Dopamine Hypothesis of Schizophrenia - Introduction

Introduction

Some researchers have suggested that dopamine systems in the mesolimbic pathway may contribute to the 'positive symptoms' of schizophrenia (whereas problems with dopamine function in the mesocortical pathway may be responsible for the 'negative symptoms', such as avolition and alogia.) Abnormal expression, thus distribution of the D₂ receptor between these areas and the rest of the brain may also be implicated in schizophrenia, specifically in the acute phase. A relative excess of these receptors within the limbic system means Broca's area which can produce illogical language, has an abnormal connection to Wernicke's area, which comprehends language, but does not create it. Note that variation in distribution is observed within individuals, so abnormalities of this characteristic likely play a significant role in all psychological illnesses. Individual alterations are produced by differences within glutaminergic pathways within the limbic system, which are also implicated in other psychotic syndromes. Among the alterations of both synaptic and global structure, the most significant abnormalities are observed in the uncinate fasciculus. (McIntosh, 2008) and the cingulate cortex(Haznedar, 2004). The combination these creates a profound dyssymmetry of prefrontal inhibitory signalling, shifted positively towards the dominant side. Eventually, the cingulate gyrus becomes atrophied towards the anterior, due to long-Term Depression (LTD) and Long-Term Potentiation (LTP) from the abnormally strong signals transversely across the brain.(Shlaug, 2009) This, combined with a relative deficit in GABAergic input to Wernicke's area, shifts the balance of bilateral communication across the corpus callosum posteriorly. (Nakamura,2005) Through this mechanism, hemispherical communication becomes highly shifted towards the left/dominant posterior. As such, spontaneous language from brocca's can propagate through the limbic system to the tertiary auditory cortex. This retrograde signalling to the temporal lobes, results in the parietal lobes not recognizing it as internal, resulting in the auditory hallucinations typical of chronic schizophrenia.(Friston, Karl J, The disconnection hypothesis, 1998)

In addition, significant cortical grey matter volume reductions are observed in this disorder. Specifically, the right hemisphere atrophies more, while both sides show a marked decrease in frontal and posterior volume. (Harvey, I, M.A. Ron, G Du Boulay, D Wicks, S.W. Lewis, RM. Murray, Reduction of cortical volume in schizophrenia on magnetic resonance imaging, Psychological Medicine, Cambridge University, 1993). This indicates abnormal synaptic plasticity occurs, where certain feedback loops become so potentiated, others receive little glutaminergic transmission. This is a direct result of the abnormal dopaminergic input to the striatum, thus (indirectly) disinhibition of thalamic activity. The excitatory nature of dopaminergic transmission means the glutamate hypothesis of schizophrenia is inextricably intertwined with this altered functioning. Also, 5-HT, which regulates a wide variety of monoamine neurotransmitters, including dopaminergic transmission. Specifically, 5-HT2A regulates cortical input to the basal ganglia. Many typical and atypical antipsychotics are antagonists at this receptor, as well as 5-HT2C, which is expressed in many parts of the basal ganglia (striatum, prefrontal cortex, nucleus accumbens, amydygalia,and the hippocampus, all structures indicated in this disease). 5-HT2C also regulates dopamine release in response to dopaminerigic drugs as well. More research is needed to explain the exact nature of the altered chemical transmission in this disorder.

Recent evidence on a variety of animal models of psychosis, such as sensitization of animal behaviour by amphetamine, or phencyclidine (PCP, Angel Dust), or excess steroids, or by removing various genes (COMT, DBH, GPRK6, RGS9, RIIbeta), or making brain lesions in newborn animals, or delivering animals abnormally by Caesarian section, all induce a marked behavioural supersensitivity to dopamine and a marked rise in the number of dopamine D₂ receptors in the high-affinity state for dopamine. This latter work implies that there are multiple genes and neuronal pathways that can lead to psychosis and that all these multiple psychosis pathways converge via the high-affinity state of the D2 receptor, the common target for all antipsychotics, typical or atypical. Combined with less inhibitory signalling from the thalamus and other basal ganglic structures, from hyoptrophy (Gur, Bilker 1998) the abnormal activation of the cingulate cortex, specifically around broca's and Wernicke's areas (Haznedar, 2004), abnormal D₂ agonism can facilitate the self-reinforcing, illogical patterns of language found in such patients. (Arinami, Gao, Hamaguchi, Toru, 1997) In schizophrenia, this feedback loop has progressed, which produced the widespread neural atrophy characteristic of this disease. Patients on neuroleptic or antipsychotic medication have significantly less atrophy within these crucial areas(Gur, Bilker 1998) As such, early medical intervention is crucial in preventing the advancement of these profound deficits in bilateral communication at the root of all psychotic disorders. (Whitford, 2010) Advanced, chronic schizophrenia can not respond even to clozapine, regarded as the most potent antipsychotic (McEvoy, 2006), as such, a cure for highly advanced schizophrenia is likely impossible, so the value of early intervention cannot be stressed enough.