Academic journal article The Psychological Record

Conditioned Suppression and the Effects of Pentobarbital with Picrotoxin, Flumazenil, and R05-3663

Academic journal article The Psychological Record

Conditioned Suppression and the Effects of Pentobarbital with Picrotoxin, Flumazenil, and R05-3663

Article excerpt

There has been continuing debate as to whether conditioned suppression (Estes & Skinner, 1941) or discriminated punishment (Geller & Seifter, 1960) are appropriate animal models for the assessment of clinical anxiolytics and related compounds. Arguably, conditioned suppression has higher face validity as it involves the signaled delivery of an unavoidable averslye event, and the conditioned suppression of positively reinforced operant behavior that occurs is not instrumental in reducing the frequency of aversire events. This procedure, however, has been criticized as not being selectively responsive to anxiolytics (e.g., Cook & Sepinwall, 1975; Dantzer, 1977; but see Millenson & Leslie, 1974, for a review that reached a different conclusion).

We examined its utility in a recent series of experiments in which conditioned suppression (of lever pressing by rats) was modified by acute or chronic treatment with an anxiolytic (chlordiazepoxide) or an anticonvulsant that acts at the GABA/benzodiazepine receptor complex (valproate), or by one of these drugs in combination with a possible antagonist. In various experiments these included bicuculline, picrotoxin, Ro15-1788 (flumazenil) and delta-amino-n-valeric acid (Leslie, Shephard, & Toal, 1994; Shephard, Toal, & Leslie, 1990; Toal, Leslie, & Shephard, 1991). The most striking findings were as follows: Chlordiazepoxide and valproate both reduced conditioned suppression; both these effects were antagonized by picrotoxin; and the effect of chlordiazepoxide was also antagonized by flumazenil. These findings are consistent with an account of the GABA/benzodiazepine receptor complex in which both valproate and picrotoxin act at the chloride ion channel, while chlordiazepoxide acts at the benzodiazepine receptor and this is antagonized by flumazenil (in earlier publications this drug was referred to as Ro15-1788). However, we have failed on several occasions to find effects on conditioned suppression of compounds believed to act at GABAa or GABAb sensitive sites, respectively, muscimol and bicuculline, and baclofen and delta-amino-n-valeric acid (Shephard et al., 1990; Toal et al., 1991).

The present experiments extended our previous findings by using a barbiturate, pentobarbital, as the anxiolytic along with some of the putative antagonists that had been effective in our previous experiments. In general, barbiturates have been found to have the same effects as benzodiazepines in paradigms used to assess the effects of anxiolytics (DeLorey, Kissin, Brown, & Brown, 1993; Leidenheimer, Whiting, & Harris, 1993; and see Iversen & Iversen, 1981; Polc, 1988, for reviews). We sought to establish the similarity of action for a barbiturate to that of benzodiazepines for our conditioned suppression paradigm and to identify the pattern of interaction with putative antagonists.

In the first experiment, pentobarbital was given at 10 mg/kg, a dose found to be effective in several behavioral paradigms, and the putative antagonists used were flumazenil and picrotoxin at 1.5 mg/kg, a dose found to be effective in our earlier experiments. Because picrotoxin had no systematic effect, a second experiment was conducted with the same dose of pentobarbital, a higher dose of picrotoxin (2.0 mg/kg), and Ro5-3663 (5.0 mg/kg), a compound believed to act in the same fashion as picrotoxin at the chloride ion channel associated with the GABA/benzodiazepine receptor complex.

Method

Subjects

Eight experimentally naive male Sprague-Dawley rats, approximately 100 days old at the start of the experiment, were used. Rats were housed two to a cage with water freely available and were maintained at close to 85% of their free-feeding weight.

Apparatus

Four two-lever Campden Instruments rat test chambers (Model CI 410) were used. Only the left lever was operative. A 2.8-W stimulus light was situated 4 cm above each lever and a third was 15 cm above the floor and midway between the two levers. …

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