Infusion Of Muscimol Research Articles

Central effects of the anabolic steroid 17α methyltestosterone in female anxiety

The androgen 17α-methyltestosterone (17α-meT) is one of the most commonly abused anabolic androgenic steroids (AAS). We assessed the impact of 17α-meT after bilateral infusion into the dorsomedial hypothalamus (DMH) in female anxiety. A paradoxical effect in Vogel conflict test (VCT) behavior was noted: while AAS infusion induced an increase in the latency to display the appetitive reaction of the task, it also increased the number of punished responses. No changes in elevated plus maze (EPM) behavior were noted. However, AAS infusion induced an increase in social interactions. Changes in social interactions were mimicked by muscimol infusion and counteracted by co-infusion of AAS plus the GABA A receptor (GABA A-R) antagonist GABAzine. A reduction of systolic blood pressure was registered after AAS infusion in the DMH. No changes in fluid intake or locomotor behaviors were noted. We conclude that the AAS 17α-meT modulates distinct anxiety domains in females through a fast-acting mechanism.

Sex-specific control of flurothyl-induced tonic–clonic seizures by the substantia nigra pars reticulata during development

The substantia nigra pars reticulata (SNR) plays an important age- and sex-specific role in control of clonic seizures. Its involvement in control of tonic–clonic seizures is contradictory. We investigated the role of the SNR in the tonic–clonic seizures induced in male, female and neonatally castrated male rats using flurothyl. In adult female rats, vaginal impedance determined the changes in progesterone/estrogen ratio. Rats at various postnatal ages received infusions of muscimol or vehicle in the SNRanterior or SNRposterior. Furthermore, in 15-day-old (P15) and adult male rats, ZAPA (a GABA(A) receptor agonist) or AP7 (an NMDA receptor antagonist) was infused. The developmental profile of tonic–clonic seizure threshold differed between male and female rats possibly due to early postnatal testosterone surge in male rats. On the other hand, changing estrogen/progesterone ratio in cycling adult female rats had no effect on seizure threshold. Intranigral muscimol had proconvulsant effects on tonic–clonic seizures only in immature rats, and this effect was dependent on the perinatal testosterone surge. ZAPA had anticonvulsant effects in P15 rats but was not effective in adult rats. Only AP7 had anticonvulsant effects in both adult and P15 rats. Results indicate that thresholds for flurothyl-induced tonic–clonic seizures develop under the control of postnatal testosterone. Although GABAergic inhibition in the SNR affects tonic–clonic seizures in developing rats, only the NMDA antagonist had consistent anticonvulsant effects throughout development.

Dorsomedial Prefrontal Cortex Resolves Response Conflict in Rats

The capacity for goal-directed behavior requires not only the encoding of the response-outcome relationship but also the ability to resolve conflict induced by competing responses. Recent neuroimaging studies have identified the prefrontal cortex as critical for resolving conflict between competing responses. At present, however, much of this evidence is indirect, and the necessity of dorsomedial prefrontal cortex (dmPFC) function for the resolution of conflict in goal-directed behavior has not been assessed. Here, we develop a rodent paradigm to investigate response conflict caused by the concurrent activation of a correct and incorrect response. In this paradigm, the outcome of one response also acts as a discriminative stimulus signaling that the other response is correct. Whereas rats with a functional dmPFC are able to resolve this conflict, inactivation of dmPFC using an infusion of muscimol produced a deficit by selectively interfering with their ability to inhibit the incorrect, competing response.

NMDA Partial Agonist Reverses Blocking of Extinction of Aversive Memory by GABAA Agonist in the Amygdala

The ability to extinguish aversive memories is of significant clinical interest. The amygdala plays an important role in emotional conditioning and its experimental extinction. It has been suggested that gamma-aminobutyric acid (GABA) agonists retard extinction and that consolidation of extinction involves N-methyl-D-aspartate receptor (NMDAR)-mediated plasticity. The aim was to further explore the interaction between GABA and NMDA in the amygdala in consolidation of experimental extinction in the rat. To that end conditioned taste aversion (CTA) was used. In CTA, the amygdala has been reported to subserve both acquisition and extinction. The GABA(A) receptor agonist, muscimol, administered into the amygdala immediately after the first extinction session, caused lasting disruption of extinction of CTA for at least 2 weeks. However, the administration of GABA(A) receptor antagonists had no effect on extinction kinetics. Microinfusing the partial NMDA agonist D-cycloserine together with or after muscimol infusion reversed the blocking effects of muscimol. These findings could bear relevance to the potential involvement of extinction abnormalities in behavioral disorders, and their amelioration.

Enhancement of extinction memory consolidation: The role of the noradrenergic and GABAergic systems within the basolateral amygdala

Evidence from previous studies indicates that the noradrenergic and GABAergic influences within the basolateral amygdala (BLA) modulate the consolidation of memory for fear conditioning. The present experiments investigated whether the same modulatory influences are involved in regulating the extinction of fear-based learning. To investigate this issue, male Sprague Dawley rats implanted with unilateral or bilateral cannula aimed at the BLA were trained on a contextual fear conditioning (CFC) task and 24 and 48 h later were given extinction training. Immediately following each extinction session they received intra-BLA infusions of the GABAergic antagonist bicuculline (50 ng), the β-adrenocepter antagonist propranolol (500 ng), bicuculline with propranolol, norepinephrine (NE) (0.3, 1.0, and 3.0 μg), the GABAergic agonist muscimol (125 ng), NE with muscimol or a control solution. To investigate the involvement of the dorsal hippocampus (DH) as a possible target of BLA activation during extinction, other animals were given infusions of muscimol (500 ng) via an ipsilateral cannula implanted in the DH. Bilateral BLA infusions of bicuculline significantly enhanced extinction, as did infusions into the right, but not left BLA. Propranolol infused into the right BLA together with bicuculline blocked the bicuculline-induced memory enhancement. Norepinephrine infused into the right BLA also enhanced extinction, and this effect was not blocked by co-infusions of muscimol. Additionally, muscimol infused into the DH did not attenuate the memory enhancing effects of norepinephrine infused into the BLA. These findings provide evidence that, as with original CFC learning, noradrenergic activation within the BLA modulates the consolidation of CFC extinction. The findings also suggest that the BLA influence on extinction is not mediated by an interaction with the dorsal hippocampus.

Enhancement of conditioned fear extinction by infusion of the GABAA agonist muscimol into the rat prefrontal cortex and amygdala

In auditory fear conditioning, repeated presentation of the tone in the absence of the shock leads to extinction of the acquired fear response. Both the infra limbic prefrontal cortex (IL) and the basolateral amygdala (BLA) are involved in extinction. In this study, we examine the involvement of these two regions in extinction by manipulating the gamma-aminobutyric acid (GABA)ergic system, in the Sprague-Dawley rat. We microinfused a low dose of the GABA(A) agonist muscimol into the IL or BLA. Muscimol infused to IL before extinction training, but not after either a short (five-trials) or long (15-trials) extinction training, resulted in long-term facilitation of extinction. Infusion of muscimol to the BLA following a short (five-trial) extinction session facilitated extinction at least 48-h post-drug infusion. The differences in the temporal parameters of the effects of muscimol in the IL or BLA, suggest differential involvement of these structures in long-term extinction of fear memory. We propose a facilitating role for GABA(A) neurotransmission in the IL in triggering the onset of fear extinction and its maintenance, whereas in the BLA, GABA(A) neurotransmission facilitates extinction consolidation. The involvement of GABA(A) receptors in fear extinction in the prefrontal cortex and amygdala is of particular interest, because of the role of these areas in emotional processes, and the role of the GABA(A) receptors in anxiety states.

The Role of the Amygdala and Olfaction in Unconditioned Fear in Developing Rats

Early in ontogeny, young rats must be able to detect dangerous stimuli and to exhibit appropriate defensive behaviors. Different nuclei of the amygdala mediate unconditioned and conditioned fear responses to threat in adult rats. The aim of this study was to determine the role of the amygdala in unlearned fear behavior in young rats. When exposed to an unfamiliar adult male rat, preweaning rat pups freeze, with peak levels on postnatal day 14 and declining levels on day 18. Pups were made anosmic to block olfactory input to the amygdala, and amygdala activation was assessed by quantifying the neuronal marker c-fos. Anosmic pups did not freeze in the presence of the male rat and had decreased c-fos expression in the medial amygdala on day 14 and in the medial and lateral amygdala on day 18. However, the decrease in freezing between days 14 and 18 was not associated with a decrease in c-fos expression in the medial amygdala. The medial and lateral amygdala were then inactivated by local muscimol infusion on day 14. Muscimol infusion into the medial amygdala decreased freezing to the male rat but not to a loud noise, whereas infusion into the lateral amygdala blocked freezing to a loud noise but not to the male. These findings indicate that different nuclei of the amygdala process sensory information of different modalities, mediate unconditioned freezing, and may be involved in developmental changes in the fear response in young rats.

Local distribution and toxicity of prolonged hippocampal infusion of muscimol

The activity of gamma-aminobutyric acid (GABA), the principal inhibitory neurotransmitter, is reduced in the hippocampus in patients with complex partial seizures from mesial temporal sclerosis. To provide preliminary safety and distribution data on using convection-enhanced delivery of agents to treat complex partial seizures and to test the efficacy and safety of regional selective neuronal suppression, the authors infused muscimol, a GABA-A receptor agonist, directly into the hippocampus of nonhuman primates using an integrated catheter electrode. Ten rhesus monkeys were divided into three groups: 1) use of catheter electrode alone (four monkeys); 2) infusion of escalating concentrations of muscimol followed by vehicle (three monkeys); and 3) infusion of vehicle and subsequent muscimol mixed with muscimol tracer (three monkeys). Infusions were begun 5 days after catheter electrode placement and continued for 5.6 days before switching to the other agent. Head magnetic resonance (MR) images and electroencephalography recordings were obtained before and during the infusions. Brain histological studies and quantitative autoradiography were performed. Neurological function was normal in controls and when muscimol concentrations were 0.125 mM or less, whereas higher concentrations (0.5 and 1 mM) produced reversible apathy and somnolence. Fluid distribution was demonstrated on MR images and muscimol distribution was demonstrated on autoradiographs throughout the hippocampus and adjacent white matter. Targeted modulation of neuronal activity is a reasonable research strategy for the investigation and treatment of medically intractable epilepsy.

NMDA receptor-dependent processes in the medial prefrontal cortex are important for acquisition and the early stage of consolidation during trace, but not delay eyeblink conditioning

Permanent lesions in the medial prefrontal cortex (mPFC) affect acquisition of conditioned responses (CRs) during trace eyeblink conditioning and retention of remotely acquired CRs. To clarify further roles of the mPFC in this type of learning, we investigated the participation of the mPFC in mnemonic processes both during and after daily conditioning using local microinfusion of the GABA(A) receptor agonist muscimol or the NMDA receptor antagonist APV into the rat mPFC. Muscimol infusions into the mPFC before daily conditioning significantly retarded CR acquisition and reduced CR expression if applied after sufficient learning. APV infusion also impaired acquisition of CRs, but not expression of well-learned CRs. When infusions were made immediately after daily conditioning, acquisition of the CR was partially impaired in both the muscimol and APV infusion groups. In contrast, rats that received muscimol infusions 3 h after daily conditioning exhibited improvement in their CR performance comparable to that of the control group. Both the pre- and post-conditioning infusion of muscimol had no effect on acquisition in the delay paradigm. These results suggest that the mPFC participates in both acquisition of a CR and the early stage of consolidation of memory in trace, but not delay eyeblink conditioning by NMDA receptor-mediated operations.

Hippocampal inactivation enhances taste learning

Learning tasks are typically thought to be either hippocampal-dependent (impaired by hippocampal lesions) or hippocampal-independent (indifferent to hippocampal lesions). Here, we show that conditioned taste aversion (CTA) learning fits into neither of these categories. Rats were trained to avoid two taste stimuli, one novel and one familiar. Muscimol infused through surgically implanted intracranial cannulae temporarily inactivated the dorsal hippocampus during familiarization, subsequent CTA training, or both. As shown previously, hippocampal inactivation during familiarization enhanced the effect of that familiarization on learning (i.e., hippocampal inactivation enhanced latent inhibition of CTA); more novel and surprising, however, was the finding that hippocampal inactivation during training sessions strongly enhanced CTA learning itself. These phenomena were not caused by specific aspects of our infusion technique--muscimol infusions into the hippocampus during familiarization sessions did not cause CTAs, muscimol infusions into gustatory cortex caused the expected attenuation of CTA, and hippocampal inactivation caused the expected attenuation of spatial learning. Thus, we suggest that hippocampal memory processes interfere with the specific learning mechanisms underlying CTA, and more generally that multiple memory systems do not operate independently.

Limbic System Participates in Mediating the Effects of General Anesthetics

In a previous study, we reported that inactivation of the medial septum or the hippocampus by muscimol, a GABA(A) receptor agonist, potentiated the effects of a general anesthetic. In this study, we further investigated whether other structures that are connected to the septohippocampal system are involved in mediating general anesthesia. In freely behaving rats, muscimol (0.25 microg) or saline was infused intracerebrally into one of four areas-the supramammillary area (SUM), nucleus accumbens (NAC), ventral pallidum (VP), and ventral tegmental area (VTA)-and righting, pain, and EEG responses were recorded following either halothane or sodium pentobarbital, representing inhalational and injectable general anesthetic, respectively. The effect of halothane (2%) or pentobarbital (20 mg/kg i.p.) in abolishing the righting, pain response, or low-voltage neocortical activity was enhanced, and the initial behavioral hyperactivity (delirium) was reduced, after muscimol as compared to after saline infusion in SUM, NAC, VP, and VTA. EEGs in the hippocampus and the sensorimotor cortex following halothane or pentobarbital showed increased delta, and decreased hippocampal theta and gamma waves after muscimol infusion as compared to saline infusion in SUM, NAC, VP, and VTA. By contrast, infusion of muscimol in the median raphe increased locomotion and did not significantly alter the behavioral or EEG effects of halothane or pentobarbital. It is suggested that structures that activate the limbic cortices (MS, SUM, and VTA but not the median raphe) or mediate the output of the hippocampus (NAC and VP) normally participate in maintaining consciousness and inactivation of these structures potentiates the response to a general anesthetic.

Hyperphagia induced by GABAA receptor-mediated inhibition of the nucleus accumbens shell: Dependence on intact neural output from the central amygdaloid region.

To investigate the role of corticolimbic input in modulating feeding-related nucleus accumbens (Acb) circuitry, researchers temporarily deactivated sites within the basolateral amygdaloid complex (BLA) or central amygdaloid region (CeA) via GABA(A) agonist (muscimol) infusions and measured feeding responses following muscimol infusions into the Acb shell. Hyperphagia elicited by intra-Acb shell muscimol was not altered by coinfusions of intra-BLA muscimol. In contrast, muscimol infusions into the CeA dose-dependently reduced feeding elicited either by intra-Acb shell GABA(A) receptor stimulation or by food deprivation and produced a syndrome of forepaw treading. Intra-CeA tetrodotoxin infusions also blocked intra-Acb shell muscimol-induced hyperphagia. Hence, feeding elicited by intra-Acb shell GABA(A) receptor stimulation requires intact neural output from the CeA but not the BLA.

Hippocampal inactivation disrupts the acquisition and contextual encoding of fear extinction.

In recent studies, inactivation of the dorsal hippocampus before the retrieval of extinguished fear memories disrupted the context-dependent expression of these memories. In the present experiments, we examined the role of the dorsal hippocampus in the acquisition of extinction. After pairing an auditory conditional stimulus (CS) with an aversive footshock [unconditional stimulus (US)], rats received an extinction session in which the CS was presented without the US. In experiment 1, infusion of muscimol, a GABAA receptor agonist, into the dorsal hippocampus before the extinction training session decreased the rate of extinction. Moreover, when later tested for fear to the extinguished CS, all rats that had received hippocampal inactivation before extinction training demonstrated renewed fear regardless of the context in which testing took place. This suggests a role for the dorsal hippocampus in both acquiring the extinction memory and encoding the CS-context relationship that yields the context dependence of extinction. In experiment 2, inactivation of the dorsal hippocampus before testing also disrupted the context dependence of fear to the extinguished CS. In experiment 3, quantitative autoradiography revealed the boundaries of muscimol diffusion after infusion into the dorsal hippocampus. Together, these results reveal that the dorsal hippocampus is involved in the acquisition, contextual encoding, and context-dependent retrieval of fear extinction. Learning and remembering when and where aversive events occur is essential for adaptive emotional regulation.

Inactivation of dorsolateral striatum enhances sensitivity to changes in the action–outcome contingency in instrumental conditioning

Actions become compulsive when they are no longer controlled by their consequences. Compulsivity can be assessed using the omission procedure in which animals are required to withhold a previously reinforced action to earn reward. The current study tested the hypothesis that inactivation of the dorsolateral striatum (DLS), a structure implicated in habitual behavior, can enhance sensitivity to changes in the action–outcome contingency during omission training, thus leading to a reduction in compulsive responding. Over 10 days rats were trained to press a freely available lever for sucrose reward delivered on interval schedules of reinforcement. After learning to press the lever at a stable and high rate, rats in the omission group received a session in which the rewards were now delayed by pressing the lever; i.e. withholding lever pressing resulted in increased access to reward. A control group was yoked to the omission group and received the same number and pattern of reward delivery but without the omission contingency. Half the rats in each group received infusions of vehicle into the DLS prior to this training whereas the remainder received an infusion of the GABA-A receptor agonist muscimol. On the next day, the effect of these treatments was assessed on a probe test in which the tendency of the various groups to press the lever was assessed in extinction and without drug infusion. Rats that received vehicle infusions prior to the omission session showed complete insensitivity to the newly imposed omission contingency. In contrast, rats given the infusion of muscimol selectively reduced lever pressing compared to yoked controls. Thus, extended training with interval schedules resulted in compulsive lever pressing that prevented the learning of the omission contingency, whereas inactivation of the DLS appeared to enhance the rats’ sensitivity to this change in the action–outcome contingency.

Hippocampal infusions of pyruvate reverse the memory-impairing effects of septal muscimol infusions

Hippocampal infusions of glucose reverse memory deficits in spontaneous alternation and in a continuous multiple trial inhibitory avoidance task. The current experiments tested whether glucose metabolism may participate in these effects of glucose. Specifically, these experiments determined whether the glycolytic metabolite pyruvate would mimic these effects of glucose. Male Sprague–Dawley rats were given septal infusions of vehicle or the gamma-aminobutyric acid (GABA) receptor agonist muscimol (0.15 nmol for spontaneous alternation or 5 nmol for continuous multiple trial inhibitory avoidance) combined with hippocampal infusions of vehicle or pyruvate (200 nmol) 15 min prior to assessing spontaneous alternation or training in a continuous multiple trial inhibitory avoidance task. The infusions of muscimol decreased percent alternation scores and continuous multiple trial inhibitory avoidance retention latencies tested 48 h after training. More importantly, hippocampal infusions of pyruvate reversed the deficits produced by septal infusions of muscimol on both tasks. These findings show for the first time that hippocampal infusions of pyruvate influence memory and suggest that glucose may affect memory via glycolytic metabolism.

The role of the GABA A agonist muscimol on memory performance: Reward contingencies determine the nature of the deficit

A matching-to-position (MTP) paradigm was altered to influence the type of associations a rat would use to solve the task. Our main behavioral manipulation was the application of the differential outcomes procedure (DOP). The DOP involves correlating each to-be-remembered event with a distinct reward condition. This procedure results in the development of unique reward expectancies that enhance and guide choice behavior. Such distinct reward expectancies are not formed when either a common or random assignment of reward is used (a non-differential outcomes procedure [NOP]). Intracerebroventricular infusions of the amnestic agent muscimol (GABA A agonist) or aCSF were delivered to male rats trained on a delayed MTP task that implemented either the DOP or the NOP. Muscimol impaired performance in a dose dependent fashion in both groups—but the nature of the deficit differed as a function of reinforcement cotingencies. Rats trained with the DOP displayed a non-mnemonic delay-independent impairment: performance at all delay intervals was disrupted. In contrast, NOP-trained rats displayed a delay-dependent impairment demonstrating that muscimol can also have memory-disrupting effects. The difference in pattern of impairment appears to be a function of the associations formed during training and the type of cognitive strategies involved in maintaining behavior on a conditional delayed discrimination task when reinforcement contingencies are varied. Thus, these results demonstrate that increasing GABA A receptor activation impairs a range of associative and memory functions.

Motor But Not Sensory Representation in Motor Cortex Depends on Postsynaptic Activity During Development and in Maturity

The movement representation in the primary motor cortex (M1) of the cat develops between postnatal weeks 7-12. The somatosensory representation in motor cortex is present by the age that the motor map begins to develop. In this study we examined the role of neural activity in development and maintenance of the M1 movement and somatosensory representations. We blocked activity of M1 neurons unilaterally for one month by intracortical infusion of the GABA agonist muscimol during the motor map development period in kittens and in mature cats. After the drug effects were no longer present, we used microstimulation and multiunit recording in the forelimb areas of M1 to determine the motor and somatosensory representations in the infused and noninfused sides. In both kittens and adults, there was a severe reduction or elimination of sites where microstimulation evoked a motor response in the inactivated compared with the control side. In contrast, there was no difference in the percentage, topography or receptive field modality of sites receiving somatosensory inputs on the inactivated and control sides. Moreover, the pattern of somatosensory input to M1 was similar before and after inactivation. This suggests that somatosensory input to M1 is stable after the connections initially develop. Since activity blockade had the same effects on the motor representation of kittens and adult cats, M1 neuronal activity, while possibly important in map development, is equally necessary for map maintenance.

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.

Unilateral Storage of Fear Memories by the Amygdala

Pavlovian fear conditioning is an associative learning task in which subjects are trained to respond defensively to a neutral conditioned stimulus (CS) by pairing it with an aversive unconditioned stimulus (US). This type of learning depends critically on the amygdala, and evidence suggests that synaptic plasticity within the lateral nucleus of the amygdala (LA) may be responsible for storing memories of the CS-US association. In the present study, we trained rats to fear an auditory CS by pairing it with a shock US delivered to one eyelid. Conditioning was assessed by measuring freezing responses evoked by the CS during a subsequent test session. The amygdala was unilaterally inactivated during either the training or the testing session by intracranial infusions of muscimol into the LA. We found that both acquisition and expression of conditioned freezing to the CS depended on the amygdala contralateral but not ipsilateral from the eyelid where the shock US was delivered. To explain this surprising result, we propose that the shock US is relayed from the eyelid to the amygdala via lateralized nociceptive sensory pathways, which causes memories of the CS-US association to be stored by the amygdala contralateral but not ipsilateral from the shocked eyelid. Our results demonstrate that the fear-learning circuitry of the amygdala is functionally lateralized according to the anatomical source of predicted threats. In future studies, the cellular mechanisms of emotional memory storage might be pinpointed by identifying cellular processes that occur only in the amygdala contralateral but not ipsilateral from the US during lateralized fear conditioning.

Intrahippocampal muscimol shifts learning strategy in gonadally intact young adult female rats

Learning strategy preferences depend upon circulating estrogen levels, with enhanced hippocampus-sensitive place learning coinciding with elevated estrogen levels. The effects of estrogen on strategy may be mediated by fluctuations in GABAergic function, given that inhibitory tone in the hippocampus is low when estrogen is high. We investigated the effects on learning strategy of intrahippocampal injections of a GABA(A) agonist in gonadally intact female rats. On the day of training, rats received 0.3 microL intrahippocampal infusions of muscimol (0.26 nmol or 2.6 nmol) or saline 20 min prior to training on a T-maze in which place (hippocampus-sensitive) or response (striatum-sensitive) strategies offer effective solutions. Muscimol treatment increased the use of the response strategy in a dose-dependent manner without influencing learning speed, indicating that muscimol modulated strategy and not learning ability. Furthermore, the muscimol-related shift to response strategies varied across the estrous cycle. The results indicate that increasing inhibition in the hippocampus biases rats away from hippocampus-sensitive place learning strategies and toward hippocampus-insensitive response learning strategies without a learning deficit. Furthermore, rats at proestrus demonstrated the most dramatic shift in learning strategy following muscimol treatment compared with control conditions, while rats at estrus demonstrated the most complete bias toward response strategies. The enhanced use of hippocampus-sensitive strategies at proestrus likely results from reduced hippocampal inhibition.