Head direction (HD) cells discharge as a function of the animal’s directional heading and are believed to underlie one’s sense of direction. They have been identified in several brain areas, although the signal is thought to be generated across the connections between the lateral mammillary (LMN) and dorsal tegmental nuclei (DTN). Computational models have proposed that a ring-attractor network underlies the mechanisms that generate the signal. These models usually contain separate populations of neurons that encode HD and angular head velocity (AHV). Currently, both cell types have been identified in the LMN and DTN. However, HD attractor models also require cells, referred to as ‘rotation’ cells, which are sensitive to both parameters conjunctively (HD+AHV). Here we sought to identify such cells in the LMN-DTN network. We identified two distinct types of HD cells. The majority of LMN HD cells (∼64%) were AHV-independent, responding only to the animal’s directional heading. However, a second population (∼36%) was sensitive to both HD and AHV. Both symmetric and asymmetric AHV cell types were found. Similar results were found in the DTN, but with a higher percentage of conjunctive HD+AHV cells (60%). Notably, many HD+AHV conjunctive cells were also sensitive to the animal’s linear velocity (LV). In contrast, HD cells in the anterodorsal thalamus were rarely sensitive to AHV or LV. These findings demonstrate that the requisite rotation-type HD cell is present in brain areas responsible for generating the HD signal and supports the view that an attractor style network underlies its generation in mammals. Statements and Declaratio This manuscript does not represent the official view of the National Institute of Neurological Disorders and Stroke (USA) (NINDS), the National Institutes of Health (USA) (NIH), or any part of the US Federal Government. No official support or endorsement of this article by the NINDS or NIH is intended or should be inferred. ### Competing Interest Statement The authors have declared no competing interest.

ArfGAP, with dual PH domain-containing protein 1/Centaurin-α1 (ADAP1/CentA1), is a brain-enriched and highly conserved Arf6 GTPase-activating and Ras-anchoring protein. CentA1 is involved in dendritic outgrowth and arborization, synaptogenesis, and axonal polarization by regulating the actin cytoskeleton dynamics. CentA1 upregulation and association with amyloid plaques in the human Alzheimer's disease (AD) brain suggest the role of this protein in AD progression. To understand the role of CentA1 in neurodegeneration, we crossbred CentA1 knock-out (KO) mice with the J20 mouse model of AD. We evaluated AD-associated behavioral and neuropathological hallmarks and gene expression profiles in J20 and J20 crossed with CentA1 KO (J20xKO) male mice to determine the impact of eliminating CentA1 expression on AD-related phenotypes. Spatial memory assessed by the Morris water maze test showed significant impairment in J20 mice, which was rescued in J20xKO mice. Moreover, neuropathological hallmarks of AD, such as amyloid plaque deposits and neuroinflammation, were significantly reduced in J20xKO mice. To identify potential mediators of AD phenotype rescue, we analyzed differentially expressed genes between genotypes. We found that changes in the gene profile by deletion of CentA1 from J20 (J20xKO vs J20) were anticorrelated with changes caused by APP overexpression (J20 vs wild type), consistent with rescue of J20 phenotypes by CentA1 KO. In summary, our data indicate that CentA1 is required for the progression of AD phenotypes in this model and that targeting CentA1 signaling might have therapeutic potential for AD prevention or treatment.

Small conductance Ca2+-activated K+ (SK) channels, expressed throughout the CNS, are comprised of SK1, SK2 and SK3 subunits, assembled as homotetrameric or heterotetrameric proteins. SK channels expressed somatically modulate the excitability of neurons by mediating the medium component of the afterhyperpolarization. Synaptic SK channels shape excitatory postsynaptic potentials and synaptic plasticity. Such SK-mediated effects on neuronal excitability and activity-dependent synaptic strength likely underlie the modulatory influence of SK channels on memory encoding. Converging evidence indicates that several forms of long-term memory are facilitated by administration of the SK channel blocker, apamin, and impaired by administration of the pan-SK channel activator, 1-EBIO, or by overexpression of the SK2 subunit. The selective knockdown of dendritic SK2 subunits facilitates memory to a similar extent as that observed after systemic apamin. SK1 subunits co-assemble with SK2; yet the functional significance of SK1 has not been clearly defined. Here, we examined the effects of GW542573X, a drug that activates SK1 containing SK channels, as well as SK2/3, on several forms of long-term memory in male C57BL/6J mice. Our results indicate that pre-training, but not post-training, systemic GW542573X impaired object memory and fear memory in mice tested 24 h after training. Pre-training direct bilateral infusion of GW542573X into the CA1 of hippocampus impaired object memory encoding. These data suggest that systemic GW542573X impairs long-term memory. These results add to growing evidence that SK2 subunit-, and SK1 subunit-, containing SK channels can regulate behaviorally triggered synaptic plasticity necessary for encoding hippocampal-dependent memory.

AbstractA central question in the field of aging research is to identify the cellular and molecular basis of neuroresilience. One potential candidate is the small GTPase, Rab10. Here, we used Rab10+/−mice to investigate the molecular mechanisms underlying Rab10-mediated neuroresilience. Brain expression analysis of 880 genes involved in neurodegeneration showed that Rab10+/−mice have increased activation of pathways associated with neuronal metabolism, structural integrity, neurotransmission, and neuroplasticity compared with their Rab10+/+littermates. Lower activation was observed for pathways involved in neuroinflammation and aging. We identified and validated several differentially expressed genes (DEGs), including Stx2, Stx1b, Vegfa, and Lrrc25 (downregulated) and Prkaa2, Syt4, and Grin2d (upregulated). Behavioral testing showed that Rab10+/−mice perform better in a hippocampal-dependent spatial task (object in place test), while their performance in a classical conditioning task (trace eyeblink classical conditioning, TECC) was significantly impaired. Therefore, our findings indicate that Rab10 differentially controls the brain circuitry of hippocampal-dependent spatial memory and higher-order behavior that requires intact cortex-hippocampal circuitry. Transcriptome and biochemical characterization of these mice suggest that glutamate ionotropic receptor NMDA type subunit 2D (GRIN2D or GluN2D) is affected by Rab10 signaling. Further work is needed to evaluate whether GRIN2D mediates the behavioral phenotypes of the Rab10+/−mice. We conclude that Rab10+/−mice described here can be a valuable tool to study the mechanisms of resilience in Alzheimer’s disease (AD) model mice and to identify novel therapeutical targets to prevent cognitive decline associated with normal and pathologic aging.

The hippocampus, a medial temporal lobe brain region, is critical for the consolidation of information from short-term memory into long-term episodic memory and for spatial memory that enables navigation. Hippocampal damage in humans has been linked to amnesia and memory loss, characteristic of Alzheimer's disease and other dementias. Numerous studies indicate that the rodent hippocampus contributes significantly to long-term memory for spatial and nonspatial information. For example, muscimol-induced depression of CA1 neuronal activity in the dorsal hippocampus impairs the encoding, consolidation, and retrieval of nonspatial object memory in mice. Here, a chemogenetic designer receptor exclusively activated by designer drugs (DREADDs) approach was used to test the selective involvement of CA1 pyramidal neurons in memory retrieval for objects and for spatial location in a cohort of male C57BL/6J mice. Activation of the inhibitory (hM4Di) DREADDs receptor expressed in CA1 neurons significantly impaired the retrieval of object memory in the spontaneous object recognition task and of spatial memory in the Morris water maze. Silencing of CA1 neuronal activity in hM4Di-expressing mice was confirmed by comparing Fos expression in vehicle- and clozapine-N-oxide-treated mice after exploration of a novel environment. Histological analyses revealed that expression of the hM4Di receptor was limited to CA1 neurons of the dorsal hippocampus. These results suggest that a common subset of CA1 neurons (i.e., those expressing hM4Di receptors) in mouse hippocampus contributed to the retrieval of long-term memory for nonspatial and spatial information. Our findings support the view that the contribution of the rodent hippocampus is like that of the primate hippocampus, specifically essential for global memory. Our results further validate mice as a suitable model system to study the neurobiological mechanisms of human episodic memory, but also in developing treatments and understanding the underlying causes of diseases affecting long-term memory, such as Alzheimer's disease.

Picture-object equivalence or recognizing a three-dimensional (3D) object after viewing a two-dimensional (2D) photograph of that object, is a higher-order form of visual cognition that may be beyond the perceptual ability of rodents. Behavioral and neurobiological mechanisms supporting picture-object equivalence are not well understood. We used a modified visual recognition memory task, reminiscent of those used for primates, to test whether picture-object equivalence extends to mice. Mice explored photographs of an object during a sample session, and 24 h later were presented with the actual 3D object from the photograph and a novel 3D object, or the stimuli were once again presented in 2D form. Mice preferentially explored the novel stimulus, indicating recognition of the “familiar” stimulus, regardless of whether the sample photographs depicted radially symmetric or asymmetric, similar, rotated, or abstract objects. Discrimination did not appear to be guided by individual object features or low-level visual stimuli. Inhibition of CA1 neuronal activity in dorsal hippocampus impaired discrimination, reflecting impaired memory of the 2D sample object. Collectively, results from a series of experiments provide strong evidence that picture-object equivalence extends to mice and is hippocampus-dependent, offering important support for the appropriateness of mice for investigating mechanisms of human cognition.

While the essential contribution of the hippocampus to spatial memory is well established, object recognition memory has been traditionally attributed to the perirhinal cortex (PRh). However, the results of several studies indicate that under specific procedural conditions, temporary or permanent lesions of the hippocampus affect object memory processes as measured in the Spontaneous Object Recognition (SOR) task. The PRh and hippocampus are considered to contribute distinctly to object recognition memory based on memory strength. Allowing mice more, or less, exploration of novel objects during the encoding phase of the task (i.e., sample session), yields stronger, or weaker, object memory, respectively. The current studies employed temporary local inactivation and immunohistochemistry to determine the differential contributions of neuronal activity in PRh and the CA1 region of the hippocampus to strong and weak object memory. Temporary inactivation of the CA1 immediately after the SOR sample session impaired strong object memory but spared weak object memory; while temporary inactivation of PRh post-sample impaired weak object memory but spared strong object memory. Furthermore, mRNA transcription and de novo protein synthesis are required for the consolidation of episodic memory, and activation patterns of immediate early genes (IEGs), such as c-Fos and Arc, are linked to behaviorally triggered neuronal activation and synaptic plasticity. Analyses of c-Fos and Arc protein expression in PRh and CA1 neurons by immunohistochemistry, and of Arc mRNA by qPCR after distinct stages of SOR, provide additional support that strong object memory is dependent on CA1 neuronal activity, while weak object memory is dependent on PRh neuronal activity. Taken together, the results support the view that both PRh and CA1 are required for object memory under distinct conditions. Specifically, our results are consistent with a model that as the mouse begins to explore a novel object, information about it accumulates within PRh, and a weak memory of the object is encoded. If object exploration continues beyond some threshold, strong memory for the event of object exploration is encoded; the consolidation of which is CA1-dependent. These data serve to reconcile the dissension in the literature by demonstrating functional and complementary roles for CA1 and PRh neurons in rodent object memory.

Medial and lateral entorhinal cortices convey spatial/contextual and item/object information to the hippocampus, respectively. Whether the distinct inputs are integrated as one cognitive map by hippocampal neurons to represent location and the objects therein, or whether they remain as parallel outputs, to be integrated in a downstream region, remains unclear. Principal, or complex spike bursting, neurons of hippocampus exhibit location-specific firing, and it is likely that the activity of “place cells” supports spatial memory/navigation in rodents. Consistent with cognitive map theory, the activity of CA1 hippocampal neurons is also critical for nonspatial memory, such as object recognition. However, the degree to which CA1 neuronal activity represents the associations of object-context or object-in-place memory is not well understood. Here, the contributions of mouse CA1 neuronal activity to object recognition memory and the emergence of object-place conjunctive representations were tested using in vivo recordings and functional inactivation. Independent of arena configuration, CA1 place fields were stable throughout testing and object-place representations were not identified in CA1, although the number of fields per cell increased during object sessions, and few object-related firing CA1 neurons (nonplace) were recorded. The results of the inactivation studies confirmed the significant contribution of CA1 neuronal activity to object recognition memory when a delay of 20 min, but not 5 min, was imposed between encoding and retrieval. Together, our results confirm the delay-dependent contribution of the CA1 region to object memory and suggest that object information is processed in parallel with the ongoing spatial mapping function that is a hallmark of hippocampal memory. NEW & NOTEWORTHY We developed variations of the object recognition task to examine the contribution of mouse CA1 neuronal activity to object memory and the degree to which object-context conjunctive representations are formed during object training. Our results indicate that, within the CA1 region, object information is processed in a parallel but delay-dependent manner, with ongoing spatial mapping.

ADAP1/Centaurin-α1 (CentA1) functions as an Arf6 GTPase-activating protein highly enriched in the brain. Previous studies demonstrated the involvement of CentA1 in brain function as a regulator of dendritic differentiation and a potential mediator of Alzheimer's disease (AD) pathogenesis. To better understand the neurobiological functions of CentA1 signaling in the brain, we developed Centa1 knock-out (KO) mice. The KO animals showed neither brain development nor synaptic ultrastructure deficits in the hippocampus. However, they exhibited significantly higher density and enhanced structural plasticity of dendritic spines in the CA1 region of the hippocampus compared with non-transgenic (NTG) littermates. Moreover, the deletion of Centa1 improved performance in the object-in-place (OIP) spatial memory task. These results suggest that CentA1 functions as a negative regulator of spine density and plasticity, and of hippocampus-dependent memory formation. Thus, CentA1 and its downstream signaling may serve as a potential therapeutic target to prevent memory decline associated with aging and brain disorders.

Visceral hypersensitivity is a highly complex and subjective phenomenon associated with multiple levels of the nervous system and a wide range of neurotransmission. The dorsal horn (DH) in spinal cord relays the peripheral sensory information into the brain. Small conductance Ca2+-activated K+ (SK) channels regulate neuronal excitability and firing by allowing K+ to efflux in response to increase in the intracellular Ca2+ level. In this study, we examined the influence of SK2 channels in the spinal DH on the pathogenesis of visceral hypersensitivity induced by colorectal distension (CRD) in rats. Electrophysiological results showed that rats with visceral hypersensitivity presented a decrease in the SK channel-mediated afterhyperpolarization current (IAHP), and an increase in neuronal firing rates and c-Fos positive staining in the spinal DH. Western blot data revealed a decrease in the SK2 channel protein in the membrane fraction. Moreover, intrathecal administration of the SK2 channel activator 1-EBIO or CyPPA alleviated visceral hypersensitivity, reversed the decrease in IAHP and the increase in neuronal firing rates in spinal DH in rats that experienced CRD. 1-EBIO or CyPPA effect could be prevented by SK2 channel blocker apamin. CRD induced an increase in c-Fos protein expression in the spinal DH, which was prevented by 1-EBIO. Together, these data suggest that visceral hypersensitivity and pain is associated with a decrease in the number and function of membrane SK2 channels in the spinal DH. Pharmacological manipulation of SK2 channels may open a new avenue for the treatment of visceral hypersensitivity and pain. Highlights: -Neonatal colorectal distension induced visceral hypersensitivity in rats.-Visceral hypersensitivity rats presented a decrease in afterhyperpolarization current (IAHP) and membrane SK2 channel protein in the spinal dorsal horn.-Visceral hypersensitivity rats presented an increase in neuronal firing rate in the spinal dorsal horn.-Intrathecal administration of SK2 channel activator 1-EBIO or CyPPA prevented visceral hypersensitivity and decrease in IAHP.

ABSTRACTBy acting on serotonin 5‐HT2A receptors (5‐HT2ARs), serotonergic psychedelic drugs induce perceptual and visual hallucinations by increasing neuronal excitability and altering visual‐evoked neuronal responses. The present study was designed to examine whether the perceptual alterations induced by a serotonergic psychedelic drug would affect the integrity of hippocampal‐dependent, visually guided spatial cognition. phenylalkylamine hallucinogen TCB‐2 is a selective agonist of 5‐HT2ARs. Mice received TCB‐2 (1.0 mg kg−1, i.p.), and spatial behaviors and hippocampal electrophysiological responses were measured with water maze tasks and in vivo single‐unit recording, respectively. TCB‐2 did not affect visual cue approach behavior in the visible platform water maze, but increased the latency of trained mice to initiate goal‐directed swimming during a probe test in the hidden platform Morris water maze, which could be prevented by 5‐HT2AR antagonist MDL 11,939. Interestingly, TCB‐2 did not affect the efficiency of the swim path or the proper use of distal visual cues during the probe test. Hippocampal place cell activity is considered to represent spatial and context‐specific episodic memory. Systemic TCB‐2 did not affect previously established place fields of CA1 neurons in mice exploring a familiar environment, or the remapping of place cells when the mice explored a novel environment. However, TCB‐2 impaired the long‐term stability of place fields for the novel environment initially encoded under the influence of TCB‐2, which could be prevented by 5‐HT2AR antagonist MDL 11,939. Our data indicate that hallucinogenic 5‐HT2AR agonist delays the initiation of spatial search behavior, but does not impair the use of visual cues to guide goal‐directed spatial behavior. Moreover, activation of 5‐HT2ARs does not impair the coding and retrieval of spatial information, but impairs the long‐term stability of new formed place fields of CA1 neurons. © 2017 Wiley Periodicals, Inc.

BACKGROUND: Despite our understanding of the significance of the prefrontal cortex in the consolidation of long-term memories, its role in the encoding of long-term memories remains elusive. Here we investigated the role of new protein synthesis in the mouse medial prefrontal cortex (mPFC) in encoding contextual fear memory.METHODS: Because a change in the association of messenger RNAs (mRNAs) to polyribosomes is an indicator of new protein synthesis, we assessed the changes in polyribosome-associated mRNAs in the mPFC following contextual fear conditioning (CFC) in the mouse. Differential gene expression in the mPFC was identified by polyribosome profiling (n = 18). The role of new protein synthesis in the mPFC was determined by focal inhibition of protein synthesis (n = 131) and by intraprelimbic cortex manipulation (n = 56) of Homer3, a candidate identified from polyribosome profiling.RESULTS: We identified several mRNAs that are differentially and temporally recruited to polyribosomes in the mPFC following CFC. Inhibition of protein synthesis in the prelimbic (PL) cortex but not in the anterior cingulate cortex region of the mPFC immediately after CFC disrupted encoding of contextual fear memory. Intriguingly, inhibition of new protein synthesis in the PL cortex 6 hours after CFC did not impair encoding. Furthermore, expression of Homer3, an mRNA enriched in polyribosomes following CFC, in the PL cortex constrained encoding of contextual fear memory.CONCLUSIONS: Our studies identify several molecular substrates of new protein synthesis in the mPFC and establish that encoding of contextual fear memories require new protein synthesis in PL subregion of mPFC.

Recognition of a previously experienced item or object depends upon the successful retrieval of memory for the object. The neural mechanisms that support object recognition memory in the mammalian brain are not well understood. The rodent hippocampus plays a well-established role in spatial memory, and we previously demonstrated that temporary inactivation of the mouse hippocampus impairs object memory, as assessed with a novel object preference (NOP) test. The present studies were designed to test some remaining issues regarding the contribution of the CA1 sub-region of the mouse dorsal hippocampus to long-term object memory. Specifically, we examined whether the retrieval of spatial memory (as assessed by the Morris water maze; MWM) and object recognition memory are differentially sensitive to inactivation of the CA1 region. The current study used pre-test local microinfusion of muscimol directly into the CA1 region of dorsal hippocampus to temporarily interrupt its function during the respective retrieval phases of both behavioral tasks, in order to compare the contribution of the CA1 to object memory and spatial memory. Histological analyses revealed that local intra-CA1 injection of muscimol diffused within, and not beyond, the CA1 region of dorsal hippocampus. The degree of memory retrieval impairment induced by muscimol was comparable in the two tasks, supporting the view that object memory and spatial memory depend similarly on the CA1 region of rodent hippocampus. Further, we confirmed that the muscimol-induced impairment of CA1 function is temporary. First, mice that exhibited impaired object memory retrieval immediately after intra-CA1 muscimol, subsequently exhibited unimpaired retrieval of object memory when tested 24h later. Secondly, a cohort of mice that exhibited impaired object memory retrieval after intra-CA1 muscimol later acquired spatial memory in the MWM comparable to that of control mice. Together, these results offer further support for the involvement of the CA1 region of mouse hippocampus in object recognition memory, and provide evidence to suggest that the NOP task is as much a test of hippocampal function as the classic MWM test.

The rodent hippocampus supports non-spatial object memory. Serotonin 5-HT2A receptors (5-HT2AR) are widely expressed throughout the hippocampus. We previously demonstrated that the activation of 5-HT2ARs enhanced the strength of object memory assessed 24 h after a limited (i.e., weak memory) training procedure. Here, we examined the subcellular distribution of 5-HT2ARs in the hippocampal CA1 region and underlying mechanisms of 5-HT2AR-mediated object memory consolidation. Analyses with immuno-electron microscopy revealed the presence of 5-HT2ARs on the dendritic spines and shafts of hippocampal CA1 neurons, and presynaptic terminals in the CA1 region. In an object recognition memory procedure that places higher demand on the hippocampus, only post-training systemic or intrahippocampal administration of the 5-HT2AR agonist TCB-2 enhanced object memory. Object memory enhancement by TCB-2 was blocked by the 5-HT2AR antagonist, MDL 11,937. The memory-enhancing dose of systemic TCB-2 increased extracellular glutamate levels in hippocampal dialysate samples, and increased the mean in vivo firing rate of hippocampal CA1 neurons. In summary, these data indicate a pre- and post-synaptic distribution of 5-HT2ARs, and activation of 5-HT2ARs selectively enhanced the consolidation of object memory, without affecting encoding or retrieval. The 5-HT2AR-mediated facilitation of hippocampal memory may be associated with an increase in hippocampal neuronal firing and glutamate efflux during a post-training time window in which recently encoded memories undergo consolidation.

The increasing prescription of opioids is fueling an epidemic of addiction and overdose deaths. Morphine is a highly addictive drug characterized by a high relapse rate - even after a long period of abstinence. Serotonin (5-HT) neurotransmission participates in the development of morphine dependence, as well as the expression of morphine withdrawal. In this study, we examined the effect of blockade of 5-HT2A receptors (5-HT2ARs) on morphine-induced behavioral sensitization and withdrawal in male mice. 5-HT2AR antagonist MDL 11,939 (0.5 mg/kg, i.p.) suppressed acute morphine (5.0 mg/kg, s.c.)-induced increase in locomotor activity. Mice received morphine (10 mg/kg, s.c.) twice a day for 3 days and then drug treatment was suspended for 5 days. On day 9, a challenge dose of morphine (10 mg/kg) was administered to induce the expression of behavioral sensitization. MDL 11,939 (0.5 mg/kg, i.p.) pretreatment suppressed the expression of morphine-induced behavioral sensitization. Another cohort of mice received increasing doses of morphine over a 7-day period to induce morphine-dependence. MDL 11,939 (0.5 mg/kg, i.p.) prevented naloxone-precipitated withdrawal in morphine-dependent mice on day 7. Moreover, chronic morphine treatment increased 5-HT2AR protein level and decreased the phosphorylation of extracellular signal-regulated kinases in the prefrontal cortex. Together, these results by the first time demonstrate that 5-HT2ARs modulate opioid dependence and blockade of 5-HT2AR may represent a novel strategy for the treatment of morphine use disorders.HIGHLIGHTS:(i)Blockade of 5-HT2A receptors suppresses the expression of morphine-induced behavioral sensitization.(ii)Blockade of 5-HT2A receptors suppresses naloxone-precipitated withdrawal in morphine-treated mice.(iii)Chronic morphine exposure induces an increase in 5-HT2A receptor protein level and a decrease in ERK protein phosphorylation in prefrontal cortex.

Serotonin 5-HT2A receptors (5-HT2ARs) are widely distributed in the central nervous system, especially in brain region essential for learning and cognition. In addition to endogenous 5-HT, several hallucinogens, antipsychotics, and antidepressants function by targeting 5-HT2ARs. Preclinical studies show that 5-HT2AR antagonists have antipsychotic and antidepressant properties, whereas agonist ligands possess cognition-enhancing and hallucinogenic properties. Abnormal 5-HT2AR activity is associated with a number of psychiatric disorders and conditions, including depression, schizophrenia, and drug addiction. In addition to its traditional activity as a G protein-coupled receptor (GPCR), recent studies have defined novel operations of 5-HT2ARs. Here we review progress in the (1) receptor anatomy and biology: distribution, signaling, polymerization and allosteric modulation; and (2) receptor functions: learning and memory, hallucination and spatial cognition, and mental disorders. Based on the recent progress in basic research on the 5-HT2AR, it appears that post-training 5-HT2AR activation enhances non-spatial memory consolidation, while pre-training 5-HT2AR activation facilitates fear extinction. Further, the potential influence that 5-HT2AR-elicited visual hallucinations may have on visual cue (i.e., landmark) guided spatial cognition is discussed. We conclude that the development of selective 5-HT2AR modulators to target distinct signaling pathways and neural circuits represents a new possibility for treating emotional, neuropsychiatric, and neurodegenerative disorders.

Abuse and dependence to heroin has evolved into a global epidemic as a significant clinical and societal problem with devastating consequences. Repeated exposure to heroin can induce long-lasting behavioral sensitization and withdrawal. Pharmacological activation of 5-HT2C receptors (5-HT2CRs) suppresses psychostimulant-induced drug-seeking and behavioral sensitization. The present study examined the effect of a selective 5-HT2CR agonist lorcaserin on behavioral sensitization and naloxone-precipitated withdrawal symptoms in heroin-treated mice. Male mice received heroin (1.0 mg/kg, s.c.) twice a day for 3 days and then drug treatment was suspended for 5 days. On day 9, a challenge dose of heroin (1.0 mg/kg) was administered to examine the expression of behavioral sensitization. Lorcaserin administered during the development, withdrawal or expression stage suppressed heroin-induced behavioral sensitization on day 9. Another cohort of mice received increasing doses of heroin over a 4.5-day period. Lorcaserin, or the positive control clonidine (an α2-adrenoceptor agonist) suppressed naloxone-precipitated withdrawal symptoms in heroin-treated mice. These findings suggest that activation of 5-HT2CRs suppresses behavioral sensitization and withdrawal in heroin-treated mice. Thus, pharmacological activation of 5-HT2CRs may represent a new avenue for the treatment of heroin addiction.

Opioid abuse and dependence have evolved into an international epidemic as a significant clinical and societal problem with devastating consequences. Repeated exposure to the opioid, for example morphine, can induce profound, long-lasting behavioral sensitization and physical dependence, which are thought to reflect neuroplasticity in neural circuitry. Central serotonin (5-HT) neurotransmission participates in the development of dependence on and the expression of withdrawal from morphine. Serotonin 5-HT(2C) receptor (5-HT(2C)R) agonists suppress psychostimulant nicotine or cocaine-induced behavioral sensitization and drug-seeking behavior; however, the impact of 5-HT(2C)R agonists on behaviors relevant to opioid abuse and dependence has not been reported. In the present study, the effects of 5-HT(2C)R activation on the behavioral sensitization and naloxone-precipitated withdrawal symptoms were examined in mice underwent repeated exposure to morphine. Male mice received morphine (10 mg/kg, s.c.) to develop behavioral sensitization. Lorcaserin, a 5-HT(2C)R agonist, prevented the induction and expression, but not the development, of morphine-induced behavioral sensitization. Another cohort of mice received increasing doses of morphine over a 7-day period to induce morphine-dependence. Pretreatment of lorcaserin, or the positive control clonidine (an alpha 2-adrenoceptor agonist), ameliorated the naloxone-precipitated withdrawal symptoms. SB 242084, a selective 5-HT(2C)R antagonist, prevented the lorcaserin-mediated suppression of behavioral sensitization and withdrawal. Chronic morphine treatment was associated with an increase in the expression of 5-HT(2C)R protein in the ventral tegmental area, locus coeruleus and nucleus accumbens. These findings suggest that 5-HT(2C)R can modulate behavioral sensitization and withdrawal in morphine-dependent mice, and the activation of 5-HT(2C)R may represent a new avenue for the treatment of opioid addiction.