Molecular pattern of a decrease in the rewarding effect of cocaine after an escalating-dose drug regimen.

BACKGROUND: Long-term cocaine exposure leads to dysregulation of the reward system and initiates processes that ultimately weaken its rewarding effects. Here, we studied the influence of an escalating-dose cocaine regimen on drug-associated appetitive behavior after a withdrawal period, along with corresponding molecular changes in plasma and the prefrontal cortex (PFC). METHODS: We applied a 5 day escalating-dose cocaine regimen in rats. We assessed anxiety-like behavior at the beginning of the withdrawal period in the elevated plus maze (EPM) test. The reinforcement properties of cocaine were evaluated in the Conditioned Place Preference (CPP) test along with ultrasonic vocalization (USV) in the appetitive range in a drug-associated context. We assessed corticosterone, proopiomelanocortin (POMC), ß-endorphin, CART 55-102 levels in plasma (by ELISA), along with mRNA levels for D2 dopaminergic receptor (D2R), κ-receptor (KOR), orexin 1 receptor (OX1R), CART 55-102, and potential markers of cocaine abuse: miRNA-124 and miRNA-137 levels in the PFC (by PCR). RESULTS: Rats subjected to the escalating-dose cocaine binge regimen spent less time in the cocaine-paired compartment, and presented a lower number of appetitive USV episodes. These changes were accompanied by a decrease in corticosterone and CART levels, an increase in POMC and ß-endorphin levels in plasma, and an increase in the mRNA for D2R and miRNA-124 levels, but a decrease in the mRNA levels for KOR, OX1R, and CART 55-102 in the PFC. CONCLUSIONS: The presented data reflect a part of a bigger picture of a multilevel interplay between neurotransmitter systems and neuromodulators underlying processes associated with cocaine abuse.

Somatostatin and Somatostatin-Containing Interneurons-From Plasticity to Pathology.

Despite the obvious differences in the pathophysiology of distinct neuropsychiatric diseases or neurodegenerative disorders, some of them share some general but pivotal mechanisms, one of which is the disruption of excitation/inhibition balance. Such an imbalance can be generated by changes in the inhibitory system, very often mediated by somatostatin-containing interneurons (SOM-INs). In physiology, this group of inhibitory interneurons, as well as somatostatin itself, profoundly shapes the brain activity, thus influencing the behavior and plasticity; however, the changes in the number, density and activity of SOM-INs or levels of somatostatin are found throughout many neuropsychiatric and neurological conditions, both in patients and animal models. Here, we (1) briefly describe the brain somatostatinergic system, characterizing the neuropeptide somatostatin itself, its receptors and functions, as well the physiology and circuitry of SOM-INs; and (2) summarize the effects of the activity of somatostatin and SOM-INs in both physiological brain processes and pathological brain conditions, focusing primarily on learning-induced plasticity and encompassing selected neuropsychological and neurodegenerative disorders, respectively. The presented data indicate the somatostatinergic-system-mediated inhibition as a substantial factor in the mechanisms of neuroplasticity, often disrupted in a plethora of brain pathologies.

Somatostatin receptors (SSTR1-5) on inhibitory interneurons in the barrel cortex.

Inhibitory interneurons in the cerebral cortex contain specific proteins or peptides characteristic for a certain interneuron subtype. In mice, three biochemical markers constitute non-overlapping interneuron populations, which account for 80-90% of all inhibitory cells. These interneurons express parvalbumin (PV), somatostatin (SST), or vasoactive intestinal peptide (VIP). SST is not only a marker of a specific interneuron subtype, but also an important neuropeptide that participates in numerous biochemical and signalling pathways in the brain via somatostatin receptors (SSTR1-5). In the nervous system, SST acts as a neuromodulator and neurotransmitter affecting, among others, memory, learning, and mood. In the sensory cortex, the co-localisation of GABA and SST is found in approximately 30% of interneurons. Considering the importance of interactions between inhibitory interneurons in cortical plasticity and the possible GABA and SST co-release, it seems important to investigate the localisation of different SSTRs on cortical interneurons. Here, we examined the distribution of SSTR1-5 on barrel cortex interneurons containing PV, SST, or VIP. Immunofluorescent staining using specific antibodies was performed on brain sections from transgenic mice that expressed red fluorescence in one specific interneuron subtype (PV-Ai14, SST-Ai14, and VIP-Ai14 mice). SSTRs expression on PV, SST, and VIP interneurons varied among the cortical layers and we found two patterns of SSTRs distribution in L4 of barrel cortex. We also demonstrated that, in contrast to other interneurons, PV cells did not express SSTR2, but expressed other SSTRs. SST interneurons, which were not found to make chemical synapses among themselves, expressed all five SSTR subtypes.

Glutamate, GABA, and Presynaptic Markers Involved in Neurotransmission Are Differently Affected by Age in Distinct Mouse Brain Regions.

Molecular synaptic aging perturbs neurotransmission and decreases the potential for neuroplasticity. The direction and degree of changes observed in aging are often region or cell specific, hampering the generalization of age-related effects. Using real-time PCR and Western blot analyses, we investigated age-related changes in several presynaptic markers (Vglut1, Vglut2, Gad65, Gad67, Vgat, synaptophysin) involved in the initial steps of glutamatergic and GABAergic neurotransmission, in several cortical regions, in young (3-4 months old), middle-aged (1 year old), and old (2 years old) mice. We found age-related changes mainly in protein levels while, apart from the occipital cortex, virtually no significant changes in mRNA levels were detected, which suggests that aging acts on the investigated markers mainly through post-transcriptional mechanisms depending on the brain region. Principal component analysis (PCA) of protein data revealed that each brain region possessed a type of "biochemical distinctiveness" (each analyzed brain region was best characterized by higher variability level of a particular synaptic marker) that was lost with age. Analysis of glutamate and γ-aminobutyric acid (GABA) levels in aging suggested that mechanisms keeping an overall balance between the two amino acids in the brain are weakened in the hippocampus. Our results unravel the differences in mRNA/protein interactions in the aging brain.

Stress changes amphetamine response, D2 receptor expression and epigenetic regulation in low-anxiety rats.

The aim of this study was to assess the influence of chronic restraint stress on amphetamine (AMPH)-related appetitive 50-kHz ultrasonic vocalisations (USVs) in rats differing in freezing duration in a contextual fear test (CFT), i.e. HR (high-anxiety responsive) and LR (low-anxiety responsive) rats. The LR and the HR rats, previously exposed to an AMPH binge experience, differed in sensitivity to AMPH's rewarding effects, measured as appetitive vocalisations. Moreover, chronic restraint stress attenuated AMPH-related appetitive vocalisations in the LR rats but had no influence on the HR rats' behaviour. To specify, the restraint LR rats vocalised appetitively less in the AMPH-associated context and after an AMPH challenge than the control LR rats. This phenomenon was associated with a decrease in the mRNA level for D2 dopamine receptor in the amygdala and its protein expression in the basal amygdala (BA) and opposite changes in the nucleus accumbens (NAc) - an increase in the mRNA level for D2 dopamine receptor and its protein expression in the NAc shell, compared to control conditions. Moreover, we observed that chronic restraint stress influenced epigenetic regulation in the LR and the HR rats differently. The contrasting changes were observed in the dentate gyrus (DG) of the hippocampus - the LR rats presented a decrease, but the HR rats showed an increase in H3K9 trimethylation. The restraint LR rats also showed higher miR-494 and miR-34c levels in the NAc than the control LR group. Our study provides behavioural and biochemical data concerning the role of differences in fear-conditioned response in stress vulnerability and AMPH-associated appetitive behaviour. The LR rats were less sensitive to the rewarding effects of AMPH when previously exposed to chronic stress that was accompanied by changes in D2 dopamine receptor expression and epigenetic regulation in mesolimbic areas.

Differences in the dopaminergic reward system in rats that passively and actively behave in the Porsolt test.

The aim of the study was to assess appetitive responses and central dopaminergic neurotransmission in passive and active rats divided according to their immobility time in the Porsolt swim test and exposed to restraint stress. Passive rats had more episodes of appetitive 50-kHz ultrasonic vocalization (USV) during rat encounter after social isolation and spent significantly more time in the amphetamine-associated context in conditioned place preference test, compared to active rats. Restraint stress decreased sucrose preference, but increased appetitive vocalization and reinforced the conditioned place preference only in passive animals that was associated with increased dopamine concentration in the amygdala. Restraint stress increased also the level of Cocaine- and Amphetamine Regulated Transcript (CART) peptide, a neuromodulator linked to dopamine neurotransmission, in the central nucleus of amygdala, while decreasing it the nucleus accumbens shell in passive rats. In the parvocellular region of paraventricular nucleus of the hypothalamus passive animals had a higher expression of CART compared to passive restraint rats and active control rats. The obtained results show that active and passive rats in the Porsolt test differ significantly in response to appetitive stimuli, which can be additionally changed under stress conditions. The underlying mechanisms are probably associated with differences in dopaminergic activity and CART signaling in reward system.

Somatostatin receptors in the brain.

Somatostatin is a peptide that participates in numerous biochemical and signaling pathways. It functions via receptors (SSTRs1-5), which belong to the family of receptors coupled with protein G. All somatostatin receptors are characterized by a certain degree of homology in molecular structure. The cell effects of their agonists in peripheral tissues rely mainly on the inhibition of the hormones release. Somatostatin is also an important neuromodulator and neurotransmitter. SSTRs may affect other receptors, forming structural and functional homodimers and heterodimers. SSTRs play also role in the regulation of physiological processes, such as itching and pain, reproductive functions, regulation of feeding or mood. Besides physiological functions, SSTRs contribute also to the pathogenesis of glial tumors, neurodegenerative diseases, or post hemorrhagic stroke changes. Recent years of research have provided new data regarding the role of somatostatin receptor signaling pathways in the brain and the knowledge in this field is developing rapidly.

The space where aging acts: focus on the GABAergic synapse.

As it was established that aging is not associated with massive neuronal loss, as was believed in the mid-20th Century, scientific interest has addressed the influence of aging on particular neuronal subpopulations and their synaptic contacts, which constitute the substrate for neural plasticity. Inhibitory neurons represent the most complex and diverse group of neurons, showing distinct molecular and physiological characteristics and possessing a compelling ability to control the physiology of neural circuits. This review focuses on the aging of GABAergic neurons and synapses. Understanding how aging affects synapses of particular neuronal subpopulations may help explain the heterogeneity of aging-related effects. We reviewed the literature concerning the effects of aging on the numbers of GABAergic neurons and synapses as well as aging-related alterations in their presynaptic and postsynaptic components. Finally, we discussed the influence of those changes on the plasticity of the GABAergic system, highlighting our results concerning aging in mouse somatosensory cortex and linking them to plasticity impairments and brain disorders. We posit that aging-induced impairments of the GABAergic system lead to an inhibitory/excitatory imbalance, thereby decreasing neuron's ability to respond with plastic changes to environmental and cellular challenges, leaving the brain more vulnerable to cognitive decline and damage by synaptopathic diseases.

Somatostatin and Somatostatin-Containing Neurons in Shaping Neuronal Activity and Plasticity.

Since its discovery over four decades ago, somatostatin (SOM) receives growing scientific and clinical interest. Being localized in the nervous system in a subset of interneurons somatostatin acts as a neurotransmitter or neuromodulator and its role in the fine-tuning of neuronal activity and involvement in synaptic plasticity and memory formation are widely recognized in the recent literature. Combining transgenic animals with electrophysiological, anatomical and molecular methods allowed to characterize several subpopulations of somatostatin-containing interneurons possessing specific anatomical and physiological features engaged in controlling the output of cortical excitatory neurons. Special characteristic and connectivity of somatostatin-containing neurons set them up as significant players in shaping activity and plasticity of the nervous system. However, somatostatin is not just a marker of particular interneuronal subpopulation. Somatostatin itself acts pre- and postsynaptically, modulating excitability and neuronal responses. In the present review, we combine the knowledge regarding somatostatin and somatostatin-containing interneurons, trying to incorporate it into the current view concerning the role of the somatostatinergic system in cortical plasticity.

Learning-Dependent Plasticity of the Barrel Cortex Is Impaired by Restricting GABA-Ergic Transmission.

Experience-induced plastic changes in the cerebral cortex are accompanied by alterations in excitatory and inhibitory transmission. Increased excitatory drive, necessary for plasticity, precedes the occurrence of plastic change, while decreased inhibitory signaling often facilitates plasticity. However, an increase of inhibitory interactions was noted in some instances of experience-dependent changes. We previously reported an increase in the number of inhibitory markers in the barrel cortex of mice after fear conditioning engaging vibrissae, observed concurrently with enlargement of the cortical representational area of the row of vibrissae receiving conditioned stimulus (CS). We also observed that an increase of GABA level accompanied the conditioning. Here, to find whether unaltered GABAergic signaling is necessary for learning-dependent rewiring in the murine barrel cortex, we locally decreased GABA production in the barrel cortex or reduced transmission through GABAA receptors (GABAARs) at the time of the conditioning. Injections of 3-mercaptopropionic acid (3-MPA), an inhibitor of glutamic acid decarboxylase (GAD), into the barrel cortex prevented learning-induced enlargement of the conditioned vibrissae representation. A similar effect was observed after injection of gabazine, an antagonist of GABAARs. At the behavioral level, consistent conditioned response (cessation of head movements in response to CS) was impaired. These results show that appropriate functioning of the GABAergic system is required for both manifestation of functional cortical representation plasticity and for the development of a conditioned response.

Inhibition of Tnf-α R1 signaling can rescue functional cortical plasticity impaired in early post-stroke period.

Tumor necrosis factor-α (TNF-α) is one of the key players in stroke progression and can interfere with brain functioning. We previously documented an impairment of experience-dependent plasticity in the cortex neighboring the stroke-induced lesion, which was accompanied with an upregulation of Tnf-α level in the brain of ischemic mice 1 week after the stroke. Because TNF receptor 1 (TnfR1) signaling is believed to be a major mediator of the cytotoxicity of Tnf-α through activation of caspases, we used an anti-inflammatory intervention aimed at Tnf-α R1 pathway, in order to try to attenuate the detrimental effect of post-stroke inflammation, and investigated if this will be effective in protecting plasticity in the infarct proximity. Aged mice (12-14 months) were subjected to the photothrombotic stroke localized near somatosensory cortex, and immediately after ischemia sensory deprivation was introduced to induce plasticity. Soluble TNF-α R1 (sTNF-α R1), which competed for TNF-α with receptors localized in the brain, was delivered chronically directly into the brain tissue for the whole period of deprivation using ALZET Micro-Osmotic pumps. We have shown that such approach undertaken simultaneously with the stroke reduced the level of TNF-α in the peri-ischemic tissue and was successful in preserving the post-stroke deprivation-induced brain plasticity.

Altered glutamate/GABA equilibrium in aged mice cortex influences cortical plasticity.

Age-related molecular changes in the synapse can cause plasticity decline. We found an impairment of experience-dependent cortical plasticity is induced by short lasting sensory conditioning in aged mice. However, extending the training procedure from 3 to 7 days triggered plasticity in the aged cortex of the same range as in young mice. Additionally, GABAergic markers (GABA, GAD67, VGAT) in young and aged groups that showed the plastic changes were upregulated. This effect was absent in the aged group with impaired plasticity, while the expression of Vglut1 increased in all trained groups. This may reflect the inefficiency of inhibitory mechanisms in the aging brain used to control increased excitation after training and to shape proper signal to noise ratio, which is essential for appropriate stimuli processing. HPLC analysis showed that the glutamate/GABA ratio was significantly reduced in aged animals due to a significant decrease in glutamate level. We also observed a decreased expression of several presynaptic markers involved in excitatory (vesicular glutamate transporter-vglut2) and inhibitory (glutamic acid decarboxylase-GAD67, vesicular GABA transporter VGAT) transmission in the aged barrel cortex. These changes may weaken the plasticity potential of neurons and impede the experience-dependent reorganization of cortical connections. We suggest that the imbalance toward inhibition resulting from a decrease of glutamate content in the aging cerebral cortex, together with GABAergic system ineffectiveness in upregulating GABA level after sensory training, contributes to the impairment of learning-dependent cortical plasticity.

Functional assessment of sensory functions after photothrombotic stroke in the barrel field of mice.

Motor, sensory and cognitive deficits are common impairments observed in human stroke as well as in animal stroke models. Using a battery of behavioural tests we assessed sensorimotor deficits after photothrombotic stroke localized within or beyond cortical representation of mouse sensory vibrissae. We found restricted, modality specific behavioural consequences in the acute post-stroke period. Among incorporated tests, adhesive removal test, novelty exploration test and sensory labyrinth task were sensitive to the somatosensory cortical deficits. Injured animals explored new objects significantly longer, they also needed distinctly more time to contact and to remove the adhesive tape placed on whiskers contralateral to the infarct. Moreover, we observed that after stroke animals were unable to solve the sensory labyrinth depending only upon tactile sensation from whiskers with injured cortical representation. Spontaneous recovery could be observed within the first post-stroke week for adhesive tape removal and within 14 days for labyrinth performance. However, for the novel object exploration we did not observed the recovery for the period of 18 days after stroke. Moreover, new object exploration test performance differed between the somatosensory and visual cortical impairments. We suggest that those three tests might be valuable in assessing the usefulness of therapies designed to support brain repair after experimental stroke.

Influence of inflammation on poststroke plasticity.

Age-related brain injuries including stroke are a leading cause of morbidity and mental disability worldwide. Most patients who survive stroke experience some degree of recovery. The restoration of lost functions can be explained by neuronal plasticity, understood as brain ability to reorganize and remodel itself in response to changed environmental requirements. However, stroke triggers a cascade of events which may prevent the normal development of the plastic changes. One of them may be inflammatory response initiated immediately after stroke, which has been found to contribute to neuronal injury. Some recent evidence though has suggested that inflammatory reaction can be also neuroprotective. This paper attempts to discuss the influence of poststroke inflammatory response on brain plasticity and stroke outcome. We also describe the recent anti-inflammatory strategies that have been effective for recovery in experimental stroke.

Experience-dependent brain plasticity after stroke: effect of ibuprofen and poststroke delay.

Despite indications that brain plasticity may be enhanced after stroke, we have described impairment of experience-dependent plasticity in rat cerebral cortex neighboring the stroke-induced lesion. Photothrombotic stroke was centered behind the barrel cortex in one cerebral hemisphere of rats. Plasticity of cortical representation of one row of vibrissae was induced by sensory deprivation of all surrounding whiskers for 1 month, and visualized with [(14)C]-2-deoxyglucose autoradiography. In control rats deprivation resulted in an enlargement of functional cortical representation of the spared row of vibrissae. After a focal stroke neighbouring the barrel cortex, no plasticity of the spared row representation was found. Investigation of plastic changes with deprivation initiated 1 week and 1 month after stroke have shown that later poststroke onset of deprivation resulted in a partial recovery of cortical plasticity in the barrel field. Western blot analysis of proinflammatory enzyme cyclooxygenase-2 (COX-2) expression revealed its strong upregulation in the barrel cortex 24 h after stroke. When chronic treatment with the anti-inflammatory drug ibuprofen (10 mg/kg or 20 mg/kg) accompanied deprivation, plasticity was restored. Ibuprofen applied before the ischemia also prevented the poststroke upregulation of COX-2. The results strongly suggest that poststroke impairment of experience-dependent cortical plasticity is caused by stroke-induced inflammatory reactions that subside with poststroke delay and can be at least partially ameliorated by pharmacological treatment.

Comparison of matrix metalloproteinase activation after focal cortical ischemia in young adult and aged mice.

Matrix metalloproteinase (MMP) activity is implicated in the degradation of the extracellular matrix during cerebral ischemia. Although many studies have demonstrated spatiotemporal patterns of activation of gelatinases (MMP-9 and MMP-2) after ischemic stroke in young adult rodents, no data exist on MMP activity in old brains. In this study, we investigated the gelatinolytic activity in young adult (3-month-old) and aged (1-year-old) mice subjected to photothrombotic stroke. Using in situ zymography and gel zymography, we found that the basal gelatinolytic activity in the intact cerebral cortex was similar at both investigated ages. Similarly, after photothrombosis, the increased gelatinolytic response up to 7 days poststroke was the same in young and aged brains. At both ages, early activation of gelatinolysis in the ischemic core and the perilesional area was present in neuronal nuclei as revealed by colocalization of gelatinolytic product with NeuN immunostaining and DAPI. Additionally, application of specific antibodies against MMP-9 and MMP-2 revealed the increase in MMP-9 immunoreactivity in cell nuclei as early as 4 hr poststroke. No differences between young and aged mice were observed concerning the level and localization of MMP-9 immunoreactivity. The lack of age-related differences in the degree and pattern of activation of gelatinolysis after focal stroke and the lack of correspondence between the results of in situ and gel zymography suggest that extracellular proteolysis is not directly responsible for the more severe outcome of ischemic stroke in aged subjects.

Bilateral plasticity of Vibrissae SII representation induced by classical conditioning in mice.

The somatosensory cortex in mice contains primary (SI) and secondary (SII) areas, differing in somatotopic precision, topographic organization, and function. The role of SII in somatosensory processing is still poorly understood. SII is activated bilaterally during attentional tasks and is considered to play a role in tactile memory and sensorimotor integration. We measured the plasticity of SII activation after associative learning based on classical conditioning, in which unilateral stimulation of one row of vibrissae was paired with a tail shock. The training consisted of three daily 10 min sessions, during which 40 pairings were delivered. Cortical activation driven by stimulation of vibrissae was mapped with 2-[(14)C]deoxyglucose (2DG) autoradiography 1 d after the end of conditioning. We reported previously that the conditioning procedure resulted in unilateral enlargement of 2DG-labeled cortical representation of the "trained" row of vibrissae in SI. Here, we measured the width and intensity of the labeled region in SII. We found that both measured parameters in SII increased bilaterally. The increase was observed in cortical layers II/III and IV. Apparently, plasticity in SII is not a simple reflection of changes in SI. It may be attributable to bilateral integrative role of SII, its lesser topographical specificity, and strong involvement in attentional processing.

Impairment of experience-dependent cortical plasticity in aged mice.

This study addresses the relationship between aging and experience-dependent plasticity in the mouse somatosensory cortex. Plasticity in the cortical representation of vibrissae (whiskers) was investigated in young (3 months), mature (14 months) and old (2 years) mice using [14C]2-deoxyglucose (2-DG) autoradiography. Plastic changes were evoked using two experimental paradigms. The deprivation-based protocol included unilateral deprivation of all but one row of whiskers for a week. In the conditioning protocol the animals were subjected to classical conditioning, where tactile stimulation of one row of whiskers was paired with an aversive stimulus. Both procedures evoked functional plasticity in the young group, expressed as a widening of the functional cortical representation of the spared or conditioned row. Aging had a differential effect on these two forms of plasticity. Conditioning-related plasticity was more vulnerable to aging: the plastic change was not detectable in mature animals, even though they acquired the behavioral response. Deprivation-induced plasticity also declined with age, but some effects were persistent in the oldest animals.

Involvement of retrosplenial cortex in classical conditioning.

The cingulate cortex, which comprises of two major subdivisions - anterior cingulate cortex (CG) and retrosplenial cortex (RSP), is implicated in many cognitive functions. The RSP is an important node in the systemic integration network. Studies point to its role in learning that involves spatial stimuli and navigation. Relatively little is known about its involvement in simple learning such as classical conditioning. We examined the involvement of the two cytoarchitectonic divisions, agranular and granular, of the rostral and caudal RSP in a delay conditioning, where stimulation of the facial vibrissae was paired with a tail shock. During the conditioning session the [(14)C]-2-deoxyglucose (2DG) brain mapping was performed. Effectiveness of conditioning was assessed with frequency of head movements, which decreased in the course of the conditioning. 2DG uptake in RSP and additionally in CG was examined in conditioned, pseudoconditioned and stimulated control groups. The metabolic labeling was elevated in caudal and rostral both RSP and CG in the conditioned group, but not in animals which received CS or UCS alone. Comparison between conditioned and pseudoconditioned groups showed the specific activation by associative learning in both divisions of the rostral RSP and rostral CG. Counts of c-Fos expressing nuclei confirmed activation of the rostral RSP in the CS+UCS group. These data support the concept of RSP as structure that, besides its recognized role in visuospatial learning, monitors and reacts to activity of brain systems responsible for other types of learning and, together with CG, subserve cognitive processes, with simple associative learning among them.

Associative pairing involving monocular stimulation selectively mobilizes a subclass of GABAergic interneurons in the mouse visual cortex.

Levels of gamma-aminobutyric acid (GABA) and its synthesizing enzyme in cerebral cortex are regulated by sensory experience. Previously we found that associative pairing of vibrissae stimulation and tail shock results in upregulation of GABAergic markers in the mouse barrel cortex. In order to ascertain whether GABAergic upregulation also accompanies associative pairing in other sensory modalities, we examined the mouse visual cortex after analogous training with visual stimulus. During pairing, visual stimulus (CS) was coupled with a tail shock (UCS). We examined the density of cells expressing glutamic acid decarboxylase (GAD) and parvalbumin (PV) in monocular and binocular segments of the primary visual cortex (V1). The auditory cortex was used as a control. After monocular training, the density of cells expressing GAD rose significantly in the monocular segment of V1 contralateral to the stimulated eye, compared with the opposite hemisphere. This effect was due to the association of CS and UCS, as no changes were found after visual stimulation alone or in the auditory cortex. No changes were noted in the density of PV(+) neurons, so the effect was attributed to GAD(+)/PV(-) neurons. Mobilization of a specific subclass of GABAergic cells, observed after associative pairing in the somatosensory and visual cortices, may reflect the necessity to restrict the activity of circuits involved in sensory association.