Dissociation of metabolic and hemodynamic levodopa responses in the 6-hydroxydopamine rat model.

Dissociation of vasomotor and metabolic responses to levodopa has been observed in human subjects with Parkinson's disease (PD) studied with PET and in autoradiograms from 6-hydroxydopamine (6-OHDA) rat. In both species, acute levodopa administration was associated with increases in basal ganglia cerebral blood flow (CBF) with concurrent reductions in cerebral metabolic rate (CMR) for glucose in the same brain regions. In this study, we used a novel dual-tracer microPET technique to measure CBF and CMR levodopa responses in the same animal. Rats with unilateral 6-OHDA or sham lesion underwent sequential 15O-water (H215O) and 18F-fluorodeoxyglucose (FDG) microPET to map CBF and CMR following the injection of levodopa or saline. A subset of animals was separately scanned under ketamine/xylazine and isoflurane to compare the effects of these anesthetics. Regardless of anesthetic agent, 6-OHDA animals exhibited significant dissociation of vasomotor (ΔCBF) and metabolic (ΔCMR) responses to levodopa, with stereotyped increases in CBF and reductions in CMR in the basal ganglia ipsilateral to the dopamine lesion. No significant changes were seen in sham-lesioned animals. These data faithfully recapitulate analogous dissociation effects observed previously in human PD subjects scanned sequentially during levodopa infusion. This approach may have utility in the assessment of new drugs targeting the exaggerated regional vasomotor responses seen in human PD and in experimental models of levodopa-induced dyskinesia.

Mechanisms of dopamine D1 receptor-mediated ERK1/2 activation in the parkinsonian striatum and their modulation by metabotropic glutamate receptor type 5.

In animal models of Parkinson's disease, striatal overactivation of ERK1/2 via dopamine (DA) D1 receptors is the hallmark of a supersensitive molecular response associated with dyskinetic behaviors. Here we investigate the pathways involved in D1 receptor-dependent ERK1/2 activation using acute striatal slices from rodents with unilateral 6-hydroxydopamine (6-OHDA) lesions. Application of the dopamine D1-like receptor agonist SKF38393 induced ERK1/2 phosphorylation and downstream signaling in the DA-denervated but not the intact striatum. This response was mediated through a canonical D1R/PKA/MEK1/2 pathway and independent of ionotropic glutamate receptors but blocked by antagonists of L-type calcium channels. Coapplication of an antagonist of metabotropic glutamate receptor type 5 (mGluR5) or its downstream signaling molecules (PLC, PKC, IP3 receptors) markedly attenuated SKF38393-induced ERK1/2 activation. The role of striatal mGluR5 in D1-dependent ERK1/2 activation was confirmed in vivo in 6-OHDA-lesioned animals treated systemically with SKF38393. In one experiment, local infusion of the mGluR5 antagonist MTEP in the DA-denervated rat striatum attenuated the activation of ERK1/2 signaling by SKF38393. In another experiment, 6-OHDA lesions were applied to transgenic mice with a cell-specific knockdown of mGluR5 in D1 receptor-expressing neurons. These mice showed a blunted striatal ERK1/2 activation in response to SFK38393 treatment. Our results reveal that D1-dependent ERK1/2 activation in the DA-denervated striatum depends on a complex interaction between PKA- and Ca(2+)-dependent signaling pathways that is critically modulated by striatal mGluR5.

Lesion of medial prefrontal dopamine terminals abolishes habituation of accumbens shell dopamine responsiveness to taste stimuli.

Taste stimuli increase extracellular dopamine (DA) in the nucleus accumbens (NAc) and in the medial prefrontal cortex (mPFC). This effect shows single-trial habituation in NAc shell but not in core or in mPFC. Morphine sensitization abolishes habituation of DA responsiveness in NAc shell but induces it in mPFC. These observations support the hypothesis of an inhibitory influence of mPFC DA on NAc DA. To test this hypothesis, we used in vivo microdialysis to investigate the effect of mPFC 6-hydroxy-dopamine (6-OHDA) lesions on the NAc DA responsiveness to taste stimuli. 6-OHDA was infused bilaterally in the mPFC of rats implanted with guide cannulae. After 1 week, rats were implanted with an intraoral catheter, microdialysis probes were inserted into the guide cannulae, and dialysate DA was monitored in NAc shell/core after intraoral chocolate. 6-OHDA infusion reduced tissue DA in the mPFC by 75%. Tyrosine hydroxylase immunohistochemistry showed that lesions were confined to the mPFC. mPFC 6-OHDA lesion did not affect the NAc shell DA responsiveness to chocolate in naive rats but abolished habituation in rats pre-exposed to the taste. In the NAc core, mPFC lesion potentiated, delayed and prolonged the stimulatory DA response to taste but failed to affect DA in pre-exposed rats. Behavioural taste reactions and motor activity were not affected. The results indicate a top-down control of NAc DA by mPFC and a reciprocal relationship between DA transmission in these two areas. Moreover, habituation of DA responsiveness in the NAc shell is dependent upon an intact DA input to the mPFC.

Increased sucrose consumption in mice gene-targeted for Vmat2 selectively in NeuroD6-positive neurons of the ventral tegmental area.

Ventral tegmental area (VTA) dopamine (DA) neurons are implicated in reward processing, motivation, reward prediction error, and in substance use disorder. Recent studies have identified distinct neuronal subpopulations within the VTA that can be clustered based on their molecular identity, neurotransmitter profile, physiology, projections and behavioral role. One such subpopulation is characterized by expression of the NeuroD6 gene, and projects primarily to the nucleus accumbens medial shell. We recently showed that optogenetic stimulation of these neurons induces real-time place preference while their targeted deletion of the Vmat2 gene caused altered response to rewarding substances, including ethanol and psychostimulants. Based on these recent findings, we wanted to further investigate the involvement of the NeuroD6-positive VTA subpopulation in reward processing. Using the same NeuroD6Cre+/wt ;Vmat2flox/flox mice as in our prior study, we now addressed the ability of the mice to process sucrose reward. In order to assess appetitive behavior and motivation to obtain sucrose reward, we tested conditional knockout (cKO) and control littermate mice in an operant sucrose self-administration paradigm. We observed that cKO mice demonstrate higher response rates to the operant task and consume more sucrose rewards than control mice. However, their motivation to obtain sucrose is identical to that of control mice. Our results highlight previous observations that appetitive behavior and motivation to obtain rewards can be served by distinct neuronal circuits, and demonstrate that the NeuroD6 VTA subpopulation is involved in mediating the former, but not the latter. Together with previous studies on the NeuroD6 subpopulation, our findings pinpoint the importance of unraveling the molecular and functional role of VTA subpopulations in order to better understand normal behavior and psychiatric disease.

Immunology and microbiology: how do they affect social cognition and emotion recognition?

Social interactions profoundly influence animals' life. The quality of social interactions and many everyday life decisions are determined by a proper perception, processing and reaction to others' emotions. Notably, alterations in these social processes characterize a number of neurodevelopmental disorders, including autism spectrum disorders and schizophrenia. Increasing evidences support an implication of immune system vulnerability and inflammatory processes in disparate behavioral functions and the aforementioned neurodevelopmental disorders. In this review, we show a possible unifying view on how immune responses, within and outside the brain, and the communication between the immune system and brain responses might influence emotion recognition and related social responses. In particular, we highlight the importance of combining genetics, immunology and microbiology factors in understanding social behaviors. We underline the importance of better disentangling the whole machinery between brain-immune system interactions to better address the complexity of social processes.

Two Different Real-Time Place Preference Paradigms Using Optogenetics within the Ventral Tegmental Area of the Mouse.

Understanding how neuronal activation leads to specific behavioral output is fundamental for modern neuroscience. Combining optogenetics in rodents with behavioral testing in validated paradigms allows the measurement of behavioral consequences upon stimulation of distinct neurons in real-time with high spatial and temporal selectivity, and thus the establishment of causal relationships between neuronal activation and behavior. Here, we describe a step-by-step protocol for a real-time place preference (RT-PP) paradigm, a modified version of the classical conditioned place preference (CPP) test. The RT-PP is performed in a three-compartment apparatus and can be utilized to answer if optogenetic stimulation of a specific neuronal population is rewarding or aversive. We also describe an alternative version of the RT-PP protocol, the so-called neutral compartment preference (NCP) protocol, which can be used to confirm aversion. The two approaches are based on extensions of classical methodology originating from behavioral pharmacology and recent implementation of optogenetics within the neuroscience field. Apart from measuring place preference in real time, these setups can also give information regarding conditioned behavior. We provide easy-to-follow step-by-step protocols alongside examples of our own data and discuss important aspects to consider when applying these types of experiments.

Selective Knockout of the Vesicular Monoamine Transporter 2 (Vmat2) Gene in Calbindin2/Calretinin-Positive Neurons Results in Profound Changes in Behavior and Response to Drugs of Abuse.

The vesicular monoamine transporter 2 (VMAT2) has a range of functions in the central nervous system, from sequestering toxins to providing conditions for the quantal release of monoaminergic neurotransmitters. Monoamine signaling regulates diverse functions from arousal to mood, movement, and motivation, and dysregulation of VMAT2 function is implicated in various neuropsychiatric diseases. While all monoamine-releasing neurons express the Vmat2 gene, only a subset is positive for the calcium-binding protein Calbindin 2 (Calb2; aka Calretinin, 29 kDa Calbindin). We recently showed that about half of the dopamine neurons in the mouse midbrain are positive for Calb2 and that Calb2 is an early developmental marker of midbrain dopamine cells. Calb2-positive neurons have also been identified in other monoaminergic areas, yet the role of Calb2-positive monoaminergic neurons is poorly understood. To selectively address the impact of Calb2-positive monoaminergic neurons in behavioral regulation, we took advantage of the Cre-LoxP system to create a new conditional knockout (cKO) mouse line in which Vmat2 expression is deleted selectively in Calb2-Cre-positive neurons. In this Vmat2lox/lox;Calb2-Cre cKO mouse line, gene targeting of Vmat2 was observed in several distinct monoaminergic areas. By comparing control and cKO mice in a series of behavioral tests, specific dissimilarities were identified. In particular, cKO mice were smaller than control mice and showed heightened sensitivity to the stereotypy-inducing effects of amphetamine and slight reductions in preference toward sucrose and ethanol, as well as a blunted response in the elevated plus maze test. These data uncover new knowledge about the role of genetically defined subtypes of neurons in the brain's monoaminergic systems.

Neurocircuitry of Reward and Addiction: Potential Impact of Dopamine-Glutamate Co-release as Future Target in Substance Use Disorder.

Dopamine-glutamate co-release is a unique property of midbrain neurons primarily located in the ventral tegmental area (VTA). Dopamine neurons of the VTA are important for behavioral regulation in response to rewarding substances, including natural rewards and addictive drugs. The impact of glutamate co-release on behaviors regulated by VTA dopamine neurons has been challenging to probe due to lack of selective methodology. However, several studies implementing conditional knockout and optogenetics technologies in transgenic mice have during the past decade pointed towards a role for glutamate co-release in multiple physiological and behavioral processes of importance to substance use and abuse. In this review, we discuss these studies to highlight findings that may be critical when considering mechanisms of importance for prevention and treatment of substance abuse.

The NeuroD6 Subtype of VTA Neurons Contributes to Psychostimulant Sensitization and Behavioral Reinforcement.

Reward-related behavior is complex and its dysfunction correlated with neuropsychiatric illness. Dopamine (DA) neurons of the ventral tegmental area (VTA) have long been associated with different aspects of reward function, but it remains to be disentangled how distinct VTA DA neurons contribute to the full range of behaviors ascribed to the VTA. Here, a recently identified subtype of VTA neurons molecularly defined by NeuroD6 (NEX1M) was addressed. Among all VTA DA neurons, less than 15% were identified as positive for NeuroD6. In addition to dopaminergic markers, sparse NeuroD6 neurons expressed the vesicular glutamate transporter 2 (Vglut2) gene. To achieve manipulation of NeuroD6 VTA neurons, NeuroD6(NEX)-Cre-driven mouse genetics and optogenetics were implemented. First, expression of vesicular monoamine transporter 2 (VMAT2) was ablated to disrupt dopaminergic function in NeuroD6 VTA neurons. Comparing Vmat2lox/lox;NEX-Cre conditional knock-out (cKO) mice with littermate controls, it was evident that baseline locomotion, preference for sugar and ethanol, and place preference upon amphetamine-induced and cocaine-induced conditioning were similar between genotypes. However, locomotion upon repeated psychostimulant administration was significantly elevated above control levels in cKO mice. Second, optogenetic activation of NEX-Cre VTA neurons was shown to induce DA release and glutamatergic postsynaptic currents within the nucleus accumbens. Third, optogenetic stimulation of NEX-Cre VTA neurons in vivo induced significant place preference behavior, while stimulation of VTA neurons defined by Calretinin failed to cause a similar response. The results show that NeuroD6 VTA neurons exert distinct regulation over specific aspects of reward-related behavior, findings that contribute to the current understanding of VTA neurocircuitry.

Targeting VGLUT2 in Mature Dopamine Neurons Decreases Mesoaccumbal Glutamatergic Transmission and Identifies a Role for Glutamate Co-release in Synaptic Plasticity by Increasing Baseline AMPA/NMDA Ratio.

Expression of the Vglut2/Slc17a6 gene encoding the Vesicular glutamate transporter 2 (VGLUT2) in midbrain dopamine (DA) neurons enables these neurons to co-release glutamate in the nucleus accumbens (NAc), a feature of putative importance to drug addiction. For example, it has been shown that conditional deletion of Vglut2 gene expression within developing DA neurons in mice causes altered locomotor sensitization to addictive drugs, such as amphetamine and cocaine, in adulthood. Alterations in DA neurotransmission in the mesoaccumbal pathway has been proposed to contribute to these behavioral alterations but the underlying molecular mechanism remains largely elusive. Repeated exposure to cocaine is known to cause lasting adaptations of excitatory synaptic transmission onto medium spiny neurons (MSNs) in the NAc, but the putative contribution of VGLUT2-mediated glutamate co-release from the mesoaccumbal projection has never been investigated. In this study, we implemented a tamoxifen-inducible Cre-LoxP strategy to selectively probe VGLUT2 in mature DA neurons of adult mice. Optogenetics-coupled patch clamp analysis in the NAc demonstrated a significant reduction of glutamatergic neurotransmission, whilst behavioral analysis revealed a normal locomotor sensitization to amphetamine and cocaine. When investigating if the reduced level of glutamate co-release from DA neurons caused a detectable post-synaptic effect on MSNs, patch clamp analysis identified an enhanced baseline AMPA/NMDA ratio in DA receptor subtype 1 (DRD1)-expressing accumbal MSNs which occluded the effect of cocaine on synaptic transmission. We conclude that VGLUT2 in mature DA neurons actively contributes to glutamatergic neurotransmission in the NAc, a finding which for the first time highlights VGLUT2-mediated glutamate co-release in the complex mechanisms of synaptic plasticity in drug addiction.

Differential effects of gaseous versus injectable anesthetics on changes in regional cerebral blood flow and metabolism induced by l-DOPA in a rat model of Parkinson's disease.

Preclinical imaging of brain activity requires the use of anesthesia. In this study, we have compared the effects of two widely used anesthetics, inhaled isoflurane and ketamine/xylazine cocktail, on cerebral blood flow and metabolism in a rat model of Parkinson's disease and l-DOPA-induced dyskinesia. Specific tracers were used to estimate regional cerebral blood flow (rCBF - [14C]-iodoantipyrine) and regional cerebral metabolic rate (rCMR - [14C]-2-deoxyglucose) with a highly sensitive autoradiographic method. The two types of anesthetics had quite distinct effects on l-DOPA-induced changes in rCBF and rCMR. Isoflurane did not affect either the absolute rCBF values or the increases in rCBF in the basal ganglia after l-DOPA administration. On the contrary, rats anesthetized with ketamine/xylazine showed lower absolute rCBF values, and the rCBF increases induced by l-DOPA were masked. We developed a novel improved model to calculate rCMR, and found lower metabolic activities in rats anesthetized with isoflurane compared to animals anesthetized with ketamine/xylazine. Both anesthetics prevented changes in rCMR upon l-DOPA administration. Pharmacological challenges in isoflurane-anesthetized rats indicated that drugs mimicking the actions of ketamine/xylazine on adrenergic or glutamate receptors reproduced distinct effects of the injectable anesthetics on rCBF and rCMR. Our results highlight the importance of anesthesia in studies of cerebral flow and metabolism, and provide novel insights into mechanisms mediating abnormal neurovascular responses to l-DOPA in Parkinson's disease.

Levodopa-induced abnormal involuntary movements correlate with altered permeability of the blood-brain-barrier in the basal ganglia.

Chronic levodopa treatment leads to the appearance of dyskinesia in the majority of Parkinson's disease patients. Neurovascular dysregulation in putaminal and pallidal regions is thought to be an underlying feature of this complication of treatment. We used microPET to study unilaterally lesioned 6-hydroxydopamine rats that developed levodopa-induced abnormal involuntary movements (AIMs) after three weeks of drug treatment. Animals were scanned with [15O]-labeled water and [18F]-fluorodeoxyglucose, to map regional cerebral blood flow and glucose metabolism, and with [11C]-isoaminobutyric acid (AIB), to assess blood-brain-barrier (BBB) permeability, following separate injections of levodopa or saline. Multitracer scan data were acquired in each animal before initiating levodopa treatment, and again following the period of daily drug administration. Significant dissociation of vasomotor and metabolic levodopa responses was seen in the striatum/globus pallidus (GP) of the lesioned hemisphere. These changes were accompanied by nearby increases in [11C]-AIB uptake in the ipsilateral GP, which correlated with AIMs scores. Histopathological analysis revealed high levels of microvascular nestin immunoreactivity in the same region. The findings demonstrate that regional flow-metabolism dissociation and increased BBB permeability are simultaneously induced by levodopa within areas of active microvascular remodeling, and that such changes correlate with the severity of dyskinesia.

Midbrain Gene Screening Identifies a New Mesoaccumbal Glutamatergic Pathway and a Marker for Dopamine Cells Neuroprotected in Parkinson's Disease.

The ventral tegmental area (VTA) and substantia nigra pars compacta (SNc) of the midbrain are associated with Parkinson's disease (PD), schizophrenia, mood disorders and addiction. Based on the recently unraveled heterogeneity within the VTA and SNc, where glutamate, GABA and co-releasing neurons have been found to co-exist with the classical dopamine neurons, there is a compelling need for identification of gene expression patterns that represent this heterogeneity and that are of value for development of human therapies. Here, several unique gene expression patterns were identified in the mouse midbrain of which NeuroD6 and Grp were expressed within different dopaminergic subpopulations of the VTA, and TrpV1 within a small heterogeneous population. Optogenetics-coupled in vivo amperometry revealed a previously unknown glutamatergic mesoaccumbal pathway characterized by TrpV1-Cre-expression. Human GRP was strongly detected in non-melanized dopaminergic neurons within the SNc of both control and PD brains, suggesting GRP as a marker for neuroprotected neurons in PD. This study thus unravels markers for distinct subpopulations of neurons within the mouse and human midbrain, defines unique anatomical subregions within the VTA and exposes an entirely new glutamatergic pathway. Finally, both TRPV1 and GRP are implied in midbrain physiology of importance to neurological and neuropsychiatric disorders.

Lactoferrin- and antitransferrin-modified liposomes for brain targeting of the NK3 receptor agonist senktide: preparation and in vivo evaluation.

The aim of this work was to evaluate the capability of lactoferrin- and antitransferrin-modified long circulating liposomes to deliver the hydrophilic peptide senktide, a selective NK3 receptor agonist unable to cross the blood brain barrier, to central nervous system by using an indirect method based on in vivo microdialysis studies to estimate the responsiveness of nucleus accumbens shell dopamine to senktide. To this purpose, senktide was encapsulated in different targeted and not-targeted stealth liposomes prepared using film hydration method. Formulations were characterized in terms of morphology, size distribution, zeta potential, encapsulation efficiency, and antibody presence on the liposome surface. In vivo microdialysis studies were performed injecting intravenously the senktide-loaded liposomes and comparing obtained dopamine levels with those found with the free senktide given intracerebroventricularly. Results showed that all vesicles were spherical, small in size (around 120 nm), homogeneously dispersed, and slightly negatively charged. TEM analysis, using an anti IgG secondary antibody with 10nm gold nanoparticles at its distal end, demonstrated the successful linkage of the antibody on the liposomal surface. Intravenously administered in rats, senktide-loaded targeted stealth liposomes elicited a significant increase of dialysate dopamine in the nucleus accumbens shell, which was comparable to that of the free senktide given intracerebroventricularly when antitransferrin-targeted liposomes were tested. On the contrary, control stealth liposomes did not affect dopamine levels. Senktide brain levels were higher using the antitransferrin-targeted liposomes in comparison with the lactoferrin ones, while the opposite was obtained in the liver tissue where the highest senktide accumulation was always found.

Endocannabinoid 2-Arachidonoylglycerol Self-Administration by Sprague-Dawley Rats and Stimulation of in vivo Dopamine Transmission in the Nucleus Accumbens Shell.

2-Arachidonoylglycerol (2-AG) is the most potent endogenous ligand of brain cannabinoid CB1 receptors and is synthesized on demand from 2-arachidonate-containing phosphoinositides by the action of diacylglycerol lipase in response to increased intracellular calcium. Several studies indicate that the endocannabinoid (eCB) system is involved in the mechanism of reward and that diverse drugs of abuse increase brain eCB levels. In addition, eCB are self-administered (SA) by squirrel monkeys, and anandamide increases nucleus accumbens (NAc) shell dopamine (DA) in rats. To date, there is no evidence on the reinforcing effects of 2-AG and its effects on DA transmission in rodents. In order to fill this gap, we studied intravenous 2-AG SA and monitored the effect of 2-AG on extracellular DA in the NAc shell and core via microdialysis in male Sprague-Dawley rats. Rats were implanted with jugular catheters and trained to self-administer 2-AG [25 mg/kg/inf intravenously (iv)] in single daily 1 h sessions for 5 weeks under initial fixed ratio (FR) 1 schedule. The ratio was subsequently increased to FR2. Active nose poking increased from the 6th SA session (acquisition phase) but no significant increase of nose pokes was observed after FR2. When 2-AG was substituted for vehicle (25th SA session, extinction phase), rate responding as well as number of injections slowly decreased. When vehicle was replaced with 2-AG, SA behavior immediately recovered (reacquisition phase). The reinforcing effects of 2-AG in SA behavior were fully blocked by the CB1 receptor inverse agonist/antagonist rimonabant (1 mg/kg intraperitoneally, 30 min before SA session). In the microdialysis studies, we observed that 2-AG (0.1-1.0 mg/kg iv) preferentially stimulates NAc shell as compared to the NAc core. NAc shell DA increased by about 25% over basal value at the highest doses tested (0.5 and 1.0 mg/kg iv). The results obtained suggest that the eCB system, via 2-AG, plays an important role in reward.

Modulating mGluR5 and 5-HT1A/1B receptors to treat l-DOPA-induced dyskinesia: effects of combined treatment and possible mechanisms of action.

l-DOPA-induced dyskinesia (LID) is a major complication of the pharmacotherapy of Parkinson's disease. Emerging approaches to the treatment of LID include negative modulation of metabotropic glutamate receptor type 5 (mGluR5) and positive modulation of serotonin receptors 5-HT1A/1B. We set out to compare the efficacy of these two approaches in alleviating the dyskinesias induced by either l-DOPA or a D1 receptor agonist. Rats with unilateral 6-OHDA lesions were treated chronically with either l-DOPA or the selective D1-class receptor agonist SKF38393 to induce abnormal involuntary movements (AIMs). Rats with stable AIM scores received challenge doses of the mGluR5 antagonist, MTEP (2.5 and 5mg/kg), or the 5-HT1A/1B agonists 8-OH-DPAT/CP94253 (0.035/0.75 and 0.05/1.0mg/kg). Treatments were given either alone or in combination. In agreement with previous studies, 5mg/kg MTEP and 0.05/1.0mg/kg 8-OH-DPAT/CP94253 significantly reduced l-DOPA-induced AIM scores. The two treatments in combination achieved a significantly greater effect than each treatment alone. Moreover, a significant attenuation of l-DOPA-induced AIM scores was achieved when combining doses of MTEP (2.5mg/kg) and 8-OH-DPAT/CP94253 (0.035/0.75mg/kg) that did not have a significant effect if given alone. SKF38393-induced AIM scores were reduced by MTEP at both doses tested, but not by 8-OH-DPAT/CP94253. The differential efficacy of MTEP and 8-OH-DPAT/CP94253 in reducing l-DOPA- versus SKF38393-induced dyskinesia indicates that these treatments have different mechanisms of action. This contention is supported by the efficacy of subthreshold doses of these compounds in reducing l-DOPA-induced AIMs. Combining negative modulators of mGluR5 with positive modulators of 5-HT1A/1B receptors may therefore achieve greater than additive antidyskinetic effects and reduce the dose requirement for these drugs in Parkinson's disease.

Influence of morphine sensitization on the responsiveness of mesolimbic and mesocortical dopamine transmission to appetitive and aversive gustatory stimuli.

RATIONALE: Repeated treatment with morphine has been shown to sensitize rats to its stimulant effects on motor activity and mesolimbic dopamine (DA) transmission. OBJECTIVES: The aim of this study is to investigate if morphine sensitization is associated to changes in the behavioral reactions to appetitive and aversive taste stimuli and in the response of in vivo DA transmission in the nucleus accumbens (NAc) shell and core and medial prefrontal cortex (PFCX) to the same stimuli. METHODS: Rats were administered twice a day for three consecutive days with increasing doses of morphine [10, 20, and 40 mg/kg, subcutaneously (sc)] or with saline. After 15 days of withdrawal, rats were infused intraorally with either an appetitive (sweet chocolate, 1 ml) or an aversive solution (quinine HCl 5 × 10(-4) M, 1 ml). The behavioral taste reactions were recorded during microdialysis of DA in the NAc shell and core and PFCX. RESULTS: Opiate sensitization did not affect behavioral reactions to intraoral chocolate or quinine. In rats naive to the taste stimuli, morphine sensitization was associated to potentiation of stimulatory DA response to appetitive and aversive taste stimuli in the NAc core. Morphine sensitization reciprocally affected habituation of DA responsiveness after one trial exposure to appetitive and aversive taste stimuli (abolition it in the shell, induction in the PFCX). No habituation of DA responsiveness to taste was observed in the NAc core in controls as well as in morphine-sensitized rats. CONCLUSIONS: These results suggest that opiate sensitization is associated to differential adaptive changes of the responsiveness of DA transmission to taste stimuli in DA terminal areas.