Wendy K. Adams

Serotonin depletion in the dorsal and ventral hippocampus : Effects on locomotor hyperactivity, prepulse inhibition and learning and memory

We present an overview of our studies on the differential role of serotonergic projections from the median raphe nucleus (MRN) and dorsal raphe nucleus (DRN) in behavioural animal models with relevance to schizophrenia. Stereotaxic microinjection of the serotonin neurotoxin 5,7-dihydroxytryptamine (5,7-DHT) into the MRN or one of its main projections regions, the dorsal hippocampus, induced a marked enhancement of phencyclidine-induced locomotor hyperactivity and a disruption of prepulse inhibition (PPI) in rats. There was no enhancement of locomotor hyperactivity induced by amphetamine or MK-801 or after 5,7-DHT lesions of the DRN or ventral hippocampus. Rats with dorsal hippocampus lesions did not show significant changes in the Y-maze test for short-term spatial memory, the Morris water maze for long-term spatial memory, or in the T-maze delayed alternation test for working memory. These chronic lesion studies suggest a modulatory influence of serotonergic projections from the MRN to the dorsal hippocampus on phencyclidine effects and prepulse inhibition, but not on different forms of learning and memory. The results provide new insight into the role of serotonin in the dorsal hippocampus in aspects of schizophrenia.

Long-term, calorie-restricted intake of a high-fat diet in rats reduces impulse control and ventral striatal D2 receptor signalling - two markers of addiction vulnerability.

High impulsivity, mediated through ventral striatal dopamine signalling, represents an established risk factor for substance abuse, and may likewise confer vulnerability to pathological overeating. Mechanistically, the assumption is that trait impulsivity facilitates the initiation of maladaptive eating styles or choices. However, whether consumption of appetitive macronutrients themselves causes deficits in impulse control and striatal signalling, thereby contributing to cognitive changes permissive of overeating behaviour, has yet to be considered. We examined the effects of chronic maintenance on restricted equicaloric, but high‐fat or high‐sugar, diets (48 kcal/day; 60 kcal% fat or sucrose) on rats’ performance in the five‐choice serial reaction time task, indexing impulsivity and attention. Markers of dopamine signalling in the dorsal and ventral striatum, and plasma insulin and leptin levels, were also assessed. Rats maintained on the high‐fat diet (HFD) were more impulsive, whereas the high‐sugar diet (HSD) did not alter task performance. Importantly, body weight and hormone levels were similar between groups when behavioural changes were observed. Maintenance on HFD, but not on HSD, reduced the levels of dopamine D2 receptor (D2R), cAMP response element‐binding protein (CREB) and phosphophorylated CREB (Ser133) proteins in the ventral, but not dorsal, striatum. D2R expression in the ventral striatum also negatively correlated with impulsive responding, independently of diet. These data indicate that chronic exposure to even limited amounts of high‐fat foods may weaken impulse control and alter neural signalling in a manner associated with vulnerability to addictions – findings that have serious implications for the propagation of uncontrolled eating behaviour in obesity and binge‐eating disorder.

Δ9-Tetrahydrocannabinol decreases willingness to exert cognitive effort in male rats.

Background Acceptance of cannabis use is growing. However, prolonged use is associated with diminished psychosocial outcomes, potentially mediated by drug-induced cognitive impairments. &Dgr;9-Tetrahydrocannabinol (THC) is the main psychoactive ingredient in cannabis, yet other phytocannabinoids in the plant, such as cannabidiol (CBD), have unique properties. Given that CBD can modulate the undesirable effects of THC, therapeutic agents, such as nabiximols, contain higher CBD:THC ratios than illicit marijuana. We tested the hypothesis that THC impairs a relevant cognitive function for long-term success, namely willingness to exert cognitive effort for greater rewards, and that CBD could attenuate such decision-making impairments. Methods Male Long–Evans rats (n = 29) performing the rat cognitive effort task (rCET) received acute THC and CBD, independently and concurrently, in addition to other cannabinoids. Rats chose between 2 options differing in reward magnitude, but also in the cognitive effort (attentional load) required to obtain them. Results We found that THC decreased choice of hard trials without impairing the animals’ ability to accurately complete them. Strikingly, this impairment was correlated with CB1 receptor density in the medial prefrontal cortex — an area previously implicated in effortful decision-making. In contrast, CBD did not affect choice. Coadministration of 1:1 CBD:THC matching that in nabiximols modestly attenuated the deleterious effects of THC in “slacker” rats. Limitations Only male rats were investigated, and the THC/CBD coadministration experiment was carried out in a subset of individuals. Conclusion These findings confirm that THC, but not CBD, selectively impairs decision-making involving cognitive effort costs. However, coadministration of CBD only partially ameliorates such THC-induced dysfunction.

Chronic D2/3 agonist ropinirole treatment increases preference for uncertainty in rats regardless of baseline choice patterns.

D2/3 receptor agonists are effective treatments for Parkinsons disease (PD), but can precipitate impulse control disorders (ICDs) including gambling disorder (GD). The neurobiological mechanisms underlying this devastating side‐effect of dopamine agonist replacement therapy (DRT), and any dependence on the dopamine depletion caused by PD, are unclear. It is also unclear whether previous biases towards risk or uncertainty are a risk factor for developing these ICDs. We investigated whether chronic D2/3 agonist administration (5 mg/kg/day ropinirole for 28 days) altered performance of a rat model of gambling‐like behaviour, the rodent betting task (rBT), and examined if baseline behaviour predicted this behavioural change. The rBT captures individual differences in subjective preference for uncertain outcomes: animals choose between guaranteed or probabilistic reinforcement of equal expected value. Chronic ropinirole dramatically increased selection of the uncertain option in two‐thirds of animals, regardless of baseline preferences. The effect on choice in the rBT was replicated in a dorsolateral striatal 6‐hydroxydopamine (6‐OHDA) rat model of early PD. These studies are the first to look at individual differences in response to chronic, rather than pulsatile, dosing of DRT in a rodent model of gambling behaviour. These findings suggest that DRT‐induced PG may stem from increases in subjective valuation of uncertainty. Such symptoms likely arise because of changes in dopaminergic striatal signalling caused by DRT rather than from an interaction between pre‐morbid behaviours or PD itself.

Hippocampal serotonin depletion facilitates the enhancement of prepulse inhibition by risperidone: Possible role of 5-HT2C receptors in the dorsal hippocampus

Abnormalities in both the hippocampal region and in serotonergic transmission are evident in patients with schizophrenia. We previously found that rats with serotonergic lesions targeting the dorsal hippocampus show altered psychotropic drug-induced hyperlocomotion and prepulse inhibition (PPI), behavioural paradigms relevant to aspects of schizophrenia. The present study explored the effect of serotonin depletion (>70%) along the dorsoventral axis of the hippocampus, or of partial serotonin depletion (∼50%) in the ventral hippocampus, on PPI modulation by acute antipsychotic drug treatment. We also used receptor binding autoradiography to investigate the neurochemical basis of behavioural effects. Following micro-injection of 5,7-dihydroxytryptamine, neither hippocampal serotonin depletion or partial serotonin depletion in the ventral hippocampus altered baseline PPI, startle magnitude or startle habituation. Acute treatment with clozapine or haloperidol had minimal effects on PPI in these lesioned rats or sham-operated controls. In contrast, risperidone treatment increased PPI to a significantly greater extent in rats with hippocampal serotonin depletion, an effect which was most prominent at low prepulse intensities. Partial serotonin depletion in the ventral hippocampus did not alter PPI modulation by risperidone. Neither type of serotonergic lesion altered the densities of 5-HT(1A) or 5-HT(2A) receptors in the hippocampus; serotonin transporters or 5-HT(1A) autoreceptors on raphe cell bodies; or dopamine transporters, D(1) or D(2) receptors in forebrain regions efferent to the hippocampus and implicated in schizophrenia, such as the nucleus accumbens. However, levels of [(3)H]mesulergine binding to 5-HT(2C) receptors were increased by approximately 70% in the dorsal hippocampus of rats with serotonin depletion in this region, while those in the ventral hippocampus were unaffected. Therefore, despite intact baseline PPI, abnormal PPI regulation in rats with >70% serotonin depletion in the hippocampus was unmasked by acute risperidone treatment. Selective upregulation of 5-HT(2C) receptors in the dorsal, but not ventral, hippocampus of these lesioned rats suggests that hippocampal 5-HT(2C) receptors vary in their adaptability to changes in serotonergic tone along the dorsoventral axis. These findings suggest that 5-HT(2C) receptors in the dorsal hippocampus may contribute to risperidone-induced enhancement of PPI.

Dissociable effects of systemic and orbitofrontal administration of adrenoceptor antagonists on yohimbine-induced motor impulsivity

ABSTRACT The &agr;2‐adrenoceptor antagonist, yohimbine, is commonly used as a pharmacological stressor. Its behavioural effects are typically attributed to elevated noradrenaline release via blockade of central, inhibitory autoreceptors. We have previously reported that yohimbine increases motor impulsivity in rats on the five‐choice serial reaction time task (5CSRTT), a cognitive behavioural assessment which measures motor impulsivity and visuospatial attention. Furthermore, this effect depended on cyclic adenomonophosphate (cAMP) signalling via cAMP response element binding (CREB) protein in the orbitofrontal cortex (OFC). However, the role of specific adrenoceptors in this effect is not well‐characterised. We therefore investigated whether the pro‐impulsive effects of systemic yohimbine could be reproduced by direct administration into the OFC, or attenuated by intra‐OFC or systemic administration of prazosin and propranolol—antagonists at the &agr;1‐ and &bgr;‐adrenoceptor, respectively. Male Long‐Evans rats were trained on the 5CSRTT and implanted with guide cannulae aimed at the OFC. Systemically administered &agr;1‐ or &bgr;‐adrenoceptor antagonists attenuated yohimbine‐induced increases in premature responding. In contrast, local infusion of yohimbine into the OFC reduced such impulsive responding, while blockade of &agr;1‐ or &bgr;‐adrenoceptors within the OFC had no effect on either basal or yohimbine‐stimulated motor impulsivity. Direct administration of selective antagonists at the &agr;1‐, &agr;2‐ or &bgr;‐adrenoceptor into the OFC therefore produce clearly dissociable effects from systemic administration. Collectively, these data suggest that the pro‐impulsivity effect of yohimbine can be modulated by adrenergic signalling in brain areas outside of the OFC, in addition to non‐adrenergic signalling pathways within the OFC.

Effects of exposure to a 50 Hz sinusoidal magnetic field during the early adolescent period on spatial memory in mice.

Adolescence is a critical developmental stage during which substantial remodeling occurs in brain areas involved in emotional and learning processes. Although a robust literature on the biological effects of extremely low frequency magnetic fields (ELF-MFs) has been documented, data on the effects of ELF-MF exposure during this period on cognitive functions remain scarce. In this study, early adolescent male mice were exposed from postnatal day (P) 23-35 to a 50 Hz MF at 2 mT for 60 min/day. On P36-45, the potential effects of the MF exposure on spatial memory performance were examined using the Y-maze and Morris water maze tasks. The results showed that the MF exposure did not affect Y-maze performance but improved spatial learning acquisition and memory retention in the water maze task under the present experimental conditions.

Serotonergic lesions of the dorsal hippocampus differentially modulate locomotor hyperactivity induced by drugs of abuse in rats: implications for schizophrenia

RationalePsychotomimetic drug-induced locomotor hyperactivity is a widely used animal model of psychotic states, such as in schizophrenia. We previously found that serotonergic lesions of the dorsal, but not ventral, hippocampus in rats result in enhanced phencyclidine-induced locomotor hyperactivity.ObjectivesThe objective of this study was to investigate the effect of serotonin depletion in the dorsal and ventral hippocampus on hyperlocomotion induced by ketamine, cocaine, 3,4-methylenedioxymethampethamine (MDMA), methamphetamine, and d-amphetamine.Materials and methodsMale Sprague–Dawley rats were bilaterally microinjected with vehicle or the serotonergic neurotoxin, 5,7-dihydroxytryptamine (5,7-DHT), into the dorsal or ventral hippocampus using a stereotaxic approach. Separate cohorts of rats were used for each drug of abuse; each rat received saline and a low, medium, and high dose of the drug in a random-sequence, repeated-measures protocol. Locomotor hyperactivity following treatment was measured using automated photocell cages.ResultsSimilar to phencyclidine, 5,7-DHT-induced lesions of the dorsal hippocampus enhanced ketamine-induced hyperlocomotion at all doses. They also reduced methamphetamine-induced hyperlocomotion at the high dose only and caused a minor, biphasic modulation of responses to cocaine. Locomotor responses to d-amphetamine and MDMA were unchanged by lesions of the dorsal hippocampus. Serotonergic lesions of the ventral hippocampus did not significantly alter locomotor hyperactivity induced by any of the drugs investigated.ConclusionsThese findings further implicate a role for serotonin in the dorsal hippocampus in modulating the behavioral effects of dissociative anesthetics, such as ketamine, with more subtle effects on psychostimulant drugs of abuse. The dorsal hippocampus may be a site of serotonergic dysfunction in aspects of schizophrenia.

Hippocampal serotonin depletion unmasks differences in the hyperlocomotor effects of phencyclidine and MK-801: quantitative versus qualitative analyses

Antagonism of N-methyl-D-aspartate (NMDA) receptors by phencyclidine (PCP) is thought to underlie its ability to induce a schizophrenia-like syndrome in humans, yet evidence indicates it has a broader pharmacological profile. Our previous lesion studies highlighted a role for serotonergic projections from the median, but not dorsal, raphe nucleus in mediating the hyperlocomotor effects of PCP, without changing the action of the more selective NMDA receptor antagonist, MK-801. Here we compared locomotor responses to PCP and MK-801 in rats that were administered 5,7-dihydroxytryptamine (5,7-DHT) into either the dorsal or ventral hippocampus, which are preferentially innervated by median and dorsal raphe, respectively. Dorsal hippocampus lesions potentiated PCP-induced hyperlocomotion (0.5, 2.5 mg/kg), but not the effect of MK-801 (0.1 mg/kg). Ventral hippocampus lesions did not alter the hyperlocomotion elicited by either compound. Given that PCP and MK-801 may induce different spatiotemporal patterns of locomotor behavior, together with the known role of the dorsal hippocampus in spatial processing, we also assessed whether the 5,7-DHT-lesions caused any qualitative differences in locomotor responses. Treatment with PCP or MK-801 increased the smoothness of the path traveled (reduced spatial d) and decreased the predictability of locomotor patterns within the chambers (increased entropy). 5,7-DHT-lesions of the dorsal hippocampus did not alter the effects of PCP on spatial d or entropy – despite potentiating total distance moved – but caused a slight reduction in levels of MK-801-induced entropy. Taken together, serotonergic lesions targeting the dorsal hippocampus unmask a functional differentiation of the hyperlocomotor effects of PCP and MK-801. These findings have implications for studies utilizing NMDA receptor antagonists in modeling glutamatergic dysfunction in schizophrenia.

Deep-Brain Stimulation of the Subthalamic Nucleus Selectively Decreases Risky Choice in Risk-Preferring Rats

Abstract Deep brain stimulation of the subthalamic nucleus (STN-DBS) can improve the motor symptoms of Parkinson’s disease (PD) and negate the problematic side effects of dopamine replacement therapy. Although there is concern that STN-DBS may enhance the development of gambling disorder and other impulse control disorders in this patient group, recent data suggest that STN-DBS may actually reduce iatrogenic impulse control disorders, and alleviate obsessive-compulsive disorder (OCD). Here, we sought to determine whether STN-DBS was beneficial or detrimental to performance of the rat gambling task (rGT), a rodent analogue of the Iowa Gambling Task (IGT) used to assess risky decision making clinically. Rats chose between four options associated with different amounts and probabilities of sugar pellet rewards versus timeout punishments. As in the IGT, the optimal approach was to favor options associated with smaller per-trial gains but lower timeout penalties. Once a stable behavioral baseline was established, electrodes were implanted bilaterally into the STN, and the effects of STN-DBS assessed on-task over 10 consecutive sessions using an A-B-A design. STN-DBS did not affect choice in optimal decision makers that correctly favored options associated with smaller per-trial gains but also lower penalties. However, a minority (∼25%) preferred the maladaptive “high-risk, high-reward” options at baseline. STN-DBS significantly and progressively improved choice in these risk-preferring rats. These data support the hypothesis that STN-DBS may be beneficial in ameliorating maladaptive decision making associated with compulsive and addiction disorders.