Abolition of latent inhibition by a single 5 mg dose ofd-amphetamine in man

Gray, Nicola S.; Pickering, Alan D.; Hemsley, David R.; Dawling, Sheila; Gray, Jeffrey A.

doi:10.1007/bf02245170

Cited by 257 publications

(108 citation statements)

References 26 publications

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“…It has been repeatedly reported that systemic application of amphetamine disrupts latent inhibition in hum ans (Gray et al 1992) as well as in rats (Solomon et al, 1981;Weiner et al 1981;Killcross et al 1994), using a variety of different learning paradigms, There is, however, m uch m ore controversy regarding the individual dopam inergic terminal fields. Thus, Solomon and Station (1982), using a conditioned avoidance approach, have reported a reduction in latent inhibition after local application of dopam ine into the nucleus accum bens, whereas similar injections into the dorsal striatum had no effect (cf.…”

Section: Introductionmentioning

confidence: 44%

The role of mesolimbic and nigrostriatal dopamine in latent inhibition as measured with the conditioned taste aversion paradigm

Ellenbroek¹,

Knobbout²,

Cools³

1997

Psychopharmacology

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Repeatedly presenting a non-reinforced stim ulus normally retards conditioning to this stimulus when it is coupled to a reinforcer. This phenomenon is called latent inhibition. Since latent inhibition is disturbed after systemic administration of am pheta mine, the present study investigated the role of the mesolimbic and nigrostriatal dopamine terminal fields in latent inhibition using a conditioned taste aversion (CTA) paradigm. In this paradigm, a 5% sucrose solution was used as the test stimulus and lithium chloride (LiCl) as the CTA inducing drug. The degree of CTA was assessed by measuring the sucrose prefer ence in a two-bottle sucrose/water choice paradigm 24 h after the LiCl injection. Since conditioned taste aversion has so far not been used to evaluate the role of dopamine in latent inhibition, we first studied the effects of systemic application of amphetamine. The results show that intraperitoneal injections of 0.25 or 0.5 mg /leg ¿/-amphetamine sulphate (given at preexposure and conditioning) significantly disrupted latent inhibition, by selectively reducing sucrose preference in the preexposed group. This could not be attributed to a reduced sucrose intake during preex posure or to a conditioned taste aversion effect of am phetamine itself, In experiment 2 local bilateral administration of 10 |xg/0.5 jil amphetamine into the nucleus accumbens or the dorsal striatum was given in the pre-exposed and the conditioning phase, after which the rats were allowed to drink for a fixed period of time. The results show a significant reduction in latent inhibition after intrastriatal, but not after intra-accumbens injections of amphetamine. Intraaccumbens injections of amphetamine, however, significantly reduced fluid intake during preexposure and conditioning. In experiment 3, we therefore repeated this experiment, but allowed the animals to drink only a restricted am o u n t of liquid during preex posure and conditioning. Again the results show a dis ruption of latent inhibition after intrastriatal, but not intra-accumbens injections of amphetamine. These experiments emphasize the importance of the nigro striatal dopamine system in the disruption of latent inhibition, at least when using the conditioned taste aversion paradigm. A possible mechanism by which the dorsal striatum m ight influence latent inhibition is discussed.

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Section: Introductionmentioning

confidence: 44%

The role of mesolimbic and nigrostriatal dopamine in latent inhibition as measured with the conditioned taste aversion paradigm

Ellenbroek¹,

Knobbout²,

Cools³

1997

Psychopharmacology

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“…Based on this pharmacological connection, LI-disruption was suggested as a potential model of the selective attention deficit found in schizophrenia. Subsequently, LI has been found to be disrupted in acute psychotic schizophrenic patients (Baruch et al, 1988), and in normal humans treated with amphetamine (Gray et al, 1992). These and other evidence support the validity of LI-disruption as a model of processing deficits in acute schizophrenia.…”

Section: Generalizing the Model To LI Disruption Introductionmentioning

confidence: 69%

Linking Animal Models of Psychosis to Computational Models of Dopamine Function

Smith

Becker

et al. 2006

Neuropsychopharmacol

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Psychosis is linked to dysregulation of the neuromodulator dopamine and antipsychotic drugs (APDs) work by blocking dopamine receptors. Dopamine-modulated disruption of latent inhibition (LI) and conditioned avoidance response (CAR) have served as standard animal models of psychosis and antipsychotic action, respectively. Meanwhile, the 'temporal difference' algorithm (TD) has emerged as the leading computational model of dopamine neuron firing. In this report TD is extended to include action at the level of dopamine receptors in order to explain a number of behavioral phenomena including the dose-dependent disruption of CAR by APDs, the temporal dissociation of the effects of APDs on receptors vs behavior, the facilitation of LI by APDs, and the disruption of LI by amphetamine. The model also predicts an APD-induced change to the latency profile of CARFa novel prediction that is verified experimentally. The model's primary contribution is to link dopamine neuron firing, receptor manipulation, and behavior within a common formal framework that may offer insights into clinical observations. Neuropsychopharmacology Keywords: dopamine; temporal difference learning; psychosis; conditioned avoidance; latent inhibition; computational modeling INTRODUCTIONPerturbations in dopamine transmission are central to a number of human illnesses including addiction, Parkinson's disease, attention-deficit hyperactivity disorder (ADHD), and schizophrenia. As a result there has been tremendous interest in understanding the psychological and behavioral functions of dopamine, and a number of overlapping hypotheses have been suggested. These hypotheses include roles for dopamine in hedonia (Wise, 1982), reward learning (Robbins and Everitt, 1996), incentive salience (Berridge and Robinson, 1998), sensorimotor function and anergia (Salamone et al, 1994). In parallel, mathematical models have been used to link some of these psychological constructs to the physiology of the dopamine system (Schultz, 1998;Seamans and Yang, 2004). Many of these models have concentrated on 'normal' dopaminergic conditions (McClure et al, 2003;Schultz et al, 1997), and the current aim is to explore how one such model can be extended to address the abnormal conditions encountered in schizophrenia and their treatment.Of all the mathematical models linking dopamine, behavior, and psychology, the Temporal Difference Learning model (TD) has enjoyed particular success (Montague et al, 1996;Redish, 2004;Schultz et al, 1997). TD is a powerful formal reinforcement learning technique that has been used to solve many challenging machine learning problems. For example, the technique has been used to train computers to play backgammon to the highest human standards by associating a simulated reward with winning a game (Tesauro, 1994). At the heart of TD is a predictionerror signal that is zero if the environment behaves as expected, positive in response to unexpected reward, and negative following omission of expected reward. Striking parallels have been observed between...

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“…Consistent with the widely documented difficulty to ignore irrelevant stimuli in schizophrenia, LI is disrupted in some subsets of schizophrenic patients (Baruch et al 1988;Dunn and Scibilia 1996;Gray et al 1992aGray et al , 1995Vaitl and Lipp 1997; but see Swerdlow et al 1996b;Williams et al 1998), and this disruption is modeled by loss of LI in amphetamine-treated rats (Killcross et al 1994a;Solomon et al 1981;Weiner et al 1981Weiner et al , 1984Weiner et al , 1988 and in normal humans (Gray et al 1992b; Thornton et al 1996). The validity of the model is further strengthened by findings that the neural substrates of LI in the rat include the hippocampal formation and the nucleus accumbens, consistent with the temporal lobe and mesolimbic pathology implicated in the pathophysiology of schizophrenia (for review, see Weiner 1990;.…”

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confidence: 72%