D1-like receptor activation improves PCP-induced cognitive deficits in animal models: Implications for mechanisms of improved cognitive function in schizophrenia
Introduction
Cognitive dysfunction in schizophrenia is becoming an increasingly important therapeutic target as one reason for the residual disability of schizophrenia appears to be the long-standing cognitive deficits of the disorder (Green and Nuechterlein, 2004). The MATRICS initiative (Measurement and Treatment Research to Improve Cognition in Schizophrenia) aims to facilitate the development of better treatments targeted at cognition (Marder and Fenton, 2004). It has been often reported that atypical antipsychotics have some beneficial effect on cognitive deficits (Hagger et al., 1993, Buchanan et al., 1994, Rossi et al., 1997, Meltzer and McGurk, 1999, Harvey et al., 2004). However, the effect is small (Lieberman, 2006, Keefe et al., 2007) and hence there remains a great unmet need for novel antipsychotics to improve cognitive function.
There is mounting evidence for the role of dopamine dysregulation in the prefrontal cortex (PFC) in schizophrenia (for review see Goldman-Rakic et al., 2004). It has been suggested that the negative symptoms and cognitive deficits seen in schizophrenia may arise from a dopaminergic deficit in the prefrontal cortex i.e. hypofrontality (Davis et al., 1991), whereas the positive symptoms are related to hyperactivity of sub-cortical dopaminergic neurons (Grace, 1991). In keeping with this, inhibitors of catechol-O-methyltransferase (COMT), the primary enzyme responsible for metabolic degradation of dopamine specifically in the medial prefrontal cortex (mPFC), have been shown to improve cortical processing in both humans (Apud et al., 2007) and rats (Tunbridge et al., 2006).
Spano et al. (1978) proposed the existence of two populations of dopamine receptors after it was shown that dopamine both stimulated and inhibited adenylate cyclase (AC) activity (Brown and Makman, 1972, Kebabian et al., 1972). D1 and D5 receptors belong to the D1-like family in that they stimulate adenylate cyclase (AC), whereas D2, D3 and D4 receptors inhibit AC. D1-like receptors are predominantly found in the PFC, while D2-like receptors are expressed in sub-cortical regions (see Guillin et al., 2007), although D4 receptors are present in the PFC and hippocampus (Lahti et al., 1998). In keeping with the dopaminergic hypothesis of schizophrenia current antipsychotics attenuate positive symptoms by blocking sub-cortical D2 receptors (Seeman et al., 1975, Creese et al., 1976) but these drugs have, at best, only limited efficacy at treating cognitive deficits.
Mounting evidence suggests that the D1 receptor in the mPFC may be important in regulating cognitive function in schizophrenic patients. Okubo et al. (1997) reported a down-regulation of D1 binding in the PFC of treatment-free/-naïve schizophrenic patients. Another study has demonstrated an association between genetic risk for schizophrenia and alterations in cortical D1 receptor binding (Hirvonen et al., 2006). It has also been shown that D1 receptors are more abundant than D2 receptors in the PFC of non-human primates (Lidow et al., 1991), and this D1 receptor subfamily has been implicated in working memory functions of the PFC (Arnsten et al., 1994, Sawaguchi and Goldman-Rakic, 1991), one aspect of cognition impaired in schizophrenia. Thus, it is possible that stimulation of the D1 receptor may represent a potential strategy for treating cognitive deficits associated with schizophrenia. Indeed, D1 agonists have been highlighted as a molecular target for cognitive enhancement in schizophrenia (see Gray and Roth, 2007).
Phencyclidine (PCP) is a non-competitive NMDA receptor antagonist, which has been shown to produce enduring cognitive deficits similar to those observed in schizophrenia (Javitt and Zukin, 1991) particularly when administered sub-chronically rather than acutely (Jentsch and Roth, 1999). Repeated and intermittent administrations of PCP have been shown to reduce dopamine turnover in the PFC of rats and monkeys (Jentsch et al., 1997a, Jentsch et al., 1997b); moreover, the use of a sub-chronic PCP regimen has been suggested to provide a superior pharmacological model of the hypodopaminergic state seen in schizophrenia (see Jentsch and Roth, 1999). Sub-chronic PCP also causes reduced density of parvalbumin-immunoreactive neurons (Abdul-Monim et al., 2007) and brain-derived neurotrophic factor (BDNF) levels in cortical regions (Snigdha et al., 2007a) in rats. Indeed, the sub-chronic PCP dosage regime has been well-validated in our laboratory producing enduring cognitive deficits which can be reversed by atypical but not classical antipsychotics in NOR (Grayson et al., 2007), reversal learning (Abdul-Monim et al., 2006, Abdul-Monim et al., 2007) and attentional set-shifting (McLean et al., 2008) tasks. Sub-chronic PCP also produces social behaviour deficits in our laboratory which are improved by atypical but not by classical antipsychotics (Snigdha and Neill, 2008a, Snigdha and Neill, 2008b). Using this model we have observed cognitive deficits in NOR lasting up to 5 months following the last dose of PCP (Grayson et al. unpublished observations). As many atypical antipsychotics have affinity for a multitude of receptors, much research is now focusing on identifying specific receptor subtypes as potential novel targets and on the development of selective compounds (Gray and Roth, 2007) for the treatment of cognitive dysfunction in schizophrenia.
The core aim of this study was to utilise the selective D1-like receptor agents SKF-38393 and SCH-23390 to elucidate the role of D1-like receptors in cognition using two rodent tests validated in our laboratory, the NOR test and the operant reversal learning task, which are both tests highlighted by the MATRICS initiative as being relevant translational models for studying visual learning and memory and reasoning and problem solving respectively (see Hagan and Jones, 2005). It is expected that SKF-38393 will ameliorate the sub-chronic PCP-induced deficit, and that the antagonist SCH-23390 will block these effects. Both ligands shall be referred to as D1-like throughout as SKF-38393 and SCH-23390 have been reported to have similar Ki values at D1 and D5 receptors; SKF-38393 having reported Ki values of 26 nM and 80 nM at D1 and D5 receptors respectively (Neumeyer et al., 2003, Qandil et al., 2003), whilst SCH-23390 has reported Ki values of 0.37 nM and 0.47 nM for D1 and D5 receptors respectively (Lawler et al., 1999).
We also sought to determine if the stage of oestrous cycle had any effect on reversal learning ability since an interaction between gonadal steroids, in particular oestrogen, and cognitive function has previously been reported (see Cahill, 2006 for review). However, we have previously shown no effect of oestrous cycle on novel object recognition (Sutcliffe et al., 2007). It is important for each task to determine whether the oestrous cycle has an effect, therefore this was assessed here in reversal learning.
Section snippets
Subjects and housing conditions
Two cohorts of fifty female hooded-Lister rats, 100 in total (Harlan, UK) housed in groups of four or five were used as subjects, rats weighed between 200 and 250 g. Animals were maintained under standard laboratory conditions at a temperature of 21 °C (± 2 °C) and humidity of 40–50%. They were maintained on a 12-h/12-h light/dark cycle (lights on at 0700 h) and experimental procedures were performed during the light phase. Cohort 1 were allowed free access to food, while cohort 2 prior to
Novel object recognition—effects of SKF-38393 and SCH-23390
There was no significant difference in time spent exploring the two identical objects during the acquisition trial in any of the treatment groups (Fig. 1a). In the retention trial, vehicle-treated rats explored the novel object significantly more than the familiar object (P < 0.05); this effect was abolished in sub-chronic PCP-treated rats (Fig. 1b). The ability to distinguish between novel and familiar objects was restored following administration of SKF-38393 (6.0 mg/kg, i.p.; P < 0.05); this
Discussion
In the current set of experiments we examined the efficacy of the D1-like receptor agonist, SKF-38398, in improving cognition in two rodent tests of cognitive dysfunction of relevance to schizophrenia. Our data show that SKF-38393 significantly improved a sub-chronic PCP-induced deficit in the novel object recognition and reversal learning tests, an improvement which was subsequently antagonised by the D1-like receptor antagonist, SCH-23390.
Furthermore, we demonstrate that reversal learning is
Role of the funding source
SL McLean is supported by a joint University of Bradford–GSK postgraduate studentship.
Contributors
S McLean and N Idris carried out the experiments. M Woolley and J Neill supervised the work and provided comments on the manuscript.
Conflict of interest
All authors declare that there are no conflicts of interest.
Acknowledgements
SM is supported by a GSK and University of Bradford postgraduate studentship.
References (81)
- et al.
The effect of atypical and classical antipsychotics on sub-chronic PCP-induced cognitive deficits in a reversal-learning paradigm
Behavioural Brain Research
(2006) - et al.
Performance- and task-dependent effects of the dopamine D1/D5 receptor agonist SKF 38393 on learning and memory in the rat
European Journal of Pharmacology
(2007) - et al.
GABAergic interneurones: implications for understanding schizophrenia and bipolar disorder
Neuropsychopharmacology
(2001) - et al.
The comparative efficacy and long-term effect of clozapine treatment on neuropsychological test performance
Biological Psychiatry
(1994) - et al.
Amphetamine sensitization impairs cognition and reduces dopamine turnover in primate prefrontal cortex
Biological Psychiatry
(2005) - et al.
A single 20 mg dose of dihydrexidine (DAR-0100), a full dopamine D(1) agonist, is safe and tolerated in patients with schizophrenia
Schizophrenia Research
(2007) - et al.
D(1) receptors in prefrontal cells and circuits
Brain Research. Brain Research Reviews
(2000) Phasic versus tonic dopamine release and the modulation of dopamine system responsivity: a hypothesis for the etiology of schizophrenia
Neuroscience
(1991)- et al.
Atypical antipsychotics attenuate a sub-chronic PCP-induced cognitive deficit in the NOR task in the rat
Behavioural Brain Research
(2007) - et al.
The MATRICS initiative: developing a consensus cognitive battery for clinical trials
Schizophrenia Research
(2004)
Neurobiology of dopamine in schizophrenia
International Review of Neurobiology
Improvement in cognitive functions and psychiatric symptoms in treatment-refractory schizophrenic patient receiving clozapine
Biological Psychiatry
Improvement in cognitive function following a switch to ziprasidone from conventional antipsychotics, olanzapine, or risperidone in outpatients with schizophrenia
Schizophrenia Research
On the nature of Wisconsin Card Sorting Test performance in schizophrenia
Psychiatry Research
Dopamine D1 receptor ligands modulate cognitive performance and hippocampal acetylcholine release in memory-impaired aged rats
Neuroscience
Atypical, but not typical, antipsychotic drugs increase cortical acetylcholine release without an effect in the nucleus accumbens or striatum
Neuropsychopharmacology
The neuropsychopharmacology of phencyclidine: from NMDA receptor hypofunction to the dopamine hypothesis of schizophrenia
Neuropsychopharmacology
Subchronic phencyclidine administration reduces mesoprefrontal dopamine utilisation and impairs prefrontalcortical-dependent cognition in the rat
Neuropsychopharmacology
Interactions of the novel antipsychotic aripiprazole (OPC-14597) with dopamine and serotonin receptor subtypes
Neuropsychopharmacology
Distribution of dopaminergic receptors in the primate cerebral cortex: quantitative autoradiographic analysis using [3H]raclopride, [3H]spiperone and [3H]SCH23390
Neuroscience
Measurement and treatment research to improve cognition in schizophrenia: NIMH MATRIICS initiative to support the development of agents for improving cognition in schizophrenia
Schizophrenia Research
Orbital prefrontal cortex mediates reversal learning and not attentional set shifting in the rat
Behavioural Brain Research
Deficits in attentional set-shifting in rats following sub-chronic phencyclidine (PCP) administration, effect of gender
European Neuropsychopharmacology
A preliminary investigation into the effects of antipsychotics on sub-chronic phencyclidine-induced deficits in attentional set-shifting in female rats
Behavioural Brain Research
Effects of orbital frontal and anterior cingulate lesions on object and spatial memory in rhesus monkeys
Neuropsychologia
A single dose of the full D1 dopamine agonist dihydrexidine (DAR-0100) increases prefrontal perfusion in schizophrenia
Schizophrenia Research
Sertindole, 5-HT2A and 5-HT6 antagonists improve a subchronic phencyclidine-induced reversal learning deficit in rats
Schizophrenia Research
Receptor affinities of dopamine D1 receptor-selective novel phenylbenzazepines
European Journal of Pharmacology
Comparison of set shifting ability in patients with chronic schizophrenia and frontal lobe damage
Schizophrenia Research
Synthesis and pharmacological evaluation of substituted napth[1,2,3-de]isoquinolines (dinapsoline analogues) as D1 and D2 dopamine receptor ligands
Bioorganic and Medicinal Chemistry
CP-809, 101, a selective 5-HT2C agonist, shows activity in animal models of antipsychotic activity
Neuropharmacology
Efficacy of antipsychotics to reverse phencyclidine-induced social interaction deficits in female rats—a preliminary investigation
Behavioural Brain Research
Improvement of phencyclidine-induced social behaviour deficits in rats: involvement of 5-HT(1A) receptors
Behavioural Brain Research
Brain-derived neurotrophic factor downregulation in rat brain following sub-chronic phencyclidine administration
European Neuropsychopharmacology
D1 agonist dihydrexidine releases acetylcholine and improves cognition performance in rats
Pharmacology Biochemistry and Behavior
Influence of gender on working and spatial memory in the novel object recognition task in the rat
Behavioural Brain Research
Catechol-o-methyltransferase, cognition, and psychosis: Val158Met and beyond
Biological Psychiatry
The atypical antipsychotic ziprasidone, but not haloperidol, improves PCP-induced cognitive deficits in a reversal learning task in the rat
Journal of Psychopharmacology
Sub-chronic psychotomimetic phencyclidine induces deficits in reversal learning and alteration in parvalbumin-immunoreactive expression in the rat
Journal of Psychopharmacology
Tolcapone improves cognition and cortical information processing in normal human subjects
Neuropsychopharmacology
Cited by (64)
The allosteric dopamine D1 receptor potentiator, DETQ, ameliorates subchronic phencyclidine-induced object recognition memory deficits and enhances cortical acetylcholine efflux in male humanized D1 receptor knock-in mice
2019, Behavioural Brain ResearchCitation Excerpt :We [18], and others [22] reported that the prolonged deficit in NOR produced by subchronic treatment with the N-methyl-d-aspartate receptor (NMDAR) antagonist, phencyclidine (PCP; [2,23]), was rescued by the orthosteric D1R agonist, SKF38393, with an inverted U-shaped dose-response curve. The amelioration in rats of the deficit in NOR, produced by subchronic PCP is blocked by the D1R antagonist, SCH23390 [24]. Thus, D1R agonism is potentially useful to improve cognitive impairment resulting, in part, from inadequate D1R stimulation, in various neuropsychiatric disorders.
Amyloid β synaptotoxicity is Wnt-PCP dependent and blocked by fasudil
2018, Alzheimer's and DementiaTowards the development of improved tests for negative symptoms of schizophrenia in a validated animal model
2016, Behavioural Brain ResearchNicotinic α7 and α4β2 agonists enhance the formation and retrieval of recognition memory: Potential mechanisms for cognitive performance enhancement in neurological and psychiatric disorders
2016, Behavioural Brain ResearchCitation Excerpt :Experiments were conducted in accordance with the Animals (Scientific Procedures) Act UK (1986), and approved by the University of Bradford ethical review process. Female rats were used in this study as we have previously shown that females can recall information about a particular object for longer than male rats and that stage of the oestrous cycle does not affect cognitive performance in several tasks such as novel object recognition [74] and reversal learning [55]. Rats were tested in the novel object recognition (NOR) task as described in detail by McLean et al. [50–52].