Estradiol modulates effort-based decision making in female rats

Disorders of the dopamine system, such as schizophrenia or stimulant addiction, are associated with impairments in different forms of cost/benefit decision making. The neural circuitry (ie amygdala, prefrontal cortex, nucleus accumbens) underlying these functions receives dopamine input, which is thought to have a central role in mediating cost/benefit decisions. Estradiol modulates dopamine activity, and estrogen receptors (ERs) are found within this neurocircuitry, suggesting that decision making may be influenced by estradiol. The present study examined the contribution of estradiol and selective ERα and β agonists on cost/benefit decision making in adult female Long-Evans rats. An effort-discounting task was utilized, where rats could either emit a single response on a low-reward lever to receive two pellets, or make 2, 5, 10, or 20 responses on a high-reward lever to obtain four pellets. Ovariectomy increased the choice on the high-reward lever, whereas replacement with high (10?μg), but not low (0.3?μg), levels of estradiol benzoate reduced the choice on the high-reward lever. Interestingly, both an ERα agonist (propyl-pyrazole triol (PPT)) and an ERβ agonist (diarylpropionitrile (DPN)) increased choice on the high-reward lever when administered independently, but when these two agonists were combined, a decrease in choice for the high-reward lever was observed. The effects of estradiol, PPT, and DPN were more pronounced 24?h post-administration, suggesting that these effects may be genomic in nature. Together, these results demonstrate that estradiol modulates cost/benefit decision making in females, whereby concomitant activation of ERα and β receptors shifts the decision criteria and reduces preference for larger, yet more costly rewards.     

NMDA GluN2A and GluN2B receptors play separate roles in the induction of LTP and LTD in the amygdala and in the acquisition and extinction of conditioned fear

Synaptic plasticity mediated by NMDA glutamate receptors is thought to be a primary mechanism underlying the formation of new memories. Activation of GluN2A NMDA receptor subunits may induce long-term potentiation (LTP), whereas low-frequency stimulation of GluN2B receptors induces long-term depression (LTD). In the present study, we show that blockade of GluN2A, but not GluN2B receptors with NVP-AAM077 and Ro25-6981 respectively, prevented LTP of auditory thalamic inputs to the lateral amygdala. Conversely, LTD induction in this pathway was prevented by blockade of GluN2B, but not GluN2A receptors. As this pathway plays a critical role in the acquisition, retrieval and extinction of a learned auditory-cue fear association, we next examined the effects of blockade of GluN2A and GluN2B receptors on the development and retention of a conditioned fear response. Administration of NVP-AAM077, but not Ro25-6981, prior to conditioning disrupted the expression of conditioned fear 24h later. Conversely, Ro25-6981 but not NVP-AAM077 impaired extinction of the conditioned fear response. These data expand on previous work showing that LTP/D in the thalamic-lateral amygdala pathway is dependent on NMDA receptors, by demonstrating selective roles for GluN2A and GluN2B NMDA receptor subunits in LTP and LTD respectively. Furthermore, GluN2A receptor activation and associated LTP may be involved specifically in the initial formation and/or stabilization of a learned fear response, whereas GluN2B receptor activation and associated LTD may facilitate the suppression of Pavlovian fear responses during extinction. This article is part of a Special Issue entitled 'Post-Traumatic Stress Disorder'.     

The role of different subregions of the basolateral amygdala in cue-induced reinstatement and extinction of food-seeking behavior

Reinstatement of previously extinguished instrumental responding for drug-related cues has been used as an animal model for relapse of drug abuse, and is disrupted by inactivation of the basolateral amygdala (BLA). However, the role that the BLA plays in reinstatement induced by cues associated with natural rewards is unclear. The present study assessed the effects of inactivation of different regions of the BLA in cue-induced reinstatement of food-seeking behavior and in the extinction of instrumental responding for food. In experiment 1, rats acquired a lever pressing response for food reward paired with a light/tone conditioned stimulus (CS). They were then subjected to extinction training, where both food and the CS were withheld. Reinstatement of extinguished responding was measured during response-contingent presentations of the CS alone. Following saline infusions into the caudal or rostral BLA, rats displayed a significant increase in lever pressing during reinstatement sessions. Inactivation of these subregions with bupivacaine did not attenuate responding for the CS in the absence of food delivery. In fact, inactivation of the caudal BLA potentiated responding relative to vehicle treatments. Analysis of within-session responding revealed that caudal BLA inactivation retarded extinction of lever pressing in response to the CS. In experiment 2, inactivation of the caudal BLA on the first or second day of extinction training significantly retarded the acquisition of extinction learning on the following day. These data indicate that that the caudal BLA may play a specific role in the extinction of appetitive conditioned responses, by monitoring changes in the reinforcing value of pavlovian conditioned stimuli linked to action-outcome associations once these associations have been formed. Moreover, these findings support a growing body of evidence indicating that separate neural circuits incorporating the BLA may play different roles in mediating reinstatement of reward-seeking behaviors induced by either drug or food related stimuli.     

Adolescent Alcohol Exposure Reduces Behavioral Flexibility,Promotes Disinhibition,and Increases Resistance to Extinction of Ethanol Self-Administration in Adulthood

The prefrontal cortex (PFC) is a brain region that is critically involved in cognitive function and inhibitory control of behavior, and adolescence represents an important period of continued PFC development that parallels the maturation of these functions. Evidence suggests that this period of continued development of the PFC may render it especially vulnerable to environmental insults that impact PFC function in adulthood. Experimentation with alcohol typically begins during adolescence when binge-like consumption of large quantities is common. In the present study, we investigated the effects of repeated cycles of adolescent intermittent ethanol (AIE) exposure (postnatal days 28–42) by vapor inhalation on different aspects of executive functioning in the adult rat. In an operant set-shifting task, AIE-exposed rats exhibited deficits in their ability to shift their response strategy when the rules of the task changed, indicating reduced behavioral flexibility. There were no differences in progressive ratio response for the reinforcer suggesting that AIE did not alter reinforcer motivation. Examination of performance on the elevated plus maze under conditions designed to minimize stress revealed that AIE exposure enhanced the number of entries into the open arms, which may reflect either reduced anxiety and/or disinhibition of exploratory-like behavior. In rats that trained to self-administer ethanol in an operant paradigm, AIE increased resistance to extinction of ethanol-seeking behavior. This resistance to extinction was reversed by positive allosteric modulation of mGluR5 during extinction training, an effect that is thought to reflect promotion of extinction learning mechanisms within the medial PFC. Consistent with this, CDPPB was also observed to reverse the deficits in behavioral flexibility. Finally, diffusion tensor imaging with multivariate analysis of 32 brain areas revealed that while there were no differences in the total brain volume, the volume of a subgroup of regions (hippocampus, thalamus, dorsal striatum, neocortex, and hypothalamus) were significantly different in AIE-exposed adults compared with litter-matched Control rats. Taken together, these findings demonstrate that binge-like exposure to alcohol during early to middle adolescence results in deficits in PFC-mediated behavioral control in adulthood.     

Medial orbitofrontal cortex dopamine D1/D2 receptors differentially modulate distinct forms of probabilistic decision-making

Efficient decision-making involves weighing the costs and benefits associated with different actions and outcomes to maximize long-term utility. The medial orbitofrontal cortex (mOFC) has been implicated in guiding choice in situations involving reward uncertainty, as inactivation in rats alters choice involving probabilistic rewards. The mOFC receives considerable dopaminergic input, yet how dopamine (DA) modulates mOFC function has been virtually unexplored. Here, we assessed how mOFC D₁ and D₂ receptors modulate two forms of reward seeking mediated by this region, probabilistic reversal learning and probabilistic discounting. Separate groups of well-trained rats received intra-mOFC microinfusions of selective D₁ or D₂ antagonists or agonists prior to task performance. mOFC D₁ and D₂ blockade had opposing effects on performance during probabilistic reversal learning and probabilistic discounting. D₁ blockade impaired, while D₂ blockade increased the number of reversals completed, both mediated by changes in errors and negative feedback sensitivity apparent during the initial discrimination of the task, which suggests changes in probabilistic reinforcement learning rather than flexibility. Similarly, D₁ blockade reduced, while D₂ blockade increased preference for larger/risky rewards. Excess D₁ stimulation had no effect on either task, while excessive D₂ stimulation impaired probabilistic reversal performance, and reduced both profitable risky choice and overall task engagement. These findings highlight a previously uncharacterized role for mOFC DA, showing that D₁ and D₂ receptors play dissociable and opposing roles in different forms of reward-related action selection. Elucidating how DA biases behavior in these situations will expand our understanding of the mechanisms regulating optimal and aberrant decision-making.Subject terms: Decision, Motivation     

Receptor-Specific Modulation of Risk-Based Decision Making by Nucleus Accumbens Dopamine

The nucleus accumbens (NAc) serves as an integral node within cortico-limbic circuitry that regulates various forms of cost–benefit decision making. The dopamine (DA) system has also been implicated in enabling organisms to overcome a variety of costs to obtain more valuable rewards. However, it remains unclear how DA activity within the NAc may regulate decision making involving reward uncertainty. This study investigated the contribution of different DA receptor subtypes in the NAc to risk-based decision making, assessed with a probabilistic discounting task. In well-trained rats, D₁ receptor blockade with SCH 23 390 decreased preference for larger, uncertain rewards, which was associated with enhanced negative-feedback sensitivity (ie, an increased tendency to select a smaller/certain option after an unrewarded risky choice). Treatment with a D₁ agonist (SKF 81 297) optimized decision making, increasing choice of the risky option when reward probability was high, and decreasing preference under low probability conditions. In stark contrast, neither blockade of NAc D₂ receptors with eticlopride, nor stimulation of these receptors with quinpirole or bromocriptine influenced risky choice. In comparison, infusion of the D₃-preferring agonist PD 128 907 decreased reward sensitivity and risky choice. Collectively, these results show that mesoaccumbens DA refines risk–reward decision biases via dissociable mechanisms recruiting D₁ and D₃, but not D₂ receptors. D₁ receptor activity mitigates the effect of reward omissions on subsequent choices to promote selection of reward options that may have greater long-term utility, whereas excessive D₃ receptor activity blunts the impact that larger/uncertain rewards have in promoting riskier choices.     

Alterations in behavioral flexibility by cannabinoid CB1 receptor agonists and antagonists

Rationale Cannabinoid CB₁ receptors are expressed in the prefrontal cortex, but their role in mediating executive functions such as behavioral flexibility is unclear.Objective The present study examined the effect of pharmacological activation or blockade of the cannabinoid CB₁ receptors on behavioral flexibility using a strategy set-shifting task conducted on a cross maze.Materials and methods In experiment 1, rats initially were trained to turn left or right while ignoring the visual cue to obtain a food; on the second test day, rats had to inhibit the previously learned rule and approach the cue to obtain the food. In experiment 2, the order of discrimination training was reversed.Results Administration of the cannabinoid CB₁ receptor agonist HU-210 before the set-shift on day 2 elicited dose-dependent effects on performance. A 20-μg/kg dose of HU-210 increased perseverative errors, whereas the effects of a lower, 5-μg/kg dose caused differential effects depending on whether rats were required to shift from a response to a visual-cue discrimination strategy or vice versa. Conversely, administration of a 2-mg/kg, but not a 5-mg/kg dose of the CB₁ receptor antagonist AM251 reduced perseverative errors.Conclusions These data demonstrate a biphasic and dose-sensitive role for the cannabinoid system in behavioral flexibility, which in turn may have clinical implications for the role of the endocannabinoid system in psychiatric disorders where behavioral flexibility is compromised.     

Impotence of vascular origin

Between 1977 and 1986, 3,500 patients were examined for the symptom of impotence; 1,250 of them received multidisciplinary investigation permitting the diagnosis of a pure organic or mixed disorder in 85% of cases, including 62% of vascular disease subdivided into arterial (40%) and venous (22%). For 1,062 patients, 1 or several of the following therapies were used: intracavernous infusion of vasoactive drugs (N = 725), auto-injections (N = 235), vascular surgery (N = 357) and prostheses (N = 23). The diagnostic approach, formerly analytical and making use of multiple non-invasive methods, such as nocturnal erection plethysmography (NPT) and invasive methods (artificial erection, arteriography) have been transformed by the use of pharmacological tests associated with visual sexual stimulation (VSS) which enable, together with Doppler velocimetric examination, simple screening of vascular impotence based on the study of 4 parameters: penile pressure index (PPI) when less than 0.91 is always a sign of an arterial problem, the severity of which is directly proportional to the lowering of this index and the association with maintenance insufficiency; the initial intracavernous flow rate (IICF) depends overall on the maintenance flow and the state of erectile tissue, resulting from pharmacological stimulation by a low dose of papaverine (8 mg); penile rigidity attained by the combined action of pharmacological and visual sexual stimulation, reflecting the functional erectile capacity; the duration of the rigidity thus obtained on stoppage of VSS indicating the capacity for maintenance of erection. In the event of suspicion of an isolated venous leak or in association with arterial problems, it is the artificial erection with cavernosography, carried out after pharmacological stimulation, which enables the severity of the leak to be assessed. The following specific investigations are carried out to investigate a specific associated etiology: electromyogram for neurological disorders, hormone assay for endocrine disorders and psychological study using the MMPI questionnaire (Multiphasic Minnesota Personality Inventory). One can thus distinguish several groups of patients suffering from vascular impotence depending on the degree of arterial involvement: minor (PPI between 0.75 and 0.9), moderate (PPI between 0.65 and 0.75) and severe (PPI less than 0.65); depending on the degree of venous leaking: absent (MI less than 0.3 and/or MF less than 25 ml/min), minor (MI between 0.3 and 0.5 and MF between 30 and 50 ml/min), moderate (MI between 0.5 and 75 ml/min) and severe (MI greater than 0.75 and/or MF greater than 75 ml/mn).(ABSTRACT TRUNCATED AT 400 WORDS)