The development of novel therapeutic agents for disorders of cognition such as Alzheimer’s disease (AD) is of paramount importance given the ever-increasing elderly population, however; there is also considerable interest in any strategy that might enhance the clinical efficacy of currently available treatments. The purpose of this study was to evaluate an adjunctive treatment strategy to memory enhancement, namely combining the commonly prescribed acetylcholinesterase inhibitor (AChEI) donepezil, with a positive allosteric modulator (PAM) of α7 nicotinic-acetylcholine receptors (α7-nAChRs), PNU-120596. The treatment strategy was evaluated in a (non-spatial) spontaneous novel object recognition (NOR) task in young rats; a water maze spatial learning and recall procedure in aged, cognitively-impaired rats, and a delayed match to sample (working/short term memory) task in aged rhesus monkeys. In all three experiments a similar drug response was observed, namely that donepezil administered alone improved task performance in a dose-dependent manner; that PNU-120596 administered alone was without significant effect, but that the combination of PNU-120596 with a subthreshold dose of donepezil was effective. The positive effect of the drug combination appeared to be α7-nAChR mediated given that it was blocked in the NOR task by the selective α7-nAChR antagonist methyllycaconitine (MLA). Collectively, these data indicate that PNU-120596 increases the effective dose range of donepezil in learning/memory-related tasks in young and age-impaired animal models. The results suggest that α7-nAChR-selective PAMs like PNU-120596 have potential as adjunctive treatments with acetylcholinesterase inhibitors (e.g., donepezil) for age-related illnesses such as AD as well memory disorders not necessarily associated with advanced age.

Cotinine, the most predominant metabolite of nicotine in mammalian species, has a pharmacological half-life that greatly exceeds its precursor. However, until recently, relatively few studies had been conducted to systematically characterize the behavioral pharmacology of cotinine. Our previous work indicated that cotinine improves prepulse inhibition of the auditory startle response in rats in pharmacological impairment models and that it improves working memory in non-human primates. Here we tested the hypothesis that cotinine improves sustained attention in rats and attenuates behavioral alterations induced by the glutamate (NMDA) antagonist MK-801. The effects of acute subcutaneous (dose range 0.03–10.0 mg/kg) and chronic oral administration (2.0 mg/kg/day in drinking water) of cotinine were evaluated in fixed and variable stimulus duration (VSD) as well as variable intertrial interval (VITI) versions of a five choice serial reaction time task (5C-SRTT). The results indicated only subtle effects of acute cotinine (administered alone) on performance of the 5C-SRTT (e.g., decreases in timeout responses). However, depending on dose, acute treatment with cotinine attenuated MK-801-related impairments in accuracy and elevations in timeout responses, and it increased the number of completed trials. Moreover, chronic cotinine attenuated MK-801-related impairments in accuracy and it reduced premature and timeout responses when the demands of the task were increased (i.e., by presenting VSDs or VITIs in addition to administering MK-801). These data suggest that cotinine may represent a prototype for compounds that have therapeutic potential for neuropsychiatric disorders (i.e., by improving sustained attention and decreasing impulsive and compulsive behaviors), especially those characterized by glutamate receptor alterations.

A common feature of the neuropsychiatric disorders for which antipsychotic drugs are prescribed is cognitive dysfunction, yet the effects of long-term antipsychotic treatment on cognition are largely unknown. In the current study, we evaluated the effects of long-term oral treatment with the first-generation antipsychotic haloperidol (1.0 and 2.0 mg/kg daily) and the secondgeneration antipsychotic risperidone (1.25 and 2.5 mg/kg daily) on the acquisition and performance of two radial-arm maze (RAM) tasks and a five-choice serial reaction-time task (5C-SRTT) in rats during days 15-60 and 84-320 days of treatment, respectively. In the RAM, neither antipsychotic significantly affected the acquisition or performance of a spatial win shift or a delayed non-match-to-position task. Conversely, in the rats administered 5C-SRTT, haloperidol was associated with profound deficits in performance, and the subjects were not able to progress through all stages of task acquisition. Depending on the dose, risperidone was associated with a greater number of trials to meet specific performance criteria during task acquisition compared with vehicle-treated controls; however, most subjects were eventually able to achieve all levels of task acquisition. Both haloperidol and risperidone also increased the number of perseverative and time-out responses during certain stages of task acquisition, and the response and reward latencies were slightly higher than controls during several stages of the study. These results in rats suggest that while long-term treatment with haloperidol or risperidone may not significantly affect spatial working or short-term memory, both antipsychotics can (depending on dose) impair sustained attention, decrease psychomotor speed, increase compulsivetype behaviors, and impair cognitive flexibility.