Patterns Of Dopamine Release Research Articles

Targeting the Actions of Muscarinic Receptors on Dopamine Systems: New Strategies for Treating Neuropsychiatric Disorders.

Cholinergic regulation of dopamine (DA) signaling has significant implications for numerous disorders, including schizophrenia, substance use disorders, and mood-related disorders. The activity of midbrain DA neurons and DA release patterns in terminal regions are tightly regulated by cholinergic neurons found in both the striatum and the hindbrain. These cholinergic neurons can modulate DA circuitry by activating numerous receptors, including muscarinic acetylcholine receptor (mAChR) subtypes. This review specifically focuses on the complex role of M2, M4, and M5 mAChR subtypes in regulating DA neuron activity and DA release and the potential clinical implications of targeting these mAChR subtypes.

New Insights into In Vivo Dopamine Physiology and Neurostimulation: A Fiber Photometry Study Highlighting the Impact of Medial Forebrain Bundle Deep Brain Stimulation on the Nucleus Accumbens.

New technologies, such as fiber photometry, can overcome long-standing methodological limitations and promote a better understanding of neuronal mechanisms. This study, for the first time, aimed at employing the newly available dopamine indicator (GRABDA2m) in combination with this novel imaging technique. Here, we present a detailed methodological roadmap leading to longitudinal repetitive transmitter release monitoring in in vivo freely moving animals and provide proof-of-concept data. This novel approach enables a fresh look at dopamine release patterns in the nucleus accumbens, following the medial forebrain bundle (mfb) DBS in a rodent model. Our results suggest reliable readouts of dopamine levels over at least 14 days of DBS-induced photometric measurements. We show that mfb-DBS can elicit an increased dopamine response during stimulation (5 s and 20 s DBS) compared to its baseline dopamine activity state, reaching its maximum peak amplitude in about 1 s and then recovering back after stimulation. The effect of different DBS pulse widths (PWs) also suggests a potential differential effect on this neurotransmitter response, but future studies would need to verify this. Using the described approach, we aim to gain insights into the differences between pathological and healthy models and to elucidate more exhaustively the mechanisms under which DBS exerts its therapeutic action.

Effects of Lisdexamfetamine, a Prodrug of D-Amphetamine, on Locomotion, Spatial Cognitive Processing and Neurochemical Profiles in Rats: A Comparison With Immediate-Release Amphetamine.

D-amphetamine has been used to enhance cognitive performance over the last few decades. Due to the rapid absorption after administration, d-amphetamine shows narrow effective window and severe abuse potential. Lisdexamfetamine, a prodrug of d-amphetamine, reduces the magnitude of plasma d-amphetamine concentration and prolongs the action duration when compared with immediate-release d-amphetamine at equimolar doses. However, the differences of these two drugs, which produce distinct pharmacokinetic characteristics, in cognition improvement still unclear. In present study, we compared the effects of d-amphetamine (i.p) and lisdexamfetamine (p.o) at equimolar doses (0.2, 0.5, 1.5, 4.5, and 13.5 mg/kg of d-amphetamine base) on locomotion, spatial working memory and recognition memory in rats. Given the crucial involvement of dopamine neurotransmitter system within the medial prefrontal cortex (mPFC) in cognitive processing, microdialysis was conducted to profile the difference in neurochemical characteristics between the two drugs. In our results, d-amphetamine ranges from 0.5 to 1.5 mg/kg significantly increased locomotor activity. However, d-amphetamine ranges from 0.2 to 13.5 mg/kg failed to improve spatial working memory and recognition memory in Y-maze-based spontaneous alternation and two-trial delayed alternation tasks of rats, respectively. In contrast, lisdexamfetamine with 4.5 mg/kg significantly increased the locomotion and improved both spatial working and recognition memory. Further, microdialysis showed that lisdexamfetamine induced lower magnitude and longer duration of extracellular dopamine increase than that of d-amphetamine. These results suggest that lisdexamfetamine was more effective than d-amphetamine in improving spatial cognitive performance, which was attributed to the steady and lasting dopamine release pattern within the mPFC.

Brain opioid segments and striatal patterns of dopamine release induced by naloxone and morphine.

Opioid receptors are expressed throughout the brain and play a major role in regulating striatal dopamine (DA) release. Clinical studies have shown that naloxone (NAL, a nonspecific opioid antagonist) in individuals with opioid use disorder and morphine (MRP, a nonspecific opioid agonist) in healthy controls, resulted in DA release in the dorsal and ventral striatum, respectively. It is not known whether the underlying patterns of striatal DA release are associated with the striatal distribution of opioid receptors. We leveraged previously published PET datasets (collected in independent cohorts) to study the brain‐wide distribution of opioid receptors and to compare striatal opioid receptor availability with striatal DA release patterns. We identified three major gray matter segments based on availability maps of DA and opioid receptors: striatum, and primary and secondary opioid segments with high and intermediate opioid receptor availability, respectively. Patterns of DA release induced by NAL and MRP were inversely associated and correlated with kappa (NAL: r(68) = −0.81, MRP: r(68) = 0.54), and mu (NAL: r(68) = −0.62, MRP: r(68) = 0.46) opioid receptor availability. Kappa opioid receptor availability accounted for a unique part of variance in NAL‐ and MRP‐DA release patterns (ΔR 2 >0.14, p <.0001). In sum, distributions of opioid receptors distinguished major cortical and subcortical regions. Patterns of NAL‐ and MRP‐induced DA release had inverse associations with striatal opioid receptor availability. Our approach provides a pattern‐based characterization of drug‐induced DA targets and is relevant for modeling the role of opioid receptors in modulating striatal DA release.

Opposite Consequences of Tonic and Phasic Increases in Accumbal Dopamine on Alcohol-Seeking Behavior

SummaryDespite many years of work on dopaminergic mechanisms of alcohol addiction, much of the evidence remains mostly correlative in nature. Fortunately, recent technological advances have provided the opportunity to explore the causal role of alterations in neurotransmission within circuits involved in addictive behaviors. Here, we address this critical gap in our knowledge by integrating an optogenetic approach and an operant alcohol self-administration paradigm to assess directly how accumbal dopamine (DA) release dynamics influences the appetitive (seeking) component of alcohol-drinking behavior. We show that appetitive reward-seeking behavior in rats trained to self-administer alcohol can be shaped causally by ventral tegmental area-nucleus accumbens (VTA-NAc) DA neurotransmission. Our findings reveal that phasic patterns of DA release within this circuit enhance a discrete measure of alcohol seeking, whereas tonic patterns of stimulation inhibit this behavior. Moreover, we provide mechanistic evidence that tonic-phasic interplay within the VTA-NAc DA circuit underlies these seemingly paradoxical effects.

Effect of traumatic brain injury on nicotine-induced modulation of dopamine release in the striatum and nucleus accumbens shell.

BackgroundTraumatic brain injury is associated with substantial alterations in reward processing, but underlying mechanisms are controversial.ObjectiveA better understanding of alterations in dopamine (DA) release patterns from the dorsal striatum and nucleus accumbens shell (NAc) may provide insights into posttraumatic reward pathology.Materials and MethodsThe patterns of DA release with or without exposure to nicotine in brain slices with striatum and NAc, isolated from Sprague-Dawley rats with 6 psi fluid percussion (FPI) or sham injury were analysis by using fast-scan cyclic voltammetry. Tonic and phasic DA releases were assessed using single pulse and 10 pulses at 25 Hz, respectively. DA release relative to stimulation intensity, frequency, number of pulses, and paired-pulse facilitation was evaluated to determine release probability and response to bursting.ResultsThere was a profound suppression in tonic DA release after nicotine desensitization after FPI, and the input/output curve for the DA release based on stimulation intensity was shifted to the right. FPI was associated with a significant decrease in frequency-dependent DA release augmentation, DA release induced by high frequency stimulation trains, and DA release in response to paired-pulse facilitation. The effect of nicotine desensitization was similar in FPI and sham-injured animals, although significantly smaller after FPI. Nicotine desensitization–induced differences between phasic and tonic release concentrations that contrasted with the reward-related signals then became less prominent in NAc after FPI.ConclusionsTBI blunts DA release from mesolimbic reward centers, and more intense stimuli are required to produce context-dependent DA release sufficient to have a physiological effect.ImplicationsThe nicotine desensitization-related suppression in tonic DA release was profound with right-ward shift of the input/output curve for DA release after FPI. FPI was associated with a significant decrease in frequency-dependent DA release augmentation, DA release induced by high frequency stimulation trains, and DA release in response to paired-pulse facilitation. Nicotine desensitization–induced differences between phasic and tonic release concentrations that contrasted with the reward-related signals then became less prominent in NAc after FPI. TBI thus blunts DA release from mesolimbic reward centers, and more intense stimuli are required to produce context-dependent DA release sufficient to have a physiological effect.

Regionally distinct phasic dopamine release patterns in the striatum during reversal learning

Striatal dopamine (DA) plays a central role in reward-related learning and behavioral adaptation to changing environments. Recent studies suggest that rather than being broadcast as a uniform signal throughout the entire region, DA release dynamics diverge between different striatal regions. In a previous study, we showed that phasic DA release patterns in the ventromedial striatum (VMS) rapidly adapt during reversal learning. However, it is unknown how DA dynamics in the dorsolateral striatum (DLS) are modulated during such adaptive behavior. Here, we used fast-scan cyclic voltammetry to measure phasic DA release in the DLS during spatial reversal learning. In the DLS, we observed minor DA release after the onset of a visual cue signaling reward availability, followed by more pronounced DA release during more proximal reward cues (e.g., lever extension) and execution of the operant response (i.e., lever press), both in rewarded and non-rewarded trials. These release dynamics (minor DA after onset of the predictive visual cue, prominent DA during the operant response) did not change significantly during or following a reversal of response-reward contingencies. Notably, the DA increase to the lever press did not reflect a general signal related to the initiation of any motivated motor response, as we did not observe DA release when rats initiated nose pokes into the food receptacle during inter-trial intervals. This suggests that DA release in the DLS occurs selectively during the initiation and execution of a learned operant response.Together with our previous results obtained in the VMS, these findings reveal distinct phasic DA release patterns during adaptation of established behavior in DLS and VMS. The VMS DA signal, which is highly sensitive to reversal of response-reward contingences, may provide a teaching signal to guide reward-related learning and facilitate behavioral adaptation, whereas DLS DA may reflect a ‘response execution signal’ largely independent of outcome, that may be involved in initiation and energizing of operant behavior.

Carbidopa levodopa enteral suspension

Introduction: The search for consistent, effective treatments in Parkinson’s disease (PD) is ongoing. The importance of continuous dopaminergic stimulation (CDS) is understood to underlie best medical therapy for PD by providing closer replication of physiological patterns of dopamine release in healthy brains.Areas covered: An overview of interventions to improve motor fluctuations in PD is presented. Significant improvements in off-time are achieved by providing continuous therapy using targeted deep brain stimulation (DBS), subcutaneous apomorphine infusion and carbidopa/levodopa enteral suspension (Duopa). Duopa is a newly approved treatment in the US for advanced PD that delivers levodopa pumped to the intestinal tract through a percutaneous gastrostomy with jejunum tube extension (PEG-J tube). Trials with carbidopa/levodopa enteral suspension show improvement in motor fluctuations, reduction in plasma levodopa variation and improvement in overall “on” time compared with oral immediate release formulation of carbidopa/levodopa.Expert opinion: The degree of improvement in number of off hours per day on carbidopa/levodopa enteral suspension infusion rivals that seen with DBS and apomorphine infusion and makes this new treatment a valuable option in advanced fluctuating PD patients, especially those who are neither candidates for DBS or who do not have access to apomorphine infusion therapy or who have failed either or both therapies.

Differential Dopamine Release Dynamics in the Nucleus Accumbens Core and Shell Reveal Complementary Signals for Error Prediction and Incentive Motivation.

Dopamine signaling in the brain is important for a variety of cognitive functions, such as learning and motivation. Typically, it is assumed that a single dopamine signal is sufficient to support these cognitive functions, though competing theories disagree on how dopamine contributes to reward-based behaviors. Here, we have found that real-time dopamine release within the nucleus accumbens (a primary target of midbrain dopamine neurons) strikingly varies between core and shell subregions. In the core, dopamine dynamics are consistent with learning-based theories (such as reward prediction error) whereas in the shell, dopamine is consistent with motivation-based theories (e.g., incentive salience). These findings demonstrate that dopamine plays multiple and complementary roles based on discrete circuits that help animals optimize rewarding behaviors.

Novel spatial analysis method for PET images using 3D moment invariants: Applications to Parkinson's disease

We present a novel analysis method for positron emission tomography (PET) data that uses the spatial characteristics of the radiotracer's distribution within anatomically-defined regions of interest (ROIs) to provide an independent feature that may aid in characterizing pathological and normal states. The analysis of PET data for research purposes traditionally involves kinetic modeling of the concentration of the radiotracer over time within a ROI to derive parameters related to the uptake/binding of the radiotracer in the body. Here we describe an analysis method to quantify the spatial changes present in PET images based on 3D shape descriptors that are invariant to translation, scaling, and rotation, called 3D moment invariants (3DMIs). An ROI can therefore be characterized not only by the radiotracer's uptake rate constant or binding potential within the ROI, but also the 3D spatial shape and distribution of the radioactivity throughout the ROI. This is particularly relevant in Parkinson's disease (PD), where both the kinetic and the spatial distribution of the tracer are known to change due to disease: the posterior parts of the striatum (in particular in the putamen) are affected before the anterior parts. Here we show that 3DMIs are able to quantify the spatial distribution of PET radiotracer images allowing for discrimination between healthy controls and PD subjects. More importantly, 3DMIs are found to be well correlated with subjects' scores on the United Parkinson's Disease Rating Scale (a clinical measure of disease severity) in all anatomical regions studied here (putamen, caudate and ventral striatum). On the other hand, kinetic parameters only show significant correlation to clinically-assessed PD severity in the putamen. We also find that 3DMI-characterized changes in spatial patterns of dopamine release in response to l-dopa medication are significantly correlated with PD severity. These findings suggest that quantitative studies of a radiotracer's spatial distribution may provide complementary information to kinetic modeling that is relatively robust to intersubject variability and may contribute novel information in PET neuroimaging studies.

Dopamine Release in the Prefrontal Cortex and Striatum: Temporal and Behavioural Aspects

Dopamine (DA) neurons originating in the substantia nigra and ventral tegmental area project to a variety of forebrain structures thereby forming a complex neuromodulatory system that is essential for numerous motor, cognitive and motivational processes. DA neurons can operate in distinct temporal modes, i. e. they display responses across varying timescales including fast phasic changes of DA release on a seconds time scale and slower phasic changes in a minutes to hour range. Furthermore, tonic levels of DA provide a DA receptor 'tone'. Here we briefly highlight findings indicating that temporally distinct responses of DA neurons in the prefrontal cortex and striatum are related to different kinds of information and may serve dissociable behavioural functions. Furthermore we consider how DA neuronal activity and temporarily distinct patterns of DA release are regulated and summarize some relevant findings on the basic neuroanatomy of ascending DA systems. A better understanding of the specific functions of phasic and tonic DA signals will be critical for determining the role of DA in behaviour in detail.

Dopamine release in the medial preoptic area is related to hormonal action and sexual motivation.

To help elucidate how general the role of dopamine (DA) release in the medial preoptic area (mPOA) is for the activation of male sexual behavior in vertebrates, we recently developed an in vivo microdialysis procedure in the mPOA of Japanese quail. Using these techniques in the present experiment, the temporal pattern of DA release in relation to the precopulatory exposure to a female and to the expression of both appetitive and consummatory aspects of male sexual behavior was investigated. Extracellular samples from the mPOA of adult sexually experienced male quail were collected every 6 min before, while viewing, while in physical contact with, and after exposure to a female. In the absence of a precopulatory rise in DA, males failed to copulate when the barrier separating them from the female was removed. In contrast, males that showed a substantial increase in mPOA DA during precopulatory interactions behind the barrier, copulated with females after its removal. However, there was no difference in DA during periods when the quail were copulating as compared to when the female was present but the males were not copulating. In addition, we show that precopulatory DA predicts future DA levels and copulatory behavior frequency. Furthermore, the size of the cloacal gland, an accurate indicator of testosterone action, is positively correlated with precopulatory DA. Taken together, these results provide further support for the hypothesis that DA action in the mPOA is specifically linked to sexual motivation as compared to copulatory behavior per se.

Effects of direct exposure of green odour components on dopamine release from rat brain striatal slices and PC12 cells

The effects of odour components on dopamine release from rat brain striatal slices and rat pheochromocytoma (PC12) cells were examined. The striatal slices were directly stimulated with 0.5% odour-including Krebs buffer using a superfusion method. In this experiment, (Z)-3-hexenol, (E)-2-hexenal, n-hexanal, 1,8-cineole or Eucalyptus globulus essential oil was used as an odour component. The concentrations of monoamines released in perfusate were measured by HPLC-ECD. Dopamine release from brain slices was significantly enhanced by perfusion of each odour-including solution. In particular, administration of n-hexanal caused a 9-fold increase in dopamine release. The dopamine release by n-hexanal increased linearly with the concentration of n-hexanal up to 0.5% and was maximal at 0.5%. Since PC12 cells have the ability to release dopamine, the effects of four green odour compounds, (Z)-3-hexenol, (E)-2-hexenal, n-hexanal and n-hexanol, on dopamine release were examined. These odour compounds dose dependently increased dopamine release from PC12 cells, and different patterns of dopamine release were observed with aldehyde or alcohol. Odour compounds thus appear to increase dopamine release from dopamine-releasing cells, with differences between aldehydes and alcohols in pattern of release. Dopamine regulates brain functions such as reward, mood, and attention. Green odours may in turn regulate such brain functions through the stimulation of dopamine release.

Heterogeneous Effects of Alcohol on Dopamine Release in the Striatum: A PET Study

A dopaminergic response to alcohol in humans has not been demonstrated consistently with positron emission tomography (PET). We hypothesized that the effect of alcohol on striatal dopamine (DA) release may be anatomically heterogeneous between subjects. Our approach was to identify voxels that exhibited alcohol-induced DA responses within the striatum, and to determine the relationships between DA responses and alcohol-related behavior. A novel method was developed to examine the anatomic extent and magnitude of striatal DA responses to alcohol across subjects. Thirteen healthy control subjects underwent 2 PET scans with [11C]raclopride (1 at baseline, 1 with an i.v. alcohol infusion to a target breath alcohol concentration of either 60 or 80 mg%). Parametric images of striatal binding potential (BP) were used to create maps of change in BP (deltaBP, an index of changes in DA levels). The anatomic extent and magnitude of DA responses were determined with voxel extraction methods. Subjective responses ("High," "Intoxication") to the alcohol infusion and behavioral data from the 90-day time-line follow back were assessed for relationships with DA responses to alcohol. A voxel-wise t-test between baseline and alcohol BP images did not show any differences in D2/D3 receptor availability between the conditions. Data from the striatal deltaBP maps nevertheless showed that the anatomic extent and magnitude of alcohol-induced DA release in the striatum are correlated with subjective responses to alcohol. The heterogeneity of dopaminergic responses to alcohol across subjects may be a reason for the lack of reports demonstrating DA involvement in alcohol-related behaviors. By allowing for different spatial patterns of DA release within each subject's striata, we showed correlations between alcohol-induced DA release in the striata and behavioral outcomes related to alcohol.

Prolactin secretory rhythm of mated rats induced by a single injection of oxytocin

Mating or vaginocervical stimulation [copulatory stimulus (CS)] induces two daily surges of the hormone prolactin (PRL) in rats. This unique secretory pattern of PRL surges is characteristic for the first half of pregnancy and is also present in ovariectomized (OVX) rats. Studies have shown that CS additionally provokes an acute release of the hormone oxytocin (OT). In this study, we tested whether a single injection of OT (iv) is sufficient to initiate the PRL secretion pattern of OVX/CS rats. Furthermore, we measured the 24-h profile of dopamine (DA) content in the anterior lobe of the pituitary gland, because DA is the major inhibitory factor of PRL secretion. The results indicated that a single injection of OT induces a PRL secretory rhythm and a DA release pattern similar to that initiated by CS. Immunocytochemical investigation showed that particular OTergic neurons in the hypothalamus express receptors for PRL, as well as for vasoactive intestinal polypeptide, which indicates an involvement in generating the PRL rhythm and entraining it to the ambient photoperiod. On the basis of this study, we suggest that the PRL-DA inhibitory feedback loop between lactotrophs and DAergic neurons plays a crucial role in generating the oscillatory PRL secretion pattern in CS rats. A timing signal, likely provided by the hypothalamic suprachiasmatic nucleus, entrains the autonomous PRL oscillation to a particular time of day. Mathematical modeling was used to illustrate the proposed network function. The experimental results further suggest an additional feedback mechanism in which certain hypothalamic OTergic neurons are influenced by PRL.

Differential Effects of Cocaine on Firing Rate and Pattern of Dopamine Neurons: Role of α1 Receptors and Comparison with l-Dopa and Apomorphine

Psychostimulants, including cocaine, have two opposing effects on dopamine (DA) neurons: a DA-mediated inhibition and a non-DA-mediated excitation. The latter, expressed as an increase in both firing rate and a slow oscillation (SO) in firing pattern, has been shown to require forebrain inputs to DA neurons and activation of adrenergic alpha(1) receptors. However, since the effect was observed when the DA-mediated inhibition was blocked by a D2 antagonist, it is uncertain whether the underlying mechanism also plays a role in cocaine's effects in normal animals where D2-like receptors are not blocked. This study showed that under such conditions, cocaine decreased firing rate and bursting without significantly inhibiting the SO in DA neurons recorded in the ventral tegmental area. Different from cocaine, l-dopa and apomorphine, two nonpsychostimulant DA agonists known to lack the alpha(1)-mediated excitatory effect, consistently inhibited all three measures of DA cell activity. Blockade of alpha(1) receptors by prazosin did not enhance cocaine's ability to inhibit firing rate and bursting, but it did enable cocaine to inhibit the SO. These results suggest that in control rats where D2-like receptors are not blocked, alpha(1) receptors play an important role in cocaine's effect on the SO but not in its effect on firing rate and bursting of DA neurons. The maintained SO after cocaine injection may reflect continued modulation of DA neurons by forebrain inputs, regulate the pattern of DA release, and provide a temporal structure for selection of synaptic inputs to DA neurons.

An assessment of the cerebroprotective potential of volatile anaesthetics using two independent methods in an in vitro model of cerebral ischaemia

Previous studies using a rat brain slice model of cerebral ‘ischaemia’ (hypoxia and hypoglycaemia) have suggested that volatile anaesthetics may have cerebroprotective potential. In this study, we tested the cerebroprotective profile of four volatile anaesthetics in this model by two independent means: voltammetric measurement of ‘ischaemia’-induced dopamine (DA) release and post-‘ischaemic’ tissue staining with 2,3,5-triphenyltetrazolium chloride (TTC). ‘Ischaemia’ caused a characteristic pattern of DA release. Halothane, isoflurane and enflurane did not affect the time from onset of ‘ischaemia’ to the initiation of DA release. However, all three volatile agents significantly increased ( P<0.01, P<0.05, P<0.001, respectively) the time taken for ‘ischaemia’-induced DA release to reach maximum and reduced the rate of DA release. Enflurane, unlike halothane or isoflurane, reduced the maximal extracellular DA concentration induced by ‘ischaemia’ ( P<0.01). The effects of sevoflurane were inconsistent. At the higher concentrations used, the volatile anaesthetics frequently changed the character of DA release from monophasic to biphasic, an effect only previously seen in this model with Na + channel blockers. ‘Ischaemia’ also diminished the subsequent level of tissue staining with TTC. When the effects of the volatile agents were analysed by TTC staining, only enflurane showed any cerebroprotective effects and these were limited to the striatum ( P<0.01). High concentrations of halothane, isoflurane and enflurane appeared to have some ‘toxic’ effects, reducing TTC staining in control slices. In summary, we do not find any consistent evidence that volatile anaesthetics are cerebroprotective in this model.

Neurokinin receptors modulate the neurochemical actions of cocaine.

The psychostimulant cocaine is an indirect agonist that increases synaptic dopamine (DA) by binding with high affinity to the DA transporter (DAT) and blocking the active transport of synaptic DA back into the terminal. The resulting increase in extracellular DA alters postsynaptic activity in the circuitry of the basal ganglia. This study examines the role of neurokinin receptors on cocaine-evoked DA overflow in the striatum. Male Sprague-Dawley rats (n = 8) were treated with cocaine (10 mg/kg body weight i.p.) acutely or chronically. The pattern of DA release was assessed using in vivo microdialysis. In separate experiments two different neurokinin-1 (NK-1) receptor antagonists (D-Arg(1), D-Pro(2), D-Trp(7,9), Leu(11), or L-733,060) were perfused via the microdialysis probe for one hour in awake and freely moving animals that were subsequently injected i.p. with cocaine. Throughout the procedure, DA release was monitored at 1/2-hour intervals at a flow rate of 1 microl/min. In the groups of rats preperfused with NK-1 antagonists into the striatum, the cocaine-evoked release of DA was significantly reduced. This result suggests a significant role for the NK-1 receptor in the striatal response to acute and chronic cocaine administration.

Patterns of dopamine overflow in mouse nucleus accumbens during intracranial self-stimulation

Dopamine (DA) overflow in the mouse nucleus accumbens during intracranial self-stimulation (ICSS) of the median forebrain bundle was estimated by chronoamperometry with removable carbon fibre electrodes. The specificity of the voltammetric signal was confirmed pharmacologically. The parameters of stimulation (50 Hz, 0.5 s train length) allowed us to obtain measurable DA release and to maintain ICSS. Continuous (CR) and fixed-ratio (FR8) schedule of reinforcement showed differing correspondence of the patterns of DA release with the patterns of stimulation/nose-poking. The CR schedule induced a high rate nose-poking and tonic increase in dopamine overflow, which became decreased following the first periods of self-stimulations. The FR schedule induced stable peaks of DA overflow during the entire period of ICSS. We conclude that the availability of a readily-releasable pool of DA in presynaptic terminals determined the pattern of dopamine overflow in the nucleus accumbens during ICSS in mice.

Effects of cocaine on dopamine in subregions of the rat prefrontal cortex and their efferents to subterritories of the nucleus accumbens

The present study sought to investigate the contributions of the ventral prelimbic/infralimbic cortices and shell subterritory of the nucleus accumbens as well as the dorsal prelimbic/anterior cingulate cortices and core subregion of the nucleus accumbens to the acute systemic effects of cocaine (20 mg/kg i.p.) on both locomotor activity and simultaneous dialysate dopamine levels using a dual-probe microdialysis design. Basal dopamine levels were significantly higher in the ventral medial prefrontal cortex compared with the dorsal medial prefrontal cortex and higher concentrations of dopamine were also observed in the core of the nucleus accumbens compared with its shell counterpart. Cocaine produced a significant decrease in dopamine levels in both the ventral and dorsal medial prefrontal cortices. In contrast, cocaine significantly increased dialysate dopamine in the shell of the nucleus accumbens, whereas only a slight increase in dopamine was observed in the core subregion of the nucleus accumbens. A significant negative relationship between dopamine levels in the ventral and dorsal medial prefrontal cortices and dialysate dopamine concentrations in the shell and core of the nucleus accumbens was observed. Finally, in both the ventral and dorsal medial prefrontal cortices, the magnitude of the locomotor response to cocaine was inversely related to dialysate dopamine levels. In contrast, the magnitude of the locomotor response to cocaine became progressively larger as dopamine levels increased in the shell of the nucleus accumbens. These results show a dissociation in the pattern of dopamine release in subterritories of both the medial prefrontal cortex and nucleus accumbens in response to the acute systemic administration of cocaine.