The partial reinforcement extinction effect in humans: effects of schizophrenia, schizotypy and low doses of amphetamine

Behavioural Brain Research 133 (2002) 333 /342 www.elsevier.com/locate/bbr

Research report

The partial reinforcement extinction effect in humans: effects of schizophrenia, schizotypy and low doses of amphetamine Nicola S. Gray a,b,*, Alan D. Pickering c, Robert J. Snowden a, David R. Hemsley d, Jeffrey A. Gray d a b

School of Psychology, Cardiff University, PO Box 901, Park Place, Cardiff CF10 3YG, South Wales, UK South Wales Forensic Psychiatric Service at Caswell Clinic, Glanrhyd Hospital, Bridgend CF31 4LN, UK c Department of Psychology, Goldsmith’s College, London, UK d Department of Psychology, Institute of Psychiatry, De Crespigny Park, London SE5 8AF, UK Received 29 October 2001; received in revised form 14 January 2002; accepted 14 January 2002

Abstract The partial reinforcement extinction effect (PREE) was studied in human subjects. It has been suggested that the PREE depends on neural mechanisms critical to the cognitive dysfunction which underlines acute schizophrenia. We therefore predicted that the PREE should be reduced, through decreased resistance to extinction in the partial reinforcement (PR) condition, in various types of individual: (a) healthy volunteers given low doses of oral amphetamine; (b) those in the acute (but not chronic) phase of a schizophrenic illness and; (c) healthy volunteers with high scores on personality measures of schizotypy. Despite obtaining robust demonstrations of PREE in all experiments, none of these predictions were confirmed. A single, low dose, of amphetamine had no effect on either continuous reinforcement (CR) or partial reinforcement (PR). Acute and chronic schizophrenic patients showed a reduced PREE compared to controls. However this was due to increased resistance to extinction in the CR groups. Finally, high schizotypy scores were associated with greater PREE, attributable to both decreased extinction in the CR condition and increased extinction in the PR condition. The results of these experiments on human PREE provide no support that PREE is a valid paradigm with which to explore the cognitive dysfunction underlying schizophrenia. # 2002 Elsevier Science B.V. All rights reserved. Keywords: Partial reinforcement extinction effect; Schizophrenia; Schizotypy; Amphetamine

1. Introduction Gray, Feldon, Rawlins, Hemsley and Smith [20] have provided a putative model of the neuropsychology of acute schizophrenia. The model draws together evidence of neurochemical and neuroanatomical abnormalities in schizophrenia, with evidence of cognitive deficits thought to underpin symptom formation. The model has three central tenets [19,20]. (1) It puts forward a hypothesis that the crucial substrate of the positive symptoms of acute schizophrenia lies in an abnormality in the projections from the septo-hippocampal system (via the subiculum and entorhinal cortex) to nucleus accumbens [33]. (2) This abnormality is proposed to

* Corresponding author. Tel:
44-29-2087-6259; fax:
44-292087-4858 E-mail address: [email protected] (N.S. Gray).

interact with the ascending dopaminergic projection to nucleus accumbens with consequences functionally equivalent to increased dopaminergic activity in the mesolimbic dopamine system. (3) This neurochemical imbalance is proposed to impair the normal, contextdependent inhibition of attention to redundant stimuli, that is hypothesised by the model to be the core cognitive deficit underlying the positive symptoms of acute schizophrenia. Gray et al. [20] proposed that the cognitive inability of acute schizophrenic patients to screen irrelevant stimuli from awareness, and thus to be able to focus attentional resources upon relevant information in order to learn about contingencies within the environment, produced the symptomatic profile of acute schizophrenia (see also [19]). The model was based upon several lines of empirical evidence from work with animals. First, a variety of sources of evidence had suggested that the nucleus

0166-4328/02/$ - see front matter # 2002 Elsevier Science B.V. All rights reserved. PII: S 0 1 6 6 - 4 3 2 8 ( 0 2 ) 0 0 0 1 9 - 0

334

N.S. Gray et al. / Behavioural Brain Research 133 (2002) 333 /342

accumbens acts as an interface between the limbic system and the basal ganglia [41]. Evidence from experimental work with rats was used to propose the hypothesis that the limbic system discharges a general comparator function and compares, on a moment-bymoment basis, the current state of the perceptual world with a predicted state [18]. Working in synchrony with the limbic system, the basal ganglia discharges the general function of motor programming. These neuroanatomical functions were thus proposed by the Gray et al. [20] model to underpin the psychological mechanism of distinguishing relevant from irrelevant stimuli, and acting upon only the relevant. Second, a series of experiments with rats, using three key behavioural paradigms, had demonstrated a similar disruption in cognitive processing (characterised by an inability to screen out irrelevant information from the control of behaviour) by both the administration of the indirect dopamine agonist amphetamine, and damage to the hippocampal formation. The experimental paradigms used in these animal experiments were latent inhibition (LI), the Kamin blocking effect (KBE; otherwise termed conditioned blocking) and the partial reinforcement extinction effect (PREE). LI refers to a retardation of learning the significance of a conditioned stimulus if it has previously been pre-exposed without consequence [37]. KBE refers to the decreased ability of a subject to form a conditioned association between a stimulus and an event if that subject has formed a previous conditioned association between another stimulus and the same event and the two predictive stimuli are presented concurrently [32]. PREE refers to an increased resistance to extinction following partial reinforcement (PR; rewarded and nonrewarded trials randomly interspersed) as compared to continuous reinforcement (CR; all trials rewarded). Behavioural responding persists far longer in the PR group than the CR group when all rewards cease (extinction). This resistance to extinction in the PR group may be interpreted to reflect that the animals have learnt to ignore non-reward in a manner analogous to how animals in the LI paradigm ignore the previously irrelevant stimulus following pre-exposure [17]. In order to test the predictions arising from the Gray et al. [20] model, human versions of these animal behavioural paradigms were developed (e.g. Ref. [1] for LI; Ref. [30] for KBE). The human tasks share the logical structure of the animal tasks but vary greatly in the actual behaviours asked of the participant. Three key predictions arise from the model. First, that all three tasks will be abolished in healthy volunteers by a low, but not high, dose of oral amphetamine. The inverse dose dependence was observed in the rat experiments

using LI [64]; whilst PREE is abolished by low doses of amphetamine [13,63] under certain conditions [15] (see Section 6). This hypothesis is as yet untested in KBE. These effects are consistent with an action of amphetamine to release dopamine preferentially in nucleus accumbens [64,65]. Second, and perhaps most fundamental to the model, is the prediction that the behavioural phenomena of LI, KBE and PREE would be absent in acute schizophrenics, but restored in chronic schizophrenics maintained on dopamine-blocking neuroleptic medication. Third, but more tentatively, is the prediction that the tasks might be reduced in normal subjects with high scores on personality traits associated with vulnerability to psychosis (schizotypy). For LI all three predictions have some support. LI can be abolished by low, but not high, doses of amphetamine [24,58]. Some studies have shown that LI is abolished in acute, but not chronic, schizophrenics [1,22,26,39,48], whereas others have failed to demonstrate this [57,67]. Finally, a number of studies using a variety of different schizotypal measures have shown that LI is abolished in people scoring high on these measures [1,5,11,21,27,35,38], although a simple linear relationship may not be present [4,68]. Human research has also shown that KBE is absent in acute schizophrenia but is intact in chronic schizophrenia [3,30,31,43]. Against predictions, KBE was unaffected by high or low doses of amphetamine [23,31] and is only marginally reduced in normal subjects scoring high on measures of schizotypy [29]. To date there has been no attempt to test the third of these key behavioural paradigms, the PREE. This is the aim of the current series of studies. Like LI and KBE, the PREE is reduced or abolished in animals by damage to the septo-hippocampal system [18,28,53]. In addition, it has been demonstrated [50] that the PREE is abolished by section of the projection from the subiculum to nucleus accumbens, the pathway treated within the Gray et al. [20] model as the most important link between the limbic system and basal ganglia. This effect has not been shown for either LI or KBE. It can therefore be predicted from the Gray et al. [20] model that the human PREE: (1) should be abolished by a low, but not high, dose of oral amphetamine; (2) should be absent in acute, but not chronic, schizophrenic patients; and (3) should be reduced in subjects high on schizotypy. Amphetamine abolishes the PREE in the rat by reducing resistance to extinction selectively in the partial reinforcement (PR) condition. Therefore the predictions for abolition of the PREE in acute schizophrenia, high schizotypal individuals, and amphetamine-treated healthy volunteers require that this takes the form of a reduction of resistance to extinction selectively in the PR group, but not in CR controls.

N.S. Gray et al. / Behavioural Brain Research 133 (2002) 333 /342

2. General method Participants in all three studies were given a written information sheet about the aims and nature of the study and asked to provide written consent. Informed consent was also obtained from patients’ responsible medical officers for the schizophrenia study. For the amphetamine study, participants were screened for contraindications to amphetamine and for illegal drug use (via both a clinical interview and urine test). Repeated measures of heart rate and blood pressure were taken throughout the amphetamine trial to check for abnormal reactions to the drug. None occurred. The method used was a modified version of one developed by Vogel /Sprott [59]. To estimate the magnitude of the PREE we measured resistance to extinction after CR and PR training. The task and instructions were presented by an Atari 1040ST microcomputer and colour monitor connected to a four-button response box. There were two phases: acquisition and extinction. The participant was told to type in a sequence of four digits. The four buttons, numbered 1 /4, were to be used, and the participant could enter any order of the four digits, but could enter each digit only once in any one sequence. The participant was further told that: the aim was to discover a correct sequence, of which there might be more than one; 20 pence would be paid for each correct sequence entered; and that all money won would be received on termination of the task. Throughout the task the total amount accumulated up to that point was numerically displayed at the top of the monitor, and further as a bar graph along the right edge of the screen. The ‘correct’ sequence was defined as the fifth distinct sequence entered by the participant. Correct responses were followed by a ‘beep’, the word ‘correct’ on the monitor, and incrementation of the cumulative displays. During acquisition the CR group was rewarded in this way for every correct response. The PR group was rewarded for 50% of the correct responses, on a quasi-random schedule. When any sequence other than the correct response was entered, and on the 50% of non-rewarded target responses for the PR group, ‘incorrect’ was displayed on the monitor. Extinction began immediately after each participant reached a criterion of 20 target responses. No further reward was given to participants in either group regardless of the type of response. No indication was given of the change from acquisition to extinction. When the subject had entered 20 sequences of any type during extinction, the experiment was terminated. The word ‘jackpot’ appeared on the monitor, and the total amount of money won was incremented to £5.00 for each subject. The number of target (i.e. previously rewarded) responses emitted during extinction was recorded, constituting the main measure of the PREE.

335

In order to match our groups on possible confounding variables, measures of verbal intelligence (Mill Hill Vocabulary Scale [49]) and age were taken.

3. Experiment 1 */the effects of low and high dose amphetamine on the PREE Both LI [54] and the KBE [9] are abolished by the indirect dopamine agonist, amphetamine, in the rat. LI is also abolished in normal human subjects by oral damphetamine [24,34,58]. As in the rat [64,66], the abolition of human LI occurred at a relatively low dose (5 mg) but not a high dose (10 mg) of amphetamine [24]. Given the hypothesis that LI and the PREE depend upon similar underlying neural processes [20], we therefore predicted that the PREE would similarly be abolished by 5 but not 10 mg oral amphetamine. 3.1. Method One hundred and twenty eight normal volunteers (65 men, 63 women), recruited by advertisement in a local newspaper and paid £50.00, were randomly assigned to three drug conditions under a double-blind protocol: 0, 5 and 10 mg oral d -amphetamine. Within each drug condition, participants were assigned to CR and PR conditions, matching as far as possible for age, and verbal intelligence (Table 1). Exclusion criteria were a history of mental illness, drug or alcohol dependency, or marked abnormalities with hearing or vision. In addition, participants were excluded if they had a body weight index outside the normal range (20 /28), because of the effect of this upon amphetamine metabolism. All participants were also screened for contra-indications to amphetamine and for illegal drug use [24]. All participants also took part, in the same session, in an experiment on LI or KBE. The data were initially collected as two separate experiments. The first experiment investigated the PREE 45 min (N /60) after drug administration, with the LI task being studied subsequently. The second experiment (n /68), measured the Table 1 Means and standard errors (in parentheses) for age, verbal intelligence, and plasma amphetamine levels scores across the experimental conditions in experiment 1 0 mg CR PR CR PR CR PR

Age Age Verbal IQ Verbal IQ Plasma level Plasma level

29.7 32.6 107.9 110.1 7.6 7.0

5 mg (1.6) (2.4) (1.6) (1.8) (0.9) (1.0)

31.0 28.1 110.1 106.4 17.3 14.4

10 mg (1.1) (1.2) (2.0) (1.4) (2.0) (2.2)

32.5 30.6 108.9 107.0

(1.9) (1.1) (1.7) (1.7)

Amphetamine levels measured in mg/l. Verbal intelligence is measured by the Mill Hill Vocabulary Scale.

336

N.S. Gray et al. / Behavioural Brain Research 133 (2002) 333 /342

PREE 110 min after drug administration, immediately following the KBE task. Venepuncture for amphetamine plasma analysis (by gas chromatography; detection limit 1 /2 mg/l) was made immediately before the PREE task began. 3.2. Results Table 1 shows plasma amphetamine levels across reinforcement schedule and drug group. The number of trials to extinction is illustrated in Fig. 1. Due to gross deviations in the variances and significant variation from normal distributions, the data were analysed by the methods recommended by Conover and Iman [8]: the extinction scores were ranked and an analysis of variance then performed. A three-way ANOVA was performed first with reinforcement schedule (CR or PR), amphetamine dose (0, 5 or 10 mg) and experiment (delay of 45 or 110 min) as variables. The variable of experiment had no main effect nor did it interact with any other variables, hence data were collapsed across this variable and a two-way ANOVA was performed. As expected there was a robust effect of reinforcement schedule, with slower extinction for the PR group [F (1, 122) /163.39, P B/0.0001] thus replicating the well documented PREE. However there was no effect of amphetamine dose [F (2, 122) B/1], nor any interaction between reinforcement schedule and drug dose [F (2, 122) /2.03, ns]. 3.3. Discussion The magnitude of the PREE was unchanged by either 5 or 10 mg d-amphetamine. Since the 5 mg treatment

Fig. 1. Mean number of target responses during extinction as a function of the dose of d -amphetamine in experiment 1. Error bars indicate 91 standard error of the mean. CR, continuous reinforcement; PR, partial reinforcement.

modified LI in the same participants, tested in the same session [24], this negative result cannot be due to the use of a generally ineffective pharmacological manipulation. The same protocol was also used to evaluate the effects of low and high dose amphetamine on the KBE and, as with the present study on the PREE, KBE was unaffected by either 5 or 10 mg d -amphetamine [23]. The lack of effect of amphetamine on the PREE is inconsistent with the hypothesis that the PREE and LI reflect similar neural processes.

4. Experiment 2 */the effects of acute and chronic schizophrenia on the PREE Both LI [1,22] and the KBE [30] are absent in acute schizophrenic patients, but present in chronic schizophrenic patients maintained on neuroleptic medication. If the PREE is mediated by the same neural processes as these phenomena then the PREE should also be absent in acute, but not chronic, schizophrenic patients. This prediction was evaluated in Experiment 2. A group of healthy control participants was also tested on the PREE to see if a diagnosis of schizophrenia per se had any effect on the PREE. 4.1. Method Participants were 16 acute (12 male, 4 female) and 16 chronic (12 male, 4 female) schizophrenic in-patients who met Research Diagnostic Criteria [55]. The acute schizophrenic patients were either suffering from their first psychotic breakdown (N /9) or were in an acute phase of an otherwise chronic disorder (N /7). All patients were tested in the first 2 weeks following the start of their current in-patient admission and commencement of neuroleptic medication. The chronic schizophrenic patients had been continuously ill for at least 6 months and had received neuroleptic medication for at least this period of time. All the schizophrenic patients were severely ill, with high levels of both positive and negative symptoms. Considerable care was taken to match patients across groups in terms of the presence and severity of positive and negative symptoms in order to try to avoid the potential confound of significant differences in degree of symptomatology. Psychotic symptoms were assessed by the Brief Psychiatric Rating Scale [45], scored separately for positive and negative symptoms [44], and by the MAINE scale of paranoid and non-paranoid schizophrenia [40]. Most of the schizophrenic patients were receiving phenothiazine drugs, but two of the acute patients were unmedicated and one had never received neuroleptic medication. Table 2 depicts the demographic and clinical information for the schizophrenic

N.S. Gray et al. / Behavioural Brain Research 133 (2002) 333 /342

337

Table 2 Means and standard errors (in parentheses) for the demographic and clinical data for schizophrenic participants across experimental condition in experiment 2

Age Verbal IQ Medication Age 1st Hosp. Positive Negative Paranoid Non-paranoid

Acute schizophrenia

Chronic schizophrenia

Healthy controls

CR

PR

CR

PR

CR

PR

31.6 (3.9) 93.0 (4.1) 612 (175) 22.9 (0.9) 48.9 (2.5) 24.6 (3.3) 19.6 (1.5) 16.8 (1.2)

34.3 (6.7) 94.0 (4.6) 450 (121) 31.1 (7.1) 36.8 (1.5) 15.8 (1.6) 13.9 (1.3) 9.6 (0.9)

31.6 (3.3) 89.0 (3.4) 700 (66) 21.4 (1.3) 32.4 (3.2) 23.1 (2.2) 13.3 (1.8) 12.9 (1.7)

34.4 (3.4) 87.0 (3.2) 600 (115) 24.1 (2.8) 36.6 (3.2) 23.8 (3.4) 17.0 (2.2) 15.8 (1.6)

24.4 (2.4) 99.0 (3.3)

26.2 (2.7) 100.0 (2.6)

CR, continuous reinforcement; PR, partial reinforcement. Verbal intelligence as measured by the Mill Hill Vocabulary Scale. Dose of phenothiazine medication converted to chlorpromazine equivalents in mg following [10]. Positive and negative symptoms assessed on the Brief Psychiatric Rating Scale. Paranoid and non-paranoid symptoms assessed by the MAINE scale.

patient groups. In addition we also tested 64 (32 male, 32 female) healthy control participants*/see Table 2. 4.2. Procedure The PREE was tested as in the experiments reported above; all participants were also tested on LI (immediately after the PREE), as reported by in Gray et al. [22]. The conditions in both the PREE and LI experiments were counterbalanced, such that half the sample completed the PREE experiment first and half the LI experiment first. Likewise, half the people who received CR in the PREE task were also in the pre-exposed condition of the LI task, whereas the other half were in the non-preexposed condition. Analysis of extinction scores revealed no significant effects of task order and therefore this variable is ignored here. 4.3. Results The mean responses in extinction for the three groups after the conditions of continuous and partial reinforcement are illustrated in Fig. 2. Once again the data showed gross inhomogeneity of variance between conditions, and significant deviations from normality. Hence the methods of Conover and Iman [8] were applied. As expected we obtained far greater scores for the PR group in comparison to the CR group [F (1, 90) /34.27, P B/0.001], demonstrating a robust PREE. In addition we also found an effect of diagnosis [F (2, 90) /3.64, P B/0.05] but no interaction between reinforcement schedule and diagnosis [F (2, 90) /1.83, ns]. Examination of Fig. 2 suggests the effect of diagnosis is due to greater resistance to extinction for the schizophrenic patients compared to the controls, particularly for the CR group (though we note the lack of significant interaction). This was supported by Tukey HSD tests

Fig. 2. Mean number of target responses during extinction as a function of the diagnosis of the participants in experiment 2. Error bars indicate 91 standard error of the mean. CR, continuous reinforcement; PR, partial reinforcement.

that showed that in the CR condition the acute schizophrenic patients had greater scores than the healthy controls (P B/0.05), whilst the chronic schizophrenic patients had marginally greater scores than the healthy controls (P B/0.09). There was no significant difference in the CR condition between the two groups of schizophrenic patients. No differences were observed for the PR condition across any of the groups.

4.4. Discussion Experiment 2 failed to find a significant reduction in PREE in acute as compared to chronic schizophrenic patients. There was some hint that the PREE was smaller for schizophrenic patients per se. However, analysis showed that even this marginal effect was due

338

N.S. Gray et al. / Behavioural Brain Research 133 (2002) 333 /342

to increased resistance to extinction in the CR schedule rather than reduced resistance to extinction in the PR schedule as predicted. The acute and chronic patients were statistically indistinguishable from one another, whereas in our parallel experiments using the LI [1,22] and KBE [30] paradigms, only acute schizophrenic patients differed from controls, showing an abolition of these behavioural phenomena. This discrepancy cannot reflect differences in the patient groups studied, since one of the relevant LI experiments [22] used the same participants as those studied here and, indeed, LI and the PREE were measured in the same session.

5. Experiment 3 */PREE and the effect of schizotypy On the assumption that psychotic tendencies exist on a continuum [7] it is predicted that those scoring highly on such measures will show comparable patterns of behaviour to those of schizophrenic patients. Thus a number of studies have demonstrated that LI is reduced in such individuals [1,11,21,35,38], as is KBE [29]. In this experiment we test the prediction that PREE will also be reduced in individuals scoring highly on a measure of schizotypy. 5.1. Method Participants were 64 paid normal volunteers (32 male, 32 female) obtained from an employment agency. Exclusion criteria were a history of mental illness, drug or alcohol dependency, or marked abnormalities with hearing or vision. As far as possible participants were matched across experimental conditions (CR and PR training) for sex, age, and verbal intelligence as tested by the Mill Hill Vocabulary Scale [49]. At the end of behavioural testing participants completed the Eysenck Personality Questionnaire (EPQ; [12]) in order to assess Psychoticism (P) scores. Whilst the P-scale of the EPQ is somewhat controversial as a measure of schizotypy (see [21] for discussion), these experiments were performed before later conceptualisations of schizotypy as a multi-dimensional construct [7], and the P-scale had already been shown to be related to LI [2] and the KBE [29]. Given the success of the P-scale in predicting reduced LI and KBE, it is the logical first candidate for examination of the PREE and schizotypy. Table 3 presents the means and standard errors of the age, verbal IQ and P-scale measures across experimental condition. Participants also took part in an experiment on LI, using the procedures described by [24]. Order of testing on the LI and PREE paradigms was randomly counterbalanced; no significant order effects were observed and this variable is therefore ignored here.

Table 3 Means and standard errors (in parentheses) for demographic and personality characteristics across the experimental conditions in experiment 1

Age Verbal IQ P-scale

CR

PR

24.8 (1.2) 103.7 (2.2) 4.6 (0.9)

24.7 (1.3) 107.2 (2.0) 4.5 (0.8)

Verbal intelligence was measured by the Mill Hill Vocabulary Scale.

5.2. Results Participants were assigned to either a ‘low’ or ‘high’ schizotypy group according to a median split based upon their P-score. Those participants (n/9) with exactly the median P-score were eliminated from the analysis. The mean responses in extinction for the two groups after the conditions of continuous and partial reinforcement are illustrated in Fig. 3. Once again the data had gross inhomogeneity of variance between conditions, and significant deviations from normality. Hence the methods of Conover and Iman [8] were applied. Once more we obtained a robust PREE [F (1, 51) / 57.62, P B/0.0001]. Overall the low and high schizotypy groups had similar mean target responses [F(1, 51) B/1]. Crucially there was a significant interaction between schizotypy group and reinforcement schedule [F (1, 51) /4.13, P B/0.05]. Examination of Fig. 3 suggests a smaller PREE for the low compared to the high schizotypy group, and that the effect is due to a decrease in score with increasing schizotypy for the CR group, but an increase for the PR group. Examination of this interaction showed that those with high scores on the P-

Fig. 3. Mean number of target responses during extinction as a function of the median split of P-scores in experiment 3. Error bars indicate 91 standard error of the mean. CR, continuous reinforcement; PR, partial reinforcement.

N.S. Gray et al. / Behavioural Brain Research 133 (2002) 333 /342

scale had a smaller learning score than the low scorers in the CR condition [t(24) /2.33, P B/0.05] whilst the groups did not differ in the PR condition [t (27) /0.46, ns]. This pattern of results was confirmed by correlating the P-score with the extinction score for the PR and CR groups separately. For the CR group, Spearman’s Rho indicated a significant negative relationship [Rho // 0.38, n/32, P B/0.05] whilst no significant correlation existed in the PR group [Rho /0.15, n/32, ns]. 5.3. Discussion Our findings with regard to schizotypal personality run counter to our predictions. To the extent that we observed any effect of schizotypy, this was in the direction opposite to observations made with the human LI [2,38] and KBE [29] paradigms. Both the latter two phenomena are reduced in participants high on the Psychoticism scale of the EPQ, whereas in the present experiment the PREE was greater in such participants. Moreover the difference was due to changes in extinction score for the CR group (in which resistance to extinction decreased with increasing P-score) rather than in the PR group as predicted.

6. General discussion In a series of three experiments examining the human PREE we have found that: 1) low and medium doses of amphetamine have no effect on resistance to extinction in either the CR or PR condition; 2) both chronic and acute schizophrenics show a reduced PREE due to greater resistance to extinction in the CR condition compared to controls; and 3) those high on schizotypy show a greater PREE due to less resistance to extinction in the CR condition. The experiments were performed to test predictions arising from Gray et al.’s [20] theory of the neuropsychology of schizophrenia. This theory predicted that the PREE would be reduced (1) by low, but not high, doses of amphetamine, (2) in acute but not chronic schizophrenia, and (3) in individuals scoring high on a schizotypy scale. Moreover all these reductions should be due to reduced resistance to extinction in the PR group, with no change in the CR group. It is clear that the results provide no support for this model. There seem to be three possible reasons for this outcome. The first is that the theory of Gray et al. [20] is, at least in part, wrong. Secondly, the PREE task may not be measuring the same psychological process as the LI and KBE tasks.

339

The latter effects occur when stimuli lose the capacity to enter into associations either because initially they appear to have no consequence (LI), or no predictive value (KBE). These processes explain why the stimulus subsequently fails to gain attention when it later becomes relevant. Thus, behaviour is absent because attentional resources are focussed away from the ‘‘thought-to-be-irrelevant’’ stimuli. In contrast, in the PREE, the PR subject is able to continue responding regardless of the occurrence of non-reward (this having lost salience due its having been previously interspersed with reward). Thus, behaviour is present because attentional resources are focussed away from the ‘‘thoughtto-be-irrelevant’’ consequence of that behaviour. Thirdly, though we purport to be measuring the PREE in human subjects, it is far from clear that the human PREE is the same as the PREE measured in other animals (mainly rats). Whilst many aspects of the findings of PREE in human and rat are similar [16,42,52], there are also striking differences between the findings [16,46,47]. The task we used was one well established in the literature [59]. However, this does not necessarily mean that it measures the PREE. One possible confounding factor in our task [59] is that the target response is exactly the same each time. It is well documented that many schizophrenic patients exhibit the phenomenon of perseveration, thought to reflect hypodopaminergic activity in the frontal cortex [60,61]. Hence schizophrenic patients may well tend to keep producing the learned response even in the absence of reward due to a process of perseveration rather than due to resistance to extinction. This may go some way to explaining why we found greater resistance to extinction in the CR schedule for the schizophrenic patients. With regard to the amphetamine experiment, it is also the case that there are many different conditions under which amphetamine abolishes the PREE in the rat. In the current study we have only investigated two of these conditions (a single low versus high dose of amphetamine administered in both acquisition and extinction). The amphetamine PREE studies in the rat present a complex picture of the conditions under which the PREE is attenuated following amphetamine. For example, Weiner et al. [62] found that repeated low doses of amphetamine administered in the acquisition phase of the task abolished the PREE, irrespective of drug treatment in extinction. Conversely, a PREE was obtained in animals that received saline in acquisition, independent of drug treatment in extinction. Amphetamine administered in extinction alone was found to increase resistance to extinction in PR animals while having no effect on CR animals. On the basis of these results, Weiner et al. [62] proposed that amphetamine disrupts performance in conflict situations that involve competing contingencies of reinforcement and non-

340

N.S. Gray et al. / Behavioural Brain Research 133 (2002) 333 /342

reinforcement and where the appropriate performance requires the subject’s responding to come under the control of the non-reinforcement contingency. Consistent with this analysis, Weiner et al. [63] found in a one trial a day paradigm that amphetamine reduces control over behaviour by stimuli associated with non-reinforcement without affecting the capacity of reinforcement to control behaviour. Amphetamine was administered to PR animals only on reinforced or only on nonreinforced trials. PR animals that were given placebo on non-reinforced trials showed a strong PREE whereas those who received amphetamine on non-reinforced trials showed no PREE, irrespective of the drug injected on reinforced trials. Again, there was found to be no effect of amphetamine on the CR animals. The neuroleptic drug haloperidol was also found to have an action on non-reinforcement and not reinforcement [14]. Thus, haloperidol increased the magnitude of the PREE by increasing the rate of extinction and this effect was entirely due to the administration of the drug in extinction, independent of drug treatment in acquisition. This complex analysis of the conditions under which amphetamine abolishes the PREE in the rat contrasts with our current study where we have only investigated the effects of amphetamine on the PREE under one set of conditions (e.g. a single low vs. high dose of amphetamine administered in both acquisition and extinction). It is, however, difficult to imagine how a ‘‘one trial a day’’ human paradigm could be developed and, of course, chronic amphetamine administration in humans would be impossible due to ethical considerations. Given the importance of the PREE to theories of schizophrenia, and the problems we have identified above, it may be unwise to discard it too soon. New PREE tasks are being developed that seem free from previous shortcomings, and may allow both within- and between-subject tasks (e.g. [56]). Such a within-subject task would be a valuable tool for researchers, but has proved difficult to establish using the LI [25,36] or KBE [31] paradigms. A final noteworthy feature of our results is that, as is the case also for LI [51], the PREE task disclosed differences in the behaviour of schizophrenic patients (increased resistance to extinction, especially in the CR condition; Fig. 2) and normal individuals identified by questionnaire as schizotypal (reduced resistance to extinction in the CR condition; Fig. 3), in each case relative to the behaviour of controls. This divergence is inconsistent with proposals that see schizophrenia as an extreme form of the same underlying behavioural trait that constitutes schizotypy [6], although the effect of neuroleptic medication in schizophrenic patients on these tasks also needs to be taken into account.

Acknowledgements Thanks are due to Professor J.D. Parkes for advice in the design of the psychopharmacological studies. We are grateful to the Medical Research Council and to Bristol /Myers Squibb Pharmaceutical Corporation for financial support and to SmithKline Beecham plc for donating amphetamine.

References [1] Baruch I, Hemsley DR, Gray JA. Differential performance of acute and chronic schizophrenics in a latent inhibition task. Journal of Nervous and Mental Disease 1988;176:598 /605. [2] Baruch I, Hemsley DR, Gray JA. Latent inhibition and ‘psychotic proneness’ in normal subjects. Personality and Individual Differences 1988;9:777 /83. [3] Bender S, Muller B, Oades RD, Sartory G. Conditioned blocking and schizophrenia: a replication and study of the role of symptoms, age, onset-age of psychosis and illness-duration. Schizophrenia Research 2001;49:157 /70. [4] Braunstein-Bercovitz H. Is the attentional dysfunction in schizotypy related to anxiety? Schizophrenia Research 2000;46:255 /67. [5] Braunstein-Bercovitz H, Lubow RE. Are high schizotypal-normal participants distractible or limited in attentional resources? A study of Latent Inhibition as a function of masking task load and schizotypy level. Journal of Abnormal Psychology 1998;107:659 / 70. [6] Claridge G. Theortical background and issues. In: Claridge G, editor. Schizotypy. Implications for Illness and Health, 1997:377 / 86. [7] Claridge GS, McCreery C, Mason O, Bentall RP, Boyle G, Slade PD, Popplewell D. The multidimensional nature of schizotypal traits: a factor analytic study with normal subjects. British Journal of Clinical Psychology 1996;35:103 /15. [8] Conover WJ, Iman RL. Ranked transformations as a bridge between parametric and non-parametric statistics. American Statistician 1981;35:1240 /9. [9] Crider A, Solomon PR, McHahon MA. Disruption of selective attention in the rat following d -amphetamine administration: relationship to schizophrenic attention disorder. Biological Psychiatry 1982;7:351 /61. [10] Davis JM. Comparative doses and costs of antipsychotic medication. Archives of General Psychiatry 1976;33:858 /61. [11] De la Casa GL, Ruiz G, Lubow RE. Latent inhibition and recall/ recognition of irrelevant stimuli as a function of preexposure duration in high and low psychotic prone normal subjects. British Journal of Psychology 1993;84:119 /32. [12] Eysenck HJ, Eysenck SBG. Manual of the Eysenck Personality Questionnaire. London: Hodder and Stoughton, 1975. [13] Feldon J, Bercovitz H, Weiner I. The effects of amphetamine on a multi-trial partial reinforcement extinction effect (PREE) in a runway. Pharmacology. Biochemistry and Behaviour 1989;32:65 / 9. [14] Feldon J, Weiner I. Effects of haloperidol on a multitrial partial reinforcement extinction effect (PREE)-evidence for neuroleptic drug-action on nonreinforcement but not on reinforcement. Psychopharmacology 1991;105:407 /14. [15] Feldon J, Weiner I. Amphetamine and the multitrial partialreinforcement extinction effect (PREE) in an operant chamberprocedural modifications that lead to an attenuation of the PREE. Pharmacology Biochemistry and Behaviour 1992;41:309 /15.

N.S. Gray et al. / Behavioural Brain Research 133 (2002) 333 /342 [16] Flora SR, Pavlik WB. Conventional and reversed partial reinforcement effects in human operant responding. Bulletin of the Psychonomic Society 1990;28:429 /32. [17] Gray JA. Elements of a two-process theory of learning. London: Academic Press, 1975. [18] Gray JA. The neuropsychology of anxiety: an enquiry into the functions of the septohippocampal system. Oxford, England: Oxford University Press, 1982. [19] Gray JA. Integrating schizophrenia. Schizophrenia Bulletin 1998;24:249 /66. [20] Gray JA, Feldon J, Rawlins JNP, Hemsley DR, Smith AD. The neuropsychology of schizophrenia. Behavioral and Brain Sciences 1991;14:1 /20. [21] Gray NS, Fernandez M, Williams J, Ruddle RA, Snowden RJ. What schizotypal dimensions abolish latent inhibition? British Journal of Clinical Psychology, in press. [22] Gray NS, Hemsley DR, Gray JA. Abolition of latent inhibition in acute, but not chronic, schizophrenics. Neurology and Psychiatric Brain Research 1992;1:83 /9. [23] Gray NS, Pickering AD, Gray JA, Jones SH, Abrahams S, Hemsley DR. Kamin blocking is not disrupted by amphetamine in human subjects. Journal of Psychopharmacology 1997;11:301 /11. [24] Gray NS, Pickering AD, Hemsley DR, Dawling S, Gray JA. Abolition of latent inhibition by a single 5 mg dose of d amphetamine. Psychopharmacology 1992;107:425 /30. [25] Gray NS, Pilowsky LS, Gray JA, Kerwin RW. Latent inhibition in drug naive schizophrenics: relationship to duration of illness and dopamine D2 binding using SPET. Schizophrenia Research 1995;17:95 /107. [26] Guterman Y, Josiassen RC, Bashoire TE, Johnson M, Lubow RE. Latent inhibition effects reflected in event-related brain potentials in healthy controls and schizophrenics. Schizophrenia Research 1996;20:315 /26. [27] Hofer I, Della Casa V, Feldon J. The interaction between schizotypy and latent inhibition: modulation by experimental parameters. Personality and Individual Differences 1999;26:1075 /88. [28] Jarrard LE, Feldon J, Rawlins JNP, Sinden JD, Gray JA. The effects of intrahippocampal ibotenate on resistance to extinction after continuous or partial reinforcement. Experimental Brain Research 1986;61:519 /30. [29] Jones SH, Gray JA, Hemsley DR. The Kamin blocking effect, incidental learning and schizotypy. Personality and Individual Differences 1992;13:57 /60. [30] Jones SH, Gray JA, Hemsley DR. Loss of Kamin blocking effect in acute but not chronic schizophrenics. Biological Psychiatry 1992;32:739 /55. [31] Jones SH, Hemsley DR, Ball S, Serra A. Disruption of the Kamin blocking effect in schizophrenia and in normal subjects following amphetamine. Behavioural Brain Research 1997;88:103 /14. [32] Kamin LJ. ’Attention-like’ processes in classical conditioning. In: Jones MR, editor. Miami symposium on the prediction of behaviour: aversive stimulation. Miami, FL: University of Miami Press, 1968. [33] Kelly AE, Domesick VB. The distribution of the projection from the hippocampal formation to the nucleus accumbens in the rat. An anterograde- and retrograde-horseradish peroxidase study. Neuroscience 1982:2321 /35. [34] Kumari V, Cotter PA, Mulligan OF, Checkley SA, Gray NS, Hemsley D, Thornton JC, Corr PJ, Toone BK, Gray JA. Effects of d -amphetamine and haloperidol on latent inhibition in healthy male volunteers. Journal of Psychopharmacology 1999;13:398 / 405. [35] Lipp OV, Vaitl D. Latent inhibition in human Pavlovian differential conditioning: effect of additional stimulation after

[36]

[37]

[38]

[39]

[40]

[41]

[42] [43]

[44]

[45] [46]

[47]

[48]

[49] [50]

[51]

[52]

[53]

[54]

341

pre-exposure and relation to schizotypal traits. Personality and Individual Differences 1992;13:1003 /12. Lubow RE. Latent inhibition as a measure of learned inattention: some problems and solutions. Behavioural Brain Research 1997;88:75 /83. Lubow RE, Gerwitz JC. Latent inhibition in humans: data, theory, and implications for schizophrenia. Psychological Bulletin 1995;117:87 /103. Lubow RE, Ingberg-Sachs Y, Zalstein-Orda N, Gewirtz JC. Latent inhibition in low and high ‘psychotic prone’ normal subjects. Personality and Individual Differences 1992;13:563 /72. Lubow RE, Kaplan O, Abramovich P, Rudnick A, Laor N. Visual search in schizophrenia: latent inhibition and novel popout effects. Schizophrenia Research 2000;45:145 /56. Magaro PA, Abrams L, Cantrell P. The MAINE scale of paranoid and non-paranoid schizophrenia: reliability and validity. Journal of Consulting and Clinical Psychology 1981;49:439 /47. Mogenson GJ, Wang CR, Yim CY. Influence of dopamine on limbic inputs to the nucleus accumbens. Annals of the New York Academy of Science 1988;537:86 /100. Nevin JA. The momentum of compliance. Journal of Applied Behavior Analysis 1996;29:535 /47. Oades RD, Zimmermann B, Eggers C. Conditioned blocking in patients with paranoid, non-paranoid psychosis or obsessive compulsive disorder: Associations with symptoms, personality and monoamine metabolism. Journal of Psychiatric Research 1996;30:369 /90. Overall JE. The Brief Psychiatric Rating Scale in psychopharmacological research. In: Pichot P, Oliver-Martin R, editors. Psychological measurements in psychopharmacology. Modern problems in pharmacopsychiatry, vol. 7. Basel: Karger, 1974:67 /78. Overall JE, Gorham DR. The Brief Psychiatric Rating Scale. Psychological Reports 1962;10:799 /812. Pavlik WB, Flora SR. Human responding on multiple variable interval schedules and extinction. Learning and Motivation 1993;24:88 /99. Pittenger DJ, Pavlik WB. Analysis of the partial reinforcement extinction effect in humans using absolute and relative comparisons of schedules. American Journal of Psychology 1993;101:1 / 14. Rascle C, Mazas O, Vaiva G, Tournant M, Raybois O, Goudemand M, Thomas P. Clinical features of latent inhibition in schizophrenia. Schizophrenia Research 2001;51:149 /61. Raven JG. Manual for Raven’s Progressive Matrices and vocabulary scales. London: HK Lewis, 1981. Rawlins JNP, Feldon J, Tonkiss J, Coffey PJ. The role of subicular output in the development of the partial reinforcement extinction effect. Experimental Brain Research 1989;77:153 /60. Serra AM, Jones SH, Toone B, Gray JA. Impaired associative learning in chronic schizophrenics and their first-degree relatives: a study of latent inhibition and the Kamin blocking effect. Schizophrenia Research 2001;28:273 /89. Shigley R, Guffey J. Resistance to extinction as a function of partial reinforcement before and after continuous reinforcement in a human operant task. Journal of General Psychology 1978;99:257 /61. Sinden JD, Jarrard LE, Gray JA. The effects of intra-subicular ibotenate on resistance to extinction after continuous or partial reinforcement. Experimental Brain Research 1988;73:315 /9. Solomon PR, Crider A, Winkelman JW, Turi A, Kamer RM, Kaplan LJ. Disrupted latent inhibition in the rat with chronic amphetamine or haloperidol- induced supersensitivity: relationship to schizophrenic attention disorder. Biological Psychiatry 1981;16:519 /37.

342

N.S. Gray et al. / Behavioural Brain Research 133 (2002) 333 /342

[55] Spitzer RL, Endicott J, Robbins E. Research Diagnostic Criteria (RDC) for a selected group of functional disorders, 3rd ed.. New York: State Psychiatric Institute, 1978. [56] Svartdal F. Persistence during extinction: conventional and reversed PREE under multiple schedules. Learning and Motivation 2000;31:21 /40. [57] Swerdlow NR, Braff DL, Hartston H, Perry W, Geyer MA. Latent inhibition in schizophrenia. Schizophrenia Research 1996;20:91 /103. [58] Thornton JC, Dawe S, Lee C, Capstick C, Porr PJ, Cotter P, Frangou S, Gray NS, Russell MAH, Gray JA. Effects of nicotine and amphetamine on latent inhibition in human subjects. Psychopharmacology 1996;127:164 /73. [59] Vogel-Sprott MD. Partial-reward training for resistance to punishment and to subsequent extinction. Journal of Experimental Psychology 1967;75:13 /140. [60] Weinberger DR. Schizophrenia and the frontal lobe. Trends in Neurosciences 1988;11:367 /70. [61] Weinberger DR, Berman KF. Prefrontal function in schizophrenia: confounds and controversies. Philosophical Transactions of the Royal Society of London B 1996;351:1495 /503.

[62] Weiner I, Bercovitz H, Lubow RE, Feldon J. The abolition of the partial reinforcement extinction effect (PREE) by amphetamine. Psychopharmacology 1985;86:318 /23. [63] Weiner I, Feldon J, Bercovitz H. The abolition of the partial reinforcement extinction effect (PREE) by amphetamine: disruption of control by non-reinforcement. Pharmacology Biochemistry and Behaviour 1987;27:205 /10. [64] Weiner I, Feldon J, Izraeli-Telerant A. Latent inhibition is not affected by acute or chronic administration of 6mg/kg d amphetamine. Psychopharmacology 1987;91:345 /51. [65] Weiner I, Lubow RE, Feldon J. Chronic amphetamine and latent inhibition. Behavioural Brain Research 1981;2:285 /6. [66] Weiner I, Lubow RE, Feldon J. Disruption of latent inhibition by acute administration of low doses of amphetamine. Pharmacology Biochemistry and Behaviour 1988;30:871 /8. [67] Williams JH, Wellman NA, Geaney DP, Cowen PJ, Feldon J, Rawlins JNP. Reduced latent inhibition in people with schizophrenia: an effect of psychosis or of its treatment. British Journal of Psychiatry 1998;172:243 /9. [68] Wuthrich V, Bates TC. Schizotypy and latent inhibition: nonlinear linkage between psychometric and cognitive markers. Personality and Individual Differences 2001;30:783 /98.