Neural mechanisms regulating different forms of risk-related decision-making: Insights from animal models

Over the past 20 years there has been a growing interest in the neural underpinnings of cost/benefit decision-making. Recent studies with animal models have made considerable advances in our understanding of how different prefrontal, striatal, limbic and monoaminergic circuits interact to promote efficient risk/reward decision-making, and how dysfunction in these circuits underlies aberrant decision-making observed in numerous psychiatric disorders. This review will highlight recent findings from studies exploring these questions using a variety of behavioral assays, as well as molecular, pharmacological, neurophysiological, and translational approaches. We begin with a discussion of how neural systems related to decision subcomponents may interact to generate more complex decisions involving risk and uncertainty. This is followed by an overview of interactions between prefrontal-amygdala-dopamine and habenular circuits in regulating choice between certain and uncertain rewards and how different modes of dopamine transmission may contribute to these processes. These data will be compared with results from other studies investigating the contribution of some of these systems to guiding decision-making related to rewards vs. punishment. Lastly, we provide a brief summary of impairments in risk-related decision-making associated with psychiatric disorders, highlighting recent translational studies in laboratory animals.     

Effects of d-amphetamine injected into the nucleus accumbens on ethanol reinforced behavior

Rats, initiated to self-administer 10% (v/v) ethanol in an operant situation using the sucrose-fading procedure, received bilateral n. accumbens microinjections of d-amphetamine prior to operant sessions. Doses of 4 micrograms, 10 micrograms and 20 micrograms/brain were administered and some animals also received a 4 microgram/brain dose of LY171555. Three different effects were observed: increased, decreased and no change in total session responding. There was no clear relation between injection area in the n. accumbens and type of effect observed. For either an increase or decrease in total session responding, momentary response rates were decreased. Both d-amphetamine and LY171555 produced similar results. The data support the hypothesis that dopamine in the n. accumbens is involved with ethanol reinforced operant responding but in a complex manner.     

Endogenous vasopressin and baroreflex mechanisms

This article reviews the anatomical and functional evidence for ascending pathways from specific brain regions to the PVN and SON which could influence AVP release. The majority of evidence favours the main projection being from a region in the caudal VLM which may coincide with the noradrenergic neurons of the A₁ cell group. However, the transmitter(s) involved have yet to be identified, and whether the pathway is excitatory and/or inhibitory remains to be fully resolved.Anatomical and functional evidence is reviewed for descending projections from the SON and PVN to specific brain regions involved in cardiovascular control, and their possible involvement in baroreflex mechanisms is discussed. However, there is little unequivocal evidence that AVP is the main neurotransmitter utilized by descending projections from PVN to NTS and DMX. While, in some situations, circulating endogenous AVP exerts cardiovascular effects, details of its putative influences on baroreflex mechanisms are lacking.     

Neurochemical studies on the mesolimbic circuitry of antinociception

Previous studies using the technique of microinjection into brain nuclei indicated that the periaqueductal gray (PAG), nucleus accumbens, habenula and amygdala play an essential role in pain modulation and that these nuclei possibly act through a ‘mesolimbic neural loop‘ to exert an analgesic effect, in which Met-enkephalin (MEK) and β-endorphin (β-EP) have been implicated as the two major opioid peptides involved in antinociception. In the present study performed in rabbits, intracranial microinjection was supplemented with push-pull perfusion and radioimmunoassay to determine whether the release of enkephalins (ENK) and β-EP was increased in these nuclei when the putative neural circuit was activated by morphine administered into one of the nuclei. The results showed: (1) microinjection of morphine into the PAG increased the release of ENK and β-EP in the N. accumbens, and vice versa; (2) microinjection of morphine into the N. accumbens increased the release of ENK and β-EP in the amygdala, and vice versa; (3) morphine microinjected into the PAG caused an increase in the release of ENK and β-EP in the amygdala and vice versa, although the release of ENK in PAG was statistically not significant. These results indicate that PAG, N. accumbens and amygdala are connected in a network served by a positive feedback circuitry.     

Activation of 5-HT3 receptor by 1-phenylbiguanide increases dopamine release in the rat nucleus accumbens

The serotonin-3 (5-HT₃) agonist 1-phenylbuguanide (0.1–1.0 mM in perfusate) caused a robust, dose-dependent enhancement of extracellular dopamine content in nucleus accumbens as measured by in vivo microdialysis. This action was antagonized by co-perfusion of the 5-HT₃ antagonists zacopride and GR38032F (1 mM in perfusate). Similar effects were observed in 5-HT-denervated rats. These findings suggest that there is a potent modulation of dopamine (DA) release in the nucleus accumbens mediated via 5-HT₃ receptors, which appear to be located presynaptically on DA terminals of the mesolimbic DA pathway.     

Mechanisms mediating the brain stem control of somatosensory transmission in the dorsal horn of the cat's spinal cord: an intracellular analysis

Summary The effect of brainstem stimulation was studied on neurones recorded intracellularly in the superficial and deeper laminae of the lumbosacral dorsal horn of the spinal cord in anaesthetised cats. Stimulation in the nucleus locus coeruleus (LC) produced a hyperpolarisation in 4/13 multireceptive neurones and produced a biphasic action consisting of a hyperpolarisation which was followed by a depolarisation in 3/13 neurones. These actions were produced irrespective of whether the multireceptive neurone was located in the superficial or deeper laminae of the dorsal horn. Stimulation failed to produce postsynaptic potentials in the remaining 6/13 multireceptive neurones. The amplitude of hyperpolarisation was increased by the passage of depolarising pulses through the recording microelectrode and decreased by hyperpolarising pulses. Stimulation in other brainstem areas such as, the lateral (FTL), paralemniscal (FTP) and central (FTC) divisions of the tegmental field and the nuclei raphe magnus (NRM) and reticularis magnocellularis (RMc) also hyperpolarised neurones in the dorsal horn. The polarity of hyperpolarisation evoked from some brainstem areas (FTP, FTC, RMc) could be reversed to depolarisation by the passive diffusion of ions from the recording microelectrode containing 3M-KCl. Brainstem (LC, NRM, FTP, FTL) stimulation generated long lasting (700 ms) hyperpolarisation on 4/4 selectively nocireceptive neurones of lamina I. There was, however, no effect on the activity of 5/5 neurones recorded in laminae I/II which in addition to receiving excitatory cutaneous inputs were inhibited by heat stimuli. Stimulation in LC also produced dorsal root potentials (DRPs) and reduced the amplitude of simultaneously recorded excitatory postsynaptic potentials (EPSPs) generated by the activation of primary afferent fibres in 3 multireceptive neurones. It is concluded that inhibition of nociceptive transmission in the spinal cord from LC and other brainstem areas may involve both pre- and postsynaptic mechanisms.     

Neurotensin injected into the nucleus accumbens blocks the psychostimulant effects of cocaine but does not attenuate cocaine self-administration in the rat

The neuropeptide neurotensin (NT) has been shown to modulate mesolimbic dopaminergic activity. Neurotensin injected into the VTA produces motor stimulation and release of dopamine in the nucleus accumbens. In contrast, when neurotensin is administered into the nucleus accumbens, it produces neuroleptic-like effects such as attenuation of the locomotor activity elicited by psychostimulants. In the present study, the hypothesis that neurotensin injected into the nucleus accumbens might modulate the psychostimulant and reinforcing actions of cocaine was tested. In experiment one, rats were trained to self-administer cocaine intravenously on an FR5 schedule of reinforcement. Following the establishment of baseline responding, rats were implanted with bilateral cannulae in the nucleus accumbens. One week later, rats were injected into the nucleus accumbens with various doses of neurotensin (4.2, 8.4 and 16.7 μg, total doses bilaterally) immediately prior to the self-administration session. No significant effects were found with any of the doses of neurotensin tested on the self-administration of cocaine. However, in experiment 2, neurotensin at doses of 4.2 and 16.7 μg injected into the nucleus accumbens significantly reduced the locomotor activation induced by an acute injection of cocaine (15 mg/kg i.p.) and a dose of 16.7 μg attenuated the locomotor activation induced by amphetamine (0.75 mg/kg i.p.). Thus, neurotensin in the nucleus accumbens appears to specifically modulate the acute locomotor activating properties of cocaine but not cocaine self-administration. Different mechanisms by which NT interacts with dopamine in the nucleus accumbens may provide a means of selectively altering psychostimulant motor actions without affecting psychostimulant reinforcement.     

Effects of accumbens DALA microinjections on brain stimulation reward and behavioral activation in intact and 6-OHDA treated rats

The effects of bilateral nucleus accumbens microinjections ofd-ala-met-enkephalinamide (DALA) were assessed in behavioral activation and lateral hypothalamic self-stimulation (LHSS) rate-frequency curve-shift paradigms in normal and accumbens 6-OHDA (4.0 µg) treated rats. Microinjections of DALA (2.5 µg/µl) in the behavioral activation paradigm had little effect on normal activity; however, DALA administered to 6-OHDA treated rats produced a significant overall increase in locomotion. The 6-OHDA DALA-induced locomotion effect peaked at 2 weeks after 6-OHDA treatment and then returned to baseline levels by week 5 posttreatment. Using LHSS, DALA tested over a range of doses (2.5, 5, 10, 20 µg/µl) displayed a weak biphasic reward effect only at the highest dose, which was characterized by an initial suppression followed by an elevation. DALA significantly depressed initial operant motor/performance in LHSS in a dose dependent fashion. Micro-injections of the normally ineffective low dose of DALA (2.5 µg/µl) following accumbens 6-OHDA treatment produced a significant LHSS reward decrease 2 weeks posttreatment, while LHSS motor/performance was relatively unaffected. Results are discussed in terms of opiate-dopamine and limbic-motor interactions.     

Repeated treatment with ascorbate or haloperidol,but not clozapine,elevates extracellular ascorbate in the neostriatum of freely moving rats

Acute administration of neuroleptic drugs alters the extracellular level of ascorbate in the neostriatum, and increasing evidence suggests a role for this vitamin in the behavioral, and possibly therapeutic, effects of these drugs. To shed further light on this issue, extracellular ascorbate was recorded in the neostriatum and nucleus accumbens of awake, behaving rats following chronic treatment with either classical (haloperidol) or atypical (clozapine) neuroleptics or ascorbate itself. Electrochemically modified, carbon-fiber microelectrodes were lowered in place the day after the last of 21 daily injections of either haloperidol (0.5 mg/kg, SC), clozapine (20 mg/kg, IP), sodium ascorbate (500 mg/kg, IP) or vehicle. Voltammetric measurements were obtained during quiet rest and following administration ofd-amphetamine (2.5 mg/kg). Repeated treatment with either haloperidol or ascorbate elevated basal extracellular ascorbate and potentiated the amphetamine-induced increase in ascorbate release in neostriatum but not nucleus accumbens. Both treatment groups also showed a significant increase in amphetamine-induced sniffing and repetitive head movements compared to vehicle-treated animals. In contrast, repeated clozapine had no effect on extracellular ascorbate in either neostriatum or nucleus accumbens, but increased the locomotor response to an amphetamine challenge. Thus, to the extent that increases in neostriatal ascorbate exert neuroleptic-like effects, such effects are likely to parallel haloperidol rather than clozapine.     

吗啡成瘾性大鼠脑内核团神经细胞[Ca 2+]i变化的研究

目的 研究吗啡成瘾对大鼠脑内与成瘾相关核团神经细胞[Ca 2 ]i的影响.方法 将50只SD大鼠随机分成吗啡成瘾组和对照组,观察成瘾后的戒断症状;应用对Ca2 敏感的探针Fluo-3与Ca2 络合后被激光激发发出荧光的特性,利用激光共聚焦显微镜观察伏核、海马、内侧额前皮质神经细胞[Ca 2 ]i变化,并用图像分析软件进行处理.结果 吗啡成瘾大鼠脑内伏核、海马及内侧额前皮质神经细胞[Ca 2 ]i和对照组比较明显增高(P<0.01).结论 长期使用吗啡可明显增高伏核、海马和内侧额前皮质神经细胞[Ca 2 ]i.