Striatal dopamine depletion in rats produces variable effects on contingency detection: task-related influences

Dopamine (DA) depletion of the posterior dorsomedial striatum (pDMS) can impair the capability of rats to detect changes in the causal efficacy of actions. Here we sought to characterize in more detail the effects of pDMS DA depletions on contingency detection as a function of different contingency degradation training protocols. In experiment 1, sham controls and rats with pDMS DA depletions received limited contingency degradation training (4 days) that involved an invariable and high degree of degradation to one of two contingencies controlling instrumental choice behaviour. The results demonstrated that lesioned rats were insensitive to contingency manipulations both during contingency degradation training and in the subsequent extinction test. Experiment 2 further indicated that rats with pDMS DA depletion subjected to extended contingency degradation training (12 days) became sensitive to contingency manipulations during the training phase but not in the subsequent extinction test. In experiment 3, an extended but more complex contingency degradation training protocol (12 days) was used that involved a gradual shift from a low to an intermediate and a high degree of contingency degradation rather than a high and invariable degree of contingency degradation as in experiments 1 and 2. Notably, lesioned rats were sensitive to contingency manipulations both during the contingency degradation training phase and in the subsequent extinction test. Thus, pDMS DA depletions can impair the capability to detect changes in the causal efficacy of actions; however, the occurrence and pattern of impairments depend on the contingency degradation training protocol being used.     

Posterior dorsomedial striatum is critical for both selective instrumental and Pavlovian reward learning

The dorsal striatum (DS) has been implicated in instrumental learning but its role in the acquisition of stimulus‐driven behaviour is not clear. To explore the contribution of the DS to both response‐outcome (R‐O) and stimulus‐outcome (S‐O) associative learning, we pharmacologically inactivated subregions (dorsolateral, anterior dorsomedial and posterior dorsomedial) of the DS during acquisition sessions in which subjects acquired two unique, novel R‐O pairs or two unique, novel S‐O pairs. To test whether specific R‐O or S‐O associations were learned under inactivation, rats were tested following selective‐satiety devaluation of one outcome under drug‐free conditions. In the instrumental task, control rats and rats with dorsolateral striatum (DLS) inactivation during learning responded less on the lever that had earned the devalued outcome than on the alternative lever at test, indicating that the DLS is not critical for the formation of R‐O associations. In contrast, rats with inactivation of the medial DS (DMS) (either anterior or posterior) during learning responded indiscriminately, suggesting failure to acquire the novel R‐O associations. In the Pavlovian task, both controls and rats with anterior DMS inactivation during learning responded less in the presence of the stimulus predicting the devalued outcome, whereas rats with DLS or posterior DMS inactivation during learning responded equally to the stimuli, indicating that they had not acquired the novel S‐O associations. These data confirm that the DLS and anterior region DMS mediate different aspects of reward‐related learning, and suggest that the posterior DMS may mediate a function common to both forms of learning (R‐O and S‐O). Finally, we demonstrate that both S‐O and R‐O associations are required for selective Pavlovian‐instrumental transfer.     

Intrastriatal excitotoxic lesion or dopamine depletion of the neostriatum differentially impairs response execution in extrapersonal space

Dysfunction of the neostriatum, a primary feature of several neurodegenerative disorders, including Parkinson’s disease and Huntington’s disease, has been found to result in impaired localisation of, and reaction to, contralateral stimuli. On the basis of previous findings, it is hypothesised that, with increasing eccentricity of the response option, striatal cell loss may impair response localisation at the furthest levels of eccentricity, whereas dopamine (DA) depletion may not impact adversely upon responses executed in this extrapersonal space. In order to elucidate more fully the function of the striatum, the present study examined the differential impact of unilateral DA depletion or excitoxic lesion on response execution in ipsilateral and contralateral space at up to four levels of eccentricity. The results confirmed that, after both types of striatal dysfunction, the sensory ability to detect stimuli remains intact, whereas the ability to direct responses in absolute contralateral space is impaired. Distinct differences in the profiles of impairment were, however, evident, with a marked increase in response omissions observed after DA depletion, which may reflect decreased motivational processing, and recovery of function observed in rats with excitotoxic lesions, which suggests the ability to re‐learn. Furthermore, the data demonstrate that, after cell loss, responding in near contralateral space is controlled by competing striata, whereas responding in extrapersonal space relies on the contralateral hemisphere. These results have implications for understanding the role of the striatum in egocentrically defined response localisation, as well as for unravelling the behavioural impact of striatal cell loss or aberrant DA transmission observed in neurodegenerative diseases.     

Lesions of dorsolateral striatum preserve outcome expectancy but disrupt habit formation in instrumental learning

Habits are controlled by antecedent stimuli rather than by goal expectancy. Interval schedules of feedback have been shown to generate habits, as revealed by the insensitivity of behaviour acquired under this schedule to outcome devaluation treatments. Two experiments were conducted to assess the role of the dorsolateral striatum in habit learning. In Experiment 1, sham operated controls and rats with dorsolateral striatum lesions were trained to press a lever for sucrose under interval schedules. After training, the sucrose was devalued by inducing taste aversion to it using lithium chloride, whereas saline injections were given to the controls. Only rats given the devaluation treatment reduced their consumption of sucrose and this reduction was similar in both the sham and the lesioned groups. All rats were then returned to the instrumental chamber for an extinction test, in which the lever was extended but no sucrose was delivered. In contrast to sham operated controls, rats with dorsolateral striatum lesions refrained from pressing the lever if the outcome was devalued. To assess the specificity of the role of dorsolateral striatum in this effect a second experiment was conducted in which a group with lesions of dorsomedial striatum was added. In relation now to both the sham and the dorsomedial lesioned groups, only rats with lesions of dorsolateral striatum significantly reduced responding after outcome devaluation. In conclusion, this study provides direct evidence that the dorsolateral striatum is necessary for habit formation. Furthermore, it suggests that, when the habit system is disrupted, control over instrumental performance reverts to the system controlling the performance of goal-directed instrumental actions.     

General and outcome-specific forms of Pavlovian-instrumental transfer: the effect of shifts in motivational state and inactivation of the ventral tegmental area

This study compared the contribution of the general activating and specific cueing properties of Pavlovian stimuli to Pavlovian-instrumental transfer (PIT) and the role of the ventral tegmental area (VTA) in mediating these effects. In Experiment 1, hungry rats initially received Pavlovian training, in which three distinct auditory stimuli predicted the delivery of three different food outcomes. Next, the rats were trained to perform two instrumental actions, each earning a unique outcome selected from the three used in Pavlovian conditioning. Finally, the effects of the three stimuli on performance of the two actions were assessed in extinction. Presentation of a stimulus that had been paired with the same outcome as an action increased its performance relative to the other action, demonstrating that PIT effects can be outcome selective. In contrast, presentation of the stimulus that predicted the outcome that was not earned during instrumental training facilitated the performance of both actions indiscriminately. This effect, but not the outcome-selective effect, was abolished by a shift from a hungry to a relatively sated state. Experiment 2 examined the effects of inactivation of the VTA on these two forms of PIT. VTA inactivation was found to attenuate PIT but, unlike satiety, did not appear to differentially affect the general or the outcome-selective forms of PIT. The VTA appears therefore to play an important but general role in the initiation of instrumental actions, enabling cues to influence performance whether they enhance responding by changes in arousal or by retrieving particular actions based on their consequences.     

Alterations in electrophysiological activity and dye coupling of striatal spiny and aspiny neurons in dopamine‐denervated rat striatum recorded in vivo

We recently reported that pharmacological manipulations of the dopamine system can produce more than a 4‐fold increase in dye coupling between dopaminoceptive neurons in the adult rat striatal complex. During in vivo intracellular recordings, striatal neurons in control rats and in rats that had been treated with 6‐hydroxydopamine were injected with either Lucifer yellow or Neurobiotin. Only rats that exhibited severe loss (i.e., larger than ∼95%) of striatal dopamine terminals displayed a significant increase in the incidence of dye coupling between neurons in adult striatum. Moreover, this increased coupling was present only between neurons of the same morphological cell class, i.e., among clusters of spiny neurons or between aspiny neurons. Combining intracellular labeling of spiny neurons with parvalbumin immunocytochemistry demonstrated that coupling did not occur between anatomically adjacent neurons that comprised immunocytochemically and morphologically distinct cell classes. Therefore, gap junction conductance as reflected by dye coupling appears to undergo upregulation as a consequence of compromises in nigrostriatal and mesolimbic dopamine transmission. Synapse 33:1–15, 1999. © 1999 Wiley‐Liss, Inc.     

The role of the dorsomedial striatum in instrumental conditioning

Considerable evidence suggests that, in instrumental conditioning, rats learn the relationship between actions and their specific consequences or outcomes. The present study examined the role of the dorsomedial striatum (DMS) in this type of learning after excitotoxic lesions and reversible, muscimol-induced inactivation. In three experiments, rats were first trained to press two levers for distinct outcomes, and then tested after training using a variety of behavioural assays that have been established to detect action-outcome learning. In Experiment 1, pre-training lesions of the posterior DMS abolished the sensitivity of rats' instrumental performance to both outcome devaluation and contingency degradation when tested in extinction, whereas lesions of the anterior DMS had no effect. In Experiment 2, both pre-training and post-training lesions of the posterior DMS were equally effective in reducing the sensitivity of performance both to devaluation and degradation treatments. In Experiment 3, the infusion of muscimol into the posterior DMS selectively abolished sensitivity of performance to devaluation and contingency degradation without impairing the ability of rats to discriminate either the instrumental actions performed or the identity of the earned outcomes. Taken together, these results suggest that the posterior region of the DMS is a crucial neural substrate for the acquisition and expression of action-outcome associations in instrumental conditioning.     

Differential representation of Pavlovian–instrumental transfer by prefrontal cortex subregions and striatum

Environmental cues that once predicted reward can restore extinguished behavior directed toward that reward. This process may be modeled by the Pavlovian–instrumental transfer (PIT) paradigm where a previously learned Pavlovian conditioned stimulus (CS) elicits a representation of the reward associated with that CS, prompts motivation toward the absent reward, and triggers an instrumental action. We recorded in the medial and orbital prefrontal cortex (mPFC and OFC) and dorsal striatum (DS) of freely moving rats during PIT and found that a Pavlovian CS, as compared with neutral or no stimuli, amplified the phasic neuronal responses to instrumental nosepokes ('transfer' event). In mPFC and OFC, but not the DS, representation of the transfer event correlated with the strength of PIT behavior. Neurons in all three regions showed CS-selective amplification of Pavlovian approaches toward the reward delivery site. Whereas striatal neurons represented transfer and approach behavior through mostly segregated neuronal subsets, overlapping subsets represented these events in the mPFC and OFC. These findings suggest that parallel phasic activation of mPFC and OFC neuronal subsets participates in the transfer from Pavlovian incentives to instrumental actions.     

Modulation of cue‐triggered reward seeking by cholinergic signaling in the dorsomedial striatum

The dorsomedial striatum (DMS) has been strongly implicated in flexible, outcome‐based decision making, including the outcome‐specific Pavlovian‐to‐instrumental transfer effect (PIT), which measures the tendency for a reward‐predictive cue to preferentially motivate actions that have been associated with the predicted reward over actions associated with different rewards. Although the neurochemical underpinnings of this effect are not well understood, there is growing evidence that striatal acetylcholine signaling may play an important role. This study investigated this hypothesis by assessing the effects of intra‐DMS infusions of the nicotinic antagonist mecamylamine or the muscarinic antagonist scopolamine on expression of specific PIT in rats. These treatments produced dissociable behavioral effects. Mecamylamine infusions enhanced rats’ tendency to use specific cue‐elicited outcome expectations to select whichever action was trained with the predicted outcome, relative to their performance when tested after vehicle infusions. In contrast, scopolamine infusions appeared to render instrumental performance insensitive to this motivational influence of reward‐paired cues. These drug treatments had no detectable effect on conditioned food cup approach behavior, indicating that they selectively perturbed cue‐guided action selection without producing more wide‐ranging alterations in behavioral control. Our findings reveal an important role for DMS acetylcholine signaling in modulating the impact of cue‐evoked reward expectations on instrumental action selection.     

A specific role for posterior dorsolateral striatum in human habit learning

Habits are characterized by an insensitivity to their consequences and, as such, can be distinguished from goal-directed actions. The neural basis of the development of demonstrably outcome-insensitive habitual actions in humans has not been previously characterized. In this experiment, we show that extensive training on a free-operant task reduces the sensitivity of participants' behavior to a reduction in outcome value. Analysis of functional magnetic resonance imaging data acquired during training revealed a significant increase in task-related cue sensitivity in a right posterior putamen–globus pallidus region as training progressed. These results provide evidence for a shift from goal-directed to habit-based control of instrumental actions in humans, and suggest that cue-driven activation in a specific region of dorsolateral posterior putamen may contribute to the habitual control of behavior in humans.     

Ethanol reverses the direction of long-term synaptic plasticity in the dorsomedial striatum

The striatum is a critical structure for the control of voluntary behaviour, and striatal synaptic plasticity has been implicated in instrumental learning. As ethanol consumption can cause impairments in cognition, learning, and action selection, it is important to understand the effects of this drug on striatal function. In this study we examined the effects of ethanol on long-term synaptic plasticity in the dorsomedial striatum (DMS), a striatal subregion that plays a central role in the acquisition and selection of goal-directed actions. Ethanol was found to impair N-methyl-d-aspartic acid receptor (NMDAR)-dependent long-term potentiation (LTP) dose-dependently in the DMS, and to promote long-term depression (LTD) at the highest concentration (50 mm) used. These results suggest that ethanol, at a concentration usually associated with mild intoxication, could significantly change experience-dependent modification of corticostriatal circuits underlying the learning of goal-directed instrumental actions.     

The expression of the calcium binding protein calretinin in the rat striatum: effects of dopamine depletion and L-DOPA treatment

The activity of the striatum is regulated by glutamate and dopamine neurotransmission. Consequent to striatal dopamine depletion the corticostriatal excitatory input is increased, which in turn can raise intracellular calcium levels. We investigated changes in the neuronal expression of the calcium binding protein calretinin related to dopamine depletion and l-DOPA administration. Immunohistochemical methods were used to assess calretinin in the striatum of rats with unilateral lesions of the nigrostriatal system. In these animals we observed a loss of the patchy distribution of calretinin fibers. Moreover, after dopaminergic depletion we detected two new, not previously described, calretinin cell types, the presence of which could be related to morphological changes induced by loss of a dopaminergic input. We also found an increase in the number of calretinin-labeled cells in the striatum ipsilateral to the lesion compared to the contralateral striatum or to the striatum of normal rats. This increase was mostly evident at 3 weeks postlesion and tended to decrease toward normal levels at 6, 10, and 18 weeks postlesion. In unlesioned animals, l-DOPA administration did not induce changes in the expression of calretinin. In unilaterally lesioned animals, l-DOPA reversed the increase in the number of calretinin-positive cells induced by the lesion. However, chronic l-DOPA administration was less effective than acute l-DOPA in reversing the effect of the lesion. The present data suggests that striatal calretinin neurons are sensitive to dopamine depletion. Increased expression of calretinin in striatal cells may be consequent to enhanced striatal excitatory input.     

Reduced dopamine D1 receptor binding in the ventral striatum of cigarette smokers.

Several drugs of abuse, including nicotine, are thought to exert their reinforcing effects through actions on the mesolimbic dopamine system. Animal and human studies suggest that chronic administration of addictive drugs may lead to impaired dopamine neurotransmission in the nucleus accumbens. We measured D1 receptor density in 11 smokers and 18 nonsmokers using positron emission tomography and the D1 receptor ligand [11C]SCH 23390. Ten of the smokers were scanned twice, once after overnight abstinence from cigarettes, and once while smoking at their usual rate, to account for possible acute effects of cigarette smoking on D1 receptor binding. In addition, eight control subjects were scanned twice to assess the reproducibility of the method. We used compartmental modeling to measure [11C]SCH 23390 binding potential, a measure of D1 receptor density. There were no differences in binding between abstinent and nonabstinent scans in smokers or in the two scans in controls. However, there was a significant reduction in [11C]SCH 23390 binding potential in smokers compared to nonsmokers in the striatum, most prominently in the ventral striatum. This suggests that there is a reduction in dopamine D1 receptor density in the ventral striatum of human cigarette smokers relative to nonsmokers, which implies that the postsynaptic mesolimbic dopamine system may be chronically underactive in smokers, either as an antecedent or consequence of addiction to cigarettes. Such a hypodopaminergic state may play an important role in sustaining nicotine-seeking behavior. Alternatively, an inherited reduction in dopamine receptors in the striatum may be associated with an increased risk of addictive behavior.     

Contingency learning in human fear conditioning involves the ventral striatum

The ability to detect and learn contingencies between fearful stimuli and their predictive cues is an important capacity to cope with the environment. Contingency awareness refers to the ability to verbalize the relationships between conditioned and unconditioned stimuli. Although there is a heated debate about the influence of contingency awareness on conditioned fear responses, neural correlates behind the formation process of contingency awareness have gained only little attention in human fear conditioning. Recent animal studies indicate that the ventral striatum (VS) could be involved in this process, but in human studies the VS is mostly associated with positive emotions. To examine this question, we reanalyzed four recently published classical fear conditioning studies (n = 117) with respect to the VS at three distinct levels of contingency awareness: subjects, who did not learn the contingencies (unaware), subjects, who learned the contingencies during the experiment (learned aware) and subjects, who were informed about the contingencies in advance (instructed aware). The results showed significantly increased activations in the left and right VS in learned aware compared to unaware subjects. Interestingly, this activation pattern was only found in learned but not in instructed aware subjects. We assume that the VS is not involved when contingency awareness does not develop during conditioning or when contingency awareness is unambiguously induced already prior to conditioning. VS involvement seems to be important for the transition from a contingency unaware to a contingency aware state. Implications for fear conditioning models as well as for the contingency awareness debate are discussed. Hum Brain Mapp, 2009. © 2009 Wiley‐Liss, Inc.     

Different effect of age on dopamine transporters in the dorsal and ventral striatum of controls and alcoholics

It is generally agreed that there is a deterioration in brain dopamine (DA) system with aging. The role of the mesolimbic DA in brain ethanol reinforcement is well established, with nucleus accumbens (NAC) serving as a major terminal area of this system, whereas dorsal striatum is more associated with motor control. The aim of this study was to compare putative age-related alterations of dopamine transporters (DAT) in dorsal and ventral striatum of healthy controls and alcoholics. We studied the effect of age on DAT in caudate (NC), putamen (Pu), and nucleus accumbens (NAC) of eight type 1 and 2 alcoholics and 10 healthy controls by using [(125)I]PE2I as a radioligand for postmortem human whole hemisphere autoradiography. In the type 1 alcoholic group age and DAT density did not correlate significantly with any of the structures studied. The mean densities of DAT declined significantly with age in controls and type 2 alcoholics in dorsal striatum (NC, Pu) (range of correlation coefficient from -0.49 to -0.94), but not statistically significantly in NAC. In type 1 alcoholics the lack of correlation between DAT density and age may indicate a preexisting dopaminergic deficit in this patient group, whereas age-related decline among type 2 alcoholics resembled that of healthy controls. Furthermore, dorsal striatal DAT may be more vulnerable to age-related decline than DAT in NAC. This is supported by the notion that DAT in NAC and dorsal striatum have different molecular weights.     

Astrocytic equilibrative nucleoside transporter type 1 upregulations in the dorsomedial and dorsolateral striatum distinctly coordinate goal‐directed and habitual ethanol‐seeking behaviours in mice

Two distinct dorsal striatum regions, dorsomedial striatum (DMS) and dorsolateral striatum (DLS), are attributed to conditioned goal‐directed and habitual reward‐seeking behaviours, respectively. Previously, our study shows that the ethanol‐sensitive adenosine transporter, equilibrative nucleoside transporter 1 (ENT1), regulates ethanol‐drinking behaviours. Although ENT1 is expressed in both neurons and astrocytes, astrocytic ENT1 is thought to regulate adenosine levels in response to ethanol. However, the role of DMS and DLS astrocytic ENT1 in goal‐directed and habitual ethanol‐seeking is not well known. Here, we identified whether the upregulation of astrocytic ENT1 in the DMS and DLS differentially regulates operant seeking behaviours towards the 10% sucrose (10S); 10% ethanol and 10% sucrose (10E10S); and 10% ethanol (10E) in mice. Using 4 days of random interval (RI), mice exhibited habitual seeking for 10S, but goal‐directed seeking towards 10E10S. Using the same mice conditioned with 10E10S, we examined 10E‐seeking behaviour on a fixed ratio (FR) for 6 days and RI for 8 days. On the other hand, during FR and the first 4 days of RI schedules, mice showed goal‐directed seeking for 10E, whereas mice exhibited habitual seeking for 10E during the last 4 days of RI schedule. Interestingly, DMS astrocytic ENT1 upregulation promotes shift from habitual to goal‐directed reward‐seeking behaviours. By contrast, DLS astrocytic ENT1 upregulation showed no effects on behavioural shift. Taken together, our findings demonstrate that DMS astrocytic ENT1 contributes to reward‐seeking behaviours.     

Relationship between dopamine deficit and the expression of depressive behavior resulted from alteration of serotonin system

Depression frequently accompanies in Parkinson's disease (PD). Previous research suggested that dopamine (DA) and serotonin systems are closely linked with depression in PD. However, comprehensive studies about the relationship between these two neurotransmitter systems are limited. Therefore, the purpose of this study is to evaluate the effect of dopaminergic destruction on the serotonin system. The interconnection between motor and depression was also examined. Two PET scans were performed in the 6‐hydroxydopamine (6‐OHDA) lesioned and sham operated rats: [¹⁸F]FP‐CIT for DA transporters and [¹⁸F]Mefway for serotonin 1A (5‐HT_1A) receptors. Here, 6‐OHDA is a neurotoxin for dopaminergic neurons. Behavioral tests were used to evaluate the severity of symptoms: rotational number for motor impairment and immobility time, acquired from the forced swim test for depression. Region‐of‐interests were drawn in the striatum and cerebellum for the DA system and hippocampus and cerebellum for the 5‐HT system. The cerebellum was chosen as a reference region. Nondisplaceable binding potential in the striatum and hippocampus were compared between 6‐OHDA and sham groups. As a result, the degree of DA depletion was negatively correlated with rotational behavior (R² = 0.79, P = 0.003). In 6‐OHDA lesioned rats, binding values for 5‐HT_1A receptors was 22% lower than the sham operated group. This decrement of 5‐HT_1A receptor binding was also correlated with the severity of depression (R² = 0.81, P = 0.006). Taken together, this research demonstrated that the destruction of dopaminergic system causes the reduction of the serotonergic system resulting in the expression of depressive behavior. The degree of dopaminergic dysfunction was positively correlated with the impairment of the serotonin system. Severity of motor symptoms was also closely related to depressive behavior. Synapse 69:453–460, 2015. © 2015 Wiley Periodicals, Inc.     

Interactions between dopamine and amino acid-induced excitation and inhibition in the striatum

Iontophoretic techniques were used to examine the effect of dopamine on glutamate-induced excitation and γ-aminobutyric acid (GABA)-induced inhibition of single striatal neurons in rat brain. When dopamine was applied at concentrations that produced little or no inhibition of spontaneous firing rate, both glutamate-induced excitation and GABA-induced inhibition were enhanced. In contrast, when dopamine was applied at doses that significantly decreased spontaneous firing, glutamate-induced excitation was greatly reduced, though GABA-mediated inhibition remained enhanced. Thus, dopamine acts to modulate the efficacy of other neurotransmitters impinging on striatal neurons, but has a qualitatively different effect on the excitatory activity of striatal cells depending on its concentration.     

Dopamine depletion induces neuron‐specific alterations of GABAergic transmission in the mouse striatum

Lack of dopamine (DA) in the striatum and the consequential dysregulation of thalamocortical circuits are major causes of motor impairments in Parkinson's disease. The striatum receives multiple cortical and subcortical afferents. Its role in movement control and motor skills learning is regulated by DA from the nigrostriatal pathway. In Parkinson's disease, DA loss affects striatal network activity and induces a functional imbalance of its output pathways, impairing thalamocortical function. Striatal projection neurons are GABAergic and form two functionally antagonistic pathways: the direct pathway, originating from DA receptor type 1‐expressing medium spiny neurons (D₁R‐MSN), and the indirect pathway, from D₂R‐MSN. Here, we investigated whether DA depletion in mouse striatum also affects GABAergic function. We recorded GABAergic miniature IPSCs (mIPSC) and tonic inhibition from D₁R‐ and D₂R‐MSN and used immunohistochemical labeling to study GABA_AR function and subcellular distribution in DA‐depleted and control mice. We observed slower decay kinetics and increased tonic inhibition in D₁R‐MSN, while D₂R‐MSN had increased mIPSC frequency after DA depletion. Perisomatic synapses containing the GABA_AR subunits α₁ or α₂ were not affected, but there was a strong decrease in non‐synaptic GABA_ARs containing these subunits, suggesting altered receptor trafficking. To broaden these findings, we also investigated GABA_ARs in GABAergic and cholinergic interneurons and found cell type‐specific alterations in receptor distribution, likely reflecting changes in connectivity. Our results reveal that chronic DA depletion alters striatal GABAergic transmission, thereby affecting cellular and circuit activity. These alterations either result from pathological changes or represent a compensatory mechanism to counteract imbalance of output pathways.