Morphometric study of synaptic patterns in the rat caudate nucleus and hippocampus under haloperidol treatment

Abstract

A morphometric study of the synapses on dendritic shafts and spines was performed in the rat caudate nucleus and the CAI area of the hippocampus under chronic haloperidol treatment. In the nucleus caudatus, the synaptic density on dendritic shafts increased by 83% and those on spines by 53%. Most of the parameters measured in axospinous synapses were significantly increased: the area of presynaptic axon terminals (20%), the number of mitochondria per axon terminal (51%), the length of active zone (11%), the area of postsynaptic density (23%), and the perimeter of postsynaptic density (12.5%). The area of postsynaptic spines showed no changes. In the synapses on dendritic shafts, the area of presynaptic terminals decreased (31%), the area of mitochondria per terminal decreased (40%), the length of active zone increased (14%), and other parameters were unchanged. There were no significant differences in the same parameters measured in the hippocampus. The data are discussed as morphological correlates of behavioral supersensitivity and dopamine D2 receptor up-regulation.

Chronic Haloperidol Promotes Corticostriatal Long-Term Potentiation by Targeting Dopamine D2L Receptors

“…The finding that D2L receptor inactivation favors striatal LTP well correlates with the evidence that, in the striatum, haloperidol increases the size of axon terminals (Benes et al, 1985;Uranova et al, 1991;Kerns et al, 1992), the number of glutamatergic synapses (Meshul and Casey, 1989;Uranova et al, 1991;Kerns et al, 1992;See et al, 1992), and the absolute number of vescicles per synapse (Benes et al, 1985). All these morphological changes indicate hyperactivity of glutamatergic transmission and represent structural correlates of LTP (Eastwood et al, 1997;Toni et al, 1999;Konradi and Heckers, 2001;Steward and Worley, 2002).…”

“…Based on this observation, it has recently been proposed that the promotion of plastic, slowly developing rearrangements of neuronal connectivity is essential for the mode of action of antipsychotics (Konradi and Heckers, 2001). In line with this idea, chronic but not acute haloperidol treatment causes complex ultrastructural changes of glutamatergic synapses in the striatum (Meshul and Casey, 1989;Uranova et al, 1991;Kerns et al, 1992;See et al, 1992), indicative of its ability to promote long-lasting potentiation of excitatory transmission (Eastwood et al, 1997;Toni et al, 1999;Konradi and Heckers, 2001;Steward and Worley, 2002). Such an effect might play a crucial role in the therapeutic effects of this drug because a reduced glutamate-mediated transmission has been recognized to mediate, at least in part, the symptoms of schizophrenia (Carlsson et al, 2001;Goff and Coyle, 2001), and the striatum serves not only motor, but also critical, cognitive and motivational functions altered in schizophrenia.…”

“…All these morphological changes indicate hyperactivity of glutamatergic transmission and represent structural correlates of LTP (Eastwood et al, 1997;Toni et al, 1999;Konradi and Heckers, 2001;Steward and Worley, 2002). In this context, particularly interesting is the evidence that haloperidol treatment also alters postsynaptic density (Uranova et al, 1991), an electron dense area that contains NMDA glutamate receptors and scaffolding proteins that anchor receptors to the membrane and facilitate the receptor and postreceptor events required for LTP induction (Elgersma et al, 2002).…”

Molecular aspects of glutamate dysregulation: implications for schizophrenia and its treatment

“…Ultrastructural alterations of synaptic structures (Benes et al, 1985;Kerns et al, 1992;Uranova et al, 1991) and increases in striatal volumes in human brain (Chakos et al, 1994;Heckers et al, 1991;Jernigan et al, 1991;Shihabuddin et al, 1998) have also been described. Interestingly, the number of glutamate-containing synapses is increased in the rat striatum after chronic haloperidol treatment (Kerns et al, 1992;Meshul & Casey, 1989;See et al, 1992;Uranova et al, 1991), and an increase in the number of perforated synapses and double synapses has been reported (Kerns et al, 1992). Thus, haloperidol seems to promote synapse splitting, a process by which synapses multiply in the mature brain (Jones & Harris, 1995;Kirov et al, 1999;Toni et al, 1999) (Fig.…”

Dopamine D2 and D3 receptors are linked to the actin cytoskeleton via interaction with filamin A

“…In a variety of cell types, D2-like receptor signaling modulates calcium, potassium, and sodium currents through specific regulation of ion channel activities (2,3). The activation of D2-like receptors also has been implicated in the regulation of cellular morphogenesis (4) and in the maintenance of neuronal structure in adult brain (5)(6)(7). Although the D2-like receptors appear to activate discrete signal transduction pathways, the question of whether individual D2-like receptors subserve distinct functional roles is an issue that has not yet been satisfactorily addressed.…”