SCHIZOPHRENIA DISORDER

Schizophrenia Disorder

Schizophrenia Disorder

Introduction

Cognitive deficits are the single strongest predictor of functional outcome in patients with schizophrenia. Furthermore, these deficits are not satisfactorily alleviated by available antipsychotic treatment. Functional outcome is also dependent upon social functioning and patients with schizophrenia display social dysfunctions including specific impairment in social cognition. Thus, cognitive deficits and social dysfunctions make up core symptoms of schizophrenia that needs to be further investigated in order to find novel treatment targets. Phencyclidine (PCP) is a psychotomimetic compound that produces symptoms in humans that closely resemble schizophrenia. Consequently, the PCP-model is consistently used for studying schizophrenia in experimental animals. Previous studies from our lab demonstrate that PCP-induced deficits in several translational animal models of schizophrenia can be blocked by inhibition of nitric oxide (NO) production. Such PCP-induced deficits range from impairment in pre-cognitive (pre-attentive) sensory information processing and habituation of acoustic startle to selective attention. In addition, several clinical studies indicate that the NO-signaling pathway may be involved in the pathophysiology of schizophrenia.

Aim of Thesis

The overall purpose of this research was to investigate the role of NO-signaling as a potential new treatment target to eliminate cognitive deficits in schizophrenia. In this thesis the role of NOS-inhibition on PCP-induced deficits in higher order cognitive functions and social behavior, was studied in animal models.

Specific aims

I. To investigate the NO-dependent effects of PCP on spatial learning, working memory, long-term memory, and cognitive flexibility using different versions of the Morris water maze

(MWM).

II. To elucidate the NO-dependent effects of PCP on social interaction and recognition memory.

Symptoms

The symptoms of schizophrenia are commonly divided into three categories namely; positive symptoms, negative symptoms, and cognitive deficits (Fuller, 2003).

Positive symptoms

Positive symptoms are characterized by functions and behaviors that are displayed in addition to normal functioning, thereof the term “positive” meaning “extra”. Hallucinations, delusions and disorganized behaviour are often the type of symptom that brings the patient to the emergency room and qualify her or him as ill. Hallucinations most often occur within the auditory domain, such as “hearing voices” that are often of an unpleasant and disparaging nature. Delusions may be grandiose or paranoid and can become very disabling, as they are incorporated in, and govern, daily living. The positive symptoms are cyclic in nature and are alleviated reliably by available antipsychotic treatment (Capuano et al., 2002).

Negative symptoms

In contrast to the positive symptoms, negative symptoms are characterized by loss of “normal” functioning, are chronic, and include anhedonia (loss of pleasurable feelings), flattened affect (e.g. blunted emotions), avolition (lack of initiative), and social withdrawal. Social withdrawal and lack of social cognition may in fact be a symptom category of its own. These losses of functioning closely resemble the symptoms apparent in states of clinical depression. In general, negative symptoms are at best only partially alleviated by available antipsychotic treatment (Murphy et al., 2006). It has even been suggested that negative symptoms are worsened by antipsychotic treatment (i.e. neuroleptic-induced dysphoria) as blockade of the dopamine (DA)ergic reward system seems to attenuate feelings of reward (Kirsch et ...