Involvement of the ventral tegmental area in the inhibitory avoidance memory in rats

The ventral tegmental area (VTA) is a neural structure that sends strong efferent projections to the hippocampus. Output from the VTA can affect hippocampal-dependent neural processes that are critical for learning and memory, including long term potentiation and theta activity. However, no study to date has elucidated what role the VTA plays in mediating the different stages of learning and memory. Therefore, the current study was designed to assess how reversible inactivation of the VTA may affect the acquisition, consolidation and retrieval of memory in rats using an inhibitory avoidance (IA) task. In this experiment, rats with chronically implanted cannulae aimed at the VTA were trained on an inhibitory avoidance task. They received intra-VTA infusions of lidocaine or saline immediately before training, after training or before a memory retention test. The results indicate that inactivation of the VTA prior to the first acquisition session increased the number of trials rats required to reach the acquisition criterion. Similarly, inactivation of the VTA after acquisition training decreased the step-through latency and increased the amount of time spent in the dark compartment relative to the saline-treated group. However, inactivation of the VTA immediately prior to the memory retention test failed to alter either step-through latency or the amount of time spent in the dark compartment. Overall, these results suggest the VTA facilitates the acquisition and consolidation of IA learning and memory.     

Modulation of DNA synthesis by muscarinic cholinergic receptors

Acetylcholine muscarinic receptors are a family of five G-protein-coupled receptors widely distributed in the central nervous system and in peripheral organs. Activation of certain subtypes of muscarinic receptors (M1, M3, M5) has been found to modulate DNA synthesis in a number of cell types. In several cell types acetylcholine, by activating endogenous or transfected muscarinic receptors, can indeed elicit cell proliferation. In other cell types, however, or under different experimental conditions, activation of muscarinic receptors has no effect, or inhibits DNA synthesis. A large number of intracellular pathways are being investigated to define the mechanisms involved in these effects of muscarinic receptors; these include among others, phospholipase D, protein kinases C and mitogen-activated-protein kinases. The ability of acetylcholine to modulate DNA synthesis through muscarinic receptors may be relevant in the context of brain development and neoplastic growth.     

Effect of lithium on morphine state-dependent memory of passive avoidance in mice

In the present study, effects of lithium chloride (LiCl) on morphine induced state-dependent memory of passive avoidance task were examined in mice. One-trial step-down paradigm was used for the assessment of memory retention in adult male NMRI mice. Administration of morphine (5 mg/kg) subcutaneously (s.c.) 30 min before training or testing induced impairment of memory performance. Injection of the same dose of the drug 30 min before testing restored memory retention impaired under pre-training morphine effect. Intraperitoneal (i.p.) injection of lithium, 60 min before training or prior to testing also impaired memory performance. Under the pre-training of morphine, the response of the opioid was restored when animals received LiCl (80 and 160 mg/kg) as pre-test injection. Pre-training administration of lower dose of lithium (20 mg/kg), but not the higher doses of the drug (80 and 160 mg/kg) impaired memory retention in passive avoidance test. LiCl-induced impairment of memory retention was restored by pre-test administration of morphine. In the animals receiving pre-training morphine, combined pre-test morphine and LiCl administration increased the restoration of memory by the opioid. It can be concluded that there may be a cross-state dependency between morphine and lithium.     

Metabotropic glutamate and muscarinic cholinergic receptor-mediated preferential inhibition of N-methyl-D-aspartate component of transmissions in rat ventral tegmental area

Presynaptic inhibition is one of the major control mechanisms in the CNS. Our laboratory recently reported that presynaptic GABA(B) and adenosine A(1) receptors mediate a preferential inhibition on N-methyl-D-aspartate receptor-mediated excitatory postsynaptic currents recorded in rat midbrain dopamine neurons. Here we extended these findings to metabotropic glutamate and muscarinic cholinergic receptors. Intracellular voltage clamp recordings were made from dopamine neurons in rat ventral tegmental area in slice preparations. (+/-)-1-Aminocyclopentane-trans-1,3-dicarboxylic acid (agonist for groups I and II metabotropic glutamate receptors) and L(+)-2-amino-4-phosphonobutyric acid (L-AP4; agonist for group III metabotropic glutamate receptors) were significantly more potent for inhibiting N-methyl-D-aspartate receptor-mediated excitatory postsynaptic currents, as compared with inhibition of excitatory postsynaptic currents mediated by alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors. Such preferential inhibition of the N-methyl-D-aspartate component was also observed for muscarine (agonist for muscarinic cholinergic receptors). Inhibitory effects of (+/-)-1-aminocyclopentane-trans-1,3-dicarboxylic acid, L-AP4, and muscarine were blocked reversibly by their respective antagonists [(RS)-alpha-methyl-4-carboxyphenylglycine, (RS)-alpha-methyl-4-phosphonophenylglycine, and 1,1-dimethyl-4-diphenylacetoxypiperidinium iodide]. In addition, all three agonists increased the ratio of excitatory postsynaptic currents in paired-pulse studies and did not reduce currents induced by exogenous N-methyl-D-aspartate and alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid. Interestingly, the glutamate release stimulator 4-aminopyridine (30 microM) and the glutamate uptake inhibitor L-anti-endo-3,4-methanopyrrolidine dicarboxylate (300 microM) preferentially increased the amplitude of N-methyl-D-aspartate excitatory postsynaptic currents.Thus, agonists for metabotropic glutamate and muscarinic cholinergic receptors act presynaptically to cause a preferential reduction in the N-methyl-D-aspartate component of excitatory synaptic transmissions. Together with the evidence for GABA(B) and adenosine A(1) receptor-mediated preferential inhibition of the N-methyl-D-aspartate component, the present results suggest that limiting glutamate spillover onto postsynaptic N-methyl-D-aspartate receptors may be a general rule for presynaptic modulation in midbrain dopamine neurons.     

Electrophysiological evidence for excitation of rat ventral tegmental area dopamine neurons by morphine

A considerable body of evidence indicates that opiates have an important influence on midbrain dopaminergic neurons. However, little data exist concerning the effects of opiates on the activity of single dopaminergic neurons, particularly the dopaminergic neurons of the ventral tegmental area. Firing rates of mesencephalic dopaminergic neurons were recorded extracellularly, and the effects of morphine, administered systemically or applied locally onto dopaminergic cells, were tested in paralyzed, unanesthetized or chloral hydrate anesthetized rats. In general, dopaminergic neurons were excited by both systemically and locally applied morphine. When mesencephalic dopaminergic neurons were subdivided into substantia nigra zona compacta (A9) and ventral tegmental area (A10) neurons, A10 neurons were excited 2–3 times more than A9 neurons by systemic morphine. Systemic administration of the specific opiate antagonist, naloxone, in large part reversed the effects of morphine. Microiontophoretic or micropressure ejection of morphine caused an apparent depolarization-induced excitation of both A10 and A9 dopaminergic neurons.These results provide direct evidence that morphine increases impulse flow of A10 dopaminergic neurons, which are known to be involved in locomotor stimulant and positive reinforcement effects of opiates.     

Anti-opioid effects of neuropeptide FF receptors in the ventral tegmental area

The present study investigates the modulatory effects of neuropeptide FF (NPFF) receptors on the mesolimbic dopaminergic pathway controlled by opioid receptors. A stable NPFF₂ receptor agonist, dNPA, was injected into the ventral tegmental area (VTA) and the release of dopamine and serotonin within the nucleus accumbens (NAc), induced by intraperitoneal injection of morphine, was monitored using the brain microdialysis, in non-constrained rat. dNPA decreased systemic morphine-induced elevation of dopamine and serotonin metabolites within the NAc. Furthermore, co-injected with morphine into the VTA, NPFF inhibited morphine-induced stereotypy 60–120 min after the injection. This neurochemical and behavioural anti-opioid effect mediated by NPFF₂ receptors at the level of VTA suggests the involvement of NPFF in the rewarding effects of opiates on the mesolimbic dopamine system.     

Anti-opioid effects of neuropeptide FF receptors in the ventral tegmental area

The aim of this study was to establish the modulation pattern of the soleus H-reflex and excitability changes of interneurones mediating presynaptic inhibition from tibialis anterior to soleus Ia afferents when the right foot approached and withdrew from a step in standing humans. The task was conducted at 40 beats per minute, and this tempo corresponded to the rhythm of a half full movement cycle. Each subject was instructed not to load and not to move forward. Soleus H-reflexes were elicited once in every full movement cycle that lasted approximately 3s. The ipsilateral knee joint angle and activity of leg muscles were recorded through a twin-axis goniometer and surface EMG, respectively. In all subjects, the soleus H-reflex was modulated in a phase-dependent pattern. The H-reflex was significantly depressed during the approach phase of the motor task and when the foot was on the step, and facilitated during the withdrawal phase and when the foot was on the ground. The soleus H-reflex conditioned by common peroneal nerve stimulation at tibialis anterior motor threshold at a long conditioning test interval was increased during the withdrawal phase or while the foot was on the ground suggesting that presynaptic inhibition was decreased. In most subjects, knee extensor activity was small, while ankle flexors and extensors were active in a reciprocal pattern. This study provides evidence that the soleus H-reflex is modulated in a phasic pattern during one-legged foot reaching and withdrawal by changes occurring at a premotoneuronal level.     

Further characterizations of the nature of the behavioral and neurochemical effects of lesions to the nucleus basalis of Meynert in the rat

Converging lines of evidence indicate an important role for the basal forebrain cholinergic system in memory processes. The principal origin of the cholinergic projection to the neocortex appears to be the magnocellular neurons in the region of the nucleus basalis of Meynert (NbM). We examined the effects of bilateral lesions of the NbM on retention of shock avoidance training by stereotaxically injecting rats with 0.5 microliter of ibotenic acid (14 micrograms/microliter) into the NbM. Two weeks later rats were given passive avoidance training and tested for retention of the original avoidance habit 5 min, 30 min, or 24 hr later. Rats with lesions of the NbM showed significantly impaired shock avoidance performance compared to non-operated controls at both 30 min and 24 hr, but not at 5 min after training. Lesioned animals also showed a significant decrease in cortical choline acetyltransferase (CAT) and acetylcholinesterase (AChE) activities. No differences in muscarinic receptor binding or plasma cholinesterase activity was observed. The results demonstrate the usefulness of NbM lesions as a model for studying the role of the basal forebrain cholinergic system in memory processes.     

Development of amygdaloid cholinergic mediation of passive avoidance learning in the rat

Summary Passive avoidance learning was studied in young rats 13–30 days of age following bilateral injections of saline or antimuscarinic and/or muscarinic agents into three amygdaloid nuclei — lateral (L), basolateral (BL), and cortical (CO). While acquisition was not influenced by saline injections into various other cerebral structures, it was significantly altered by similar injections into these amygdaloid nuclei, especially by those into the BL nucleus, suggesting that this nucleus is particularly involved in passive avoidance learning. Atropine induced significant deficits from as early as 13 days on. These deficits increased and were of similar strength after injections into any of the three studied nuclei until day 16; after that age, they diminished slightly following CO and L nuclei administration, while remaining substantial after BL nucleus injections at all ages, even at 30 days. No facilitatory effects could be elicited by arecoline injected alone, while arecoline could antagonize the disturbing effect of atropine, when given in combination, from day 13 on. These results suggest a muscarinic cholinergic mediation of passive avoidance learning through the synaptic elements located in the basal lateral part of the amygdala in the young rat.     

Potential roles of GABA receptors in morphine self-administration in rats

It is well established that the reinforcing effect of drugs of abuse is linked to the mesolimbic dopamine (DA) system. Morphine produces an increase in DA release in the brain, which may provide positive reinforcement contributing to the development of motivational aspects of drug-seeking and maintenance behavior. Several studies suggest that the GABA receptor system may play a significant role in the modulating the mesolimbic DA system. The purpose of this study was to investigate potential roles for GABA agonists in morphine self-administration behavior. Male Sprague-Dawley rats were trained to self-administrated morphine (0.1 mg/kg per injection) during daily 1-h sessions under a fixed ratio 1 schedule. Rats received an intravenous injection of the selective GABA(B) antagonist SCH 50911 (2.0 mg/kg) or an intraperitoneal injection of the GABA(A) antagonist bicuculline (1.0 mg/kg), immediately followed by either an intraperitoneal injection of baclofen (1.25 or 1.8 mg/kg) or muscimol (0.5 or 1.0 mg/kg, i.p.), 30 min prior to the start of test session. Results showed that pretreatment with baclofen or muscimol reduced morphine-maintenance response in a dose-dependent fashion and that baclofen and muscimol effects were reversed by injections of SCH 50911 and bicuculline, respectively. These data suggest that activation of both GABA(A) and GABA(B) receptors may be effective in suppressing the reinforcing effects of morphine.     

Dual modulation of gabaergic transmission by metabotropic glutamate receptors in rat ventral tegmental area

The effects of metabotropic glutamate receptor (mGluR) activation on non-dopamine (putative GABAergic) neurons and inhibitory synaptic transmission in the ventral tegmental area were examined using intracellular recordings from rat midbrain slices. Perfusion of (+/-)-1-aminocyclopentane-trans-1,3-dicarboxylic acid (t-ACPD; agonist for group I and II mGluRs), but not L-amino-4-phosphonobutyric acid (L-AP4; agonist for group III mGluRs), produced membrane depolarization (current clamp) and inward current (voltage clamp) in non-dopamine neurons. The t-ACPD-induced depolarization was concentration-dependent (concentration producing 50% maximal depolarization [EC(50)]=6.1+/-2.5 microM), and was blocked by the antagonist (+/-)-alpha-methyl-4-carboxyphenylglycine, but not by tetrodotoxin and ionotropic glutamate-receptor antagonists. The t-ACPD-evoked responses were mimicked comparably by selective group I mGluR agonist (RS)-3,5-dihydroxyphenylglycine (DHPG). Furthermore, the DHPG-induced depolarization in non-dopamine neurons was greatly reduced by mGluR1-specific antagonist 7(hydroxyimino)cyclopropachromen-1a-carboxylate ethyl ester. When recorded in dopamine neurons, the frequency of spontaneous GABA(A) receptor-mediated inhibitory postsynaptic potentials was increased by t-ACPD but not L-AP4. However, the amplitude of evoked inhibitory postsynaptic currents in dopamine neurons was reduced by all three group mGluR agonists.These results reveal a dual modulation of mGLuR activation on inhibitory transmission in midbrain ventral tegmental area: enhancing putative GABAergic neuronal excitability and thus potentiating tonic inhibitory synaptic transmission while reducing evoked synaptic transmission at inhibitory terminals.     

Augmentation of ventral tegmental area stimulation-induced feeding by both stimulation and lesion of the contralateral ventral tegmental area in the rat

Unilateral lesions of the ventral tegmental area (VTA) facilitate behavioral responses (feeding and exploration) induced by electrical stimulation of the VTA in the contralateral hemisphere. It was hypothesized that this facilitation may result from a lesion-induced compensatory increase in dopamine transmission in the intact hemisphere. In the present study we tested on the functional level the hypothesis that the activity of bilateral mesocorticolimbic systems is inversely related. For this purpose we compared the effect of unilateral subthreshold activation with the effect of subsequent unilateral lesion of VTA on feeding response evoked by electrical stimulation of the contralateral VTA. In male Wistar rats implanted with bilateral VTA electrodes stimulation-induced feeding was tested in a latency to feed-stimulation frequency curve-shift paradigm. One electrode was used for induction of feeding reaction and the other electrode was used for concurrent stimulation (with the subthreshold current) and subsequent electrolytic lesioning of the contralateral VTA. It was found that both contralateral stimulation and subsequent lesion performed through the same electrode facilitated a feeding response that manifested as a decrease in the reaction's threshold and a leftward shift of the latency-frequency curve. The paradoxical similarity of the effects of the stimulation and lesion is discussed in terms of functional organization of the mesocorticolimbic system and adaptive changes in dopaminergic transmission.     

Distribution of serotonin 5-HT2C receptors in the ventral tegmental area

Serotonin 2C receptors (5-HT2CR) appear to exert tonic inhibitory influence over dopamine (DA) neurotransmission in the ventral tegmental area (VTA), the origin of the mesolimbic DA system, thought to be important in psychiatric disorders including addiction and schizophrenia. Current literature suggests that the inhibitory influence of 5-HT2CR on DA neurotransmission occurs via indirect activation of GABA inhibitory neurons, rather than via a direct action of 5-HT2CR on DA neurons. The present experiments were performed to establish the distribution of 5-HT2CR protein on DA and GABA neurons in the VTA of male rats via double-label immunofluorescence techniques. The 5-HT2CR protein was found to be co-localized with the GABA synthetic enzyme glutamic acid decarboxylase (GAD), confirming the presence of the 5-HT2CR on GABA neurons within the VTA. The 5-HT2CR immunoreactivity was also present in cells that contained immunoreactivity for tyrosine hydroxylase (TH), the DA synthetic enzyme, validating the localization of 5-HT2CR to DA neurons in the VTA. While the degree of 5-HT2CR+GAD co-localization was similar across the rostro-caudal levels of VTA subnuclei, 5-HT2CR+TH co-localization was highest in the middle relative to rostral and caudal levels of the VTA, particularly in the paranigral, parabrachial, and interfascicular subnuclei. The present results suggest that the inhibitory influence of the 5-HT2CR over DA neurotransmission in the VTA is a multifaceted and complex interplay of 5-HT2CR control of the output of both GABA and DA neurons within this region.     

Ultrastructural localization of enkephalin and mu-opioid receptors in the rat ventral tegmental area

Enkephalins are endogenous ligands for opioid receptors whose activation potently modulates the output of mesocorticolimbic dopaminergic neurons within the ventral tegmental area. Many of the reinforcing effects of enkephalins in the mesocorticolimbic system are mediated by mu-opioid receptors. To determine the sites for Leu(5)-enkephalin activation of mu-opioid receptors in the ventral tegmental area, we examined the dual electron microscopic immunocytochemical localization of their respective antigens in this region of rat brain. Enkephalin immunoperoxidase reaction product and mu-opioid receptor immunogold-silver labeling showed similar cellular and subcellular distribution in both the paranigral and parabrachial subdivisions of the ventral tegmental area. Enkephalin immunoreactivity was mainly localized in small unmyelinated axons (50.4%) and in axon terminals (40.4%). The majority of these terminals formed symmetric, inhibitory-type synapses, many of which were on dendrites expressing plasmalemmal mu-opioid receptors. Appositional contacts were also often seen between axons or terminals that were differentially labeled for the two antigens. In addition, some of the enkephalin-labeled terminals and a few somatodendritic profiles showed a plasmalemmal or vesicular localization of mu-opioid receptors.Our results indicate that dendritic targets of inhibitory terminals, as well as nearby axon terminals, are potential sites for enkephalin activation of mu-opioid receptors throughout the ventral tegmental area. Moreover, co-localization of enkephalin and mu-opioid receptors in selective neuronal profiles may indicate an autoregulatory role for these receptors or their internalization along with the bound ligand in this brain region.     

Organization of ventral tegmental area projections to the ventral tegmental area-nigral complex in the rat

The ventral tegmental area (VTA) is a nodal link in reward circuitry. Based on its striatal output, it has been subdivided in a caudomedial part which targets the ventromedial striatum, and a lateral part which targets the ventrolateral striatum [Ikemoto S (2007) Dopamine reward circuitry: two projection systems from the ventral midbrain to the nucleus accumbens-olfactory tubercle complex. Brain Res Rev 56:27-78]. Whether these two VTA parts are interconnected and to what extent the VTA innervates the substantia nigra compacta (SNc) and retrorubral nucleus (RR) are critical issues for understanding information processing in the basal ganglia. Here, VTA projections to the VTA-nigral complex were examined in rats, using Phaseolus vulgaris leucoagglutinin (PHA-L) as anterograde tracer. The results show that the dorsolateral VTA projects to itself, as well as to the dorsal tier of the SNc and RR, largely avoiding the caudomedial VTA. The ventrolateral VTA innervates mainly the interfascicular nucleus. The components of the caudomedial VTA (the interfascicular, paranigral and caudal linear nuclei) are connected with each other. In addition, the caudomedial VTA (especially the paranigral and caudal linear nuclei) innervates the lateral VTA, and, to a lesser degree, the SNc and RR. The caudal pole of the VTA sends robust, bilateral projections to virtually all the VTA-nigral complex, which terminate in the dorsal and ventral tiers. Modest inputs from the medial supramammillary nucleus to ventromedial parts of the VTA-nigral complex were also identified. In double-immunostained sections, PHA-L-labeled varicosities were sometimes found apposed to tyrosine hydroxylase-positive neurons in the ventral mesencephalon. Overall, the results underscore that VTA projections to the VTA-nigral complex are substantial and topically organized. In general, these projections, like the spiralated striato-nigro-striatal loops, display a medial-to-lateral organization. This anatomical arrangement conceivably permits the ventromedial striatum to influence the activity of the lateral striatum. The caudal pole of the VTA appears to be a critical site for a global recruitment of the mesotelencephalic system.     

Multiplexed neurochemical signaling by neurons of the ventral tegmental area

The ventral tegmental area (VTA) is an evolutionarily conserved structure that has roles in reward-seeking, safety-seeking, learning, motivation, and neuropsychiatric disorders such as addiction and depression. The involvement of the VTA in these various behaviors and disorders is paralleled by its diverse signaling mechanisms. Here we review recent advances in our understanding of neuronal diversity in the VTA with a focus on cell phenotypes that participate in ‘multiplexed’ neurotransmission involving distinct signaling mechanisms. First, we describe the cellular diversity within the VTA, including neurons capable of transmitting dopamine, glutamate or GABA as well as neurons capable of multiplexing combinations of these neurotransmitters. Next, we describe the complex synaptic architecture used by VTA neurons in order to accommodate the transmission of multiple transmitters. We specifically cover recent findings showing that VTA multiplexed neurotransmission may be mediated by either the segregation of dopamine and glutamate into distinct microdomains within a single axon or by the integration of glutamate and GABA into a single axon terminal. In addition, we discuss our current understanding of the functional role that these multiplexed signaling pathways have in the lateral habenula and the nucleus accumbens. Finally, we consider the putative roles of VTA multiplexed neurotransmission in synaptic plasticity and discuss how changes in VTA multiplexed neurons may relate to various psychopathologies including drug addiction and depression.     

The effect of iron deficiency during development on passive avoidance learning in the adult rat

Offspring of iron-deprived and normal female Long Evans rats were placed on either iron deficient or a normal diet from weaning to 115 days. At 100 days of age, they were trained on a single trial passive avoidance shuttlebox task. At 115 days of age they were sacrificed for measures of liver and brain non-haem iron, and haemoglobin concentrations. Brain iron levels were shown to be affected more by maternal iron diet than postweaning iron diet. The reverse was true for liver iron and haemoglobin, while bodyweight was dependent only on maternal diet. At the behavioural level, no effects were observed on number of trials to extinction. However, maternally deprived offspring showed significantly shorter escape latency on the learning trial and fewer false entries on extinction trials, with postweaning diet exerting no effect on these behaviours. The behavioural results may be interpreted in terms of increased sensitivity to noxious stimuli in maternally deprived rats. No simple explanation for the iron status results is apparent.     

Combined effects of ECS and Metrazol on passive avoidance learning

The combined effects of a non-convulsant dosage (10 mg/kg of body weight) of Metrazol and 60 min ECS were investigated in order to find out if the interaction of the two would produce an amnesic effect upon passive avoidance learning. The main group of rats was given FS, with an immediate posttrial injection of Metrazol, followed by ECS at 60 min. Four other groups were given footshock (FS) followed by saline injection. Three of these 4 groups received ECS following FS at 30, 45, and 60 min respectively, leaving one group receiving only footshock. The footshock only and 60 min ECS groups had the same mean starting and running times, indicating no amnesia with 60 min ECS. The Metrazol 60 min ECS group had a significant retention deficit, falling between the 45 and 30 min groups. The results support the consolidation disruption hypothesis of ECS induced amnesia, and are contrary to the incubation interpretation of these effects.     

Time-dependent effects of post-trial reinforcement,punishment or ECS on passive avoidance learning

Three studies were performed to assess the effects of posttrial food reinforcement, ice-water punishment, and ECS on step-down passive avoidance learning in mice. The treatments were each administered at <5, 30, 60 and 90 sec after the footshock. One-half min of feeding beginning either 10 or 30 sec after the footshock increased the step-down latencies 24 hr later. This was considered to support the hypothesis that reinforcement facilitates learning by a direct influence on short-term memory processes. Posttrial ice-water punishment (10 sec immersion) disrupted learning only in the 60 sec postshock delay group. ECS (5.4 mA, 0.35 sec, across the ears) disrupted learning at all posttrial delays except 90 sec, with maximal effects immediately and at 60 sec, and minimal disruption at 30 sec. Similarities in the topography of the ECS and punishment curves suggested that some of the effects of posttrial ECS could be due to aversive properties of the ECS (acting directly on memory processes).     

Fibroblast growth factor-1 within the ventral tegmental area participates in motor sensitizing effects of morphine

Drug addiction is viewed as a form of neural plasticity, and neurotrophic factors have been implicated in many forms of plasticity in the adult nervous system. Here we show that the fibroblast growth factor-1 (FGF-1), that is expressed on dopamine and GABA neurons of the ventral tegmental area (VTA), is involved in the sensitizing effects of morphine. The receptor FGFR-1 is expressed on VTA astrocytes, as well as dopamine and GABA neurons. FGF-1 or anti-FGF-1 infusions into the VTA during the induction (not expression) phase of sensitization advanced or blocked morphine's activating motor effects respectively, in a dose–dependent manner. Infusions into the adjacent substantia nigra, whose neurons also express FGF-1 and FGFR-1, did not modify normal morphine-induced sensitization. Biochemical traits related to morphine's sensitizing effects were altered by intra-VTA anti-FGF-1 because morphine-induced upregulation of both tyrosine hydroxylase (TH) and N-methyl d-aspartate glutamate receptor 1 (NMDAR1) in the VTA was blocked after anti-FGF-1. Changes in the activation state of VTA calcium/calmodulin-dependent kinase type II seem to participate in FGF-1-induced effects as well. We conclude that the FGF-1 system of the ventral tegmental area is required for biochemical and behavioral sensitization to this drug.