alone, and a combination of ALP with IMD during repeated administration of IMD (1.25 μmol/kg) on response rates in each component of the multiple schedule for three subjects. All drug doses, symbols, keys, and schedule of treatments and subjects are the same as in A.