Dopamine Hypothesis The most widely accepted original hypothesis of the etiology of schizophrenia and of the action of antipsychotic

drugs has implicated the neurotransmitter dopamine (DA). Dopaminergic neurons arise from two midbrain nuclei: (1) The nigrostriatal tract originates in the substantia nigra terminates in the striatum and is in!ol!ed in modulation of motoric beha!ior cognition and sensory gating" and (#) the mesolimbic and mesocortical tracts originate in the !entral tegmental area and terminate in limbic and cortical structures respecti!ely affecting cogniti!e moti!ational and reward systems. The dopamine 1 (D1) receptor family which includes D1 and D$ receptors is present in high concentration in the corte% and striatum. The dopamine # (D#) receptor family consists of D# D& and D' receptors and is concentrated in the limbic and striatal regions. (resynaptic DA receptors (ie D# and D&) can consist of either somatodendritic autoreceptors localized to cell bodies in the substantia nigra and !entral tegmental area or terminal autoreceptors limited to a%ons of these DA cells. The somatodendritic and terminal autoreceptors affect firing of DA cells and synthesis and release of DA respecti!ely. Decreased DA acti!ity in the prefrontal corte% may mediate the negati!e symptoms and cogniti!e dysfunction associated with schizophrenia. The DA hypothesis of schizophrenia as originally postulated proposed that schizophrenia was due to an e%cess of DA acti!ity in limbic brain areas especially the nucleus accumbens as well as the stria terminalis lateral septum and olfactory tubercle. This hypothesis was based on e!idence that chronic administration of the stimulant D )amphetamine produced a psychosis that resembled paranoid schizophrenia. D )Amphetamine increased the release of DA and norepinephrine (*+) and inhibited their reupta,e. -somers of D )amphetamine with different effects on the a!ailability of *+ and DA in rodents were used to show that increased locomotor acti!ity which correlates best with psychosis in humans was due to an increased release of DA rather than *+. The second line of e!idence relating DA to schizophrenia was that drugs that pro!ed to be antipsychotics decreased DA acti!ity by receptor bloc,ade (reserpine) and depletion (neuroleptics). The most compelling e!idence that lin,ed DA to the positi!e symptoms of schizophrenia was the finding that chlorpromazine was an effecti!e antipsychotic drug and that it bloc,ed DA receptors in !i!o which inhibited the effect of D )amphetamine on locomotor acti!ity. The disco!ery that a number of different chemical classes of DA)receptor antagonists were effecti!e as antipsychotic drugs and that there was a high correlation between the drug.s a!erage daily dosage and its affinity for the D# receptor family led to the !iew that increased stimulation of these receptors caused schizophrenia. The concept of increased DA acti!ity as the core deficit in schizophrenia was de!eloped at the time when delusions and hallucinations were central to the diagnosis of schizophrenia and negati!e symptoms affecti!e symptoms and

cogniti!e dysfunction were relegated to a secondary role. These latter aspects of schizophrenia ha!e ne!er been associated with e%cessi!e DA acti!ity. As mentioned earlier in this chapter researchers ha!e proposed that decreased DA acti!ity may lead to cogniti!e impairment and possibly depression. There is little e!idence that bloc,ade of D# or D' receptors induces depression or cogniti!e impairment. /ecent studies in primates ha!e implicated the D1 receptor family in the control of wor,ing memory a cogniti!e function that is impaired in schizophrenia. (ostmortem studies of patients with schizophrenia ha!e not found consistent abnormalities in the density of any of the fi!e DA receptors or changes in their affinities for DA with the possible e%ception of the D& receptor which may ha!e an abnormal form. 0e!eral research groups ha!e also reported a lin, between D& polymorphisms and schizophrenia. There is no reliable e!idence from either postmortem studies or positron emission tomography ((+T) studies for an increase in the density of D# receptors in schizophrenia. /ecent (+T studies of the release of DA in the striatum of patients with schizophrenia ha!e suggested that the e%tracellular concentration of DA in this region is increased compared to normal sub1ects. (lasma and cerebrospinal fluid (203) le!els of homo!anillic acid the ma1or metabolite of DA are not ele!ated in patients who ha!e schizophrenia. 0ome researchers ha!e suggested that DA receptor sensitization occurs in schizophrenia but only indirect e!idence supports this hypothesis. 0erotonin Hypothesis 0erotonin ($)HT) neurons originate in the midbrain dorsal and median raphe nuclei which pro1ect to the corte% striatum hippocampus and other limbic regions. There are at least 1$ types of $)HT receptors" of these the most rele!ant to schizophrenia are the $)HT1 $)HT1D $)HT# $)HT& $)HT4 and $)HT5 receptors. 0omatodendritic autoreceptors (of the $)HT1A type) are present on the cell bodies of $)HT raphe neurons and inhibit firing of serotonergic neurons. Terminal autoreceptors ($)HT1D in humans) regulate the synthesis and release of $)HT. $)HT& receptors stimulate DA release. (ostsynaptic $)HT#A receptors are localized on pyramidal neurons in mesocortical areas. The comple% interaction between $)HT and DA !aries by brain region and by types of $)HT and DA receptors. An early theory of the etiology of schizophrenia was that it was due to an e%cess of brain serotonergic acti!ity. This theory was based on the belief that the psychotomimetic properties of lysergic acid diethylamide (60D) an indole compound were due to its $)HT agonist properties. This led to a search for endogenous indole hallucinogens in the brain blood and urine of schizophrenic patients. The enzymes that synthesize and catabolize indoles of which $)HT is the most important were also studied in detail" howe!er none of the putati!e abnormalities was confirmed by subse7uent careful study.

The notion that the effects of 60D and other indole hallucinogens such as psilocybin and N,N)dimethyltryptamine pro!ide an ade7uate model of schizophrenia was also re1ected because the primary effect of these drugs is to cause !isual hallucinations. The potency of these agents as hallucinogens is highly correlated with their $)HT#A)receptor antagonist affinity. The thought disorder auditory hallucinations and bizarre beha!ior usually present in schizophrenia are generally absent in normal indi!iduals who are gi!en these agents. Howe!er ingestion of these agents can cause an e%acerbation of positi!e symptoms in schizophrenic patients. *euroleptic drugs are not particularly useful in decreasing the effects of the indole hallucinogens. *ewer antipsychotic drugs such as clozapine olanzapine risperidone 7uetiapine and sertindole are potent antagonists of the $)HT#A receptor. 0ome of the ad!antages of these drugs may result from their greater potency as $)HT#A)receptor antagonists relati!e to D#) receptor bloc,ade. The most li,ely ad!antages of these drugs related to their higher affinity to $)HT#A !ersus DA receptors are their low D#)induced +(0 profile and their ability to impro!e negati!e symptoms. -ncreased stimulation of $)HT#A receptors may be important in the etiology of negati!e symptoms and +(0. Although this concept of the role of $)HT in schizophrenia is no longer considered !iable alternati!e theories of the role of $)HT are of interest and are discussed in subse7uent sections. 8lutamate Hypothesis 2linical and e%perimental e!idence has supported a comple% role for glutamate in the etiology of schizophrenia. +!idence indicates that decreased glutamatergic acti!ity is the result of decreased le!els of glutamate receptors of the N)methyl)D) aspartate (*9DA) subtype. Decreased le!els of glutamate in the 203 of patients with schizophrenia ha!e also been reported. 2onsistent with the role of glutamate in schizophrenia three noncompetiti!e antagonists of *9DA receptors (phencyclidine :(2(; ,etamine and 9<)=>1) and three competiti!e antagonists cerebral perfusion pressure (2(() 2(()ene and 280 1?5$$) can produce a range of positi!e and negati!e symptoms and cogniti!e dysfunction in normal control sub1ects and in schizophrenic patients. *euroleptics can bloc, some of the clinical effects of (2(. The ability of the $)HT#A) and D#)receptor antagonists such as clozapine and olanzapine to bloc, the clinical effects of these *9DA) receptor antagonists is un,nown. Howe!er the preclinical effects of (2( such as disruption of sensory gatings can be bloc,ed by selecti!e $)HT#A)receptor antagonists such as 9D61>>?>5 and by clozapine. 8lycine which can enhance the ability of glutamate to stimulate the glutamate receptor has been reported to decrease negati!e but not positi!e symptoms in patients with schizophrenia when administered in con1unction with typical neuroleptic drugs. -t has also been suggested that increased le!els of glutamate can ha!e neuroto%ic effects on !arious neurons" howe!er there is no conclusi!e e!idence for neurodegenerati!e changes in schizophrenia. A recent report shows that mice e%pressing $@ of normal *)methyl)D)aspartate)receptor (*9DA/-) le!els e%hibit schizophrenia)

li,e beha!ioral abnormalities when they reach adulthood supporting a hypoglutamatergic hypothesis of schizophrenia. *eurode!elopmental Hypothesis According to the neurode!elopmental hypothesis the etiology of schizophrenia may in!ol!e pathologic processes that begin before the brain approaches its adult anatomical state in adolescence. These neurode!elopmental abnormalities de!eloping in utero for some and thereafter for others ha!e been suggested to lead to the acti!ation of pathologic neural circuits during adolescence or young adulthood (sometimes owing to se!ere stress) which leads to the emergence of positi!e or negati!e symptoms or both. +arlier neuropathologic wor, indicated that some cases of schizophrenia result from embryologic malde!elopment. +. 0later also referred to malde!elopmental similarities between temporal lobe epilepsy and schizophrenia and stressed their possible neuropathologic basis. The emergence of e!idence for cortical malde!elopment in schizophrenia and the de!elopment of se!eral plausible animal models of schizophrenia which are based on neonatal lesions that produce beha!ioral abnormalities or altered sensiti!ity to dopaminergic drugs only in adolescent or adult animals ha!e strengthened the lin, between malde!elopment and schizophrenia. The concept of schizophrenia as a neurode!elopmental disorder is also consistent with other epidemiologic and clinical lines of e!idence discussed in the following sections.