Original Investigation

Psychopharmacology

, Volume 197, Issue 4, pp 591-600

Discriminative stimulus effects of tiagabine and related GABAergic drugs in rats

  • L. M. McDonaldAffiliated withMerck, Sharp and Dohme, Terlings Park, CM21 2QR Email author 
  • , W. F. SheppardAffiliated withMerck, Sharp and Dohme, Terlings Park, CM21 2QRMerck and Co. West Point
  • , S. M. StaveleyAffiliated withMerck, Sharp and Dohme, Terlings Park, CM21 2QRDiscovery Biology Pfizer Ltd.
  • , B. SohalAffiliated withMerck, Sharp and Dohme, Terlings Park, CM21 2QRNovartis Horsham Research Centre
  • , F. D. TattersallAffiliated withMerck, Sharp and Dohme, Terlings Park, CM21 2QRDiscovery Biology Pfizer Ltd.
  • , P. H. HutsonAffiliated withMerck, Sharp and Dohme, Terlings Park, CM21 2QRMerck and Co. West Point

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Abstract

Rationale

Tiagabine is an anticonvulsant drug which may also have sleep-enhancing properties. It acts by inhibiting reuptake at the gamma-aminobutyric acid (GABA) transporter (GAT-1).

Objectives

The aim of the study was to determine whether tiagabine acted as a discriminative stimulus and, if so, whether other GABAergic compounds would generalise to it.

Materials and methods

Rats were trained to discriminate tiagabine (30 mg/kg p.o.) from vehicle, and generalisation to drugs that modulate GABA was assessed.

Results

Gaboxadol (5–20 mg/kg p.o.), a selective extrasynaptic GABAA agonist, generalised to tiagabine, although the extent of the generalisation was inconclusive. Indiplon (1 mg/kg p.o.), a benzodiazepine-like hypnotic, also partially generalised to tiagabine, although zolpidem and S-zopiclone did not. Baclofen, a GABAB receptor agonist, and gabapentin, which increases synaptic GABA, did not generalise to tiagabine. (+)-Bicuculline (3 mg/kg i.p.), a GABAA receptor antagonist, blocked the tiagabine cue, but the less brain-penetrant salt form, bicuculline methochloride, had no effect.

Conclusions

These data suggest that tiagabine generates a discriminative stimulus in rats, and provides a central GABA-mediated cue, but is distinct from the other GABAergic compounds tested.

Keywords

Tiagabine GABA Drug discrimination Rat Gaboxadol Indiplon Baclofen Gabapentin Bicuculline Bicuculline methochloride