Psychopharmacology (t994) 115:185-195 Psychopharmacology © Springer-Verlag 1994 Amphetamine-induced disruptions mediated: implications for animal dysfunction A. S. Killcross, A. Dickinson, T. W. Robbins of latent inhibition are reinforcer models of schizophrenic attentional Department of Experimental Psychology, University of Cambridge Downing Street, Cambridge CB2 3EB, UK Received: 25 March 1993 / Final version: 4 November 1993 Abstract. Latent inhibition (LI) is a phenomenon ob- served when repeated, non-reinforced presentation of a stimulus results in a retardation of subsequent condition- ing to that stimulus. Several recent experiments have sug- gested that LI is abolished in conditioned suppression paradigms following acute, low doses of amphetamine given during pre-exposure and conditioning. Experiment 1 sought to increase the generality of this finding in an appetitive LI paradigm, using a dose of amphetamine previously shown to disrupt the LI effect in an aversive paradigm (Killcross and Robbins t993). However, no ev- idence for any disruption of LI was found. Experiment 2 extended this investigation to additional, higher doses of d-amphetamine, and also examined the role of reinforcer magnitude in the effect. A non-significant trend towards an attenuated LI effect was found, which was reversed by decreases in the concentration of the sucrose reinforcer. Experiments 3 and 4 investigated the influence of sys- temic amphetamine in aversive paradigms, with specific attention to the increased response to the aversive foot- shock reinforcer found in amphetamine-treated animals. These experiments revealed that the influence of am- phetamine on the LI effect in conditioned suppression paradigms could be reversed by reducing the intensity of footshock used in conditioning, thereby paralleling the effect found in the appetitive paradigm. Therefore it is unlikely that a simple attentional account of the aboli- tion of the LI effect in previous experiments can be sus- tained. Key words: Dopamine - Latent inhibition - Schizophre- nia - Amphetamine - Conditioning - Context -- Atten- tion Recently, there has been substantial interest in animal models designed to reflect attentional impairments ob- served in acute schizophrenia. One model is that based Correspondence to: A. S. Killcross on latent inhibition (LI), a phenomenon which is manifest when repeated, non-reinforced pre-exposure to a stimu- lus retards conditioning to that stimulus when it is subse- quently paired with reinforcement (Lubow 1973). This effect has been interpreted by some as reflecting processes of selective attention by which irrelevant stimuli come to be ignored (Mackintosh 1975, 1983; Lubow et al. 1976; Lubow 1989), although this is by no means the only ex- planation (Pearce and Hall 1980; Wagner 1981; Bouton 1991). The rationale for this model lies in a possible par- allel between the effects of dopaminergic drugs on LI and the deficits in selective attention seen in acute schizophre- nia (Joseph et al. 1979; Lubow et al. 1987; Baruch et al. 1988; Gray et al. 1991, 1992). Several experiments appear to have demonstrated that the LI effect is abolished in rats following systemic injections of either d- or dl-amphetamine; (Solomon et al. 1981; Weiner et al. 1981, 1984, 1987b, 1988; Solomon and Staton 1982, 1984; Killcross and Robbins 1993), but not following injections of direct dopamine (DA) agonists (Feldon et al. 1991). The model is also supported by find- ings of enhanced LI effects following treatment with neu- roleptic drugs, such as haloperidol (Weiner and Feldon 1987; Weiner et al. 1987a; Christison et al. t988), and also following systemic injections of atypical neuroleptics, such as sulpiride (Feldon and Weiner 1991), but not clozapine (Dunn et al. 1993). The neural locus of these effects on LI has often been attributed to the dopaminergic innervation of the nucleus accumbens (NAc; Weiner 1990; Gray et al. 1991). More specifically, the abolition of the LI effect by amphetamine is claimed to result from the potentiating effect of am- phetamine on dopaminergic transmission in the mesolimbic DA projections which innervate the NAc and related areas of the ventral striatum. However, recent results have provided some evidence against this hypoth- esis. Killcross and Robbins (1993) demonstrated that whereas systemic injections of amphetamine can abolish the LI effect in a within-subject conditioned suppression paradigm, no such influence is seen in the same paradigm following intra-accumbens infusions of either 3gg/gl or