Long-lasting nicotinic modulation of GABAergic synaptic transmission in the rat nucleus accumbens associated with behavioural sensitization to amphetamine

A robust increase in dopaminergic transmission in the nucleus accumbens (NAc) shell has been reported to be consistently associated with the long-term expression of behavioural sensitization to drugs of abuse. However, little is known about how this affects the neuronal network of the NAc. We made cellular recordings in NAc slices of saline- and amphetamine-pretreated adult rats and found that expression of behavioural sensitization was associated with long-lasting changes in the basal firing pattern of cholinergic interneurons up to 3 weeks after the last drug injection. Consequently, upon amphetamine sensitization, an inhibiting effect of the nicotinic receptor blocker mecamylamine on the amplitudes of spontaneous GABAergic synaptic currents as well as on the failure rate of electrically evoked GABAergic currents was found that was not present under control conditions. Thus, behavioural sensitization to amphetamine is associated with an up-regulation of the endogenous activation of nicotinic receptors that, in turn, stimulate the GABAergic synaptic transmission within the NAc shell. This is a new mechanism by which drugs of abuse may induce alterations in the processing and integration of NAc inputs involved in psychomotor sensitization.     

The AT₁ angiotensin II receptor blockade attenuates the development of amphetamine-induced behavioral sensitization in a two-injection protocol

It has been shown that a single exposure to amphetamine is sufficient to induce long‐term behavioral, neurochemical, and neuroendocrine sensitization in rats. Dopaminergic neurotransmission in the nucleus accumbens and the caudate‐putamen plays a critical role in the addictive properties of drugs of abuse. Angiotensin (Ang) II receptors are found on the soma and terminals of mesolimbic dopaminergic neurons and it has been shown that Ang II acting through its AT₁ receptors facilitates dopamine release. The hypothesis was tested that Ang II AT₁ receptors are involved in the neuroadaptative changes induced by a single exposure to amphetamine and that such changes are related to the development of behavioral and neurochemical sensitization. For this purpose, the study examined the expression of amphetamine‐enhanced (0.5 mg kg⁻¹ i.p.) locomotor activity in animals pretreated with candesartan, an AT₁ blocker, (3 mg kg⁻¹ p.o × 5 days), 3 weeks after an amphetamine injection (5 mg kg⁻¹ i.p.). Dopaminergic hyperreactivity was tested by measuring the 3H‐DA release in vitro from caudate‐putamen and nucleus accumbens slices, induced by K⁺ stimulus. It was confirmed the behavioral sensitization in the two‐injection protocol and candesartan pretreatment attenuate this response. It was also found that AT₁ blockade pretreatment did not affect the locomotor response to dopamine agonists. In respect to the neurochemical sensitization tested using ex vivo 3H‐DA release experiments it was found that AT₁ receptor pretreatment blunted the enhanced response induced by K⁺ stimulus. The results support the idea that the development of neuroadaptive changes induced by amphetamine involves brain AT₁ Ang II receptor activation. Synapse, 2011. © 2010 Wiley‐Liss, Inc.     

Compartment-specific changes in striatal neuronal activity during expression of amphetamine sensitization are the result of drug hypersensitivity

Repeated exposure to drugs of abuse induces behavioural sensitization, i.e. a persistent hypersensitivity to the psychomotor stimulant effects of these drugs. This may be the result of increased responsiveness, to drugs, of mesostriatal dopamine systems and their projections, but it has also been suggested that acute and sensitized behavioural responses to psychostimulant drugs involve activation of distinct neuronal circuits. In order to distinguish between these possibilities, we studied amphetamine-induced c-fos immunoreactivity in subregions of rat striatum (patch and matrix compartments of caudate-putamen and nucleus accumbens core and shell) in drug-naive rats, as well as during long-term expression of amphetamine sensitization. We found that, in sensitized animals, amphetamine (1.0 mg/kg) evoked an increase in the ratio of c-fos-immunopositive cells in striatal patch and matrix compartments, suggesting a preferential involvement of striatal patches in the sensitized response to amphetamine. In drug-naive rats, amphetamine (0.5-5.0 mg/kg) dose-dependently increased c-fos expression in all striatal subregions. Remarkably, the highest dose of amphetamine also evoked an increase in patch : matrix ratio of c-fos immunoreactivity. In nucleus accumbens core and shell of amphetamine- and saline-pretreated animals, amphetamine (1.0 mg/kg) evoked comparable increases in c-fos expression. These data indicate that distinct striatal compartments display a differential sensitivity to amphetamine in both drug-naive and amphetamine-sensitized animals. In addition, they suggest that the shift in amphetamine-induced c-fos expression from striatal matrix to patches in sensitized animals is the consequence of a change in the sensitivity to amphetamine, rather than a long-term circuitry reorganization that is exclusive to the sensitized state.     

Morphine acutely and persistently attenuates nonvesicular GABA release in rat nucleus accumbens

Withdrawal from repeated exposure to morphine causes a long-lasting increase in the reactivity of nucleus accumbens nerve terminals towards excitation. The resulting increase in action potential-induced exocytotic release of neurotransmitters, associated with behavioral sensitization, is thought to contribute to its addictive properties. We recently showed that activation of N-methyl-D-aspartate (NMDA) as well as dopamine (DA) D1 receptors in rat striatum causes tetrodotoxin-insensitive transporter-dependent GABA release. Since sustained changes in extracellular GABA levels may play a role in drug-induced neuronal hyperresponsiveness, we examined the acute and long-lasting effect of morphine on this nonvesicular GABA release in rat nucleus accumbens slices. The present study shows that morphine, through activation of mu-opioid receptors, reduces nonvesicular NMDA-induced [(3)H]GABA release in superfused nucleus accumbens slices. Moreover, prior repeated morphine treatment of rats (10 mg/kg, sc, 14 days) caused a reduction in NMDA-stimulated [(3)H]GABA release in vitro until at least 3 weeks after morphine withdrawal. This persistent neuroadaptive effect was not observed studying dopamine D1 receptor-mediated [(3)H]GABA release in nucleus accumbens slices. Moreover, this phenomenon appeared to be absent in slices of the caudate putamen. Interestingly, even a single exposure of rats to morphine (>2 mg/kg) caused a long-lasting inhibition of NMDA-induced release of GABA in nucleus accumbens slices. These data suggest that a reduction in nonvesicular GABA release within the nucleus accumbens, by enhancing the excitability of input and output neurons of this brain region, may contribute to the acute and persistently enhanced exocytotic release of neurotransmitters from nucleus accumbens neurons in morphine-exposed rats.     

Selective psychostimulant sensitization by food restriction: differential changes in accumbens shell and core dopamine

We have recently reported that behavioural sensitization to morphine, amphetamine, cocaine and nicotine is associated with an increased response of dialysate dopamine to the same drugs in the nucleus accumbens core and/or a reduced response in the shell. Prolonged exposure to stressful stimuli also induces behavioural sensitization to drugs of abuse. We therefore investigated the effect of different drugs of abuse on behaviour and on dopamine transmission in the nucleus accumbens shell and core of rats stressed by 1 week schedule of food restriction. Food-restricted rats (80% of their initial body weight) were implanted with microdialysis probes in the nucleus accumbens shell and core and challenged with cocaine (5 and 10 mg/kg i.p.), amphetamine (0.25 and 0.5 mg/kg s.c.), morphine (1 and 2 mg/kg s.c.), nicotine (0.2 and 0.4 mg/kg s.c.) and the changes in dialysate dopamine transmission were monitored together with the behaviour. Food restricted rats showed strong behavioural sensitization to cocaine and amphetamine but not to morphine or nicotine as compared to ad libitum fed controls. Behavioural sensitization to psychostimulants was associated with an increased response of dialysate dopamine in the core and with an unchanged or even reduced response in the shell. No significant differences were observed between controls and food-restricted animals in the ability of morphine and nicotine to stimulate dopamine transmission in the shell and core. The present results indicate that a sensitized dopamine response in the nucleus accumbens core is a general feature of the expression of behavioural sensitization.     

A single administration of interleukin-1 or amphetamine induces long-lasting increases in evoked noradrenaline release in the hypothalamus and sensitization of ACTH and corticosterone responses in rats

Single administration of the cytokine interleukin-1beta (IL-1) or the psychostimulant amphetamine causes long-term sensitization of the hypothalamus pituitary adrenal (HPA) axis, i.e. enhanced adrenocorticotropine hormone (ACTH) and corticosterone responses weeks later. HPA responses to these stimuli involve activation of hypothalamic corticotropin-releasing hormone (CRH) neurons by noradrenergic projections to the paraventricular nucleus (PVN). In search of the underlying mechanisms, we studied the temporal pattern of HPA sensitization in relation to (1) the reactivity of noradrenergic projections to the PVN and (2) altered secretagogue production in hypothalamic CRH neurons. Single exposure to IL-1 or amphetamine induced cross-sensitization of ACTH and corticosterone responses 11 and 22 days later, but not after 42 days. Amphetamine-induced HPA sensitization was not accompanied by increased costorage of arginine vasopressin (AVP) in CRH terminals, as found previously after IL-1 pretreatment. The reactivity of noradrenergic terminals was assessed by measuring the electrically evoked release of [3H]-noradrenaline from superfused PVN slices. Single administration of amphetamine and IL-1 induced a long-lasting (up to 22 days) increase (up to 165%) of evoked noradrenaline release. This indicates that single exposure to psychostimulants or to cytokines can induce a long-lasting increase in stimulus-secretion coupling in brainstem noradrenergic neurons that innervate the PVN. This common, long-lasting functional change may underlie, at least in part, IL-1- and amphetamine-induced HPA cross-sensitization. In addition, increased AVP signalling by hypothalamic CRH neurons appears to play a role in IL-1-induced, but not in amphetamine-induced, HPA sensitization.     

Exposure to nicotine and sensitization of nicotine-induced behaviors

Evidence for an important link between sensitization of midbrain dopamine (DA) neuron reactivity and enhanced self-administration of amphetamine and cocaine has been reported. To the extent that exposure to nicotine also sensitizes nucleus accumbens DA reactivity, it is likely that it will also impact subsequent drug taking. It is thus necessary to gain an understanding of the long-term effects of exposure to nicotine on nicotinic acetylcholine receptors (nAChRs), neuronal excitability and behavior. A review of the literature is presented in which different regimens of nicotine exposure are assessed for their effects on upregulation of nAChRs, induction of LTP in interconnected midbrain nuclei and development of long-lasting locomotor and DA sensitization. Exposure to nicotine upregulates nAChRs and nAChR currents and produces LTP of excitatory inputs to midbrain DA neurons. These effects appear in the hours to days following exposure. Exposure to nicotine also leads to long-lasting sensitization of nicotine's nucleus accumbens DA and locomotor activating effects. These effects appear days to weeks after drug exposure. A model is proposed in which nicotine exposure regimens that produce transient nAChR upregulation and LTP consequently produce long-lasting sensitization of midbrain DA neuron reactivity and nicotine-induced behaviors. These neuroadaptations are proposed to constitute critical components of the mechanisms underlying the initiation, maintenance and escalation of drug use.     

Repeated amphetamine administration outside the home cage enhances drug-induced Fos expression in rat nucleus accumbens

Induction of the immediate early gene protein product Fos has been used extensively to assess neural activation in the striatum after repeated amphetamine administration to rats in their home cages. However, this technique has not been used to examine striatal activation after repeated administration outside the home cage, an environment where repeated drug administration produces more robust psychomotor sensitization. We determined the dose-response relationship for amphetamine-induced psychomotor activity and Fos expression in nucleus accumbens and caudate-putamen 1 week after repeated administration of amphetamine or saline in locomotor activity chambers. Repeated administration of amphetamine enhanced amphetamine-induced locomotor activity and stereotypy and Fos expression in nucleus accumbens, but not in caudate-putamen. In comparison, levels of Fos expression induced by 1mg/kg amphetamine were not altered in nucleus accumbens or caudate-putamen by repeated amphetamine administration in the home cage. Double-labeling of Fos protein and enkephalin mRNA indicates that Fos is expressed in approximately equal numbers of enkephalin-negative and enkephalin-positive neurons in nucleus accumbens and caudate-putamen following injections outside the home cage. Furthermore, repeated amphetamine administration increased drug-induced Fos expression in enkephalin-positive, but not enkephalin-negative, neurons in nucleus accumbens. We conclude that repeated amphetamine administration outside the home cage recruits the activation of enkephalin-containing nucleus accumbens neurons during sensitized amphetamine-induced psychomotor activity.     

The amphetamine-induced sensitized state as a model of schizophrenia

Schizophrenia is a serious psychiatric disorder which impacts a broad range of cognitive, behavioural and emotional domains. In animals, exposure to an intermittent, escalating dose regimen of amphetamine induces a sensitized state that appears to share a number of behavioural and neurochemical similarities with schizophrenia. In humans repeated exposure to amphetamine, or other psychomotor stimulants, can induce sensitization as well as psychosis. The following paper evaluates the evidence for the amphetamine-induced sensitized state as an animal model of schizophrenia, focussing separately on the positive, cognitive and negative symptoms associated with this disease. Current evidence supports the use of amphetamine sensitization as a model of the positive symptoms observed in schizophrenia. Additionally, there is increasing evidence for long-lasting cognitive deficits in sensitized animals, especially in the area of attention and/or cognitive flexibility. Other areas of cognition, such as long-term memory, appear to be unaltered in sensitized animals. Finally, little evidence currently exists to either support or refute the use of amphetamine sensitization as a model of negative symptoms. It is concluded that amphetamine sensitization likely impacts behaviour by altering the functioning of mesolimbic dopamine systems and prefrontal cortical function and can serve as a model of certain domains of schizophrenia.     

Intermittent morphine treatment induces a long-lasting increase in cholinergic modulation of GABAergic synapses in nucleus accumbens of adult rats

Repeated exposure to drugs of abuse causes persistent behavioral sensitization and associated adaptations of striatal neurotransmission, which is thought to play an important role in certain aspects of drug addiction. Microdialysis and neurochemical studies suggest that intermittent morphine treatment may lead to a long-term increase in both ACh and dopaminergic neurotransmission in the nucleus accumbens (NAc). This implies that both cholinergic modulation of GABA synapses and their sensitivity to dopaminergic transmission might be changed, ultimately leading to a modified NAc output. Here we investigate to what extent cholinergic modulation and sensitivity to amphetamine, causing endogenous dopamine efflux, of GABAergic transmission in the nucleus accumbens are affected 3 weeks after a period of daily morphine injections in adult rats. To this end, we recorded medium spiny neurons using whole cell voltage clamp and monitored the frequency and amplitude of spontaneous GABAergic synaptic currents. We observed that the effect of nicotine on the frequency of spontaneous inhibitory postsynaptic currents (sIPSCs) was suppressed in rats pretreated with morphine, whereas the effects of mecamylamine and tetrodotoxin (TTX) were increased. These results indicate that the probability of GABA release was increased and that this effect resulted from an upregulation of the endogenous activation of presynaptic nicotinic receptors. In addition, we observed an increased sensitivity to in vitro application of amphetamine. This suggests that the long-term increase in dopaminergic transmission caused by the morphine treatment affects GABA synapses in the NAc. Hence, there may be two parallel synaptic mechanisms by which drugs of abuse may affect processing and integration of NAc inputs.     

Nitrous oxide and xenon prevent amphetamine-induced carrier-mediated dopamine release in a memantine-like fashion and protect against behavioral sensitization.

BACKGROUND: Amphetamine administration induces stimulation-independent dopamine release in the nucleus accumbens (NAcc) through reverse dopamine transport, a critical neurochemical event involved in its psychostimulant action, and furthermore decreases stimulation-dependent vesicular dopamine release. These effects may involve possible indirect glutamatergic mechanisms. METHODS: We investigated the effects of nitrous oxide and xenon, which possess antagonistic action at the N-methyl-D-aspartate (NMDA) receptor, on brain slices ex vivo on amphetamine-induced changes in carrier-mediated and KCl-evoked dopamine release in the NAcc, and in vivo on amphetamine-induced locomotor sensitization. RESULTS: Like the low-affinity NMDA receptor antagonist memantine, but not the prototypical compound MK-801, nitrous oxide and xenon at appropriate concentrations blocked both the increase in carrier-mediated dopamine release and locomotor sensitization produced by amphetamine. CONCLUSIONS: In contrast to what has generally been found using prototypical NMDA receptor antagonists, these data regarding the effect of memantine, nitrous oxide, and xenon support the hypothesis that activation of certain NMDA receptors (possibly those containing the NR1a/NR2D subunit) in the NAcc is involved in the amphetamine-induced increase in carrier-mediated dopamine release and the development of behavioral sensitization to amphetamine. Nitrous oxide, xenon, and memantine may be of therapeutic interest for treating drug dependence.     

Rapid desensitization of presynaptic dopamine autoreceptors during exposure to exogenous dopamine

When nomifensine is employed to inhibit neuronal uptake, exposure to dopamine (DA) (0.1–0.3 μM) or apomorphine (0.01–0.1 μM) inhibited, in a concentration-dependent manner, the electrically evoked release of [³H]dopamine from slices of the rabbit caudate nucleus. Apomorphine inhibited transmitter release independently of the time of exposure to the drug (6–32 min). On the other hand, the inhibitory effect of exogenous dopamine occurred only if a short period (4–12 min) of exposure was employed. In studies on the electrically evoked release of [³H]acetylcholine in slices of the rabbit caudate nucleus there was no evidence for desensitization to apomorphine or exogenous dopamine at the level of the dopamine receptors that inhibit [³H]acetylcholine release. These results indicate that the dopamine autoreceptors modulating [³H]dopamine release in the caudate nucleus become subsensitive after a few minutes of exposure to exogenous dopamine. This effect does not occur at the level of the dopamine receptors which inhibit the release of [³H]acetylcholine.     

Short- and long-lasting behavioral and neurochemical adaptations: relationship with patterns of cocaine administration and expectation of drug effects in rats

Cocaine dependence is a significant public health problem, characterized by periods of abstinence. Chronic exposure to drugs of abuse induces important modifications on neuronal systems, including the dopaminergic system. The pattern of administration is an important factor that should be taken into consideration to study the neuroadaptations. We compared the effects of intermittent (once daily) and binge (three times a day) cocaine treatments for 1 (WD1) and 14 (WD14) days after the last cocaine injection on spontaneous locomotor activity and dopamine (DA) levels in the nucleus accumbens (Nac). The intermittent treatment led to a spontaneous increase in DA (WD1/WD14), and in locomotor activity (WD1) at the exact hour which rats were habituated to receive a cocaine injection. These results underline that taking into consideration the hours of the day at which the experiments are performed is crucial. We also investigated these behavioral and neurochemical adaptations in response to an acute cocaine challenge on WD1 and WD14. We observed that only the binge treatment led to sensitization of locomotor effects of cocaine, associated to a DA release sensitization in the Nac, whereas the intermittent treatment did not. We demonstrate that two different patterns of administration induced distinct behavioral and neurochemical consequences. We unambiguously demonstrated that the intermittent treatment induced drug expectation associated with higher basal DA level in the Nac when measured at the time of chronic cocaine injection and that the binge treatment led to behavioral and sensitization effects of cocaine.     

Intermittent morphine administration induces a long-lasting synergistic effect of corticosterone on dopamine D1 receptor functioning in rat striatal GABA neurons

Glucocorticoid receptor (GR)-mediated facilitation of striatal dopaminergic (DA) neurotransmission has been proposed to play a role in behavioral sensitization induced by intermittent exposure to drugs of abuse or stressors. Searching for possible common neuronal substrates acted upon by drugs of abuse and corticosterone, we addressed the question as to whether such a facilitatory effect is apparent (i.e., persists) in primary cultures of rat striatum subsequent to intermittent (prenatal) morphine administration. As previously observed in striatal slices of morphine-treated rats, intermittent morphine exposure in vivo caused a long-lasting increase in DA D1 receptor-stimulated adenylyl cyclase activity, that appeared to persist in primary cultures of rat striatal γ-aminobutyric acid (GABA) neurons. Subsequent in vitro exposure of these striatal neurons to corticosterone or dexamethasone, simultanously activating GR and mineralocorticoid receptors (MR), about doubled this adaptive effect of previous in vivo morphine administration. The selective MR agonist aldosterone was ineffective in this respect. Prior in vivo morphine treatment also enhanced the stimulatory in vitro effect of corticotropin releasing hormone (CRH) on adenylyl cyclase in cultured GABA neurons. However, the enhanced CRH receptor functioning was not potentiated by in vitro corticosterone exposure. Activation of GR by corticosterone did not facilitate the increase in D1 receptor efficacy induced by sustained activation of muscarinic receptors in cultured striatal neurons. These data indicate that previous intermittent morphine administration induces a long-lasting synergistic effect of corticosterone on enhanced striatal DA neurotransmission at the level of postsynaptic D1 receptors. Moreover, the induction of this neuroadaptation seems to display opioid receptor selectivity and its long-term expression may be confined to D1 receptors. Since exposure to drugs of abuse or stressors not only increase striatal DA release but also plasma corticosterone levels, we hypothesize that this adaptive phenomenon in DA-sensitive GABA neurons is involved in the expression of morphine-induced long-term behavioral sensitization to drugs of abuse and stressors. Synapse 25:381–388, 1997. © 1997 Wiley-Liss, Inc.     

Robust sensitization to amphetamine following intra-VTA cholera toxin administration

Studies were conducted regarding the hypothesis that enhanced cAMP formation in the ventral tegmental area (VTA) affects the magnitude of the behavioral responses elicited by psychostimulant drugs. In the first paradigm, spontaneous and amphetamine-elicited locomotor activity was measured at various times following injection of cholera toxin (CTX), a known activator of adenylate cyclase, into the VTA. Adult male rats showed enhanced amphetamine-stimulated locomotor activity when tested 1 or 3 days after treatment with 0.5 μg CTX into the VTA. Spontaneous activity was markedly increased 1 and 3 days following treatment with the higher dose of 1.0 μg CTX into the VTA, and amphetamine was still capable of eliciting an increased level of locomotor activity above this high baseline. Using a paradigm in which repeated amphetamine injections were given on an intermittent schedule following injection of CTX into the VTA, it was observed that a single low dose of amphetamine (0.5 mg/kg) given 1 day after CTX (0.5 μg) injection into the VTA led to a markedly potentiated locomotor activity response to subsequent treatment with amphetamine. Evaluation of this protocol (initial amphetamine dose 24 h after CTX injection, and challenge treatment of amphetamine at various times thereafter) showed that the sensitization was long-lasting and could be observed after an initial dose of amphetamine as low as 0.1 mg/kg. A sensitized response was also expressed when the challenge dose was given directly into the nucleus accumbens. These data suggest that injection of CTX into the VTA enhances the induction of locomotor sensitization to amphetamine. Synapse 25:335–344, 1997. © 1997 Wiley-Liss, Inc.     

Repeated exposure to amphetamine disrupts dopaminergic modulation of excitatory synaptic plasticity and neurotransmission in nucleus accumbens

The mesolimbic dopamine system is essential for reward-seeking behavior, and drugs of abuse perturb the normal functioning of this pathway. The nucleus accumbens (NAc) is a major terminal field of the mesolimbic dopamine neurons and modifications in neuronal structure and function in NAc accompany repeated exposure to psychomotor stimulants and other addictive drugs. Glutamatergic afferents to the NAc are thought to be crucial to the development of several aspects of addictive behavior, including behavioral sensitization and relapse to cocaine self-administration. Here we examine glutamatergic neurotransmission and synaptic plasticity in NAc neurons in vitro before and after repeated amphetamine treatment in vivo. We find that dopamine attenuates the response of NAc neurons to repetitive activation of glutamatergic afferents and thereby blocks long-term potentiation (LTP) induced by high-frequency afferent stimulation. Dopamine's effects are mimicked by dopamine receptor agonists and by amphetamine. In a second set of experiments, animals were treated with amphetamine daily for 6 days and brain slices were prepared after 8-10 days of withdrawal. In these slices, LTP in the NAc appears normal. However, acute exposure of such slices to amphetamine no longer modulates synaptic transmission or LTP induction. Thus, repeated exposure to amphetamine produces long-lasting changes in the modulation of glutamatergic synaptic transmission by amphetamine in the NAc. Our results support the notion that after psychostimulant exposure, excitatory synapses on NAc neurons alter their response to further psychostimulant for long periods of time.     

Behavioural sensitization and enhanced dopamine response in the nucleus accumbens after intravenous cocaine self-administration in mice

The behavioural effects of cocaine are enhanced in animals with a prior history of repeated cocaine administration. This phenomenon, referred to as sensitization, is also associated with an increase in cocaine-evoked extracellular dopamine levels in the nucleus accumbens. Behavioural and neurochemical sensitization has been demonstrated in rats with a prior history of cocaine self-administration and in those that had received experimenter-administered cocaine. Although it is clear that the repeated non-contingent administration also results in behavioural sensitization in the mouse, the issue of whether behavioural and neurochemical sensitization also occur in this species following intravenous cocaine self-administration has not been assessed. The present study used the technique of in vivo microdialysis in conjunction with operant self-administration to characterize cocaine-evoked locomotor activity and dopamine levels in the nucleus accumbens in mice with a prior history of intravenous cocaine self-administration or those that had received yoked infusions of cocaine. Mice that had received contingent or non-contingent infusions of cocaine exhibited an enhanced behavioural response to cocaine and increased cocaine-evoked dopamine levels in the nucleus accumbens. There was no difference between groups in the magnitude of this effect. Prior exposure to cocaine did not modify baseline dopamine levels in the nucleus accumbens. These data demonstrate that mice with previous cocaine self-administration experience show an enhanced behavioural and dopamine response to cocaine in the nucleus accumbens. Furthermore, control over cocaine infusion does not significantly alter the magnitude of the sensitized behavioural and presynaptic dopamine responses observed in response to a challenge dose of cocaine.     

Altered dopaminergic function in the prefrontal cortex, nucleus accumbens and caudate-putamen of an animal model of attention-deficit hyperactivity disorder — the spontaneously hypertensive rat

The spontaneously hypertensive rat (SHR) has been proposed as an animal model for Attention-Deficit Hyperactivity Disorder (ADHD). The behavioural problems of ADHD have been suggested to be secondary to altered reinforcement mechanisms resulting from dysfunction of the mesolimbic and mesocortical dopaminergic systems. The present study therefore investigated whether there are regional differences in dopamine (DA) and acetylcholine (ACh) release and DA D₂-receptor function in SHR compared to their normotensive Wistar-Kyoto (WKY) controls. The DA D₂-receptor agonist, quinpirole, caused significantly greater inhibition of DA release from caudate-putamen but not from nucleus accumbens or prefrontal cortex slices of SHR relative to WKY. DA D₂-receptor blockade by the antagonist, sulpiride, caused a significantly greater increase in DA release from nucleus accumbens slices of SHR compared to WKY suggesting increased efficacy of DA autoreceptors at low endogenous agonist concentrations in the nucleus accumbens of SHR. The electrically-stimulated release of DA was significantly lower in caudate-putamen and prefrontal cortex slices of SHR than in slices of WKY. This could be attributed to increased autoreceptor-mediated inhibition of DA release in caudate-putamen slices but not in the prefrontal cortex. No difference was observed between SHR and WKY with respect to DA D₂-receptor-mediated inhibition of ACh release from caudate-putamen or nucleus accumbens slices, suggesting that postsynaptic DA D₂-receptor function is not altered in SHR relative to WKY.     

Argon blocks the expression of locomotor sensitization to amphetamine through antagonism at the vesicular monoamine transporter-2 and mu-opioid receptor in the nucleus accumbens

We investigated the effects of the noble gas argon on the expression of locomotor sensitization to amphetamine and amphetamine-induced changes in dopamine release and mu-opioid neurotransmission in the nucleus accumbens. We found (1) argon blocked the increase in carrier-mediated dopamine release induced by amphetamine in brain slices, but, in contrast, potentiated the decrease in KCl-evoked dopamine release induced by amphetamine, thereby suggesting that argon inhibited the vesicular monoamine transporter-2; (2) argon blocked the expression of locomotor and mu-opioid neurotransmission sensitization induced by repeated amphetamine administration in a short-term model of sensitization in rats; (3) argon decreased the maximal number of binding sites and increased the dissociation constant of mu-receptors in membrane preparations, thereby indicating that argon is a mu-receptor antagonist; (4) argon blocked the expression of locomotor sensitization and context-dependent locomotor activity induced by repeated administration of amphetamine in a long-term model of sensitization. Taken together, these data indicate that argon could be of potential interest for treating drug addiction and dependence.     

5-HT2A and alpha1b-adrenergic receptors entirely mediate dopamine release, locomotor response and behavioural sensitization to opiates and psychostimulants

Addictive properties of drugs of misuse are generally considered to be mediated by an increased release of dopamine (DA) in the ventral striatum. However, recent experiments indicated an implication of α1b‐adrenergic receptors in behavioural responses to psychostimulants and opiates. We show now that DA release induced in the ventral striatum by morphine (20 mg/kg) is completely blocked by prazosin (1 mg/kg), an α1‐adrenergic antagonist. However, morphine‐induced increases in DA release in the ventral striatum were found to be similar in mice deleted for the α1b‐adrenergic receptor (α1b‐AR KO) and in wild‐type (WT) mice, suggesting the presence of a compensatory mechanism. This acute morphine‐evoked DA release was completely blocked in α1b‐AR KO mice by SR46349B (1 mg/kg), a 5‐HT_2A antagonist. SR46349B also completely blocked, in α1b‐AR KO mice, the locomotor response and the development of behavioural sensitization to morphine (20 mg/kg) and d ‐amphetamine (2 mg/kg). Accordingly, the concomitant blockade of 5‐HT_2A and α1b‐adrenergic receptors in WT mice entirely blocked acute locomotor responses but also the development of behavioural sensitization to morphine, d ‐amphetamine or cocaine (10 mg/kg). We observed, nevertheless, that inhibitory effects of each antagonist on locomotor responses to morphine or d ‐amphetamine were more than additive (160%) in naïve WT mice but not in those sensitized to either drug. Because of these latter data and the possible compensation by 5‐HT_2A receptors for the genetic deletion of α1b‐adrenergic receptors, we postulate the existence of a functional link between these receptors, which vanishes during the development of behavioural sensitization.