Effects of DPTQ, a novel positive allosteric modulator of the dopamine D1 receptor, on spontaneous eye blink rate and spatial working memory in the nonhuman primate.

RATIONALE: Dopamine (DA) signaling through the D1 receptor has been shown to be integral to multiple aspects of cognition, including the core process of working memory. The discovery of positive allosteric modulators (PAMs) of the D1 receptor has enabled treatment modalities that may have alternative benefits to orthosteric D1 agonists arising from a synergism of action with functional D1 receptor signaling. OBJECTIVES: To investigate this potential, we have studied the effects of the novel D1 PAM DPTQ on a spatial delayed response working memory task in the rhesus monkey. Initial studies indicated that DPTQ binds to primate D1R with high affinity and selectivity and elevates spontaneous eye blink rate in rhesus monkeys in a dose-dependent manner consistent with plasma ligand exposures and central D1activation. RESULTS: Based on those results, DPTQ was tested at 2.5 mg/kg IM in the working memory task. No acute effect was observed 1 h after dosing, but performance was impaired 48 h later. Remarkably, this deficit was immediately followed by a significant enhancement in cognition over the next 3 days. In a second experiment in which DPTQ was administered on days 1 and 5, the early impairment was smaller and did not reach statistical significance, but statistically significant enhancement of performance was observed over the following week. Lower doses of 0.1 and 1.0 mg/kg were also capable of producing this protracted enhancement without inducing any transient impairment. CONCLUSIONS: DPTQ exemplifies a class of D1PAMs that may be capable of providing long-term improvements in working memory.

Intermittent theta burst stimulation can improve the spatially-delayed responses of working memory / 中华物理医学与康复杂志

Objective:To observe any effect of intermittent theta burst stimulation (iTBS) on the spatially-delayed responses of working memory using cynomolgus macaques.Methods:The working memory of six male cynomolgus macaques (8-9 years old) was trained using a spatially-delayed response task. They were then randomly divided into an iTBS group and a control group, each of 3. The iTBS group was given iTBS at an intensity of 35% of the maximum output, with 2 seconds of stimulation followed by 8 seconds of rest with trains of 50Hz bursts repeated at a frequency of 5Hz over a period of 192 seconds once daily for 5 days, while the control group was given sham iTBS. Before and after the 5 days, the body weight and working memory of each animal were evaluated. The total number of effective feeding episodes, and of effective feeding episodes with short and long delay periods were recorded.Results:There was no significant change in the average body weight of either group before and after the modeling and iTBS intervention. After the intervention the number of total effective feeding cases and those with a short delay period were both significantly higher in the iTBS group than in the control group. However, no significant inter-group differences in the effective feeding cases with a long delay period were observed.Conclusions:iTBS is effective in improving the spatially-delayed responses of working memory, at least in cynomolgus macaques.

Chronic phencyclidine treatment impairs spatial working memory in rhesus monkeys.

RATIONALE: Phencyclidine (PCP) could induce schizophrenia (Sz) like behavior in both humans and animals, therefore, has been widely utilized to establish Sz animal models. It induced cognitive deficits, the core symptom of Sz, mainly through influencing frontal dopaminergic function. Nonhuman primate (NHP) studies demonstrated impaired object retrieval detour (ORD) and spatial delayed response (SDR) task performance by acute or chronic PCP treatment. However, NHP investigations, continually monitoring SDR performance before, during and after PCP treatment, are lacking. OBJECTIVES: Present study investigated the long-term influence of chronic PCP treatment on SDR performance and the possible increase of SDR deficit severity and duration by the incremental dosing procedure in rhesus monkeys. METHODS: SDR task was performed repeatedly up to eight weeks after constant dosing procedure (i.m., 0.3 mg/kg, day 12-25), during which drug effects on locomotor activity and blood cortisol concentration were assessed. Incremental dosing procedure (starting dose 0.3 mg/kg, day 6-19) began five months later. RESULTS: Constant dosing procedure induced differential level of hyperactivity across testing days, without significant influence on blood cortisol concentration. It reduced SDR performance, until occurrence of the first and worst impairment on day 15 and 23 respectively. The impaired performance recovered to pretreatment level over one week after drug cessation. In contrast, incremental dosing procedure impaired SDR performance on the first treatment day, which recovered within treatment period. CONCLUSION: Results suggested increase of SDR deficit severity by repeated PCP administrations, whereas the incremental dosing procedure did not increase SDR deficit severity and duration.