Serotonergic modulation of suicidal behaviour: integrating preclinical data with clinical practice and psychotherapy.

Many studies have provided important information regarding the anatomy, development and functional organization of the 5-HT system and the alterations in this system that are present within the brain of the suicidal patient. There is also a growing interest in genetic factors associated with suicide, since these may lead to the emergence of personality traits that prove to be long-term predictors of suicidal behaviour. This review will focus on presenting the scientific literature on the role of the serotonergic system in suicidal behaviour as well as dysfunctional attitudes and personality traits associated with the suicidal patient. The association of the serotonin transporter gene, the 5-HT2 receptors and its metabolite 5-hydroxyindoleacetic acid with suicidal behaviour and animal models that may capture the complexity of suicidal behaviour will be discussed. Finally, the relationship between neurobiological models and psychotherapeutic interventions for suicide prevention will be considered with a focus on Schema Therapy (an approach that has shown particular promise in the treatment of suicidal individuals with personality disorders), aiming to invite the reader to integrate some aspects of the neurobiology of human suicidal behaviour into a model of suicide that can be used in a clinical encounter.

5-HT2C receptor involvement in the control of persistence in the reinforced spatial alternation animal model of obsessive-compulsive disorder.

OBJECTIVE: The serotonergic system is implicated in the pathophysiology of obsessive-compulsive disorder (OCD). However, the distinct role of serotonin (5-HT) receptor subtypes remains unclear. This study investigates the contribution of 5-HT2A and 5-HT2C receptors in the modulation of persistence in the reinforced spatial alternation model of OCD. METHODS: Male Wistar rats were assessed for spontaneous and pharmacologically induced (by m-chlorophenylpiperazine: mCPP) directional persistence in the reinforced alternation OCD model. Systemic administration of mCPP (non-specific 5-HT agonist, 2.5mg/kg), M100907 (selective 5-HT2A receptor antagonist, 0.08 mg/kg), SB242084 (selective 5-HT2C receptor antagonist, 0.5 mg/kg) and vehicle was used. Experiment 1 investigated M100907 and SB242084 effects in animals spontaneously exhibiting high and low persistence during the early stages of alternation training. Experiment 2 investigated M100900 and SB242084 effects on mCPP-induced persistence. RESULTS: Under the regime used in Experiment 1, 5-HT2A or 5-HT2C receptor antagonism did not affect spontaneous directional persistence in either high or low persistence groups. In Experiment 2, 5-HT2C but not 5-HT2A receptor antagonism significantly reduced, but did not abolish, mCPP-induced directional persistence. CONCLUSIONS: These findings suggest that 5-HT2C but not 5-HT2A receptors contribute to the modulation of mCPP-induced persistent behaviour, raising the possibility that the use of 5-HT2C antagonists may have a therapeutic value in OCD.

Enhancement of spatial reversal learning by 5-HT2C receptor antagonism is neuroanatomically specific.

We have recently demonstrated that systemic administration of 5-HT(2C) and 5-HT(2A) receptor antagonists significantly enhanced and impaired spatial reversal learning, respectively. In this study, the role of 5-HT(2C) and 5-HT(2A) receptor subtypes in the mediation of these opposing effects was further investigated with respect to neuroanatomical specificity. The roles of 5-HT(2C) and 5-HT(2A) receptors were examined within some of the brain regions implicated in cognitive flexibility, namely the orbitofrontal cortex (OFC), medial prefrontal cortex (mPFC), and nucleus accumbens (NAc), by means of targeted infusions of selective 5-HT(2C) and 5-HT(2A) receptor antagonists (SB 242084 and M100907, respectively). Intra-OFC 5-HT(2C) receptor antagonism produced dose-dependent effects similar to those of systemic administration, i.e., improved spatial reversal learning by reducing the number of trials (all doses: 0.1, 0.3, and 1.0 microg) and perseverative errors to criterion (0.3 and 1.0 microg) compared with controls. However, the highest dose (1.0 microg) showed a nonselective effect, as it also affected retention preceding the reversal phase and decreased learning errors. Intracerebral infusions of SB 242084 into the mPFC or NAc produced no significant effects on any behavioral measures. Similarly, no significant differences were observed with intra-OFC, -mPFC, or -NAc infusions of M100907. These data suggest that the improved performance in reversal learning observed after 5-HT(2C) receptor antagonism is mediated within the OFC. These data also bear on the issue of whether 5-HT(2C) receptor antagonism within the OFC might help elucidate the biological substrate of obsessive-compulsive disorder, offering the potential for therapeutic application.

Cross-species models of OCD spectrum disorders.

Several axis-I neuropsychiatric disorders are characterised by repetitive motor habits suggestive of underlying inhibitory dyscontrol, and may constitute members of a putative obsessive-compulsive (OC) spectrum. Notable examples include obsessive-compulsive disorder (OCD) and trichotillomania (repetitive hair-pulling). Multiple tiers of evidence link these conditions with underlying dysregulation of fronto-striatal circuitry and monoamine systems. These abnormalities represent key targets for existing and novel treatment interventions. Nonetheless, the brain bases of these conditions, and treatment mechanisms, remain poorly characterised. Animal models of repetitive habits and inhibitory control problems show great potential for augmenting our understanding of the pathophysiology and treatment of OC spectrum conditions. Here, we begin by describing clinical features of OC spectrum disorders, and 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) behavioral models. Key future research directions are highlighted.

Trichotillomania: neurobiology and treatment.

Trichotillomania is a disorder characterized by repetitive hair pulling, leading to noticeable hair loss and functional impairment. This paper provides an overview of what is known of trichotillomania from several perspectives. We begin by considering historical descriptions of hair pulling that ultimately contributed to the inclusion of trichotillomania as a formal diagnostic entity in the Diagnostic and Statistical Manual. Psychological factors involved in the mediation of symptoms are examined, including positive and negative reinforcement. The relationships between trichotillomania, other body-focused repetitive behaviours, and disorders of the putative obsessive-compulsive (OC) spectrum are surveyed. The review then explores findings from the available controlled treatment trials that utilized psychotherapy, pharmacotherapy, or both. Neural circuitry involved in the manifestation of hair pulling is then identified by considering data from animal models of the condition, along with neurocognitive and neuroimaging results from patients. Finally, we highlight important areas for future neurobiological and treatment research.

Lithium and cognitive enhancement: leave it or take it?

RATIONALE: Lithium is established as an effective treatment of acute mania, bipolar and unipolar depression and as prophylaxis against bipolar disorder. Accumulating evidence is also delineating a neuroprotective and neurotrophic role for lithium. However, its primary effects on cognitive functioning remain ambiguous. OBJECTIVES: The aim of this paper is to review and combine the relevant translational studies, focusing on the putative cognitive enhancement properties of lithium, specifically on learning, memory, and attention. DISCUSSION: These properties are also discussed in reference to research demonstrating a protective action of lithium against cognitive deficits induced by various challenges to the nervous system, such as stress, trauma, neurodegenerative disorders, and psychiatric disorders. CONCLUSIONS: It is suggested on the basis of the evidence that the cognitive effects of lithium are best expressed and should, therefore, be sought under conditions of functional or biological challenge to the nervous system.

Dopamine D2/D3 receptor agonist quinpirole impairs spatial reversal learning in rats: investigation of D3 receptor involvement in persistent behavior.

RATIONALE: Dopamine is strongly implicated in the ability to shift behavior in response to changing stimulus-reward contingencies. OBJECTIVES: We investigated the effects of systemic administration of the D2/D3 receptor agonist quinpirole (0.1, 0.3 mg/kg), the D2/D3 receptor antagonist raclopride (0.1, 0.3 mg/kg), the selective D3 antagonist nafadotride (0.3, 1.0 mg/kg), and combined administration of raclopride (0.1 mg/kg) or nafadotride (1.0 mg/kg) with quinpirole (0.3 mg/kg) on spatial discrimination and reversal learning. MATERIALS AND METHODS: Rats were trained on an instrumental two-lever spatial discrimination and reversal learning task. 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 reversal was introduced. RESULTS: None of the drugs altered performance during retention of the previously reinforced contingencies. Quinpirole (0.3 mg/kg) significantly impaired reversal learning by increasing both trials and incorrect responses to criterion in reversal phase, a pattern of behavior manifested as increased perseverative responding on the previously reinforced lever. In contrast, neither raclopride nor nafadotride when administered alone altered reversal performance. However, raclopride blocked the quinpirole-induced reversal deficit, whereas combined administration of nafadotride and quinpirole affected not only performance during the reversal but also the retention phase. The reversal impairment resulting from co-administration of nafadotride and quinpirole was associated with both perseverative and learning errors. CONCLUSIONS: Our data indicate distinct roles for D2 and D3 receptors in the capacity to modify behavior flexibly in the face of environmental change.

Pre-surgical training ameliorates orbitofrontal-mediated impairments in spatial reversal learning.

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.

Serotonergic and dopaminergic modulation of attentional processes.

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.

Dopaminergic and serotonergic modulation of persistent behaviour in the reinforced spatial alternation model of obsessive-compulsive disorder.

RATIONALE: We have proposed rewarded T-maze alternation as a model of obsessive-compulsive disorder (OCD): the serotonin agonist m-chlorophenylpiperazine (mCPP) increments persistence therein, 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 increase, counteracted by mCPP pretreatment. OBJECTIVES: This study (a) further explores the cross-tolerance between fluoxetine and mCPP and (b) extends the model by investigating its sensitivity to dopaminergic manipulations (D2, 3 agonism--quinpirole). MATERIALS AND METHODS: In both experiments, baseline and drug testing were 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 (2.5 mg/kg), (3) low-dose mCPP (0.5 mg/kg) or (4) combined fluoxetine + mCPP. One group per pretreatment then received a 4-day challenge with high-dose fluoxetine (10 mg/kg), the other with high-dose mCPP (2.5 mg/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.

Dissociable effects of selective 5-HT2A and 5-HT2C receptor antagonists on serial spatial reversal learning in rats.

Serotonin (5-hydroxytryptamine, or 5-HT) is strongly implicated in the ability to shift behavior in response to changing stimulus-reward contingencies. However, there is little information on the contribution of different 5-HT receptors in reversal learning. Thus, we investigated the effects of systemic administration of the 5-HT(2A) antagonist M100907 (0, 0.01, 0.03, and 0.1 mg/kg, i.p.) and the 5-HT(2C) antagonist SB 242084 (0, 0.1, 0.3, and 1.0 mg/kg, i.p.) on the performance of an instrumental two-lever spatial discrimination and serial spatial reversal learning task, where both levers were presented and only one 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 within-session reversals was presented. Neither M100907 nor SB 242084 altered performance during spatial discrimination and retention of the previously reinforced contingencies. M100907 significantly impaired reversal learning by increasing both trials to criterion (only at the highest dose) and incorrect responses to criterion in Reversal 1, a pattern of behavior manifested as increased perseverative responding on the previously reinforced lever. In contrast, SB 242084 improved reversal learning by decreasing trials and incorrect responses to criterion in Reversal 1, with significantly fewer perseverative responses. These data support the view that 5-HT(2A) and 5-HT(2C) receptors have distinct roles in cognitive flexibility and response inhibition. The improved performance in reversal learning observed following 5-HT(2C) receptor antagonism suggests these receptors may offer the potential for therapeutic advances in a number of neuropsychiatric disorders where cognitive deficits are a feature, including obsessive-compulsive disorder.

Effects of orbitofrontal, infralimbic and prelimbic cortical lesions on serial spatial reversal learning in the rat.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Enhancing effects of chronic lithium on memory in the rat.

BACKGROUND: 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. METHODS: In three discrete experiments, rats subjected to 30 daily intraperitoneal injections (2mmol/kg) of lithium (lithium groups: serum lithium=0.5+/-0.4mEq/l, 12h 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 (0.5mA, 1s). Retention was assessed 6h later. Daily lithium or saline injections continued throughout behavioural testing. RESULTS: 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. CONCLUSIONS: 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.