A preclinical screen to evaluate pharmacotherapies for the treatment of agitation in dementia

Agitation associated with dementia is frequently reported
clinically but has received little attention in preclinical
models of dementia. The current study used a 7PA2 CM
intracerebroventricular injection model of Alzheimer’s
disease (AD) to assess acute memory impairment, and a
bilateral intrahippocampal (IH) injection model of AD
(aggregated Aβ1–42 injections) and a bilateral IH injection
model of dementia with Lewy bodies (aggregated NAC61–95
injections) to assess chronic memory impairment in the rat.
An alternating-lever cyclic-ratio schedule of operant
responding was used for data collection, where incorrect
lever perseverations measured executive function
(memory) and running response rates (RRR) measured
behavioral output (agitation). The results indicate that
bilateral IH injections of Aβ1–42 and bilateral IH injections of
NAC61–95 decreased memory function and increased RRRs,
whereas intracerebroventricular injections of 7PA2 CM
decreased memory function but did not increase RRRs.
These findings show that using the aggregated peptide IH
injection models of dementia to induce chronic
neurotoxicity, memory decline was accompanied by
elevated behavioral output. This demonstrates that IH
peptide injection models of dementia provide a preclinical
screen for pharmacological interventions used in the
treatment of increased behavioral output (agitation), which
also establish detrimental side effects on
memory.