5-HT2A/C receptors do not mediate the attenuation of compulsive checking by mCPP in the quinpirole sensitization rat model of obsessive-compulsive disorder (OCD).

There is emerging evidence for a dopamine (DA)-serotonin (5-HT) interaction underlying obsessive-compulsive disorder (OCD). In the quinpirole sensitization rat model of OCD, compulsive checking is induced by chronic treatment with the DA agonist quinpirole, and is attenuated by the 5-HT agonist drug mCPP. However, mCPP has affinity for a number of 5-HT receptor subtypes, and it is unknown by which receptors mCPP exerts its effects on quinpirole-treated animals. The present study tested in rats whether mCPP activity at 5-HT2A/C receptors mediates the attenuation of compulsive checking in quinpirole-treated animals. Rats were chronically treated with quinpirole on the open field for the induction of compulsive checking. Following the induction phase, animals were treated with mCPP (1.25 mg/kg) and the selective 5-HT2A/C receptor antagonist ritanserin (1 mg/kg or 5 mg/kg) to test whether blockade of 5-HT2A/C receptors inhibits attenuation of checking by mCPP. Results showed that as expected, quinpirole induced compulsive checking, and mCPP reduced its performance. However, 5-HT2A/C receptor blockade by ritanserin did not inhibit the attenuation of compulsive checking by mCPP. These results suggest that the reduction in compulsive checking by mCPP is not mediated by activity at 5-HT2A/C receptors, but by another receptor subtype.

Performance of compulsive behavior in rats is not a unitary phenomenon - validation of separate functional components in compulsive checking behavior.

A previous analysis of the quinpirole sensitisation rat model of obsessive-compulsive disorder revealed that the behavioral phenotype of compulsive checking consists of three constitutive components - vigor of checking performance, focus on the task of checking, and satiety following a bout of checking. As confirmation of this analysis, the aim of the present study was to reconstitute, without quinpirole treatment, each of the putative components, with the expectation that these would self-assemble into compulsive checking. To reconstitute vigor and satiety, the employed treatment was a bilateral lesion of the nucleus accumbens core (NAc), as this treatment was shown previously to exaggerate these components. To reconstitute focus, the employed treatment was a low dose of the serotonin-1A receptor agonist 8-hydroxy-2-(di-n-propylamino) tetralin hydrochloride (DPAT) (0.0625 mg/kg), as high doses of this drug induce compulsive behavior and exacerbate focus. Results showed that injection of DPAT to NAc lesion rats did yield compulsive checking. Neither the drug alone nor the NAc lesion by itself produced compulsive checking. The demonstrated synthesis of compulsive checking by the combined treatment of low-dose DPAT and NAc lesion strengthened the previous fractionation of the model obsessive-compulsive disorder phenotype into three constitutive components, and suggested a role for serotonin-1A receptors outside the NAc in enhanced focus on the task of checking.

Separate mechanisms for development and performance of compulsive checking in the quinpirole sensitization rat model of obsessive-compulsive disorder (OCD).

RATIONALE: Acute administration of serotonergic agonist, meta-chlorophenylpiperazine (mCPP), attenuates performance of compulsive checking in an animal model of obsessive-compulsive disorder (OCD). It is not known whether mCPP has a similar effect on development of compulsive checking. OBJECTIVES: The objective of the study was to examine whether similar mechanisms mediate the development versus the performance of compulsive checking in the rat model. METHODS: Four groups of male rats (N = 14/group) were tested: two experimental groups co-injected with D2/D3 dopamine agonist quinpirole (0.25 mg/kg) and mCPP (0.625 mg/kg or 1.25 mg/kg), and two control groups, one co-injected with quinpirole and saline, the other receiving injections of saline. The time course of development of compulsive checking across injections 1 to 10 in quinpirole-treated rats was compared to rats co-injected with quinpirole and mCPP. RESULTS: Results showed that during the course of chronic treatment, mCPP (1.25 mg/kg) significantly attenuated performance of checking behavior. However, when these rats were retested for expression of compulsive checking (that is, with an injection of quinpirole only), their profile of compulsive checking was no different from the control rats treated throughout with quinpirole only. CONCLUSIONS: Findings show that mCPP inhibits performance of compulsive checking but does not block quinpirole from inducing the neural substrate underlying this compulsive behavior. Hence, a separate mechanism underlies the induction of compulsive checking and the performance of it. It is suggested that development of the OCD endophenotype reflects neuroplastic changes produced by repeated dopamine D2/D3 receptor stimulation, while stimulation of serotonergic receptors mediates a negative feedback signal that shuts down the motor performance of checking.

Effects of the serotonergic agonist mCPP on male rats in the quinpirole sensitization model of obsessive-compulsive disorder (OCD).

RATIONALE: The serotonergic agonist, meta-chlorophenylpiperazine (mCPP), produces inconsistent effects on obsessive-compulsive disorder (OCD) symptoms, perhaps because clinical studies have not utilized a homogenous OCD subgroup of patients. OBJECTIVES: This study aimed to evaluate mCPP effects on functional components of compulsive checking, using the quinpirole sensitization rat model of OCD. METHODS: In study 1, the effects of mCPP were evaluated in quinpirole rats with compulsive checking. Two experimental groups were co-injected with quinpirole (0.125 mg/kg) and mCPP (0.625 or 1.25 mg/kg), while one control group was co-injected with quinpirole (0.125 mg/kg) and saline and the other control group received co-injections of saline. In study 2, mCPP (0, 0.3125, 0.625, and 1.25 mg/kg) was administered repeatedly to naïve rats and induction of compulsive checking evaluated. RESULTS: mCPP significantly attenuated quinpirole-induced compulsive checking behavior by reducing vigor of checking (indexed by frequency of checking and length of check) and increasing rest after a bout of checking (indexed by time to the next checking bout), but it did not affect focus on the task of checking (indexed by recurrence time of checking and number of stops before returning to check). In naïve rats, mCPP did not induce compulsive behavior, but the highest dose reduced vigor of checking performance compared to saline controls. CONCLUSIONS: mCPP did not exacerbate or induce compulsive checking behavior. Instead, it ameliorated compulsive checking by reducing vigor of checking and increasing post-checking satiety, without affecting focus on checking. Ameliorative effects of mCPP may involve 5HT2A/2C receptors in substantia nigra pars reticulata that inhibit expression of motor vigor.

On the dynamic nature of the engram: evidence for circuit-level reorganization of object memory traces following reactivation.

Research has implicated the perirhinal cortex (PRh) in several aspects of object recognition memory. The specific role of the hippocampus (HPC) remains controversial, but its involvement in object recognition may pertain to processing contextual information in relation to objects rather than object representation per se. Here we investigated the roles of the PRh and HPC in object memory reconsolidation using the spontaneous object recognition task for rats. Intra-PRh infusions of the protein synthesis inhibitor anisomycin immediately following memory reactivation prevented object memory reconsolidation. Similar deficits were observed when a novel object or a salient contextual change was introduced during the reactivation phase. Intra-HPC infusions of anisomycin, however, blocked object memory reconsolidation only when a contextual change was introduced during reactivation. Moreover, disrupting functional interaction between the HPC and PRh by infusing anisomycin unilaterally into each structure in opposite hemispheres also impaired reconsolidation when reactivation was done in an altered context. These results show for the first time that the PRh is critical for reconsolidation of object memory traces and provide insight into the dynamic process of object memory storage; the selective requirement for hippocampal involvement following reactivation in an altered context suggests a substantial circuit level object trace reorganization whereby an initially PRh-dependent object memory becomes reliant on both the HPC and PRh and their interaction. Such trace reorganization may play a central role in reconsolidation-mediated memory updating and could represent an important aspect of lingering consolidation processes proposed to underlie long-term memory modulation and stabilization.

Older and stronger object memories are selectively destabilized by reactivation in the presence of new information.

Reactivation can destabilize previously consolidated memories, rendering them vulnerable to disruption and necessitating a process of reconsolidation in order for them to be maintained. This process of destabilization and reconsolidation has commonly been cited as a means by which established memories can be updated or modified. However, little direct evidence exists to support this view. The present study addressed this issue by analyzing the influence of novel salient information present at the time of memory reactivation on the likelihood of the reactivated memory to become destabilized and vulnerable to disruption. Rats explored sample objects and, some time later, received systemic injections of the N-methyl-D-aspartic acid (NMDA) receptor antagonist MK-801 or saline prior to memory reactivation. When object memories were relatively young or weakly encoded, MK-801 significantly disrupted reconsolidation regardless of the reactivation conditions. However, increasing the amount of sample object exploration or the interval between the sample phase and reactivation abolished the effect of MK-801 on reconsolidation unless salient novel contextual information was present during memory reactivation. These results highlight the dynamic nature of memory storage and retrieval and indicate an important interaction between the age and strength of a memory, its probability of being destabilized upon reactivation, and the stimulus conditions during reactivation. The essential involvement of novel encoding in destabilizing certain memories supports the idea that the reconsolidation process enables modification of existing memories.