Association Basolateral amygdala stimulation evokes glutamate receptor-dependent dopamine efflux in the nucleus accumbens of the anaesthetized rat

Afferents from the basolateral amygdala and dopamine projections from the ventral tegmental area to the nucleus accumbens have both been implicated in reward-related processes. The present study used in vivo chronoamperometry with stearate-graphite paste electrodes in urethane-anaesthetized rats to determine how basolateral amygdala efferents to the nucleus accumbens synaptically regulate dopamine efflux. Repetitive-pulse (20 Hz for 10 s) electrical stimulation of the basolateral amygdala evoked a complex pattern of changes in monitored dopamine oxidation currents in the nucleus accumbens related to dopamine efflux. These changes were characterized by an initial increase that was time-locked to stimulation, a secondary decrease below baseline, followed by a prolonged increase in the dopamine signal above baseline. The effects of burst-patterned stimulation (100 Hz, 5 pulses/burst, 1-s interburst interval, 40 s) of the basolateral amygdala on the basal accumbens dopamine signal were similar to those evoked by 20 Hz stimulation, with the lack of a secondary suppressive component. Infusions of the ionotropic glutamate receptor antagonists (±)-2-amino-5-phosphonopentanoic acid (APV) or 6,7-dinitroquinoxaline-2,3-dione (DNQX) into the nucleus accumbens dose-dependently blocked or attenuated the initial and prolonged increases in the dopamine signal following 20 Hz or burst-patterned basolateral amygdala stimulation. Infusions of the metabotropic glutamate receptor antagonist (+)-α-methyl-4-carboxyphenylglycine selectively blocked the intermediate suppressive effect of 20 Hz basolateral amygdala stimulation on dopamine oxidation currents. Blockade of glutamate receptors or inhibition of dopamine neuronal activity via infusions of either APV + DNQX, lidocaine or γ-hydroxybutyric acid, respectively, into the ventral tegmental area did not effect the pattern of changes in the accumbens dopamine signal evoked by basolateral amygdala stimulation. These data suggest that the glutamatergic basolateral amygdala inputs to nucleus accumbens dopamine terminals synaptically facilitate or depress dopamine efflux, and these effects are independent of dopamine neuronal firing activity. Moreover, these results imply that changes in nucleus accumbens dopamine levels following presentation of reward-related stimuli may be mediated, in part, by the basolateral amygdala.     

Late results on the treatment of neurogenic impotence by self-intracavernous-injection (SICI) of vasoactive drugs

Summary This study included 31 patients with an established neurological lesion as their sole cause of impotence. All were submitted to our multidisciplinary assessment. Patients presented with a normal PBPI, mini-test, VSS, and MMPI. However, abnormalities of BCR data and curves were noted in all cases. Consenting patients and/or their permanent sexual partners were instructed in the technique of self-intracavernous-injection (SICI) of vasoactive drugs; drug dosage determination was undertaken simultaneously. Papaverine alone was given to 19 patients with erections quoted at 3, in a mean dose of 22.34±14.31 mg for a mean duration of 40±20 min. Other drug mixtures were employed with papaverine such as ifenprodil or piribedil or moxysilyte. The physician on call was permanently available to solve problems encountered, such as subcutaneous hematomas, pharmacologically induced prolonged erection (PIPE), or subcutaneous nodules following SICI. During the follow-up period ranging from 3 to 54 months, 93% of these patients have successfully applied the technique with excellent global results.     

Impairment of shear-stress-mediated vasodilation of cavernous arteries in erectile dysfunction

Penile NO release test (PNORT) has been designed to try to evaluate clinically the penile endothelial function (PEF). The shear-stress flow-mediated vasodilation (FMD) of the cavernous arteries is evaluated in two groups of patients with neurogenic (n=23) and vasculogenic (n=23) erectile dysfunction (ED) by measuring their percent of increase after a 5 min occlusion of the flow. Both groups show an important FMD decrease (17.78+/-11.78 and 17.82+/-13%) as compared to the age-matched control group (n=12) (65.14+/-30.5%, P<0.001). In the vasculogenic and control groups, mean FMD is lower in patients with one or more arterial risk factors(41 vs 67%, P=0.025), and show a positive correlation with the plasmatic levels of bioavailable testosterone (r=0.37, P=0.03) and of DHEA-S (r=0.46, P=0.014). Patients achieving full erection at pharmacological test with visual sexual stimulation have a higher FMD (43.8+/-38%) than those who did not (18.52+/-14.37%, P=0.008). We confirm clinically that PEF is strongly impaired in organic ED linked to neurological, vascular and endocrine factors.     

Reversible lesions of the rhinal cortex produce delayed non-matching-to-sample deficits in rats

Rats with cannulae guides implanted in the rhinal cortex were tested on a delayed non-matching-to-sample task, following either lidocaine or sham microinfusions. Bilateral lidocaine microinfusions to the rhinal cortex produced significant delayed non-matching-to-sample deficits. These results are consistent with the putative role of the rhinal cortex in object recognition but because the deficits were not shown to be time dependent, non-mnemonic interpretations cannot be ruled out. These results also illustrate the utility of reversible lidocaine lesions in the study of the neuroanatomical basis of delayed non-matching-to-sample.     

Dopamine Antagonism Decreases Willingness to Expend Physical,But Not Cognitive,Effort: A Comparison of Two Rodent Cost/Benefit Decision-Making Tasks

Successful decision making often requires weighing a given option''s costs against its associated benefits, an ability that appears perturbed in virtually every severe mental illness. Animal models of such cost/benefit decision making overwhelmingly implicate mesolimbic dopamine in our willingness to exert effort for a larger reward. Until recently, however, animal models have invariably manipulated the degree of physical effort, whereas human studies of effort have primarily relied on cognitive costs. Dopamine''s relationship to cognitive effort has not been directly examined, nor has the relationship between individuals'' willingness to expend mental versus physical effort. It is therefore unclear whether willingness to work hard in one domain corresponds to willingness in the other. Here we utilize a rat cognitive effort task (rCET), wherein animals can choose to allocate greater visuospatial attention for a greater reward, and a previously established physical effort-discounting task (EDT) to examine dopaminergic and noradrenergic contributions to effort. The dopamine antagonists eticlopride and SCH23390 each decreased willingness to exert physical effort on the EDT; these drugs had no effect on willingness to exert mental effort for the rCET. Preference for the high effort option correlated across the two tasks, although this effect was transient. These results suggest that dopamine is only minimally involved in cost/benefit decision making with cognitive effort costs. The constructs of mental and physical effort may therefore comprise overlapping, but distinct, circuitry, and therapeutic interventions that prove efficacious in one effort domain may not be beneficial in another.     

Dopaminergic Circuitry and Risk/Reward Decision Making: Implications for Schizophrenia

Abnormal reinforcement learning and representations of reward value are present in schizophrenia, and these impairments can manifest as deficits in risk/reward decision making. These abnormalities may be due in part to dopaminergic dysfunction within cortico-limbic-striatal circuitry. Evidence from studies with laboratory animal have revealed that normal DA activity within different nodes of these circuits is critical for mediating dissociable processes that can refine decision biases. Moreover, both phasic and tonic dopamine transmission appear to play separate yet complementary roles in these processes. Tonic dopamine release within the prefrontal cortex and nucleus accumbens, serves as a “running rate-meter” of reward and reflects contextual information such as reward uncertainty and overt choice behavior. On the other hand, manipulations of outcome-related phasic dopamine bursts and dips suggest these signals provide rapid feedback to allow for quick adjustments in choice as reward contingencies change. The lateral habenula is a key input to the DA system that phasic signals is necessary for expressing subjective decision biases; as suppression of activity within this nucleus leads to catastrophic impairments in decision making and random patterns of choice behavior. As schizophrenia is characterized by impairments in using positive and negative feedback to appropriately guide decision making, these findings suggest that these deficits in these processes may be mediated, at least in part, by abnormalities in both tonic and phasic dopamine transmission.Key words: dopamine, decision making, phasic, tonic, habenula     

Dopaminergic and glutamatergic regulation of effort- and delay-based decision making.

Cost/benefit decisions regarding the relative effort or delay costs associated with a particular response are mediated by distributed dopaminergic and glutamatergic neural circuits. The present study assessed the contribution of dopamine and NMDA glutamate receptors in these different forms of decision making using novel effort- and delay-discounting procedures. In the effort-discounting task, 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 (HR) lever to obtain four pellets. In the delay-discounting task, one press of the HR lever delivered four pellets after a delay (0.5-8 s). A third task (effort-discounting with equivalent delays) was similar to the effort-discounting procedure, except that the relative delay to reward delivery was equalized across response options. The dopamine receptor antagonist flupenthixol reduced choice of the HR lever under all three testing conditions, indicating that dopamine antagonism alters effort-based decision making independent of any contribution of delay. Amphetamine exerted dose-dependent, biphasic effects; a higher dose (0.5 mg/kg) increased effort discounting, whereas a lower dose (0.25 mg/kg) reduced delay discounting. The noncompetitive NMDA antagonist ketamine (5 mg/kg) increased effort and delay discounting, but did not affect choice on the effort with equivalent delays task, indicating a reduced tolerance for delayed rewards. These findings highlight the utility of these procedures in pharmacologically dissociating the neurochemical mechanisms underlying these different, yet interrelated forms of decision making. Furthermore, they suggest that dopamine and NMDA receptors make dissociable contributions to these different types of cost-benefit analyses.     

Intracavernous self-injection of vasoactive drugs in the treatment of impotence: 8-year experience with 615 cases.

Of 615 patients with impotence of varying etiologies who were followed from 12 to 96 months after the institution of intracavernous self-injection therapy with vasoactive drugs (papaverine alone, papaverine and alpha-blockers, and Ceritine, a new multilevel acting drug) 87% (533 patients) returned for followup visits or were regularly contacted. Of these patients sexual activity was restored in 91%. The dropout rate was 11.25%. The 114 episodes of prolonged erections among 51 patients (4.57%) represented less than 3 per 1,000 of the 34,875 recorded injections. All patients were treated without complications. The percentage of patients suffering from nodules or permanent deformations was 2.8%. There were no cases of intracavernous fibrosis. The percentage of satisfied patients (satisfaction index 7 or greater) was 84.8%. Improvement in spontaneous erections during sexual intercourse was obtained in 65% of the cases: 15% no longer needed self-injections and 50% only used them occasionally while 35% remained entirely dependent.