EFFECTS OF GABA_A MODULATORS ON THE REPEATED ACQUISITION OF RESPONSE SEQUENCES IN SQUIRREL MONKEYS

Abstract

The present study investigated the effects of positive and negative GABA(A) modulators under three different baselines of repeated acquisition in squirrel monkeys in which the monkeys acquired a three-response sequence on three keys under a second-order fixed-ratio (FR) schedule of food reinforcement. In two of these baselines, the second-order FR schedule and the discriminative stimuli for the response sequence were manipulated ("chain-strained" and "tandem-strained"). In the third baseline condition, response-independent tail shock was presented during acquisition of the response sequence. All of these baselines maintained high error levels and produced slow rates of acquisition. Under both the chain-strained and tandem-strained conditions, the positive GABA(A) modulator triazolam (0.0032-0.1 mg/kg) and the negative GABA(A) modulators beta-CCE (ethyl-beta-carboline-3-carboxylate; 0.01-1 mg/kg), beta-CCM (methyl-beta-carboline-3-carboxylate; 0.0032-0.1 mg/kg), and FG-7142 (methyl-beta-carboline-3-carboxamide; 0.18-10 mg/kg) dose-dependently decreased overall response rate compared to administration of saline (control). Under the same two conditions, triazolam and the negative GABA(A) modulators also increased the percentage of errors; however, the effects on accuracy frequently depended on the baseline condition and the particular modulator. In contrast, triazolam only decreased errors and enhanced acquisition in the presence of concurrent response-independent tail shock when compared to saline administration under this condition. The neutral GABA(A) modulator, flumazenil (1 mg/kg), had no effect on rate or accuracy of responding when administered alone, but antagonized the rate-decreasing and error-increasing effects produced by the negative GABA(A) modulators. Together, these data suggest that the effects of both the positive and negative GABAA modulators on acquisition can be similar in squirrel monkeys (i.e., both types of modulator may produce rate-decreasing and error-increasing effects) and that their effects on acquisition depend, in part, on the environmental conditions maintaining acquisition.

Chlordiazepoxide and dizocilpine, but not morphine, selectively impair acquisition under a novel repeated-acquisition and performance task in rats

“…The present data with CDP are consistent with those obtained in the RAP/MST with rats (Keith and Galizio 1997;Keith et al 2003;Padlubnaya et al 2005) and with those from other RAP tasks in a variety of species (e.g., Bickel et al 1991;Auta et al 1995;Winsauer et al 1996;Campbell et al 2004). It should be noted, however, that positive GABA A modulation does not guarantee that acquisition-selective effects will be observed.…”

“…The benzodiazepines chlordiazepoxide (CDP) and midazolam (MDZ) consistently impair spatial acquisition in this RAP/MST at doses that do not affect performance (Keith and Galizio 1997;Keith et al 2003;Padlubnaya et al 2005). These selective effects on spatial acquisition are similar to those typically reported with benzodiazepines under RAP procedures with response sequences (e.g., Auta et al 1995;Winsauer et al 1996;Campbell et al 2004). …”

“…It should be noted, however, that positive GABA A modulation does not guarantee that acquisition-selective effects will be observed. For example, Keith et al (2003) found that pentobarbital affected acquisition in a RAP/MST procedure only at doses that also affected performance, and Campbell et al (2004) found that error-increasing effects of several positive GABA A modulators on acquisition were highly dependent on the particular environmental conditions maintaining acquisition. Furthermore, the selective effects of CDP in the present study were relatively small.…”

Interaction of cocaine with positive GABAA modulators on the repeated acquisition and performance of response sequences in rats

“…A similar profile of effects was shown in a study by Campbell et al (2004), where the benzodiazepine triazolam increased errors in squirrel monkeys responding on a repeated acquisition of behavioral chains procedure, but the same dose decreased errors when responding in the repeated-acquisition procedure was disrupted by response-independent tail shocks. These findings support the idea that the effects of benzodiazepines on learning are dependent on the presence or absence of specific environmental events.…”

Relative potency and effectiveness of flunitrazepam, ethanol, and beta-CCE for disrupting the acquisition and retention of response sequences in rats

“…Consistent with this relationship, positive GABA A modulators have been shown to disrupt the acquisition of behavioral tasks in numerous species, including humans (Bickel et al, 1990), whereas the negative modulators have been shown to enhance acquisition and retention in certain behavioral tasks in several species (e.g., Venault et al, 1986; Mayo et al, 1992). With regard to their effects on repeated-acquisition procedures, however, the negative modulators have thus far only been shown to be disruptive to responding (Auta et al, 1997; Campbell et al, 2004). For example, in squirrel monkeys responding under two different repeated-acquisition procedures (one involving tandem stimuli similar to the present study, and another involving “chain” stimuli), three negative GABA A modulators (β-CCE, β-CCM and FG-7142) decreased overall response rate and increased percent errors in a manner similar to the positive modulator triazolam (Campbell et al, 2004).…”