Male and female rats show opiate withdrawal-induced place aversion and extinction in a Y-maze paradigm.

Gender differences have been observed in the vulnerability to drug abuse and in the different stages of the addictive process. In opiate dependence, differences between sexes have been shown in humans and laboratory animals in various phases of opiate addiction, especially in withdrawal-associated negative affective states. Using a Y-maze conditioned place aversion paradigm, we investigated potential sex differences in the expression and extinction of the aversive memory of precipitated opiate withdrawal state in morphine-dependent rats. No significant difference between sexes was observed in the occurrence of withdrawal signs following naloxone injection during conditioning. Moreover, opiate withdrawal memory expression and extinction following repeated testing was demonstrated in both male and female rats, with no significant differences between sexes. Finally, we report spontaneous recovery following extinction of opiate withdrawal memory. Altogether these data provide further evidence that persistent withdrawal-related memories may be strong drivers of opiate dependence, and demonstrate that both males and females can be used in experimental rodent cohorts to better understand opiate-related effects, reward, aversive state of withdrawal, abstinence and relapse.

Arc reactivity in accumbens nucleus, amygdala and hippocampus differentiates cue over context responses during reactivation of opiate withdrawal memory.

Opiate withdrawal induces an early aversive state which can be associated to contexts and/or cues, and re-exposure to either these contexts or cues may participate in craving and relapse. Nucleus accumbens (NAC), hippocampus (HPC) and basolateral amygdala (BLA) are crucial substrates for acute opiate withdrawal, and for withdrawal memory retrieval. Also HPC and BLA interacting with the NAC are suggested to respectively mediate the processing of context and cue representations of drug-related memories. Here we used a paradigm of conditioned suppression of operant food seeking, allowing to differentiate context and cue related responses, to study the influence of withdrawal memories on operant behavior and the underlying neural substrates. catFISH for Arc mRNA expression was used to discriminate cellular responses during context and cue (flashing light) periods in this paradigm. We show that reactivation of the memory of the negative affective state of withdrawal suppresses active lever pressing for food, and this conditioned suppression is generalized to the context. Interestingly the behavioral responses during the context and cue light periods are associated with differential Arc mRNA activations within the NAC, BLA, and HPC. Indeed both periods led to NAC shell activation whereas the NAC core was responsive only following the cue light period. Moreover, BLA and HPC were more responsive during cue-light and context period respectively. These data further support the already reported differential role of these brain structures on cue vs context-induced reinstatement of operant behaviors, and highlight the existence of common mechanisms for the processing of positive and aversive emotional memories.

Unlimited sucrose consumption during adolescence generates a depressive-like phenotype in adulthood.

Depression is highly prevalent worldwide, but its etiology is not fully understood. An overlooked possible contributor to the epidemic of depression is feeding styles, particularly at early age when the brain is intensely changing. We have previously reported that unlimited sucrose consumption during adolescence leads to enduring changes in brain reward function. Here, we tested the hypothesis that sucrose consumption during adolescence would lead to a 'depressive-like' phenotype. Adolescent male rats were given unlimited access to 5% sucrose in their home cages from postnatal day 30 to postnatal day 46 and their emotional behavior was subsequently examined at adulthood. Sucrose consumption during adolescence caused anhedonia, decreased motivation for saccharin, increased immobility in the forced swim test and exacerbated anxiety-like behavior. Additionally, sucrose consumption during adolescence decreased cell proliferation in the hippocampus in adulthood. Chronic treatment with imipramine (10 mg/kg) normalized behavior and restored cell proliferation in the hippocampus of adult rats with a history of sucrose consumption during adolescence. A similar sucrose consumption starting at adulthood only increases immobility in the forced swim test, suggesting that sucrose intake affects also adults' behavior but to a lesser degree. Overall, our findings reveal an unsuspected protracted effect of sucrose consumption on behavior and suggest that unlimited sucrose consumption during critical periods of brain development may play an important role in the etiology of reward-related disorders such as depression.

Corticotropin-releasing factor receptor 2-deficiency eliminates social behaviour deficits and vulnerability induced by cocaine.

BACKGROUND AND PURPOSE: Poor social behaviour and vulnerability to stress are major clinical features of stimulant use disorders. The corticotropin-releasing factor (CRF) system mediates stress responses and might underlie substance use disorders; however, its involvement in social impairment induced by stimulant substances remains unknown. CRF signalling is mediated by two receptor types, CRF1 and CRF2 . In the present study we investigated the role of the CRF2 receptor in social behaviour deficits, vulnerability to stress and related brain alterations induced by cocaine administration and withdrawal. EXPERIMENTAL APPROACH: CRF2 receptor-deficient (CRF2 -/-) and littermate wild-type mice were repeatedly tested in the three-chamber task for sociability (i.e. preference for an unfamiliar conspecific vs. an object) and social novelty preference (SNP; i.e. preference for a novel vs. a familiar conspecific) before and after chronic cocaine administration. An in situ hybridization assay was used to assess gene expression of the stress-responsive arginine vasopressin (AVP) and oxytocin (OT) neuropeptides in the hypothalamus. KEY RESULTS: CRF2 receptor deficiency eliminated the sociability deficit induced by cocaine withdrawal. Moreover, CRF2 -/- mice did not show either the stress-induced sociability deficit or the increased AVP and OT expression associated with long-term cocaine withdrawal, indicating resilience to stress. Throughout, wild-type and CRF2 -/- mice displayed SNP, suggesting that cocaine withdrawal-induced sociability deficits were not due to impaired detection of social stimuli. CONCLUSIONS AND IMPLICATIONS: These findings demonstrate a central role for the CRF2 receptor in social behaviour deficits and biomarkers of vulnerability induced by cocaine withdrawal, suggesting new therapeutic strategies for stimulant use disorders.

Inter-individual differences in decision-making, flexible and goal-directed behaviors: novel insights within the prefronto-striatal networks.

Inflexible behavior is a hallmark of several decision-making-related disorders such as ADHD and addiction. As in humans, a subset of healthy rats makes poor decisions and prefers immediate larger rewards despite suffering large losses in a rat gambling task (RGT). They also display a combination of traits reminiscent of addiction, notably inflexible behavior and perseverative responses. The goal of the present work was twofold: (1) to elucidate if behavioral inflexibility of poor decision-makers could be related to a lower quality of goal-directed behavior (action-outcome associations); (2) to uncover the neural basis of inter-individual differences in goal-directed behavior. We specifically assessed inter-individual differences in decision-making in the RGT, flexibility in the RGT-reversed version and goal-directed behavior in a contingency degradation test, i.e., response adaptation when dissociating reward delivery from the animal's action. The contributions of the medial prefrontal cortex and the dorsal striatum to action-outcome associations were assessed using Zif268 immunodetection. Inflexible behavior was related to a lower sensitivity to contingency degradation in all poor decision-makers and only in a few good decision-makers. This poorer sensitivity was associated with a lower immunoreactivity in prelimbic and infralimbic cortices and a higher one in the dorsomedial and dorsolateral striatum. These findings suggest that an imbalanced prefronto-striatal activity could underlie inaccurate goal representation in changing environments and may promote maladaptive habit formation among poor decision-makers. These data strengthen our previous work identifying biomarkers of vulnerability to develop psychiatric disorders and demonstrate the relevance of inter-individual differences to model maladaptive behaviors.

Memories of Opiate Withdrawal Emotional States Correlate with Specific Gamma Oscillations in the Nucleus Accumbens.

Affective memories associated with the negative emotional state experienced during opiate withdrawal are central in maintaining drug taking, seeking, and relapse. Nucleus accumbens (NAC) is a key structure for both acute withdrawal and withdrawal memories reactivation, but the NAC neuron coding properties underpinning the expression of these memories remain largely unknown. Here we aimed at deciphering the role of NAC neurons in the encoding and retrieval of opiate withdrawal memory. Chronic single neuron and local field potentials recordings were performed in morphine-dependent rats and placebo controls. Animals were subjected to an unbiased conditioned placed aversion protocol with one compartment (CS+) paired with naloxone-precipitated withdrawal, a second compartment with saline injection (CS-), and a third being neutral (no pairing). After conditioning, animals displayed a typical place aversion for CS+ and developed a preference for CS- characteristic of safety learning. We found that distinct NAC neurons code for CS+ or CS-. Both populations also displayed highly specific oscillatory dynamics, CS+ and CS- neurons, respectively, following 80 Hz (G80) and 60 Hz (G60) local field potential gamma rhythms. Finally, we found that the balance between G60 and G80 rhythms strongly correlated both with the ongoing behavior of the animal and the strength of the conditioning. We demonstrate here that the aversive and preferred environments are underpinned by distinct groups of NAC neurons as well as specific oscillatory dynamics. This suggest that G60/G80 interplay-established through the conditioning process-serves as a robust and versatile mechanism for a fine coding of the environment emotional weight.

Subthalamic nucleus high-frequency stimulation modulates neuronal reactivity to cocaine within the reward circuit.

The subthalamic nucleus (STN) is a critical component of a complex network controlling motor, associative and limbic functions. High-frequency stimulation (HFS) of the STN is an effective therapy for motor symptoms in Parkinsonian patients and can also reduce their treatment-induced addictive behaviors. Preclinical studies have shown that STN HFS decreases motivation for cocaine while increasing that for food, highlighting its influence on rewarding and motivational circuits. However, the cellular substrates of these effects remain unknown. Our objectives were to characterize the cellular consequences of STN HFS with a special focus on limbic structures and to elucidate how STN HFS may interfere with acute cocaine effects in these brain areas. Male Long-Evans rats were subjected to STN HFS (130 Hz, 60 µs, 50-150 µA) for 30 min before an acute cocaine injection (15 mg/kg) and sacrificed 10 min following the injection. Neuronal reactivity was analyzed through the expression of two immediate early genes (Arc and c-Fos) to decipher cellular responses to STN HFS and cocaine. STN HFS only activated c-Fos in the globus pallidus and the basolateral amygdala, highlighting a possible role on emotional processes via the amygdala, with a limited effect by itself in other structures. Interestingly, and despite some differential effects on Arc and c-Fos expression, STN HFS diminished the c-Fos response induced by acute cocaine in the striatum. By preventing the cellular effect of cocaine in the striatum, STN HFS might thus decrease the reinforcing properties of the drug, which is in line with the inhibitory effect of STN HFS on the rewarding and reinforcing properties of cocaine.

Prefronto-subcortical imbalance characterizes poor decision-making: neurochemical and neural functional evidences in rats.

A major challenge of decision-making research in recent years has been to develop models of poor decision-making to identify its neural bases. Toward this goal, we developed a Rat Gambling Task that discerns good and poor decision-makers in a complex and conflicting situation such as the human Iowa Gambling Task. Nothing is known about the role of the monoaminergic modulatory systems in shaping these phenotypes. Moreover, functional and temporal contributions of brain areas during poor compared to good decision-making remains elusive. Good and poor decision-makers were identified in the Rat Gambling Task. We investigated neurobiological correlates of decision-making capacities in (1) dopamine and serotonin turnovers using post-mortem tissue measurements, (2) the neural circuits differentially recruited during decision-making within the prefronto-subcortical network using cellular Fos immunodetection. Imbalance in monoamine metabolism was revealed in poor decision-makers, i.e. a higher infralimbic vs. lower amygdala serotonergic metabolism. Moreover, good decision-making recruited a wide prefronto-subcortical network but once good choices had been made, a disengagement of key prefrontal areas (insular and infralimbic cortices notably) and the amygdala was observed. By contrast, poor decision-making was associated with a strikingly low recruitment of the prefronto-subcortical network, together with sustained amygdala activity. Our results identify two complementary neurobiological substrates characterizing poor decision-makers: imbalanced monoaminergic systems at rest, congruent with their previously identified complex behavioral phenotype, and an aberrant low recruitment of key brain areas for executive functions and affective valence during the process of decision-making. These biomarkers could sustain vulnerability to developing poor decision-making related disorders.

CRF2 receptor-deficiency reduces recognition memory deficits and vulnerability to stress induced by cocaine withdrawal.

Psychostimulant drug abuse, dependence and withdrawal are associated with cognitive dysfunction and impact stress-sensitive systems. The corticotropin-releasing factor (CRF) system orchestrates stress responses via CRF1 and CRF2 receptors and is implicated in substance use disorders. However, CRF2 role in psychostimulant drug-induced cognitive dysfunction remains to be elucidated. In the present study, wild-type and CRF2-/- mice are injected with cocaine and memory assessed by the novel object recognition (NOR) task throughout relatively long periods of drug withdrawal. Following recovery from the drug-induced memory deficits, the mice are stressed prior to the NOR task and brain gene expression evaluated by in situ hybridization. Cocaine impairs NOR memory in wild-type and CRF2-/- mice. However, following cocaine withdrawal NOR memory deficits last less time in CRF2-/- than in wild-type mice. Furthermore, a relatively mild stressor induces the re-emergence of NOR deficits in long-term cocaine-withdrawn wild-type but not CRF2-/- mice. Cocaine-withdrawn mice show a genotype-independent higher c-fos expression in the NOR memory-relevant perirhinal cortex than drug-naïve mice. However neither genotype nor drug withdrawal affect the expression of tyrosine hydroxylase in the ventral tegmental area or the locus coeruleus and CRF in the central nucleus of the amygdala or the paraventricular nucleus of the hypothalamus, brain regions implicated in stress and drug responses. These data indicate a new role for the CRF2 receptor in cognitive deficits induced by cocaine withdrawal, both as regards to their duration and their re-induction by stress. Interestingly, prototypical brain stress systems other than CRF do not appear to be involved.

Diverse effects of 5-HT2C receptor blocking agents on c-Fos expression in the rat basal ganglia.

Serotonin(2C) receptors (5-HT(2)C) exert continuous control on the activity of specific populations of neurons in the basal ganglia. While antagonists block the effect of endogenous 5-HT at 5-HT(2C) receptors, the actions of inverse agonists may also involve interruption of activity at constitutively active populations of 5-HT(2C) receptors. We have evaluated the regional impact of these controls by studying, in rats, the expression of the product of the proto-oncogene c-Fos in rat basal ganglia after peripheral doses of the 5-HT(2C) antagonist SB 243213 (5-methyl-1-[[2-[(2-methyl-3-pyridyl)oxy]-5-pyridyl]carbamoyl]-6-trifluoromethylindoline) and the 5-HT(2B/2C) inverse agonists SB 206553 (5-methyl-1-(3-pyridylcarbamoyl)-1,2,3,5-tetrahydropyrrolo[2,3-f]indole.hydrochloride) and S32006 (N-pyridin-3-yl-1,2-dihydro-3H-benzo[e]indole-3-carboxamide). The results show that 1 and 10mg/kg SB 243213 enhanced equally c-Fos expression in the subthalamic nucleus (STN) and dose-dependently in the striatum and nucleus accumbens core (NAcc). SB 206553 (1-10mg/kg), at 10mg/kg only, enhanced c-Fos expression in STN, striatum (except the dorsomedial part), NAcc, entopeduncular nucleus, substantia nigra pars reticulata (SNr) and compacta (SNc) and ventral tegmental area. S32006 induced a similar increase in c-Fos expression in the medial parts of the striatum and NAcc at doses of 1-10mg/kg while it dose-dependently enhanced c-Fos expression in medial parts of the STN and SNr. None of these drugs induced c-Fos expression in the globus pallidus. The distinct pattern of c-Fos expression elicited by the 5-HT(2C) antagonist and inverse agonists suggests the existence of cellular and functional heterogeneity in the response of the basal ganglia to drugs inhibiting 5-HT(2C) receptors.

Evolution of the dynamic properties of the cortex-basal ganglia network after dopaminergic depletion in rats.

It is well established that parkinsonian syndrome is associated with alterations of neuronal activity temporal pattern basal ganglia (BG). An increase in synchronized oscillations has been observed in different BG nuclei in Parkinson's disease patients as well as animal models such as 6-hydroxydopamine treated rats. We recently demonstrated that this increase in oscillatory synchronization is present during high-voltage spindles (HVS) probably underpinned by the disorganization of cortex-BG interactions. Here we investigated the time course of both oscillatory and motor alterations. For that purpose we performed daily simultaneous recordings of neuronal activity in motor cortex, striatum and substantia nigra pars reticulata (SNr), before and after 6-hydroxydopamine lesion in awake rats. After a brief non-dopamine-specific desynchronization, oscillatory activity first increased during HVS followed by progressive motor impairment and the shortening of SNr activation delay. While the oscillatory firing increase reflects dopaminergic depletion, response alteration in SNr neurons is closely related to motor symptom.

Remodeling of the neuronal circuits underlying opiate-withdrawal memories following remote retrieval.

Several types of memory display time-dependent reorganization of their underlying neural substrates, but it remains unclear whether affective memories associated with drug effects also follow similar reorganization. Here, we analyzed the neural circuits reactivated by the re-exposure of former dependent rats to the withdrawal-paired environment 1month after conditioning (remote memory) as compared with recent memory (Frenois, F., Stinus, L., Di Blasi, F., Cador, M., & Le Moine, C. (2005) A specific limbic circuit underlies opiate withdrawal memories The Journal of Neuroscience, 25, 1366-1374). C-fos expression showed that the circuits involved in the retrieval of withdrawal memories are partly different when comparing recent and remote reactivation, showing that, like other type of memories, affective memories linked to opiate withdrawal undergo anatomical reorganization, with a shift from extended amygdala regions toward cortical areas.

The synergy of working memory and inhibitory control: behavioral, pharmacological and neural functional evidences.

Concomitant deficits in working memory and behavioral inhibition in several psychiatric disorders like attention-deficit/hyperactivity disorder, addiction or mania, suggest that common brain mechanisms may underlie their etiologies. Based on the theoretical assumption that a continuum exists between health and mental disorders, we explored the relationship between working memory and inhibition in healthy individuals, through spontaneous inter individual differences in behavior, and tested the hypothesis of a functional link through the fronto-striatal dopaminergic system. Rats were classified into three groups, showing good, intermediate and poor working memory and were compared for their inhibitory abilities. These two functions were simultaneously modulated by a dose-effect of d-amphetamine and in situ hybridization was used to quantify dopaminergic receptor (RD1) mRNAs in prefrontal cortex and striatal areas. A functional relationship between working memory and inhibition abilities was revealed. Both functions were similarly modulated by d-amphetamine according to an inverted-U shaped relationship and depending on initial individual performances. D-amphetamine selectively improved working memory and inhibition of poor and intermediate performers at low doses whereas it impaired both processes in good performers at a higher dose. D1 receptors were less expressed in prelimbic, infralimbic and anterior cingulate cortices of good compared to intermediate and poor performers, whereas no difference was observed between groups in striatal areas. The synergy of working memory and inhibitory abilities, observed in both healthy and psychiatric populations, may originate from endogenous variability in dopaminergic prefrontal cortex activity. Such findings confirm the validity of a dimensional approach, based on the concept of continuity between health and mental disorders for identifying endophenotypes of mental disorders.

Power fluctuations in beta and gamma frequencies in rat globus pallidus: association with specific phases of slow oscillations and differential modulation by dopamine D1 and D2 receptors.

Modulation of oscillatory activity through basal ganglia-cortical loops in specific frequency bands is thought to reflect specific functional states of neural networks. A specific negative correlation between beta and gamma sub-bands has been demonstrated in human basal ganglia and may be key for normal basal ganglia function. However, these studies were limited to Parkinson's disease patients. To confirm that this interaction is a feature of normal basal ganglia, we recorded local field potential (LFP) from electrodes in globus pallidus (GP) of intact rats. We found significant negative correlation between specific frequencies within gamma (≈ 60 Hz) and beta (≈ 14 Hz) bands. Furthermore, we show that fluctuations in power at these frequencies are differentially nested within slow (≈ 3 Hz) oscillations in the delta band, showing maximum power at distinct and different phases of delta. These results suggest a hierarchical organization of LFP frequencies in the rat GP, in which a low-frequency signal in the basal ganglia can predict the timing and interaction of power fluctuations across higher frequencies. Finally, we found that dopamine D(1) and D(2) receptor antagonists differentially affected power in gamma and beta bands and also had different effects on correlation between them and the nesting within delta, indicating an important role for endogenous dopamine acting on direct and indirect pathway neurons in the maintenance of the hierarchical organization of frequency bands. Disruption of this hierarchical organization and subsequent disordered beta-gamma balance in basal ganglia disorders such as Parkinson's disease may be important in the pathogenesis of their symptoms.

Selective blockade of serotonin 2C receptor enhances Fos expression specifically in the striatum and the subthalamic nucleus within the basal ganglia.

Serotonin(2C) (5-HT(2C)) receptors are widely expressed in the basal ganglia, a group of brain regions involved in the control of motor behavior. However, it remains unclear whether their tonic influence on neuronal activity is distributed in these regions. We have addressed this question by measuring the product of the proto-oncogene c-Fos in rats after peripheral administration of the non-selective 5-HT antagonist mianserin, the 5-HT(2C/2B) antagonist SER-082 or the selective 5-HT(2C) antagonist SB 243213. The intraperitoneal administration of 1mg/kg of SB 243213 or SER-082, but not mianserin, enhanced Fos-immunoreactive cells in the subthalamic nucleus and the striatum, primarily its medial portion. None of these treatments significantly affected Fos expression in the external globus pallidus, the entopeduncular nucleus (the internal globus pallidus in primate) or the substantia nigra pars reticulata. The data suggest that selective blockade of 5-HT(2C) receptors is necessary to unmask a tonic regulation of neuronal activity by this receptor in the basal ganglia and that this effect is restricted to the two structures receiving cortical entries, the striatum and the subthalamic nucleus.

The hippocampus plays a critical role at encoding discontiguous events for subsequent declarative memory expression in mice.

The hypothesis that hippocampal activity at encoding is causally related to subsequent declarative memory expression is tested in the mouse, by using lidocaine inactivation of the hippocampus in combination with c-fos neuroimaging analysis. We employed a two-stage radial maze paradigm of spatial discrimination, which was previously shown to dissociate between declarative and nondeclarative expression of memory related to the same acquired material. In Stage 1 (encoding), mice learnt the constant location of food among a set of six arms (three baited, three unbaited) by being submitted repeatedly to discontiguous experiences with each arm separately ("go/no-go" discrimination). In Stage 2 (test-session), they are challenged with novel presentations of the arms, which are either combined into pairs of opposite valence ("two-choice" discrimination), or opened all six together ("six-choice" discrimination). Previous experiments have demonstrated that the "two-choice" situation is a critical test for declarative memory while "six-choice" discrimination may rely on procedural memory. We observed that (i) hippocampal activity measured by c-fos mRNA expression was increased by "go/no-go" learning, and this activation was blocked by pre-training local infusions of lidocaine; (ii) when performed just before each session of Stage 1, such inactivation spared the acquisition of "go/no-go" discrimination but produced, subsequently, a selective deficit in the "two-choice" test (not in the "six-choice" test). This study indicates that the hippocampus is "spontaneously" engaged in encoding processes necessary for long-term storage of discontiguous experiences under a form enabling flexible declarative memory expression.

No effect of morphine on ventral tegmental dopamine neurons during withdrawal.

Substantial evidence indicates that the ventral tegmental area (VTA) of the mesocorticolimbic dopaminergic (DA) system has a key role in mechanisms of opiate dependence. Although DA neurons have been studied extensively, little is known about their activity and their response to acute morphine during morphine dependence. We recorded the activity of VTA DA neurons in five groups of anesthetized rats: drug-naive (naive) rats, morphine-dependent [(MD) implanted with pellets] rats, and three groups of withdrawn rats. Withdrawals either were precipitated by naltrexone or occurred spontaneously 24 h or 15 d after pellet removal. We confirmed that acute morphine in naive rats produced a marked increase in the firing of VTA DA neurons. We also found that the basal firing rate of VTA DA neurons was markedly higher in MD than in naive rats; however, in MD rats, acute morphine failed to increase DA activity. We confirmed inhibition of VTA DA activity in MD rats in response to precipitated withdrawal; however, this inhibition resulted only in a normalization of the firing rate to that of naive animals. In rats that had spontaneous withdrawal after 24 h or 15 d, the activity of VTA DA neurons was similar to that of naive rats, and an acute injection of morphine failed to alter their activity. Our results indicate that VTA DA neurons show long-lasting tolerance to the acute effect of morphine after withdrawal. These findings show that VTA DA neural activity is unlikely to be a factor in the altered behavioral responses that occur with acute morphine or naltrexone administration after chronic opiate exposure.

Cortical inputs and GABA interneurons imbalance projection neurons in the striatum of parkinsonian rats.

The striatum receives massive cortical excitatory inputs and is densely innervated by dopamine. Striatal projection neurons form either the direct or indirect pathways. Models of Parkinson's disease propose that dopaminergic degeneration imbalances both pathways, although direct electrophysiological evidence is lacking. Here, striatal neurons were identified by electrophysiological criteria and Neurobiotin labeling combined with either immunohistochemistry or in situ hybridization. Their spontaneous discharge activity and spike response to cortical stimulation were recorded in vivo in anesthetized rats rendered hemi-parkinsonian by 6-hydroxydopamine. We showed that striatonigral neurons (direct pathway) were inhibited whereas striatopallidal neurons (indirect pathway) were activated by dopaminergic lesion. We also identified, with antidromic stimulations, corticostriatal neurons that preferentially innervate striatonigral or striatopallidal neurons and showed that dopaminergic depletion selectively decreased the spontaneous activity of the former. Therefore, dopamine degeneration induces a cascade of imbalances that spread out of the basal ganglia and affect the whole basal ganglia-thalamo-cortical circuits. Fast-spiking GABA interneurons provide potent feedforward inhibition of striatal projection neurons. We showed here that these interneurons narrowed the time window of the responses of projection neurons to cortical stimulation. In the dopamine-depleted striatum, because the intrinsic activity of these interneurons was not altered, their feedforward inhibition worsened the striatal imbalance. Indeed, the time window of the evoked responses was narrower for striatonigral neurons and wider for striatopallidal neurons. Therefore, after dopaminergic depletion, cortical inputs and GABA interneurons might imbalance striatal projection neurons and represent two novel nondopaminergic mechanisms that might secondarily contribute to the pathophysiology of Parkinson's disease.

Excitatory response of prefrontal cortical fast-spiking interneurons to ventral tegmental area stimulation in vivo.

Prefrontal cortical (PFC) pyramidal neurons (PN) and fast spiking interneurons (FSI) receive dopaminergic (DA) and non-DA inputs from the ventral tegmental area (VTA). Although the responses of PN to VTA stimulation and DA administration have been extensively studied, little is known about the response of FSI to mesocortical activation. We explored this issue using single and double in vivo juxtacellular recordings of medial PFC PN and FSI with chemical VTA stimulation. Electrophysiological characteristics combined with Neurobiotin staining and parvalbumin immunohistochemistry allowed identification of recorded cells as FSI or PN. NMDA injection into the VTA increased firing in all FSI tested (n = 7), whereas most PN (7/11) responded with an inhibition. Furthermore, FSI excitation matching the temporal course of PN inhibition was observed with FSI-PN paired recordings (n = 5). These divergent electrophysiological responses to mesocortical activation could reflect PFC GABAergic interneurons contributing to silencing PN. Thus, the mesocortical system could provide a critical control of PFC circuits by simultaneously affecting FSI and PN firing.