Mode of action of atypical neuroleptics in relation to the phencyclidine model of schizophrenia: role of 5-HT2 receptor and alpha 1-adrenoceptor antagonism [corrected].
In experiments in rats, by the use of single-cell recordings from midbrain dopamine (DA) neurons of the ventral tegmental area (VTA), the systemic administration of the schizophrenomimetic N-methyl-D-aspartate receptor antagonists phencyclidine (PCP) or dizocilpine (MK-801) caused an increased firing rate but reduced the variability of firing in VTA DA neurons. Burst firing was increased in cells predominantly located in the paranigral nucleus, a subdivision of the VTA largely projecting to the nucleus accumbens and other limbic regions, but reduced in DA cells predominantly located in the parabrachial pigmented nucleus, another subdivision of the VTA that projects largely to the prefrontal cortex (PFC). Thus, a severely impaired signal-to-noise ratio within the PFC DA projection was obtained, concomitant with an overactive mesolimbic DA system. The administration of high doses of ritanserin or atypical neuroleptics with prominent serotonin (5-hydroxytrypyamine) 5-HT2 receptor antagonist action, such as clozapine or amperozide, produced preferential activation of the PFC DA projection. In contrast, the selective D2 receptor antagonist raclopride caused a greater activation of the subcortical than cortical DA projections, as assessed by microdialysis experiments in vivo from our laboratory. Adding ritanserin treatment to raclopride markedly enhanced the raclopride-induced increase in DA levels in the medial PFC, an effect probably mediated by augmentation of the raclopride-induced increase in the burst firing of meso-cortical DA neurons, but failed to affect the action of raclopride on striatal DA levels.(ABSTRACT TRUNCATED AT 250 WORDS)
Svensson
T H
TH
Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.
Mathé
J M
JM
Andersson
J L
JL
Nomikos
G G
GG
Hildebrand
B E
BE
Marcus
M
M
D000200:Action Potentials / Q000187:drug effects; D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology*; D000704:Analysis of Variance; D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D009043:Motor Activity / Q000187:drug effects; D009474:Neurons / Q000187:drug effects; D010622:Phencyclidine / Q000494:pharmacology*; D051381:Rats; D012559:Schizophrenia / Q000378:metabolism*; D012702:Serotonin Antagonists / Q000494:pharmacology*; D013997:Time Factors
D000317:Adrenergic alpha-Antagonists; D014150:Antipsychotic Agents; D012702:Serotonin Antagonists; D010622:Phencyclidine