Análisis del ambiente interno

1.8.1 Dopamine hypothesis

The dopamine hypothesis emerged in the 1960s as the result o f two observations. Firstly, the antipsychotic action o f the neuroleptic drugs and secondly, the psychosis- inducing properties o f amphetamine and other stimulant drugs. It argues that an overactive dopaminergic system underlies this widespread neuropsychiatrie disorder. Recent findings have provided more evidence for the implication o f D2-like dopamine receptors in schizophrenia. These are discussed followed by the two major observations.

(i) The affinity o f the antipsychotics for the D2-like receptors correlate well with their clinical potencies. Long after the initial use o f neuroleptics for treatment for schizophrenia in 1952, several lines o f evidence converged to suggest that DRD2 blockade was the important pharmacological action. The atypical neuroleptic drug, clozapine, which is more clinically effective than any other neuroleptic drug, mediates its action via DRD4 blockade. For a detailed account o f neuroleptic treatment refer to section 1.5. It is evident that dopamine receptor blockade is a prerequisite for antipsychotic effectiveness.

(ii) Amphetamines and other stimulant drugs are able to induce psychosis (reviewed by McKenna, 1994). Amphetamine drugs (amphetamine, methamphetamine, methylphenidate and some other compounds) exert their principal pharmacological actions on brain catecholamine neurones. They cause a functional excess o f dopamine and noradrenaline via a number o f mechanisms, such as enhancement o f synaptic release, blockade o f re-uptake and reduction o f degradation by inhibition o f monoamine oxidase. This class o f dmgs has little effect on serotonin neurones and is not known to have any other important central nervous system actions.

The first report o f psychosis resembling schizophrenia due to amphetamine administration was made by Young and Sioville in 1938. This idea that amphetamine induces a schizophrenia-like state was confirmed by two studies. The first one was by Connell (1958), who collected a series o f 42 patients who had developed schizophrenia­ like status whilst taking amphetamine. The form taken by the psychosis was typically that o f paranoid hallucinatory state, with delusions o f reference and persecution which

Introduction were accompanied by auditory hallucination in some cases. In the second study, Tatetsu et al. (1964) examined 492 chronic abusers, o f which 92% showed some form o f psychiatric disorder. In 19% it took the form o f a schizophrenia-like state, with symptoms of delusions, hallucinations as well as formal thought disorder. Some negative symptoms were also observed. Within ten years o f these two publications, over tw o hundred cases o f amphetamine psychosis were reported world wide and it also became clear that other stimulant drugs can also induce schizophrenia-like symptoms.

Two pieces o f evidence showed that dopamine is the critical neurotransmitter involved in amphetamine psychosis. Firstly, pharmacological experiments established that the effects produced by amphetamine are also produced by drugs with pure dopamine agonist effect but not by drugs with noradrenergic agonist effect. These effects were also shown to be reversed by dopamine but not by noradrenaline antagonists. Secondly, there is evidence that dopamine agonists other than stimulants can also induce a schizophrenia­ like psychotic state. Mental changes are a well known complication o f L-DOPA treatment in Parkinson’s disease. However the frequency o f psychosis in clear consciousness is low (1-4%). Nevertheless it has not been proven beyond doubt that the effects o f amphetamine are due to dopaminergic rather than adrenergic effects.

(iii) A selective increase in the D2-like receptor (DRD2, DRD3 and DRD4) density has been found in the brains o f neuroleptic-treated and drug-naive schizophrenic patients. Initially it was thought that the DRD2 sites were elevated in schizophrenia post-m ortem brain striatum (Seeman et al., 1987). This was also shown to be the case by Wong et al. (1986) using [^’C]-methylspiperone. This finding was not replicated by another study that used [’ ^C]-raclopride (Farde et al., 1990), despite the fact that the radioligand used in the Wong et al. study and this study have a high affinity for DRD2.

Several groups subsequently examined the density o f the D2-like dopamine receptors in control and schizophrenic post-mortem brain striata. Seeman et al. (1993a) was the first to report a six fold elevation o f the D4-like sites in schizophrenic brain. In this study the difference in binding o f [^H]-emonapride to the D2-like receptors and the binding o f [^H]- raclopride to the DRD2 and DRD3 was examined. It was concluded that the combined density of DRD2 and DRD3 (labelled by [^H]-raclopride) was increased by only 10% in the schizophrenia brain, compared to controls. Whereas the density o f the DRD4 or

Introduction D4-like sites (due to the lack o f pharmacological characterisation o f the site that exhibits this increased binding, the term ‘D4-like’ has been used) was elevated six fold in schizophrenia post-mortem brain. Experiments involving the competing o f clozapine molecules with [^H]-spiperone in the control and in the schizophrenia brain striatum, confirmed these results. The DRD4 density in the control striatum was found to be low, less than 10% o f the DRD2 density, whereas in the schizophrenia striatum, the DRD4 density was found to be 20 fold higher.

Two other independent studies (Murray et a l, 1995; Seeman et a l, 1995) also confirmed the findings o f Seeman et a l (1993a). The elevation o f the DRD4 receptor in the schizophrenia post-mortem brain has been questioned by several groups. In a number of studies performed either using a similar method, or by introducing a new dopamine receptor-specific ligand, or by applying a different method, a significant elevation o f DRD4-like sites has not been detected (Reynolds and Mason, 1994, 1995; Mulcrone and Kerwin, 1996). The results o f some o f the studies performed to date have been summarised in table 1.1. Figure 1.4 shows the data accumulated by Murray et a l (1995), for the various levels o f putative DRD4 in schizophrenic compared to normal controls, neuroleptic controls and schizophrenic suicides.

The study o f DRD4 elevation by a number o f groups have provided contradicting results even though very similar techniques were used. One explanation that has been provided for such discrepancies is minor differences in the competition assays employed. In addition, methodological differences may also explain the discrepant results obtained. For example, Seeman et a l (1984) reported a loss o f 30-60% o f dopamine receptors resulting from the customary two washes o f the homogenised human striatal tissue. This has been clearly demonstrated in the recent replication study by Seeman et a l (1995) o f the study o f Reynolds and Mason (1995). In the replication study, the tissue homogenate was not washed, whieh is in contrast to the two washes performed in the earlier study, and a three fold increase in D4-like sites was observed, which contradicted the previous findings. Other faetors that could contribute to such inconsistencies are subtle differences in the selectivity o f the radioligands used. For example, emonapride binds to 5-HTl A receptors which may make a small contribution to binding (Assie et al,

1993). Either way, all the studies carried to date suffer from the lack o f a DRD4 specific ligand. As mentioned in most o f these reports, much controversy still exists regarding

Table 1.1: Summary of studies investigating the elevation of the D2-like receptors in post-mortem schizophrenia brain. Reference Seeman et al., 1993a Reynolds and M ason, 1994 M u rra y et al.. 1995 Reynolds and M ason, 1995 Seem an et al., 1995 M ulcrone and K erw in, 1996 Subjects 5 Controls, 5 Alzheimer brains, 11 Huntington brains, 18 Schizophrenia brains. 12 Controls,

18 Schizophrenic patients - all except three individuals had received chronic treatm ent with antipsychotic drugs until a few days before death.

7 Controls,

8 Neuroleptic controls, 7 Schizophrenic suicides, 7 Schizophrenic patients. 6 Controls,

5 Schizophrenic patients - all had received chronic treatment with antipsychotic drugs until a few days before death.

10 Controls,

9 Schizophrenia brain putamen samples, who had received antipsychotic drugs up to several days before death. Examined the frontal cortex of 9 Controls,

8 Schizophrenics, who had been treated

Method Results

Difference in binding with

[^H]-raclopride and [ H]-emonapride. Competing clozapine with

[^H]-spiperone.

Scatchard analysis of [^H]-emonapride b in d in g

Raclopride displacement of ['^H]-emonapride binding.

Difference in binding with

[■^H]-raclopride and [ 'H]-emonapride.

Difference in binding with

['^■‘'l]-epidepride and [^H]-emonapride.

• Used the same method as Reynolds and Mason. 1995.

Examined DRD4 mRNA levels using the reverse transcription polymerase chain reaction (RT-PCR) method.

Six fold elevation in the density o f D4-like sites in brain striata.

10% increase in the density o f DRD2 and DRD3 Increase in D4-like receptors is independent o f treatment with clozapine.

A significant {P < 0.001) increase in total D2-like receptor density in schizophrenia.

No evidence for the presence o f DRD4 in the putamen in either controls or schizophrenics.

Their results showed that increase in D2-like receptor density relates to prior drug treatment.

Two fold increase in the level o f D4-like receptors in the striatum and nueleus accumbens.

An overall increase in DRD2/ DRD3 density in schizophrenics, reflecting prior treatm ent with antipsychotic drugs.

No significant detection o f DRD4 in brain striata in either controls or schizophrenics.

D4-like component was detectable in controls and was elevated three fold in schizophrenia tissues.

No significant difference in DRD4 mRNA levels was found between the two groups.