Anti-conflict effects of benzodiazepines in rhesus monkeys: relationship with therapeutic doses in humans and role of GABAA receptors

Rowlett, James K.; Lelas, Snjezana; Tornatzky, Walter; Licata, Stephanie C.

doi:10.1007/s00213-005-0228-8

Cited by 29 publications

(47 citation statements)

References 42 publications

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“…Procedures that assess the effects of drugs on experimentally induced conflict are often used to assess the potential anxiolytic effects of these drugs in humans (Geller and Seifter, 1962;Spealman, 1979;Kleven and Koek, 1999;Rowlett et al, 2006). In the conflict procedure used in the current study, strong positive correlations between the potency of benzodiazepines to increase suppressed responding and therapeutic doses in humans have been reported (Rowlett et al, 2006).…”

Section: Discussionmentioning

confidence: 68%

“…In the conflict procedure used in the current study, strong positive correlations between the potency of benzodiazepines to increase suppressed responding and therapeutic doses in humans have been reported (Rowlett et al, 2006). Therefore, this model may be particularly predictive of the anxiolytic potency of benzodiazepines, other positive GABA A receptor modulators, and novel drug combinations.…”

Section: Discussionmentioning

confidence: 75%

“…Three rhesus monkeys were trained as described in detail by Rowlett et al (2006). A daily session consisted of four cycles, each preceded by a 10-min timeout period in which all lights in the chamber were off and responding had no programmed consequences.…”

Section: Methodsmentioning

confidence: 99%

“…Both components were 5 min in duration or ended after the monkey obtained five food pellets or received three foot shocks, whichever occurred first. Test sessions were conducted once or twice per week when monkeys reached stable performance, as described by Rowlett et al (2006).…”

Section: Methodsmentioning

confidence: 99%

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Anticonflict and Reinforcing Effects of Triazolam + Pregnanolone Combinations in Rhesus Monkeys

Fischer¹,

Rowlett²

2011

J Pharmacol Exp Ther

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Combinations of positive modulators of benzodiazepine and neuroactive steroid sites on GABA A receptors have been shown to act in an additive or supra-additive manner depending on the endpoint under study, but they have not been assessed on experimentally induced conflict or drug self-administration. The present study examined the interactive effects of the benzodiazepine triazolam and the neuroactive steroid pregnanolone in a rhesus monkey conflict procedure (a model of anxiolysis) and on a progressive-ratio schedule of drug selfadministration (a model of abuse potential). Both triazolam and pregnanolone decreased rates of nonsuppressed responding, whereas only triazolam consistently increased rates of suppressed responding (i.e., had an anticonflict effect). Fixed-ratio mixtures of triazolam and pregnanolone also decreased rates of nonsuppressed responding and did so in an additive manner. In contrast, mixtures of triazolam and pregnanolone produced either additive or supra-additive rate-increasing effects on suppressed responding, depending on the proportion of drugs in the mixture. Both triazolam and pregnanolone were self-administered significantly, and triazolam and pregnanolone mixtures had either proportion-dependent additive or infra-additive reinforcing effects. These results suggest that combinations of triazolam and pregnanolone may have enhanced anxiolytic effects with reduced behavioral disruption and abuse potential compared with either drug alone.

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Section: Discussionmentioning

confidence: 68%

Section: Discussionmentioning

confidence: 75%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Anticonflict and Reinforcing Effects of Triazolam + Pregnanolone Combinations in Rhesus Monkeys

Fischer¹,

Rowlett²

2011

J Pharmacol Exp Ther

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“…For example, many, if not all, effects of benzodiazepines are mediated by benzodiazepine sites on GABA A receptors, including their discriminative stimulus, therapeutic, and adverse effects. Although absolute potency of drugs acting at benzodiazepine sites can vary across procedures, relative potencies do not change (Lelas et al, 1999;Rowlett et al, 2006). Drug discrimination has been used extensively to examine interactions between GABA A modulators that vary in efficacy and site of action on GABA A receptors (Lelas et al, 2000;McMahon and France, 2005;Gerak and France, 2011; current study), providing an empirical and theoretical framework against which results could be compared and demonstrating that drug discrimination studies are highly reliable and predictable.…”

Section: Discussionmentioning

confidence: 83%

Quantitative Analyses of Antagonism: Combinations of Midazolam and Either Flunitrazepam or Pregnanolone in Rhesus Monkeys Discriminating Midazolam

Gerak

2011

J Pharmacol Exp Ther

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Adverse effects of benzodiazepines limit their clinical use; these effects might be reduced without altering therapeutic effects by administering other positive GABA A modulators (i.e., neuroactive steroids) with benzodiazepines. One concern with this strategy involves reversing these combined effects in case of overdose. The current study examined whether flumazenil can attenuate the combined effects of two benzodiazepines, midazolam and flunitrazepam, and the combined effects of midazolam and the neuroactive steroid pregnanolone, in four monkeys discriminating midazolam. Each positive modulator produced Ն80% midazolam-lever responding. Interactions between midazolam and either flunitrazepam or pregnanolone were additive. Flumazenil antagonized the benzodiazepines when they were administered alone or in combination. Schild analyses yielded slopes that did not deviate from unity, regardless of whether benzodiazepines were administered alone or together; the pA 2 value for flumazenil was 7.58. In contrast, flumazenil enhanced the effects of pregnanolone with 0.32 mg/kg flumazenil shifting the pregnanolone dose-effect curve 2-fold leftward. Flumazenil attenuated the combined effects of midazolam and pregnanolone, although antagonism was not dose-dependent. Thus, the interaction between two benzodiazepines was similar to that of a benzodiazepine and a neuroactive steroid; however, flumazenil more efficiently attenuated a combination of two benzodiazepines compared with a combination of a benzodiazepine and a neuroactive steroid. Although the magnitude of antagonism of a benzodiazepine combined with a neuroactive steroid was reduced, these results support continued exploration of the use of combinations of positive modulators to enhance therapeutic effects while reducing adverse effects.

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“Watch out!”: Effects of instructed threat and avoidance on human free‐operant approach–avoidance behavior

Schlund

Treacher

Preston

et al. 2017

J Exper Analysis Behavior

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Approach-avoidance paradigms create a competition between appetitive and aversive contingencies and are widely used in nonhuman research on anxiety. Here, we examined how instructions about threat and avoidance impact control by competing contingencies over human approach-avoidance behavior. Additionally, Experiment 1 examined the effects of threat magnitude (money loss amount) and avoidance cost (fixed ratio requirements), whereas Experiment 2 examined the effects of threat information (available, unavailable and inaccurate) on approach-avoidance. During the task, approach responding was modeled by reinforcing responding with money on a FR schedule. By performing an observing response, participants produced an escalating "threat meter". Instructions stated that the threat meter levels displayed the current probability of losing money, when in fact loss only occurred when the level reached the maximum. Instructions also stated pressing an avoidance button lowered the threat level. Overall, instructions produced cycles of approach and avoidance responding with transitions from approach to avoidance when threat was high and transitions back to approach after avoidance reduced threat. Experiment 1 revealed increasing avoidance cost, but not threat magnitude, shifted approach-avoidance transitions to higher threat levels and increased anxiety ratings, but did not influence the frequency of approach-avoidance cycles. Experiment 2 revealed when threat level information was available or absent earnings were high, but earnings decreased when inaccurate threat information was incompatible with contingencies. Our findings build on prior nonhuman and human approach-avoidance research by highlighting how instructed threat and avoidance can impact human AA behavior and self-reported anxiety.

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Anti-conflict effects of benzodiazepines in rhesus monkeys: relationship with therapeutic doses in humans and role of GABAA receptors

Abstract: A rhesus monkey conflict procedure was established with predictive validity for therapeutic doses in people and provided evidence that anxiolytic-like effects of BZs can occur with relatively low intrinsic efficacy at GABAA receptors and are reduced by alpha1GABAA receptor selectivity.

Cited by 29 publications

References 42 publications

Anticonflict and Reinforcing Effects of Triazolam + Pregnanolone Combinations in Rhesus Monkeys

Anticonflict and Reinforcing Effects of Triazolam + Pregnanolone Combinations in Rhesus Monkeys

Quantitative Analyses of Antagonism: Combinations of Midazolam and Either Flunitrazepam or Pregnanolone in Rhesus Monkeys Discriminating Midazolam

“Watch out!”: Effects of instructed threat and avoidance on human free‐operant approach–avoidance behavior

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