Obsessive‐compulsive disorder (OCD) is characterized by obsessions (intrusive thoughts) and compulsions (repetitive ritualistic behaviours) leading to functional impairment. Accumulating evidence ...links these conditions with underlying dysregulation of fronto‐striatal circuitry and monoamine systems. These abnormalities represent key targets for existing and novel treatment interventions. However, the brain bases of these conditions and treatment mechanisms are still not fully elucidated. Animal models simulating the behavioural and clinical manifestations of the disorder show great potential for augmenting our understanding of the pathophysiology and treatment of OCD. This paper provides an overview of what is known about OCD from several perspectives. We begin by describing the clinical features of OCD and the criteria used to assess the validity of animal models of symptomatology; namely, face validity (phenomenological similarity between inducing conditions and specific symptoms of the human phenomenon), predictive validity (similarity in response to treatment) and construct validity (similarity in underlying physiological or psychological mechanisms). We then survey animal models of OC spectrum conditions within this framework, focusing on (i) ethological models; (ii) genetic and pharmacological models; and (iii) neurobehavioural models. We also discuss their advantages and shortcomings in relation to their capacity to identify potentially efficacious new compounds. It is of interest that there has been rather little evidence of ‘false alarms’ for therapeutic drug effects in OCD models which actually fail in the clinic. While it is more difficult to model obsessive cognition than compulsive behaviour in experimental animals, it is feasible to infer cognitive inflexibility in certain animal paradigms. Finally, key future neurobiological and treatment research areas are highlighted.
LINKED ARTICLES This article is part of a themed issue on Translational Neuropharmacology. To view the other articles in this issue visit http://dx.doi.org/10.1111/bph.2011.164.issue‐4
Recent evidence suggests that the neural correlates of reversal learning are localised to the orbitofrontal cortex whereas studies on the contribution of the medial prefrontal cortex to this capacity ...have produced equivocal results. This study examines the behavioural effects of selective lesions centred on orbitofrontal, infralimbic and prelimbic cortex on serial spatial reversal learning in the rat.
Rats were trained on a novel instrumental two-lever spatial discrimination and reversal learning task, measuring both ‘cognitive flexibility’ and constituent processes including response inhibition. Both levers were presented, only one of which was reinforced. The rat was required to respond on the reinforced lever under a fixed ratio 3 schedule of reinforcement. Following attainment of criterion, a series of reversals was presented.
Bilateral excitotoxic lesions of the orbitofrontal cortex did not affect retention of a preoperatively acquired spatial discrimination but did impair reversal learning. This deficit manifested as increased perseverative responding on the previously correct lever. Although impairments were evident during reversal 1, OFC-lesioned animals performed significantly better than controls on reversal 2. There were no significant effects of infralimbic and prelimbic lesions on the retention of a spatial discrimination or reversal learning.
These results indicate that the orbitofrontal cortex is critical for flexible responding in serial spatial reversal learning. The present findings may be relevant to deficits in reversal learning and response inhibition in such neuropsychiatric disorders as obsessive-compulsive disorder.
Disturbances in attentional processes are a common feature of several psychiatric disorders such as schizophrenia, attention deficit/hyperactivity disorder and Huntington's disease. The use of animal ...models has been useful in defining various candidate neural systems thus enabling us to translate basic laboratory science to the clinic and vice-versa. In this chapter, a comparative and integrated account is provided on the neuroanatomical and neurochemical modulation of basic behavioural operations such as selective attention, vigilance, set-shifting and executive control focusing on the comparative functions of the serotonin and dopamine systems in the cognitive control exerted by the prefrontal cortex. Specifically, we have reviewed evidence emerging from several behavioural paradigms in experimental animals and humans each of which centres on a different aspect of the attentional function. These paradigms offering both human and animal variants include the five-choice serial reaction time task (5CSRTT), attentional set-shifting and stop-signal reaction time task. In each case, the types of operation that are measured by the given paradigm and their neural correlates are defined. Then, the role of the ascending dopaminergic and serotonergic systems in the neurochemical modulation of its behavioural output are examined, and reference is made to clinical implications for neurological and neuropsychiatric disorders which exhibit deficits in these cognitive tests.
Rationale In the rewarded alternation model of obsessive compulsive disorder (OCD), the serotonin agonist m-chlorophenylpiperazine (mCPP) increases persistent behaviour, while chronic pretreatment ...with selective serotonin reuptake inhibitor (SSRI-fluoxetine) but not benzodiazepine or desipramine abolishes mCPP effects. However, we noted that acute SSRI administration also causes transient persistence increases, counteracted by mCPP pretreatment. Objectives This study a. further explores the apparent cross-tolerance between fluoxetine and mCPP and b. extends the model by investigating its sensitivity to dopaminergic manipulations (D2,3 agonism - quinpirole). Methods In both experiments, baseline and drug testing was carried out under daily T-maze alternation training. Exp.1 Matched group (n=8) pairs of rats received one of the following 20-day pretreatments (daily intraperitoneal administration): 1. saline, 2. low-dose fluoxetine (2.5mg/kg), 3. low-dose mCPP (0.5mg/kg) or 4. combined fluoxetine+mCPP. One group per pretreatment then received a 4-day challenge with high-dose fluoxetine (10mg/kg), the other with high-dose mCPP (2.5mg/kg). Exp.2 One group (n=12) of rats received 20-day treatment with saline, another with quinpirole (0.5 mg/kg). Results Exp.1 Saline and low-dose mCPP- or fluoxetine-pretreated animals showed significant persistence increases under both challenges, while combined low-dose fluoxetine+mCPP pretreatment afforded full protection from either challenge. Exp.2 Quinpirole significantly increased directional persistence after 13 administration days. Conclusions These results establish the sensitivity of the rewarded alternation OCD model to D2,3 receptor activation, thereby extending its profile of pharmacological isomorphism with OCD. Furthermore, they suggest a common mechanism of action of an SSRI and a serotonin agonist in the control of directional persistence.
Background We reported that the non-specific 5HT agonist m-chlorophenylpiperazine (mCPP) and the SSRI fluoxetine (FLX) both cause acute persistence increases in the rewarded alternation (RA) model of ...OCD. Chronic pretreatment with either substance or their combined subclinical doses protects from this ‘pathogenic’ effect, so mCPP and fluoxetine exhibit cross-tolerance and synergy. Aims Using specific 5HT2A and 5HT2C receptor antagonists we investigated whether these receptors participate in a common mechanism of action mediating the acute mCPP/fluoxetine effect in our model. Methods Naïve, male Wistars were used. Drugs used (intraperitoneally): FLX (10mg/kg), mCPP (2.5mg/kg), M100907 (5HT2A antagonist, 0.03mg/kg), SB242084 (5HT2C antagonist, 0.5mg/kg), vehicle. Experiments included a drug-free training/baseline phase in T-maze RA (group-matching for spontaneous persistence: SP). Experiment 1: Effects of M100907, SB242084, vehicle were assessed on 3 matched low SP and 3 high SP groups. Experiment 2: The acute effect of FLX, mCPP and saline were examined on RA in 3 SP-matched groups. Experiment 3: Effects of Vehicle+FLX, M100900+FLX, SB242084+FLX and Vehicle were examined on RA, in 4 SP-matched groups. Experiment 4: Correspondingly for mCPP. Results Experiment 1: Neither M100907 nor SB242084 affected high or low SP. Experiment 2 replicated the pathogenic effects of FLX/mCPP. Experiment 3: Neither M100907 nor SB242084 affected the pathogenic effect of FLX. Experiment 4: In contrast, SB242084 (but not M100907) significantly reduced the pathogenic mCPP effect. Conclusions The acute pathogenic action of mCPP, but not of FLX, involves 5HT2C but not 5HT2A receptors. The similar acute action of mCPP and FLX on persistence cannot be attributed to 5HT2 mediation.
Closed-form solutions, including arbitrary functions, of the system of nonlinear partial differential equations in plane rigid perfect plasticity are extracted. This system is reduced to a strongly ...nonlinear ordinary differential equation which brings, to the solution of the Abel equation of the second kind, exact analytic solutions examples of which were recently constructed. The stress and strain-velocity fields are given and an example for an obtuse wedge under unilateral, uniformly distributed load, under plane-stress conditions, is described indicating that the present method can treat problems yet unsolved. The stress field is described analytically and results for the limiting load are analogous to the classical Prandtl formula
We recently reported that orbitofrontal cortical (OFC) lesions impaired reversal learning of an instrumental two-lever spatial discrimination task, a deficit manifested as increased perseveration on ...the pre-potent response. Here we examine whether exposure to reversal learning test pre-operatively may have a beneficial effect for future reversal learning of OFC-lesioned animals. Rats were trained on a novel instrumental two-lever spatial discrimination and reversal learning task, measuring both ‘cognitive flexibility’ and constituent processes including response inhibition. Both levers were presented, only one of which was reinforced. The rat was required to respond on the reinforced lever under a fixed ratio 3 schedule of reinforcement. Following attainment of criterion, two reversals were introduced. Rats were then matched according to their reversal performance and subjected to bilateral excitotoxic OFC lesions. Following recovery, a series of four reversals was presented. OFC lesions impaired neither retention nor reversal phases. These data, together with the previously reported reversal deficit following OFC lesions, suggest that OFC is not needed when task experience has been gained but it is necessary when task demands are relatively high.
In spite of recent enrichment of neurochemical and behavioural data establishing a neuroprotective role for lithium, its primary effects on cognitive functioning remain ambiguous. This study examines ...chronic lithium effects on spatial working memory and long-term retention.
In three discrete experiments, rats subjected to 30 daily intraperitoneal injections (2
mmol/kg) of lithium (lithium groups: serum lithium
=
0.5
±
0.4
mEq/l, 12
h post-injection) or saline (controls) were trained in 0-s delay T-maze alternation and then tested in 30-, 45- and 60-s delay alternation (Experiments 1, 2, 3, respectively). Animals from Experiment 1 were further tested in one-trial step-through passive avoidance under mild shock parameters (0.5
mA, 1
s). Retention was assessed 6
h later. Daily lithium or saline injections continued throughout behavioural testing.
Lithium animals were indistinguishable from controls during 0-delay alternation baseline (Experiments 1–3, accuracy
>
88%) but showed significantly higher accuracy than controls at 30- and 45-s delays (93% versus 85% and 92% versus 82%, Experiments 1 and 2, respectively). At 60-s delay (Experiment 3) this beneficial effect of lithium was no longer apparent (lithium and control accuracy
=
78%). In Experiment 4, the shock used did not support 6-h passive avoidance retention in controls, whereas lithium animals showed significant step-through latency increases.
Chronic lithium enhanced spatial working memory and promoted long-term retention of a weak aversive contingency. The results suggest that lithium may have potential as a cognitive enhancer.
Background:
We reported that the non-specific 5HT agonist m-chlorophenylpiperazine (mCPP) and the SSRI fluoxetine (FLX) both cause acute persistence increases in the rewarded alternation (RA) model ...of OCD. Chronic pretreatment with either substance or their combined subclinical doses protects from this ‘pathogenic’ effect, so mCPP and fluoxetine exhibit cross-tolerance and synergy.
Aims:
Using specific 5HT2A and 5HT2C receptor antagonists we investigated whether these receptors participate in a common mechanism of action mediating the acute mCPP/fluoxetine effect in our model.
Methods:
Naïve, male Wistars were used. Drugs used (intraperitoneally): FLX (10mg/kg), mCPP (2.5mg/kg), M100907 (5HT2A antagonist, 0.03mg/kg), SB242084 (5HT2C antagonist, 0.5mg/kg), vehicle. Experiments included a drug-free training/baseline phase in T-maze RA (group-matching for spontaneous persistence: SP).
Experiment 1: Effects of M100907, SB242084, vehicle were assessed on 3 matched low SP and 3 high SP groups.
Experiment 2: the acute effect of FLX, mCPP and saline were examined on RA in 3 SP-matched groups.
Experiment 3: Effects of Vehicle+FLX, M100900+FLX, SB242084+FLX and Vehicle were examined on RA, in 4 SP-matched groups.
Experiment 4: Correspondingly for mCPP.
Results:
Experiment 1: Neither M100907 nor SB242084 affected high or low SP.
Experiment 2 replicated the pathogenic effects of FLX/mCPP.
Experiment 3: Neither M100907 nor SB242084 affected the pathogenic effect of FLX.
Experiment 4: in contrast, SB242084 (but not M100907) significantly reduced the pathogenic mCPP effect.
Conclusions:
The acute pathogenic action of mCPP, but not of FLX, involves 5HT2C but not 5HT2A receptors. the similar acute action of mCPP and FLX on persistence cannot be attributed to 5HT2 mediation.
PDF
