Roles of neuropeptide PACAP in regulating psychomotor functions

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To investigate the physiological roles of endogenous PACAP in higher-order brain/psychological processes, behavioral and electrophysiological analyses were carried out in PACAP gene knockout (PACAP-l-) mice which was recently generated in this laboratory, and the following results were obtained:1. PACAP-l- mice displayed markedly increased locomotor activity and explosive jumping behavior. These aberrant behaviors were ameliorated by the antipsychotic drug haloperidol and selective serotonin reuptake inhibitor (SSRI).2. Increased exploratory-related and reduced anxiety-related behavior in PACAP-l- mice was demonstrated by zone monitoring in the open field, on the elevated plus maze, and by the emergence and novel object tests.3. PACAP-l- mice exhibited normal prepulse inhibition (PPI) of the acoustic startle response at 4 weeks of age; however, they suffer impairment of PPI after 6 weeks of age.4. This reduced PPI was ameliorated by the psychostimulant, but unaffected by haloperidol.5. In PACAP-l- mice, the induction of long-term potentiation (LTP) of hippocampal synaptic strength was reduced. In addition, PACAP heterozygous mutant mice and PACAP (PAC1) receptor exon 2-targeted mice showed a moderate defect in LTP, suggesting a gene-dosage effect for the PACAP gene.6. The behavioral study revealed impaired memory retention of PACAP-l- mice in several behavioral paradigms.In conclusion, the present study proposes a role of PACAP-ergic neurons in regulating psychomotor behaviors and suggests that the phenotype of PACAP-l- mice in part resembles those in human psychiatric disorders. The present study also provides an insight into the role of PACAP in higher brain functions.