Dopamine transporter, but not tyrosine hydroxylase, may be implicated in determining individual differences in behavioral sensitization to amphetamine

Repeated administration of psychostimulants, such as amphetamine and cocaine, results in a long-lasting enhancement of behavioral responses elicited by a subsequent challenge injection of these drugs. This phenomenon has been termed behavioral sensitization. A well established model of individual differences based on the locomotor response to a novel environment has been shown to reliably predict the degree of behavioral sensitization to amphetamine. Rats that have high locomotor response in a novel environment (high responders or HR) develop greater behavioral sensitization to psychostimulants when compared to rats that show low locomotor activity in the same novel environment (low Responders or LR). Therefore, this model is ideal to study genetic factors that may underlie behavioral sensitization to psychostimulants. In this study, adult Sprague-Dawley rats were daily injected with amphetamine (1 mg/kg, i.p.) or saline for 9 days. Locomotor activity was recorded every other day. Following a one week-withdrawal a subsequent challenge of a lower dose of amphetamine (0.5 mg/kg, i.p.) was given to all rats (amphetamine pretreated and saline pretreated) and their locomotor activity was recorded. Our results show that HR rats, but not LR rats, develop behavioral sensitization to the locomotor activating effects of amphetamine. Furthermore, only HR rats pretreated with amphetamine exhibited an increase in dopamine transporter mRNA in the ventral tegmental area (VTA) and substantia nigra (SN). Tyrosine hydroxylase mRNA in the VTA and SN was upregulated in both HR and LR rats pretreated with amphetamine when compared to HR and LR rats pretreated with saline. These results demonstrate the existence of individual differences in behavioral sensitization to amphetamine and suggest that dopamine transporter, but not tyrosine hydroxylase, may be a critical factor in the development and expression of behavioral sensitization to the locomotor activating effects of amphetamine.     

Differential activation of dopamine release in the nucleus accumbens core and shell after acute or repeated amphetamine injections: a comparative study in the Roman high- and low-avoidance rat lines

The selectively bred Roman high- and low-avoidance rats differ in emotionality and responsiveness to the motor effects of acute and repeated psychostimulant administration. These lines also show drastic differences in the neurochemical responses of their mesolimbic dopamine systems to addictive drugs. The nucleus accumbens is critically involved in the locomotor activation produced by psychostimulants and in the augmentation of this effect observed upon repeated drug administration (i.e. behavioral sensitization), although there is not a general consensus as to whether the nucleus accumbens-core or the nucleus accumbens-shell is preferentially involved in such alterations. This study was designed to evaluate the effects of acute amphetamine (0.20mg/kg, s.c.) on dopamine output in the nucleus accumbens-shell and nucleus accumbens-core of the Roman lines under basal conditions (i.e. naïve rats) and after the repeated administration of amphetamine (1mg/kg, s.c.×10 days) or saline. We show that (1) in naïve rats, amphetamine caused a larger increment in dopamine output in the nucleus accumbens-shell vs the nucleus accumbens-core only in the Roman high-avoidance line; (2) repeated amphetamine elicits behavioral sensitization in Roman high-avoidance, but not Roman low-avoidance, rats; (3) in sensitized Roman high-avoidance rats, amphetamine provokes a larger increment in dopamine output in the nucleus accumbens-core, and an attenuated dopaminergic response in the nucleus accumbens-shell, as compared with Roman high-avoidance rats repeatedly treated with saline; and (4) such neurochemical changes are not observed in the mesoaccumbens dopaminergic system of the sensitization-resistant Roman low-avoidance line. We propose that (1) Roman high-avoidance and Roman low-avoidance rats differ in the vulnerability to develop psychostimulant sensitization, (2) the nucleus accumbens-core and nucleus accumbens-shell subserve distinct functional roles in this phenomenon, and (3) comparative studies in the Roman lines may provide insight into the influence of neural substrates and genetic background on the individual vulnerability to addiction.     

Epigenetic modifications induced by early enrichment are associated with changes in timing of induction of BDNF expression

Recent studies have supported the hypothesis that pregnancy and parturition are associated with altered sensitivity of brain dopamine systems. An increased behavioral sensitivity to a direct-acting D1/D2 receptor agonist (apomorphine) has also been observed several weeks after lactation, suggesting that these adaptations are long-lasting. To further characterize this phenomenon, the effects of reproductive experience on behavioral sensitization to an indirect-acting dopamine agonist (amphetamine) in female rats were studied. In two separate experiments, nulliparous and primiparous (12-16 weeks post-weaning) female rats were pretreated with amphetamine (1.0 or 5.0 mg/kg) or vehicle (saline) once daily for 5 consecutive days. After 10 days of withdrawal, all animals were challenged with a low dose of amphetamine (25% of pretreatment dose). Locomotor activity was measured following each drug or vehicle administration. Locomotor sensitization to amphetamine challenge was observed in all animals pretreated with 1 mg/kg, regardless of reproductive experience. In contrast, primiparous animals pretreated with 5 mg/kg amphetamine displayed a significantly larger locomotor response to the challenge compared to nulliparous controls. The findings indicate enhanced behavioral sensitization to amphetamine in reproductively experienced rats, and confirm previous reports of lasting adaptations of dopamine systems following pregnancy and lactation.     

Individual differences in amphetamine sensitization, behavior and central monoamines

Repeated amphetamine treatment results in behavioral sensitization in a high percentage of rats. Alterations to plasma corticosterone, neural monoamines and stress behavior can accompany amphetamine sensitization. Whether these changes occur following repeated amphetamine treatment in the absence of behavioral sensitization is not known. Male Sprague-Dawley rats were treated with amphetamine (2.5 mg/kg, i.p.) or saline once daily for 6 days. Amphetamine-induced locomotion and stereotypy, open-field anxiety behavior, plasma corticosterone and limbic monoamines were measured during withdrawal. Sixty-two percent of amphetamine-treated rats showed behavioral sensitization over the test periods. Only amphetamine-sensitized rats showed increased latency to enter the center of the open-field, as well as increased plasma corticosterone when compared to saline-treated controls. Amphetamine-sensitized rats showed increased dopamine concentrations in the shell of the nucleus accumbens and increased serotonin concentrations in the dorsal hippocampus, which were not observed in amphetamine-treated non-sensitized rats. These findings suggest that anxiety behavior, plasma corticosterone and limbic monoamines concentrations are altered by repeated amphetamine (2.5 mg/kg) treatment, and that these neuroendocrine and behavioral changes are often associated with sensitization to the psychostimulant effects of amphetamine.     

Regional adaptations in PSD-95, NGFI-A and secretogranin gene transcripts related to vulnerability to behavioral sensitization to amphetamine in the Roman rat strains

Genetically selected for high or low two-way active avoidance, Roman high-avoidance (RHA) and Roman low-avoidance (RLA) rats differ in their central dopaminergic activity, sensation/novelty- and substance-seeking profiles. These animals are, therefore, well suited to identify anatomical and neurochemical concomitants of behavioral sensitization, a phenomenon linked to addictive liability. We submitted inbred RHA (RHA-I), inbred RLA (RLA-I) and Sprague-Dawley-OFA (SD-OFA) rats to a sensitization regimen with amphetamine and studied the behavioral response to an amphetamine challenge after a 2-week withdrawal period. The expression patterns of nerve growth factor inducible clone A (NGFI-A), secretogranin, post-synaptic density protein of 95 Kd (PSD-95), prodynorphin and proenkephalin mRNA were also analyzed using in situ hybridization, after the challenge with amphetamine. RHA-I rats showed stronger sensitization than SD-OFA rats. RLA-I rats did not show sensitization but were hyper-reactive to amphetamine. Expression of behavioral sensitization in RHA-I rats activated secretogranin and PSD-95 mRNA in the nucleus accumbens core. On the other hand, high induction of NGFI-A mRNA in the central amygdala was observed in RLA-I rats when they experienced amphetamine for the first time in the challenge. Our results reveal that 1) the acute locomotor response to amphetamine does not predict vulnerability to behavioral sensitization and 2) differences in vulnerability to sensitization may involve distinctive cellular adaptations at particular brain locations which may be related to addictive vulnerability.     

D-amphetamine-induced behavioral sensitization: implication of a glutamatergic medial prefrontal cortex-ventral tegmental area innervation

Behavioral sensitization to amphetamine is expressed as a progressive enhancement of the behavioral activating effects of the drug when repeated injections are performed as well as a long-lasting hypersensitivity to later environmental or pharmacological challenges. The mesoaccumbens dopamine system has been proposed to be the major candidate so far responsible for the induction and expression of this process, which are dependent on the action of amphetamine in the ventral tegmental area and nucleus accumbens, respectively. The development of this process has been proposed to be the result of an interaction between somatodendritically released dopamine and dopaminergic D1 receptors localized on different inputs to the ventral tegmental area, including glutamate afferents arising in part from mesocorticolimbic areas such as the medial prefrontal cortex and the amygdala. Three groups of experiments were designed to test the role of each of these components in the behavioral sensitization to amphetamine. First, the intervention of the glutamatergic transmission of the ventral tegmental area in the induction of sensitization to amphetamine was tested. The effects of an N-methyl-D-aspartate antagonist, 3-(R-2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid. on the behavioral sensitization induced by amphetamine administered repeatedly in the ventral tegmental area was tested. It was found that the blockade of N-methyl-D-aspartate receptors with 3-(R-2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid coadministered with amphetamine in the ventral tegmental area dose-dependently prevented the induction of sensitization. In a second step, the role of the structures which send glutamatergic inputs to the ventral tegmental area in the process of behavioral sensitization was tested. We evaluated the effects of ibotenic acid lesion of the medial prefrontal cortex and the amygdala on behavioral sensitization induced by peripheral or intra-ventral tegmental area administration of amphetamine. We found that ibotenic acid lesion of the medial prefrontal cortex blocked the behavioral sensitization induced by both intra-ventral tegmental area and peripheral treatment with amphetamine. In contrast, ibotenic acid lesion of the amygdala produced no effect on behavioral sensitization induced peripherally or centrally. These experiments confirmed (i) that the ventral tegmental area, where dopaminergic cell bodies are located, is a critical site for the induction of behavioral sensitization, (ii) that this process implicates the glutamatergic transmission in the ventral tegmental area, and (iii) that the medial prefrontal cortex is crucially implicated merely because of its direct glutamatergic inputs on to ventral tegmental area neurons. Together, these results reinforce the view that the behavioral sensitization to amphetamine implicates not only the mesoaccumbens dopaminergic neurons, but also other structures of the mesocorticolimbic system, such as the medial prefrontal cortex and more specifically its glutamatergic component.     

Dopamine D(4) receptors in rat forebrain: unchanged with amphetamine-induced behavioral sensitization

Dopamine D(2) receptors are implicated in stimulant-induced behavioral sensitization.(7,10) Studies using selective receptor antagonists also implicate the D(4) receptor, a member of the dopamine D(2)-like receptor family.(3) Accordingly, dopamine D(4) and D(2)-like receptor levels in rat forebrain were examined by computed autoradiography after repeated (+)-amphetamine treatment that induced behavioral sensitization. Receptor binding was quantified in critical brain regions including caudate-putamen, nucleus accumbens septi, medial prefrontal cortex and hippocampus. No significant differences in D(4) or D(2)-like receptor levels were detected among rats sensitized to amphetamine, those exposed to amphetamine but killed before behavioral sensitization emerged or vehicle-treated controls. The findings indicate that expression of amphetamine-induced behavioral sensitization is not associated with altered D(4) (or D(2)) receptor density in rat forebrain.     

A single social defeat induces short-lasting behavioral sensitization to amphetamine

Repeated, intermittent exposure to psychostimulants or stressors results in long-lasting, progressive sensitization of the behavioral effects of a subsequent amphetamine (AMPH) challenge. Although behavioral sensitization has also been observed following a single drug pretreatment, the sensitizing potential of a single exposure to stress is not clear. Both drug- and stress-induced sensitization depend on an enhanced dopaminergic neurotransmission in the mesolimbic DA system. Apart from responding to rewards, this system is also involved in responding towards aversive social stimuli. Therefore, social stressors may be particularly effective in inducing cross-sensitization to stimulant drugs. We examined the time course of sensitization to the locomotor effects of the stimulant, AMPH, following a single social stressor: a social defeat. Wistar rats were exposed in a resident-intruder paradigm to an unfamiliar dominant male conspecific (Wild-Type Groningen), resulting in defeat. The locomotor effects of a subsequent AMPH challenge (0.25 or 1.0 mg/kg) were evaluated 3, 14, and 21 days later by scoring horizontal movement in an open field. AMPH had significantly larger locomotor-activating effects in animals that had been defeated 3 days earlier compared to nondefeated controls. However, this sensitized response was no longer present 14 or 21 days after defeat. Therefore, we conclude that social defeat induces short-lasting cross-sensitization to the locomotor effects of AMPH in rats, but is not sufficient for long-term sensitization. The transient enhancement of responses to dopaminergic drugs may be indicative of a temporary role of dopamine in the cascade of physiological and behavioral changes following social defeat.     

Expression of cocaine sensitization: regulation by the medial prefrontal cortex.

Extracellular levels of dopamine are increased in response to systemic administration of cocaine in several brain areas including the nucleus accumbens and medial prefrontal cortex. While the cocaine-induced increase in extracellular dopamine levels in the nucleus accumbens is augmented after repeated daily cocaine, the response of extracellular dopamine levels in the medial prefrontal cortex is attenuated. Since dopamine in the medial prefrontal cortex has an inhibitory effect on nucleus accumbens dopamine levels and locomotor activity, the role of medial prefrontal cortex dopamine tolerance in the expression of sensitized locomotor behavior was further examined by injection of D-amphetamine sulfate into the prelimbic portion of the medial prefrontal cortex just prior to cocaine challenge in cocaine-sensitized rats. Male Sprague-Dawley rats were non-handled (naive) or injected with either saline (1 ml/kg, i.p.) or cocaine (15 mg/kg, i.p.) for five consecutive days. After a seven to 12 day withdrawal period, rats were microinjected with either saline or various doses of amphetamine into primarily the prelimbic region of the medial prefrontal cortex followed by systemic injection of saline or cocaine. In naive rats, intramedial prefrontal cortex amphetamine produced a trend toward decreased locomotor responding to cocaine challenge while no effect of amphetamine was evident in daily saline pretreated rats. Daily cocaine pretreated rats that received saline in the medial prefrontal cortex demonstrated a sensitized locomotor response compared to their daily saline pretreated counterparts. This sensitization was blocked by a low dose of amphetamine (0.175 microg/side) in the medial prefrontal cortex, an effect which disappeared in animals administered higher amphetamine doses. The results suggest that in rats sensitized to cocaine, decreased medial prefrontal cortex dopamine levels in response to cocaine challenge may contribute to behavioral sensitization. Furthermore, the data indicate the possibility that there is an optimal range at which medial prefrontal cortex amphetamine exerts maximal behavioral inhibition. These findings implicate a role for decreased cortical control in producing sensitized behavioral responding to cocaine.     

Reciprocal changes in dopamine responsiveness in the nucleus accumbens shell and core and in the dorsal caudate-putamen in rats sensitized to morphine

In this study, we describe a model of opiate sensitization characterized by a brief schedule of treatment with repeated morphine administrations. In this model, we investigated the changes produced by repeated morphine treatment on dopamine transmission at the level of the two major terminal dopaminergic areas, the dorsolateral caudate-putamen and the nucleus accumbens in its two subdivisions, the shell and the core. Rats were treated twice a day for three days with increasing doses of morphine (10, 20 and 40 mg/kg, s.c.) or with saline. After 15 days of withdrawal, rats were challenged with 1 and 5 mg/kg (s.c.) of morphine, and dopamine transmission was monitored by microdialysis. In this model, we show that repeated morphine produces a strong behavioral sensitization accompanied by increased stimulation of dopamine transmission in the core of the nucleus accumbens and in the caudate-putamen, and by a decreased stimulation of dopamine transmission in the shell of the nucleus accumbens, as compared to control rats. Moreover, we administered to these animals amphetamine (0.5 mg/kg, s.c.) and cocaine (10 mg/kg, i.p.) to assess whether cross-sensitization occurs between opiates and psychostimulants in conditions independent of the context. In the present study, we did not observe either behavioral or biochemical sensitization to amphetamine and to cocaine in rats sensitized to morphine. These results suggest that rats behaviorally sensitized to morphine show opposite changes in the stimulant effect of morphine in the nucleus accumbens shell and core and in the dorsal caudate-putamen. Moreover, this study suggests that sensitization of the dopamine system to a given agent does not necessarily extend to drugs of abuse of different pharmacological classes.     

The laterodorsal tegmentum contributes to behavioral sensitization to amphetamine

A critical event in the development of behavioral sensitization is a transient increase in excitatory drive to dopamine neurons of the ventral tegmental area (VTA). This is likely to be due, in part, to the ability of drugs of abuse to produce long-term potentiation, expressed as increased AMPA receptor transmission, at excitatory synapses onto VTA dopamine neurons. We investigated the role of the laterodorsal tegmentum (LDT) in behavioral sensitization because LDT neurons provide an important source of excitatory drive to VTA dopamine neurons, through mixed glutamate and cholinergic inputs. To test the role of the LDT in amphetamine sensitization, ibotenic acid or sham lesions of the LDT were performed 1 week before the first of six daily amphetamine injections. When challenged with amphetamine 13 days after the last injection, sham rats expressed sensitization of stereotypy and post-stereotypy locomotor hyperactivity, whereas the latter was attenuated by ibotenic acid lesions of the LDT. To determine whether plasticity occurs in the LDT during amphetamine sensitization, we used a previously developed microdialysis assay in which increased ability of AMPA to activate a pathway serves as a marker for long-term potentiation. Two days after discontinuing repeated saline or amphetamine injections, the responsiveness of LDT-VTA neurons to AMPA was determined by microinjecting AMPA (0.4 nmol) into the LDT and measuring glutamate efflux in the ipsilateral VTA. Glutamate efflux was transiently increased in both groups but a delayed group difference was apparent with relatively higher glutamate efflux in amphetamine rats 30-60 min after AMPA injection. In parallel experiments, dopamine efflux in the nucleus accumbens (NAc) following intra-LDT AMPA declined in saline rats but remained relatively stable in amphetamine rats. Both results suggest relatively greater excitability of the LDT-VTA-NAc pathway after repeated amphetamine treatment. Our results provide the first evidence that neuronal plasticity in the LDT contributes to behavioral sensitization.     

Delusions, superstitious conditioning and chaotic dopamine neurodynamics.

Excessive mesolimbic dopaminergic neurotransmission is closely related to the psychotic symptoms of schizophrenia. A mathematical model of dopamine neuron firing rates, developed by King and others, suggests a mechanism by which excessive dopaminergic transmission could produce psychotic symptoms, especially delusions. In this model, firing rates varied chaotically when the efficacy of dopaminergic transmission was enhanced. Such non-contingent changes in firing rates in mesolimbic reward pathways could produce delusions by distorting thinking in the same way that non-contingent reinforcement produces superstitious conditioning. Though difficult to test in humans, the hypothesis is testable as an explanation for a common animal model of psychosis--amphetamine stereotypy in rats. The hypothesis predicts that: (1) amphetamine will cause chaotic firing rates in mesolimbic dopamine neurons; (2) non-contingent brain stimulation reward will produce stereotypy; (3) non-contingent microdialysis of dopamine into reward areas will produce stereotypy; and (4) dopamine antagonists will block all three effects.     

Age-dependent effects of κ-opioid receptor stimulation on cocaine-induced stereotyped behaviors and dopamine overflow in the caudate–putamen: an in vivo microdialysis study

κ-Opioid receptor stimulation attenuates psychostimulant-induced increases in extracellular dopamine in the caudate–putamen (CPu) and nucleus accumbens of adult rats, while reducing cocaine-induced locomotor activity and stereotyped behaviors. Because κ-opioid receptor agonists (e.g., U50,488 or U69,593) often affect the behavior of preweanling rats in a paradoxical manner, the purpose of the present study was to determine whether κ-opioid receptor stimulation differentially affects dopaminergic functioning in the CPu depending on age. In vivo microdialysis was used to determine whether U50,488 (5 mg/kg) attenuates cocaine-induced dopamine overflow in the dorsal CPu on postnatal day (PD) 17 and PD 85. In the microinjection experiment, cocaine-induced stereotyped behaviors were assessed in adult and preweanling rats after bilateral infusions of vehicle or U50,488 (1.6 or 6.4 μg per side) into the CPu. Results showed that U50,488 attenuated the cocaine-induced increases in CPu dopamine overflow on PD 85, while the same dose of U50,488 did not alter dopamine dialysate levels on PD 17. Cocaine also increased stereotyped behaviors (repetitive motor movements, behavioral intensity scores, and discrete behaviors) at both ages, but adult rats appeared to exhibit more intense stereotypic responses than the younger animals. Consistent with the microdialysis findings, bilateral infusions of U50,488 into the dorsal CPu decreased the cocaine-induced stereotypies of adult rats, while leaving the behaviors of preweanling rats unaffected. These results suggest that the neural mechanisms underlying κ-opioid/dopamine interactions in the CPu are not fully mature during the preweanling period. This lack of functional maturity may explain why κ-opioid receptor agonists frequently induce different behavioral effects in young and adult rats.     

Ethanol-induced behavioral sensitization is associated with dopamine receptor changes in the mouse olfactory tubercle

Accumulating evidence points to the mesolimbic and the nigrostriatal dopamine systems as critical to behavioral sensitization induced by several drugs of abuse. In the present study, we analyzed D1 and D2 binding to brain regions related to these dopaminergic systems during the expression of ethanol-induced behavioral sensitization. The first experiment was performed to demonstrate the effectiveness of the ethanol treatment schedule and challenge used to induce the expression of the behavioral sensitization phenomenon. The second experiment was conducted to study D1 and D2 alterations in several brain regions during the expression of this phenomenon. Mice were ip treated with ethanol or saline for 21 consecutive days and 24 h after the last injection they received an ethanol or a saline challenge injection. Five minutes later, the animals were observed in an open-field for locomotion quantification or were sacrificed and their brains were submitted to autoradiographic binding analyses. No differences among the groups were found for D1 binding levels in all the brain regions analyzed. However, ethanol-sensitized mice showed reduced levels of D2 binding in the olfactory tubercle when compared to the other groups. Our data suggest that D2 receptor changes in the olfactory tubercle seem to play an important role in the expression of ethanol-induced behavioral sensitization.     

Dopamine-D1 and δ-opioid receptors co-exist in rat striatal neurons

Cocaine's enhancement of dopaminergic neurotransmission in the mesolimbic pathway plays a critical role in the initial reinforcing properties of this drug. However, other neurotransmitter systems are also integral to the addiction process. A large body of data indicates that opioids and dopamine together mediate emotional and reinforced behaviors. In support of this, cocaine-mediated increases in activation of dopamine D1 receptors (D1R) results in a desensitization of δ-opioid receptor (DOR) signaling through adenylyl cyclase (AC) in striatal neurons. To further define cellular mechanisms underlying this effect, the subcellular distribution of DOR and D1R was examined in the rat dorsolateral striatum. Dual immunoperoxidase/gold-silver detection combined with electron microscopy was used to identify DOR and D1R immunoreactivities in the same section of tissue. Semi-quantitative analysis revealed that a subset of dendritic cellular profiles exhibited both DOR and D1R immunoreactivities. Of 198 randomly sampled D1R immunoreactive profiles, 43% contained DOR. Similarly of 165 DOR-labeled cellular profiles, 52% contained D1R. The present data provide ultrastructural evidence for co-existence between DOR and D1R in striatal neurons, suggesting a possible mechanism whereby D1R modulation may alter DOR function.     

Hippocampal and cortical sensory gating in rats: effects of quinpirole microinjections in nucleus accumbens core and shell

Sensory processing disturbances, as measured in the P50/sensory gating paradigm, have been linked to aberrant auditory information processing and sensory overload in schizophrenic patients. In this paradigm, the response to the second of paired-click stimuli is attenuated by an inhibitory effect of the first stimulus. Sensory gating has been observed in most healthy human subjects and normal laboratory rats. Because mesolimbic dopamine has been implicated in other filtering disturbances such as prepulse inhibition of the acoustic startle response and given the fact that amphetamine and apomorphine have been shown to disrupt gating, this study was performed to investigate the role of mesolimbic dopamine in sensory gating. The dopamine D2 receptor agonist quinpirole (10 microg/0.5 microl) was injected bilaterally in nucleus accumbens core and shell and effects on cortical and hippocampal sensory gating were investigated. Also, effects of the dopamine D2 receptor antagonist haloperidol (0.1 mg/kg, subcutaneously) as pretreatment were studied. First, quinpirole significantly reduced both the amplitude to the first click and gating as measured in the cortex and in the hippocampus. There was a tendency for the quinpirole effects on hippocampal gating to be more pronounced in rats injected in the shell. Secondly, haloperidol did not antagonize effects of quinpirole on hippocampal parameters, whereas haloperidol pretreatment fully antagonized quinpirole effects on cortical parameters. In conclusion, gating can be significantly reduced when a dopamine agonist is specifically targeted at mesolimbic dopamine D2 receptors. However, an important consideration is that the dopaminergic effects in the present study on gating are predominantly mediated by the effects on the amplitude to the first click. This has also been suggested for systemic amphetamine injections in rats and schizophrenic patients. This casts doubt on whether dopamine receptor activation affects the putative inhibitory process between the first and the second stimulus.     

D-amphetamine-induced behavioral sensitization: effect of lesioning dopaminergic terminals in the medial prefrontal cortex, the amygdala and the entorhinal cortex

The behavioral sensitization produced by the repeated administration of D-amphetamine is known to involve dopaminergic neurons in the mesoaccumbens pathway. Induction of this process is dependent on action of the drug in the ventral tegmental area while its expression involves action in the nucleus accumbens. We studied here the putative involvement of dopaminergic projections other than the mesoaccumbens in this phenomenon. We examined the influence of dopaminergic lesion of the medial prefrontal cortex, the amygdala and the entorhinal cortex in the behavioral sensitization produced by repeated injections of amphetamine either peripherally or directly into the ventral tegmental area of the brain. The repeated administration of amphetamine induced a behavioral sensitization, with the ventral tegmental area a critical site for induction of the process. This sensitization to amphetamine cross-reacted with morphine and was still observed 2 weeks after cessation of the treatment. Bilateral 6-hydroxydopamine lesion of dopaminergic terminals in either the medial prefrontal cortex or the amygdala, but not in the entorhinal cortex, prevented the development of behavioral sensitization to amphetamine and the cross-sensitization with morphine, whether the amphetamine pretreatment was administered peripherally or directly into the ventral tegmental area.In conclusion, these results indicated that behavioral sensitization to amphetamine, which involves dopaminergic neurons of the ventral tegmental area, is also dependent on dopaminergic neurotransmission of the medial prefrontal cortex and amygdala but not of the entorhinal cortex.     

Age-related changes of dopamine receptors in the rat hippocampus: a light microscope autoradiography study

Hippocampus is a brain region involved in learning and memory and is particularly sensitive to ageing. It is supplied with a dopaminergic innervation arising from the midbrain, which is part of the mesolimbic dopaminergic pathway. Dysfunction of the dopaminergic mesolimbic system is probably involved in the pathophysiology of psychosis and behavioural disturbances occurring in the elderly. The present study was designed to assess the density and localisation of dopamine D1- and D2-like receptor subtypes in the hippocampus of male Sprague-Dawley rats aged 3 months (young), 12 months (adult) and 24 months (old). Dopamine D1-like receptors, labelled by [3H]-SCH 23390, in young rats displayed a dentate gyrus-CA1 subfield gradient. The expression was increased in the cell body of dentate gyrus, CA4 and CA3 subfield of old rats compared to younger cohorts, as well as in the neuropil of dentate gyrus. A decreased density of dopamine D1-like receptors was found in the stratum oriens of CA1 and CA3 subfields. Dopamine D2-like receptors, labelled using [3H]-spiperone as radioligand, were expressed rather homogeneously throughout different subfields of the hippocampus. In old rats, the density of dopamine D2-like receptors was decreased in the dentate gyrus, unchanged in the CA4 and CA1 subfields and increased in the CA3 subfield. The above results indicate the occurrence of inhomogeneous changes in the density of dopamine D1- and D2-like receptors in specific portions of hippocampus of old rats. These findings support the hypothesis of an involvement of dopaminergic system in behavioural abnormalities or psychosis occurring in ageing.     

Acupuncture normalizes the release of accumbal dopamine during the withdrawal period and after the ethanol challenge in chronic ethanol-treated rats

Many studies have shown that acupuncture can contribute to the biochemical balance in the central nervous system and maintenance or recovery of homeostasis. It is well known that chronic administration of ethanol may produce depletion or sensitization of extracellular dopamine levels in the nucleus accumbens. The present study was designed to investigate the effects of acupuncture on chronic ethanol-induced changes in extracellular dopamine levels in the nucleus accumbens shell (using in vivo microdialysis in unanesthetized rats). Male Sprague-Dawley rats were treated with 3 g/kg/day of ethanol (20%, w/v) or saline by intraperitoneal injection for 21 days. Following 72 h of ethanol withdrawal, acupuncture was applied at bilateral Shenmen (HT7) points for 1 min. Different group of rats using the same paradigm of ethanol treatment were acupunctured at the same points after the systemic ethanol challenge (3 g/kg, i.p.). Acupuncture at the specific acupoint HT7, but not at control points (PC6 or tail) significantly prevented both a decrease of extracellular dopamine levels in the nucleus accumbens during ethanol withdrawal and an increase in accumbal dopamine levels induced by the ethanol challenge. These results provided strong evidence that stimulation of the specific acupoint HT7 helps to normalize the release of dopamine in the mesolimbic system following chronic ethanol treatment.