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Biomedical subjects

Paul E M Phillips

Publications and source records attributed to Paul E M Phillips.

17 recordsLinked to original sources

Calculating utility: preclinical evidence for cost-benefit analysis by mesolimbic dopamine.

RATIONALE: Throughout our lives we constantly assess the costs and benefits of the possible future outcomes of our actions and use this information to guide behavior. There is accumulating evidence that dopamine contributes to a fundamental component of this computation-how rewards are compared with the costs incurred when obtaining them. OBJECTIVE: We review the evidence for dopamine's role in cost-benefit decision making and outline a simple mathematical framework in which to represent the interactions between rewards, costs, behavioral state and dopamine. CONCLUSIONS: Dopamine's effects on cost-benefit decision making can be modeled using simple utility-function curves. This approach provides a useful framework for modeling existing data and generating experimental hypotheses that can be objectively and quantitatively tested by observing choice behavior without the necessity to account for subjective psychological states such as pleasure or desire. We suggest that dopamine plays a key role in overcoming response costs and enabling high-effort behaviors. A particularly important anatomical site of this action is the core of the nucleus accumbens. Here, dopamine is able to modulate activity originating from the frontal cortical systems that also assess costs and rewards. Internal deprivation states (e.g., hunger and thirst) also help to energize goal-seeking behaviors, probably in part by their rich influence on dopamine, which can in turn modify decision making policies.

Animals↗

Cre recombinase-mediated restoration of nigrostriatal dopamine in dopamine-deficient mice reverses hypophagia and bradykinesia.

A line of dopamine-deficient (DD) mice was generated to allow selective restoration of normal dopamine signaling to specific brain regions. These DD floxed stop (DDfs) mice have a nonfunctional Tyrosine hydroxylase (Th) gene because of insertion of a NeoR gene flanked by lox P sites targeted to the first intron of the Th gene. DDfs mice have trace brain dopamine content, severe hypoactivity, and aphagia, and they die without intervention. However, they can be maintained by daily treatment with l-3,4-dihydroxyphenylalanine (L-dopa). Injection of a canine adenovirus (CAV-2) engineered to express Cre recombinase into the central caudate putamen restores normal Th gene expression to the midbrain dopamine neurons that project there because CAV-2 efficiently transduces axon terminals and is retrogradely transported to neuronal cell bodies. Bilateral injection of Cre recombinase into the central caudate putamen restores feeding and normalizes locomotion in DDfs mice. Analysis of feeding behavior by using lickometer cages revealed that virally rescued DDfs mice are hyperphagic and have modified meal structures compared with control mice. The virally rescued DDfs mice are also hyperactive at night, have reduced motor coordination, and are thigmotactic compared with controls. These results highlight the critical role for dopamine signaling in the dorsal striatum for most dopamine-dependent behaviors but suggest that dopamine signaling in other brain regions is important to fine-tune these behaviors. This approach offers numerous advantages compared with previous models aimed at examining dopamine signaling in discrete dopaminergic circuits.

Adenoviridae↗

Cocaine increases dopamine release by mobilization of a synapsin-dependent reserve pool.

Cocaine primarily exerts its behavioral effects by enhancing dopaminergic neurotransmission, amplifying dopamine-encoded sensorimotor integration. The presumed mechanism for this effect is inhibition of the dopamine transporter, which blocks dopamine uptake and prolongs the duration of dopamine in the extracellular space. However, there is growing evidence that cocaine can also augment dopamine release. Here, we directly monitored the actions of cocaine on dopamine release by using electrochemical detection to measure extracellular dopamine in the striatum of anesthetized mice. Cocaine enhanced the levels of striatal dopamine produced by electrical stimulation of dopaminergic neurons. Even after pretreatment with alpha-methyl-p-tyrosine, which depletes the readily releasable pool of dopamine, cocaine was still capable of elevating dopamine levels. This suggests that cocaine enhances dopamine release by mobilizing a reserve pool of dopamine-containing synaptic vesicles. To test this hypothesis, we examined electrically evoked dopamine release in synapsin I/II/III triple knock-out mice, which have impaired synaptic vesicle reserve pools. Knock-out of synapsins greatly reduced the ability of cocaine to enhance dopamine release with long stimulus trains or after depletion of the newly synthesized pool. We therefore conclude that cocaine enhances dopamine release and does so by mobilizing a synapsin-dependent reserve pool of dopamine-containing synaptic vesicles. This capacity to enhance exocytotic release of dopamine may be important for the psychostimulant actions of cocaine.

Animals↗

Real-time measurement of dopamine fluctuations after cocaine in the brain of behaving rats.

Dopamine neurotransmission has been implicated in the modulation of many cognitive processes. Both rapid (phasic) and slower (tonic) changes in its extracellular concentration contribute to its complex actions. Fast in vivo electrochemical techniques can measure extracellular dopamine on a rapid time scale but without the selectivity afforded with slower techniques that use chemical separations. Cyclic voltammetry improves chemical resolution over other electrochemical methods, and it can resolve dopamine changes in the brains of behaving rodents over short epochs (<10 s). With this method, however, selective detection of slower dopamine changes is still elusive. Here we demonstrate that principal component regression of cyclic voltammetry data enables quantification of changes in dopamine and extracellular pH. Using this method, we show that cocaine modifies dopamine release in two ways: dopamine concentration transients increase in frequency and magnitude, whereas a gradual increase in steady-state dopamine concentration occurs over 90 s.

Animals↗

Mesocortical dopamine neurons operate in distinct temporal domains using multimodal signaling.

In vivo extracellular recording studies have traditionally shown that dopamine (DA) transiently inhibits prefrontal cortex (PFC) neurons, yet recent biophysical measurements in vitro indicate that DA enhances the evoked excitability of PFC neurons for prolonged periods. Moreover, although DA neurons apparently encode stimulus salience by transient alterations in firing, the temporal properties of the PFC DA signal associated with various behaviors is often extraordinarily prolonged. The present study used in vivo electrophysiological and electrochemical measures to show that the mesocortical system produces a fast non-DA-mediated postsynaptic response in the PFC that appears to be initiated by glutamate. In contrast, short burst stimulation of mesocortical DA neurons that produced transient (<4 s) DA release in the PFC caused a simultaneous reduction in spontaneous firing (consistent with extracellular in vivo recordings) and a form of DA-induced potentiation in which evoked firing was increased for tens of minutes (consistent with in vitro measurements). We suggest that the mesocortical system might transmit fast signals about reward or salience via corelease of glutamate, whereas the simultaneous prolonged DA-mediated modulation of firing biases the long-term processing dynamics of PFC networks.

Action Potentials↗

Psychophysiological mediators of caregiver stress and differential cognitive decline.

The authors examined relationships between chronic stress and cognitive decline and whether such relationships were mediated by psychophysiological factors. Ninety-six caregivers of spouses with Alzheimer's disease (AD) were compared with 95 similar noncaregiver spouses. All were free of diabetes. Although the groups started similarly, over 2 years caregivers declined by a small but significant amount (1 raw score point and 4 percentile points, each p<.05) on Shipley Vocabulary. In contrast, noncaregivers did not change. Higher hostile attribution (beta=-.09; p<.05) and metabolic risk (beta=-.10; p<.05) in caregivers mediated the cognitive decline. This is the first study of cognitive decline and mediators in caregivers. This work has implications for caregiver and care-recipient health and for research on cognition, psychophysiology, diabetes, and AD.

Aged↗

Rapid dopamine signaling in the nucleus accumbens during contingent and noncontingent cocaine administration.

Cocaine acts as a reinforcer through its pharmacological effects on brain monoaminergic systems, which, through repeated pairings with environmental stimuli, lead to the development of conditioned effects of the drug. Both the pharmacological and conditioned aspects of cocaine are implicated in several facets of acquisition and maintenance of addiction, including drug craving. Here, we compare the effects of contingent (response dependent) and noncontingent (response independent) cocaine on rapid dopaminergic signaling in the core of the nucleus accumbens. Dopamine was monitored using fast-scan cyclic voltammetry. Noncontingent cocaine administered to both naive and animals with a history of self-administration resulted in a profound increase in the frequency of transient dopamine release events that are not time-locked to any specific environmental stimuli. Pharmacological effects were detectable approximately 40 s after cocaine administration. In contrast, when animals where allowed to self-administer cocaine on an FR-1 schedule, dopamine transients (69+/-12 nM) were consistently observed time-locked to each reinforced response (peaking approximately 1.5 s after response completion). Importantly, no pharmacological effect of cocaine was observed within the 10 s following noncontingent cocaine administration, indicating that dopamine signals time-locked to the reinforced response are a result of the pairing of the operant behavior, the drug-associated cues, and cocaine. These data demonstrate that this pharmacological action of cocaine occurs for an extended period following either contingent or noncontingent administration, but is distinct from those dopamine transients that are time-locked to each lever-press in self-administering animals.

Animals↗

Cannabinoids enhance subsecond dopamine release in the nucleus accumbens of awake rats.

Dopaminergic neurotransmission has been highly implicated in the reinforcing properties of many substances of abuse, including marijuana. Cannabinoids activate ventral tegmental area dopaminergic neurons, the main ascending projections of the mesocorticolimbic dopamine system, and change their spiking pattern by increasing the number of impulses in a burst and elevating the frequency of bursts. Although they also increase time-averaged striatal dopamine levels for extended periods of time, little is known about the temporal structure of this change. To elucidate this, fast-scan cyclic voltammetry was used to monitor extracellular dopamine in the nucleus accumbens of freely moving rats with subsecond timescale resolution. Intravenous administration of the central cannabinoid (CB1) receptor agonist, R(+)-[2,3-dihydro-5-methyl-3-[(morpholinyl)methyl]pyrrolo[1,2,3-de]-1,4-benzoxazin-6-yl]-(1-naphthalenyl) methanone mesylate, dose-dependently produced catalepsy, decreased locomotion, and reduced the amplitude of electrically evoked dopamine release while markedly increasing the frequency of detected (nonstimulated) dopamine concentration transients. The CB1 receptor antagonist [N-piperidino-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methylpyrazole-3-carboxamide] reversed and prevented all agonist-induced effects but did not show effects on dopamine release when injected alone. These data demonstrate that doses of a cannabinoid agonist known to increase burst firing produce ongoing fluctuations in extracellular dopamine on a previously unrecognized temporal scale in the nucleus accumbens.

Animals↗

Dynamic gain control of dopamine delivery in freely moving animals.

Activity changes in a large subset of midbrain dopamine neurons fulfill numerous assumptions of learning theory by encoding a prediction error between actual and predicted reward. This computational interpretation of dopaminergic spike activity invites the important question of how changes in spike rate are translated into changes in dopamine delivery at target neural structures. Using electrochemical detection of rapid dopamine release in the striatum of freely moving rats, we established that a single dynamic model can capture all the measured fluctuations in dopamine delivery. This model revealed three independent short-term adaptive processes acting to control dopamine release. These short-term components generalized well across animals and stimulation patterns and were preserved under anesthesia. The model has implications for the dynamic filtering interposed between changes in spike production and forebrain dopamine release.

Adaptation, Physiological↗

Dopamine operates as a subsecond modulator of food seeking.

The dopamine projection to the nucleus accumbens has been implicated in behaviors directed toward the acquisition and consumption of natural rewards. The neurochemical studies that established this link made time-averaged measurements over minutes, and so the precise temporal relationship between dopamine changes and these behaviors is not known. To resolve this, we sampled dopamine every 100 msec using fast-scan cyclic voltammetry at carbon-fiber microelectrodes in the nucleus accumbens of rats trained to press a lever for sucrose. Cues that signal the opportunity to respond for sucrose evoked dopamine release (67 +/- 20 nm) with short latency (0.2 +/- 0.1 sec onset). When the same cues were presented to rats naive to the cue-sucrose pairing, similar dopamine signals were not observed. Thus, cue-evoked increases in dopamine in trained rats reflected a learned association between the cues and sucrose availability. Lever presses for sucrose occurred at the peak of the dopamine surges. After lever presses, and while sucrose was delivered and consumed, no further increases in dopamine were detected. Rather, dopamine returned to baseline levels. Together, the results strongly implicate subsecond dopamine signaling in the nucleus accumbens as a real-time modulator of food-seeking behavior.

Acoustic Stimulation↗

Overoxidation of carbon-fiber microelectrodes enhances dopamine adsorption and increases sensitivity.

The voltammetric responses of carbon-fiber microelectrodes with a 1.0 V and a 1.4 V anodic limit were compared in this study. Fast-scan cyclic voltammetry was used to characterize the response to dopamine and several other neurochemicals. An increase in the adsorption properties of the carbon fiber leads to an increase in sensitivity of 9 fold in vivo. However the temporal response of the sensor is slower with the more positive anodic limit. Increased electron transfer kinetics also causes a decrease in the relative sensitivity for dopamine vs. other neurochemicals, and a change in their cyclic voltammograms. Stimulated release in the caudate-putamen was pharmacologically characterized in vivo using Ro-04-1284 and pargyline, and was consistent with that expected for dopamine.

Animals↗

Subsecond dopamine release promotes cocaine seeking.

The dopamine-containing projection from the ventral tegmental area of the midbrain to the nucleus accumbens is critically involved in mediating the reinforcing properties of cocaine. Although neurons in this area respond to rewards on a subsecond timescale, neurochemical studies have only addressed the role of dopamine in drug addiction by examining changes in the tonic (minute-to-minute) levels of extracellular dopamine. To investigate the role of phasic (subsecond) dopamine signalling, we measured dopamine every 100 ms in the nucleus accumbens using electrochemical technology. Rapid changes in extracellular dopamine concentration were observed at key aspects of drug-taking behaviour in rats. Before lever presses for cocaine, there was an increase in dopamine that coincided with the initiation of drug-seeking behaviours. Notably, these behaviours could be reproduced by electrically evoking dopamine release on this timescale. After lever presses, there were further increases in dopamine concentration at the concurrent presentation of cocaine-related cues. These cues alone also elicited similar, rapid dopamine signalling, but only in animals where they had previously been paired to cocaine delivery. These findings reveal an unprecedented role for dopamine in the regulation of drug taking in real time.

Animals↗

Presynaptic dopaminergic function is largely unaltered in mesolimbic and mesostriatal terminals of adult rats that were prenatally exposed to cocaine.

Fast-scan cyclic voltammetry in brain slices and postmortem tissue content assessment were used to evaluate presynaptic dopaminergic function in the caudate putamen and nucleus accumbens of adult male rats (180+ days old) that were prenatally treated with either cocaine or saline. Experiments were carried out to test whether there were differences in dopamine release, reuptake, autoreceptor function or the tissue levels of dopamine and its metabolites between cocaine- and saline-exposed rats. We report that presynaptic dopaminergic function remains largely intact in adult rats that were prenatally exposed to cocaine. The ability of terminals in the caudate putamen and nucleus accumbens to release and regulate dopamine is unaltered by prenatal cocaine exposure. However the tissue content of dopamine in the caudate putamen was decreased, representing a diminution in the dopamine storage pool. We conclude, therefore, that behavioral changes that have previously been observed in rats that were prenatally exposed to cocaine are not mediated through alteration of presynaptic dopaminergic mechanisms in these brain regions.

3,4-Dihydroxyphenylacetic Acid↗

Real-time decoding of dopamine concentration changes in the caudate-putamen during tonic and phasic firing.

The fundamental process that underlies volume transmission in the brain is the extracellular diffusion of neurotransmitters from release sites to distal target cells. Dopaminergic neurons display a range of activity states, from low-frequency tonic firing to bursts of high-frequency action potentials (phasic firing). However, it is not clear how this activity affects volume transmission on a subsecond time scale. To evaluate this, we developed a finite-difference model that predicts the lifetime and diffusion of dopamine in brain tissue. We first used this model to decode in vivo amperometric measurements of electrically evoked dopamine, and obtained rate constants for release and uptake as well as the extent of diffusion. Accurate predictions were made under a variety of conditions including different regions, different stimulation parameters and with uptake inhibited. Second, we used the decoded rate constants to predict how heterogeneity of dopamine release and uptake sites would affect dopamine concentration fluctuations during different activity states in the absence of an electrode. These simulations show that synchronous phasic firing can produce spatially and temporally heterogeneous concentration profiles whereas asynchronous tonic firing elicits uniform, steady-state dopamine concentrations.

Action Potentials↗

Time window of autoreceptor-mediated inhibition of limbic and striatal dopamine release.

Forebrain dopamine release is under the local control of D2 family (D2 and D3) autoreceptors. In this study, autoreceptor-mediated modulation of forebrain dopamine release was investigated using amperometry in brain slices following local electrical stimulation. 350 microm-thick slices of nucleus accumbens or dorsolateral neostriatum were prepared from male Wistar rats (150-200 g) and superfused with artificial cerebrospinal fluid at 32 degrees C. Dopamine release was evoked by electrical pulses (0.1 ms, 10 mA) across bipolar tungsten stimulating electrodes and measured at carbon fibre microelectrodes using fixed potential amperometry (+300 mV vs. Ag/AgCl). Peak dopamine release on stimulation (single pulse) was 0.75 microM (neostriatum) and 1.37 microM (nucleus accumbens). Metoclopramide (1 microM) had no significant effect on DA efflux from a single pulse in either region. Using paired pulse stimuli, dopamine release on the second pulse varied according to the interval between the two pulses. At very long intervals (>20 sec), dopamine release was similar to that for the first pulse. At shorter intervals, dopamine efflux was attenuated. Metoclopramide had no effect on second pulse dopamine release when the pulse was applied at short (<0.1 sec) or long (>5.0 sec) intervals after the first. At intermediate intervals, metoclopramide significantly increased second pulse dopamine release. The peak dopamine autoreceptor effect occurred at approximately 550 ms in neostriatum and approximately 700 ms in nucleus accumbens. The onset time is due both to diffusion of dopamine from the release sites to the autoreceptors and receptor-effector mechanisms. These findings may have implications for the local control of forebrain dopamine function in physiological and pathological states.

Animals↗