Schizophrenia, Dopamine and the Striatum: From Biology to Symptoms

Abstract

The mesolimbic hypothesis has been a central dogma of schizophrenia for decades, positing that aberrant functioning of midbrain dopamine projections to limbic regions causes psychotic symptoms. Recently, however, advances in neuroimaging techniques have led to the unanticipated finding that dopaminergic dysfunction in schizophrenia is greatest within nigrostriatal pathways, implicating the dorsal striatum in the pathophysiology and calling into question the mesolimbic theory. At the same time our knowledge of striatal anatomy and function has progressed, suggesting new mechanisms via which striatal dysfunction may contribute to the symptoms of schizophrenia. This Review draws together these developments, to explore what they mean for our understanding of the pathophysiology, clinical manifestations, and treatment of the disorder.

Keywords: antipsychotic; magnetic resonance imaging; neuroimaging; nigrostriatal; positron emission tomography; psychosis.

Figure 1

Striatal Connectivity. (A) Summary of primate tracing studies mapping connections between cortex (top row), striatum (middle), and midbrain (bottom). The primate striatum can be divided into NAcc, olfactory tubercle, caudate nucleus, and putamen (for simplicity, not indicated in the figure). The division between caudate and putamen, however, has little biological relevance . Tract tracing studies showed that striatocortical connections run in three parallel pathways. Motor areas project to the caudal putamen ; dorsolateral prefrontal cortex to caudate and rostral putamen ; and limbic areas to the ventral striatum . These subdivisions were termed the sensorimotor, associative, and limbic striatum. Subsequent research used retrograde tracers injected into striatum to determine midbrain connections , . This showed that ventral tegmental area and medial SN project primarily to limbic striatum, while central/ventrolateral parts of the SN project to the associative and sensorimotor striatum. The striatum in turn has efferents projecting back to the midbrain. In addition to these reciprocal connections, feedforward striato-nigro-striatal connections allow information to pass along the striatum from limbic to motor regions via the associative striatum , , . (B) Summary of rodent–primate differences in mesostriatal connectivity. In rodents, the ventral striatum is proportionally larger than in primates. The NAcc shell is innervated by the medial VTA, and the NAcc core by the central VTA, whereas the lateral VTA innervates a region homologous to the associative striatum; the SN also has some connections to the associative region in addition to the more dorsal regions of the striatum. In primates, the VTA is proportionally smaller; it innervates the ventral striatum, whereas the dorsal tier SN innervates the associative striatum, and the ventral tier innervates the sensorimotor striatum (for a more detailed review of differences between primates and rodents see 14, 121). Abbreviations: NAcc, nucleus accumbens; omPFC, orbitomedial PFC; PFC, prefrontal cortex; SN, substantia nigra; vmPFC, ventromedial PFC; VTA, ventral tegmental area.

Figure 2

Striatal Neurochemistry and Neurotransmission. (A) The role of cholinergic interneurons in mediating extrapyramidal side effects . (i) In wild-type mice, D2Rs mediate inhibitory actions both by directly reducing firing of the indirect pathway MSN, and by reducing firing of cholinergic interneurons. (ii) In knockout mice without D2Rs on cholinergic interneurons, D2 antagonism of the MSN by itself is insufficient to induce catalepsy. (iii) Activating, in addition, M1Rs, results in catalepsy, which occurs due to increased firing of the cholinergic interneuron secondary to D2 antagonism. (B) The relationship between striatal dopamine, lateral inhibition, and behavioural selection . The figure illustrates three scenarios, based on a hypothetical pair of functional units (A and B) each controlling a specific behavioural outcome (behaviour A and B, respectively). (i) Localized dopaminergic signalling in functional unit A activates D1 direct pathway MSNs, while suppressing D2 indirect pathway MSNs, enabling the execution of desired behaviour A. GABAergic lateral inhibition suppresses competing behaviour coded for by functional unit B. (ii) Spatially disorganised dopaminergic signalling means that there is nonspecific activation of multiple functional units, and undesirable behaviours are no longer suppressed. (iii) Dopamine antagonists enhances the activity of indirect pathway neurons, but without regional specificity, meaning that desirable behaviours are also suppressed. Abbreviations: Ach, acetylcholine; DA, dopamine; D2R, dopamine D2 receptor; M1R, M1 muscarinic receptor; MSN, medium spiny neuron.

Figure 3

Mechanisms via Which Excess Striatal Dopamine May Impair Efference Copy Transmission. With normal striatal dopamine signalling (left), neurons carrying the efference copy signal preferentially synapse onto dopamine-D2-expressing GABAergic medium spiny neurons of the indirect pathway. Increased dopamine release within the striatum (right) inhibits these D2-expressing neurons. Excess striatal dopamine may therefore interfere with appropriate transmission of the efference copy signal. In the auditory areas of the dorsal striatum this could result in inner speech being mischaracterised as externally generated.

Figure I

Results of a Meta-analysis Examining Positron Emission Tomography Measures of Presynaptic Dopamine in Schizophrenia Patients and Controls . Abbreviations: Assoc, associative striatum; Limbic, limbic striatum; Smst, sensorimotor striatum. *Statistically significant difference between patients and controls (P<0.05 in a random effects meta-analysis).