Articles
Discriminative Stimulus Properties of Antipsychotics

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Abstract

Drug discrimination methodology has been used in a number of ways to analyze the actions of novel and putative novel antipsychotics in vivo. Recent studies suggest (a) in contrast to earlier theorizing, antagonism of the low-dose d-amphetamine stimulus in rats may not be an effective screen for novel antipsychotics; (b) dopamine D2-like agonists and antagonists, some of which are putative antipsychotics, can be studied in vivo as discriminative cues, although there is a pressing need for more selective drugs that differentiate the various members of the D2 family; (c) antagonism of the cue induced by the noncompetitive NMDA antagonist MK-801, which has been proposed as a possible screen for clozapine-like compounds, may be an unreliable assay; and (d) the clozapine stimulus is probably a compound cue (a drug “mixture”), which can be used to screen for novel clozapine-like antipsychotics, although the precise receptor mechanisms involved in mediating the clozapine stimulus, and its direct relevance to the antipsychotic action of clozapine remains to be proven conclusively.

Section snippets

The Low-Dose Amphetamine Cue as a Putative Screen for Antipsychotics

Antagonist actions at D2 receptors have been linked for many years to the actions of typical antipsychotics. Such drugs inhibit mesolimbic DA mediated amphetamine-induced hyperactivity. Both typical and novel antipsychotics have preferential effects against low dose (0.5 mg/kg in rats) amphetamine (AMP)-induced hyperactivity (1). Antipsychotic drugs may also have inhibitory actions on nigrostriatal DA systems mediating stimulant-induced stereotypy. Agents selectively inhibiting hyperactivity

Dopamine D2-like Antagonists and Agonists as Discriminative Stimuli

Molecular biological techniques have isolated two families of dopamine receptors, D1-like receptors, including D1 and D5 receptors; and D2-like receptors, including D2, D3, and D4 receptors (65). We are not concerned here with the D1 family, as there is no evidence that drugs acting at this receptor are effective antipsychotics; indeed D1 antagonists may actually exacerbate psychoses (8). However, the D2 family has consistently been linked with antipsychotic drug actions, and the effects of a

MK-801 Discrimination as a Selective Screen for Clozapine-Like Antipsychotics

It has been reported (19) that, in rats discriminating the noncompetitive NMDA antagonist MK-801 at 0.075 mg/kg from saline in a discrete-trial shock-avoidance paradigm, clozapine, but not haloperidol, blocked the MK-801 cue. Haloperidol was tested up to the highest dose at which rats would respond, but failed to attenuate the MK-801 cue even partially. In direct contrast, clozapine produced full dose-related antagonism of the cue. These data were taken to suggest that the MK-801 cue may be

The Clozapine Cue

Although the older typical antipsychotics are difficult to train, it has been known for some years that clozapine is more readily discriminable, and that typical antipsychotics do not generalize to clozapine 11, 25. Following these early studies, clozapine DD has been studied extensively in rats 22, 27, 29, 35, 44, 45, 48, 51, 54, 71, 74, pigeons (31), and monkeys (15). Three major conclusions have arisen from this work. First, the clozapine cue is probably a compound cue, requiring concurrent

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