Repeated administration of the selective kappa-opioid receptor agonist U-69593 increases stimulated dopamine extracellular levels in the rat nucleus accumbens

Reinforcing properties of drugs of abuse are reduced by the coadministration of kappa opioid receptor (KOR) agonists. This effect is related to the inhibition of dopamine (DA) release in the nucleus accumbens (NAc) produced by the acute administration of KOR agonists. The present study was undertaken to investigate the in vivo effect of the repeated administration of KOR agonist on extracellular DA levels in the NAc. Rats were injected once daily with the selective KOR agonist U-69593 (0.16-0.32 mg/kg) or vehicle for 4 days. Microdialysis studies assessing extracellular concentration of DA in the NAc under basal and K(+)-stimulatory conditions were conducted 1 day later. The microdialysis studies revealed that preexposure to U-69593 had no effect on basal extracellular DA levels but significantly augmented the amount of extracellular DA induced by high K(+) compared with vehicle pretreated rats. The D2 receptor agonist quinpirole perfused through the dialysis probe in the NAc, although it produced a significant decrease on basal and K(+)-stimulated DA levels in control rats, it did not decrease significantly either basal or K(+)-stimulated DA levels in U-69593 preexposed rats. Preexposure to U-69593 did not alter the expression of tyrosine hydroxylase or dopamine transporter in the ventral tegmental area. These results show that repeated administration of U-696593 increases the amount of extracellular DA induced by high K in the NAc, an effect that may be related to decreased D2 autoreceptor function. It is suggested that repeated activation of KOR changes the response status of dopaminergic neurons in the NAc.     

Repeated treatment with the κ-opioid agonist U-69593 increases K+-stimulated dopamine release in the rat medial prefrontal cortex

Acute activation of κ-opioid receptors (KOR) decreases dopamine (DA) extracellular levels in both the medial prefrontal cortex (mPFC) and the nucleus accumbens (NAc). Also, the acute activation of KOR prevents alterations in behavior and neurochemistry occurring after repeated use of psychostimulants. Opposing to the acute effects, repeated administration of the KOR agonist, U-6593, potentiates both high-potassium and amphetamine induced DA release in the NAc, suggesting that repeated activation of KOR sensitizes mesolimbic dopaminergic neurotransmission. This study investigated the effect of repeated treatment with U-69593 on basal and stimulated DA and serotonin (5HT) extracellular levels in the rat mPFC. Rats were injected once daily with U-69593 (0.16-0.32 mg/kg) or vehicle for 4 days. One day after the last injection, microdialysis experiments assessing DA and 5HT extracellular levels in mPFC were conduced. The repeated treatment with U-69593 significantly augmented potassium-stimulated DA extracellular levels, without affecting potassium-stimulated 5HT extracellular levels, suggesting an increase in DA releasability.     

Modulation of pre- and postsynaptic dopamine D2 receptor function by the selective kappa-opioid receptor agonist U69593

The repeated administration of selective kappa-opioid receptor agonists prevents the locomotor activation produced by acute cocaine administration and the development of cocaine-induced behavioral sensitization. Previous studies have shown that dopamine (DA) D2 autoreceptors modulate the synthesis and release of DA in the striatum. Evidence that kappa agonist treatment downregulates DA D2 receptors in this same brain region has recently been obtained. Accordingly, the present studies were undertaken to examine the influence of repeated kappa-opioid receptor agonist administration on pre- and postsynaptic DA D2 receptor function in the dorsal striatum using pre- and postsynaptic receptor-selective doses of quinpirole. Rats were injected once daily with the selective kappa-opioid receptor agonist U69593 (0.16-0.32 mg/kg s.c.) or vehicle for 3 days. Microdialysis studies assessing basal and quinpirole-evoked (0.05 mg/kg s.c.) DA levels were conducted 2 days later. Basal and quinpirole-stimulated locomotor activity were assessed in a parallel group of animals. The no-net flux method of quantitative microdialysis revealed no effect of U69593 on basal DA dynamics, in that extracellular DA concentration and extraction fraction did not differ in control and U69593-treated animals. Acute administration of quinpirole significantly decreased striatal DA levels in control animals, but in animals treated with U69593, the inhibitory effects of quinpirole were significantly reduced. Quinpirole produced a dose-related increase in locomotor activity in control animals, and this effect was significantly attenuated in U69593-treated animals. These data reveal that prior repeated administration of a selective kappa-opioid receptor agonist attenuates quinpirole-induced alterations in DA neurotransmission and locomotor activity. These results suggest that both pre- and postsynaptic striatal DA D2 receptors may be downregulated following repeated kappa-opioid receptor agonist administration. Synapse 39:343-350, 2001. Published 2001 Wiley-Liss, Inc.     

Paradoxical effects of prodynorphin gene deletion on basal and cocaine-evoked dopaminergic neurotransmission in the nucleus accumbens

Quantitative and conventional microdialysis were used to investigate the effects of constitutive deletion of the prodynorphin gene on basal dopamine (DA) dynamics in the nucleus accumbens (NAc) and the responsiveness of DA neurons to an acute cocaine challenge. Saline- and cocaine-evoked locomotor activity were also assessed. Quantitative microdialysis revealed that basal extracellular DA levels were decreased, while the DA extraction fraction, an indirect measure of DA uptake, was unchanged in dynorphin (DYN) knockout (KO) mice. The ability of cocaine to increase NAc DA levels was reduced in KO. Similarly, cocaine-evoked locomotor activity was decreased in KO. The selective kappa opioid receptor agonist U-69593 decreased NAc dialysate DA levels in wildtype mice and this effect was enhanced in KO. Administration of the selective kappa opioid receptor (KOPr) antagonist nor-binaltorphimine to KO mice attenuated the decrease in cocaine-induced DA levels. However, it was ineffective in altering the decreased locomotor response to cocaine. These studies demonstrate that constitutive deletion of prodynorphin is associated with a reduction of extracellular NAc DA levels and a decreased responsiveness to acute cocaine. Data regarding the effects of U-69593 and nor-binaltorphimine in KO suggest that the kappa opioid receptor is up-regulated as a consequence of prodynorphin gene deletion and that this adaptation underlies the decrease in basal DA dynamics and cocaine-evoked DA levels observed in DYN KO mice. These findings suggest that the phenotype of DYN KO mice is not solely due to loss of endogenous opioid peptide but also reflects developmental compensations that occur at the level of the opioid receptor.     

Repeated ventral tegmental area amphetamine administration alters dopamine D1 receptor signaling in the nucleus accumbens

Neuroadaptations of the mesoaccumbens dopamine (DA) system likely underlie the emergence of locomotor sensitization following the repeated intermittent systemic administration of amphetamine (AMPH). In the nucleus accumbens (NAc), such neuroadaptations include enhanced DA overflow in response to a subsequent AMPH challenge as well as increased sensitivity to the inhibitory effects of D1 DA receptor (D1R) activation and an altered profile of D1R-dependent induction of immediate early genes (IEGs). Previous results indicate that AMPH acts in the ventral tegmental area (VTA) to initiate those changes leading to sensitization of the locomotor activity and NAc DA overflow produced by systemic administration of this drug. These observations are intriguing, given that acute infusion of AMPH into the VTA does not stimulate locomotor activity or, as we report presently, increase extracellular NAc DA concentrations. Two experiments, therefore, assessed the ability of repeated VTA AMPH to produce adaptations in D1R signaling in the NAc. Rats were administered three bilateral VTA infusions of saline or AMPH (2.5 microg/0.5 microl/side, one every third day). In the first experiment, in vivo extracellular electrophysiological recordings revealed that previous exposure to VTA AMPH enhanced the sensitivity of NAc neurons to the inhibitory effects of iontophoretic application of the D1R agonist SKF 38393. This effect was observed early (2-3 days) and at 1 month of withdrawal, but not after 2 months. Similarly, in the second experiment it was found that the D1R-dependent induction by AMPH of Fos, FosB, and JunB, but not NGFI-A, in the NAc was enhanced in rats exposed 1 week earlier to repeated VTA AMPH. These findings indicate that repeated VTA AMPH administration initiates relatively long-lasting adaptations in D1R signaling in the NAc that may, together with presynaptic adaptations affecting DA overflow, contribute to the expression of locomotor sensitization by this drug.     

Increased responsiveness of mesolimbic and mesostriatal dopamine neurons to cocaine following repeated administration of a selective κ-opioid receptor agonist

Previous data have shown that the repeated administration of κ-opioid receptor agonists attenuates the acute behavioral effects of cocaine. The site and mechanism by which κ-agonists interact with this psychostimulant, however, are unknown. Accordingly, the present microdialysis study characterized the effects of prior, repeated administration of the selective κ-opioid receptor agonist U69593 on basal and cocaine-evoked DA levels within the nucleus accumbens (NAC) and caudate putamen (CPU). The influence of U69593 treatment on the locomotor-activating effects of an acute cocaine challenge was also assessed. Rats received once daily injections of U69593 (0.16–0.32 mg/kg/day) or vehicle (1.0 ml/kg/day) for 3 days. The behavioral and neurochemical effects produced by an acute cocaine challenge (20 mg/kg i.p.) were assessed 2 days following treatment cessation. Administration of cocaine to control animals increased locomotor activity. This effect was attenuated in animals which had previously received U69593 (0.32 mg/kg/day × 3 days). Prior administration of U69593 failed to modify basal DA levels in either the NAC or CPU. Thus, 2 days following the cessation of U69593 treatment, dialysate DA levels did not differ from that of controls. Administration of cocaine to vehicle-treated animals increased dialysate levels of DA in both brain regions. However, in animals previously exposed to U69593 (0.32 mg/kg/day × 3 days), a significant enhancement in the response of DA neurons to cocaine was seen. These data demonstrate that prior, repeated administration of a selective κ-opioid receptor agonist attenuates the locomotor-activating effects of cocaine and increases cocaine-evoked DA overflow in terminal projection areas of mesostriatal and mesolimbic DA neurons. These findings indicate that the behavioral interactions of κ-agonists with cocaine observed in this and previous studies cannot be attributed to a presynaptic inhibition of DA release. Rather, they suggest that postsynaptic or non-DA mechanisms mediate the interaction of these agents with cocaine. Synapse 30:255–262, 1998. © 1998 Wiley-Liss, Inc.     

Effects of acute cocaine or dopamine receptor agonists on AMPA receptor distribution in the rat nucleus accumbens

Changes in α‐amino‐3‐hydroxy‐5‐methylisoxazole‐4‐propionate receptor (AMPAR) surface expression in the rodent nucleus accumbens (NAc) are produced by cocaine exposure and implicated in addiction‐related behaviors. The direction of change depends on the animal's prior drug history. However, little is known about the effect of a single exposure to cocaine on AMPAR distribution in the NAc of untreated rats. This is essential information for interpreting the literature on AMPAR trafficking after repeated cocaine exposure. In this study, we used a protein crosslinking assay to determine the effect of a single cocaine injection on surface and intracellular AMPAR subunit levels in the rat NAc. We found increased AMPAR surface expression in the NAc 24 h, but not 30 min or 2 h, after cocaine injection. A major effect of cocaine is to increase extracellular dopamine (DA) levels, leading to DA receptor activation. Therefore, we also evaluated the effects of directly acting DA receptor agonists. In contrast to the effects of cocaine, AMPAR surface expression was significantly decreased 24 h after injection of the D2‐class agonist quinpirole, whereas no significant effects were produced by the D1‐class agonist SKF 81297 or the mixed DA agonist apomorphine. Our results show that the effects of a single cocaine exposure in drug‐ and injection‐naïve rats are distinct from those previously reported after repeated cocaine administration. They further suggest that cocaine exerts these effects by influencing neuronal circuits rather than simply stimulating NAc DA transmission. Synapse 65:54–63, 2011. © 2010 Wiley‐Liss, Inc.     

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.     

Reduction in cholinergic interneuron density in the nucleus accumbens attenuates local extracellular dopamine release in response to stress or amphetamine

Depletion of cholinergic interneurons in the ventral striatum (nucleus accumbens or N.Acc.) in adult rats increases the locomotor activating effects of amphetamine. It also impairs sensorimotor gating processes, an effect reversed by the antipsychotic haloperidol. These behavioral effects are suggestive of pronounced hyper‐responsiveness of the mesolimbic dopamine (DA) projection to the N.Acc. However, it is unclear whether local cholinergic depletion results predominantly in exaggerated presynaptic DA release or a postsynaptic upregulation of DAergic function. The purpose of the present study is to test the former possibility by employing in vivo voltammetry to examine changes in the levels of extracellular DA within the N.Acc. in response to either mild tail pinch stress or amphetamine administration. While both cholinergic‐lesioned and control rats showed reliable stress‐induced increases in extracellular DA on two consecutive test days, those in the lesioned rats were significantly less pronounced. In response to amphetamine, a separate cohort of lesioned rats also exhibited smaller increases in extracellular DA release than controls, despite showing greater locomotor activity. Moreover, the increased behavioral response to amphetamine in lesioned rats coincided temporally with decreasing levels of DA in the N.Acc. The results confirm that cholinergic depletion within the N.Acc. suppresses presynaptic DA release and suggest that lesion‐induced behavioral effects are more likely due to postsynaptic DA receptor upregulation. The results are also discussed in the context of schizophrenia, where post mortem studies have revealed a selective loss of cholinergic interneurons within the ventral striatum. Synapse, 2013. © 2012 Wiley Periodicals, Inc.     

Histone deacetylase inhibitors modulates the induction and expression of amphetamine-induced behavioral sensitization partially through an associated learning of the environment in mice

The behavioral sensitization produced by repeated amphetamine treatment may represent the neural adaptations underlying some of the features of psychosis and addiction in humans. Chromatin modification (specifically histone hyperacetylation) was recently recognized as an important regulator of psychostimulant-induced plasticity. We have investigated the effects of treatment with the histone deacetylase (HDAC) inhibitors butyric acid (BA, 630mg/kg, i.p.) and valproic acid (VPA, 175mg/kg, i.p.) on the psyhcostimulant locomotor sensitization induced by amphetamine (AMPH, 2.0mg/kg, i.p.). Neither BA nor VPA had locomotor effects alone, but both significantly potentiated the amphetamine-induced behavioral sensitization in mice. At the molecular level, VPA and amphetamine produced an increase of histone H4 acetylation in the striatum as detected by Western blot analysis, while co-treatment with VPA and AMPH produced an additive effect on histone H4 acetylation. We then administered the HDAC inhibitors after treatment with amphetamine for 8 days to establish locomotor sensitization. We found that repeated administration of VPA or BA for 6 days inhibited the expression of sensitized response following amphetamine challenge. Finally, in a context-specific model we studied the effect of HDAC inhibitors on amphetamine-induced association of the treatment environment (associative learning). We found that VPA and BA enhance the context-specificity of expression of amphetamine sensitization. Thus, HDAC inhibitors differentially modulate the induction and expression of amphetamine-induced effects. Together, these results suggest that dynamic changes in chromatin modification may be an important mechanism underlying amphetamine-induced neuronal plasticity and associative learning.     

Kappa opioid receptor stimulation decreases amphetamine-induced behavior and neuropeptide mRNA expression in the striatum

The purpose of this study was to investigate the role that kappa opioid receptor stimulation has upon stimulant-induced behavior and neuropeptide gene expression in the striatum. Acute administration of amphetamine (2.5 mg/kg i.p.) caused an increase in behavioral activity and preprodynorphin, substance P, and preproenkephalin mRNA expression. When amphetamine-treated rats were pretreated with U69593, a kappa agonist (0.16 or 0.32 mg/kg s.c.), there was a significant decrease in behavioral activity. Quantitative in situ hybridization histochemistry revealed that 0.32 mg/kg U69593 significantly decreased amphetamine-induced mRNA expression of all three neuropeptides; however, only the induction of preproenkephalin mRNA was decreased by 0.16 mg/kg. These data suggest that stimulation of kappa receptors decreases acute amphetamine-induced behavior and mRNA expression of neuropeptides in the rat striatum.     

Basal and morphine-evoked dopaminergic neurotransmission in the nucleus accumbens of MOR- and DOR-knockout mice

Conventional and no net flux microdialysis were used to quantify basal and morphine-induced extracellular dopamine (DA) levels and the basal extraction fraction, which provides an estimate of the rate of DA uptake, in the nucleus accumbens (NAc) of wild-type mice and those with a constitutive deletion of mu (MOR)- or delta (DOR)-opioid receptors. Locomotor activity was assessed in these same animals. No difference between genotypes in basal dialysate DA levels was seen. No net flux studies revealed significant decreases in the DA extraction fraction in both MOR- and DOR-knockout mice, indicating decreased basal DA uptake in both genotypes. Extracellular DA, however, was unchanged. Because extracellular neurotransmitter levels are determined by the dynamics of both release and uptake, these findings provide suggestive evidence that basal DA release is decreased in mutant mice. Systemic administration of morphine significantly increased locomotor activity and dialysate DA levels in wild-type mice. MOR-knockout mice failed to exhibit a behavioural response to morphine. The ability of morphine to increase DA levels, however, was reduced but not prevented. No alteration in the effects of morphine was observed in DOR-knockout mice. These data provide genetic evidence for the existence of tonically active MOR and DOR systems that modulate basal DA neurotransmission in the NAc. Furthermore, they demonstrate that in contrast to the locomotor-activating effects of morphine, a small component of morphine-evoked DA release occurs independently of MOR activation.     

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.     

Electrophysiological evidence for the existence of both D-1 and D-2 dopamine receptors in the rat nucleus accumbens

Extracellular single-unit recording and microiontophoretic techniques were used to characterize the pharmacological properties of dopamine (DA) receptors within the rat nucleus accumbens (NAc), a forebrain structure that receives a dense innervation from mesolimbic DA-containing neurons (A10 DA neurons) located in the ventral tegmental area (VTA). Of the NAc neurons tested, 75% were inhibited by microiontophoretic administration of the selective D-2 receptor agonist, LY-141865, whereas 38% were inhibited by microiontophoretic administration of the selective D-1 receptor agonist, SKF-38393. Of the 30 NAc neurons that were tested with both of these agonists, nine were inhibited by both agonists, 11 were inhibited only by LY-141865, five were inhibited only by SKF-38393, and five were not affected by either of these compounds. The inhibitory effects of LY-141865 were blocked and reversed by either intravenous or iontophoretic administration of the selective D-2 antagonist (-)-sulpiride, which, however, failed to alter the inhibitory effects of SKF-38393. In contrast, the purportedly selective D-1 antagonist, SCH-23390, selectively blocked and reversed the inhibitory effects of SKF-38393, suggesting that the two agonists were producing their inhibitory effects via distinct DA receptors. Additional experiments indicated that intravenous administration of LY-141865 caused a biphasic increase/decrease in the activity of NAc neurons. The initial rate increase was apparently due to disinhibition since it was also shown that D-2 DA receptors located on A10 DA neurons exhibited a 3-10-fold greater sensitivity to LY-141865 and DA as compared to the NAc D-2 receptors.(ABSTRACT TRUNCATED AT 250 WORDS)     

Contribution of Blockade of the Noradrenaline Carrier to the Increase of Extracellular Dopamine in the Rat Prefrontal Cortex by Amphetamine and Cocaine

This study was performed to investigate the relative role of noradrenaline (NA) and dopamine (DA) carrier blockade in the effects of psychostimulants on DA transmission in the rat prefrontal cortex (PFCX). To this end, changes of extracellular DA and NA in the PFCX and of extracellular DA in the nucleus accumbens (NAc) were measured following the administration of amphetamine and cocaine, which are known to bind to both DA and NA carriers, or GBR 12909, a selective DA carrier blocker. After non-intravenous injection, amphetamine (0.25 and 0.5 mg/kg, s.c.) and cocaine (5 and 10 mg/kg, i.p.) increased extracellular DA in the PFCX to a larger extent than in the NAc, while the reverse applied to GBR 12909 (2.5 and 5 mg/kg, i.p.). These differences were obtained in spite of the fact that the three drugs elicited at each dose level a similar peak increase of extracellular DA in the NAc. Amphetamine and cocaine also increased extracellular NA in the PFCX and this effect was quantitatively similar to that on extracellular DA in the same area. Intravenous doses of cocaine and GBR 12909, corresponding to those which maintain self-administration in the rat, while equieffective in raising extracellular DA in the NAG, had different effects on extracellular DA in the PFCX. In fact, in contrast to cocaine, GBR 12909 increased extracellular DA in the PFCX to a lesser extent than in the NAc or did not modify it at all. The peak increase of extracellular DA in the PFCX was highly correlated to that of NA in the same area but was poorly correlated to the increase of extracellular DA in the NAc. These results suggest that amphetamine and cocaine increase extracellular DA in the PFCX largely through the blockade of the NA carrier. Direct evidence for this hypothesis was provided by the observation that, when the NA carrier was blocked by reverse dialysis of the PFCX with desipramine (1 μM), cocaine and GBR 12909 lost their differences in the ability to increase extracellular DA in the PFCX.     

Behavioral sensitization to ethanol results in cross-sensitization to MK-801 but not to NMDA administered intra-accumbens

In mice, repeated ethanol administration may induce behavioral sensitization - a process of progressive potentiation of its stimulant effects, associated with neuroadaptations in the brain reward system. Few studies have directly investigated the subsequent neuroadaptations in the nucleus accumbens (NAc), the central area of the brain reward system, after chronic ethanol administration. The goal of the present study was to analyze the involvement of accumbal glutamate NMDA receptors in the locomotion behavioral response to an NMDA agonist or to an NMDA antagonist in mice previously treated with ethanol. Swiss Albino mice received repeated daily administrations of 2.2g/kg ethanol or saline for 21 days. According to their locomotor response on the last day of treatment, ethanol-treated mice were classified into sensitized or non-sensitized groups. They were then submitted to a surgical procedure to implement intra-NAc cannulae. After recovery, mice were challenged with intra-NAc administration of saline and, two days later, with NMDA (NMDA agonist) or MK-801 (NMDA antagonist), having their locomotor activity recorded for 1h. The administration of NMDA induced similar locomotor behavior in all groups. On the other hand, the administration of 3μg/side MK-801 induced a significant stimulant effect which was more prominent during the first 15min in the sensitized group than in the non-sensitized or saline groups. Despite no effect of the agonist administration, only in sensitized mice did we observe cross-sensitization between repeated ethanol treatment and the intra-NAc administration of MK-801.     

Netrin-1 receptor-deficient mice show enhanced mesocortical dopamine transmission and blunted behavioural responses to amphetamine

The mesocorticolimbic dopamine (DA) system is implicated in neurodevelopmental psychiatric disorders including schizophrenia but it is unknown how disruptions in brain development modify this system and increase predisposition to cognitive and behavioural abnormalities in adulthood. Netrins are guidance cues involved in the proper organization of neuronal connectivity during development. We have hypothesized that variations in the function of DCC (deleted in colorectal cancer), a netrin-1 receptor highly expressed by DA neurones, may result in altered development and organization of mesocorticolimbic DA circuitry, and influence DA function in the adult. To test this hypothesis, we assessed the effects of reduced DCC on several indicators of DA function. Using in-vivo microdialysis, we showed that adult mice that develop with reduced DCC display increased basal DA levels in the medial prefrontal cortex and exaggerated DA release in response to the indirect DA agonist amphetamine. In contrast, these mice exhibit normal levels of DA in the nucleus accumbens but significantly blunted amphetamine-induced DA release. Concomitantly, using conditioned place preference, locomotor activity and prepulse inhibition paradigms, we found that reduced DCC diminishes the rewarding and behavioural-activating effects of amphetamine and protects against amphetamine-induced deficits in sensorimotor gating. Furthermore, we found that adult DCC-deficient mice exhibit altered dendritic spine density in layer V medial prefrontal cortex pyramidal neurones but not in nucleus accumbens medium spiny neurones. These findings demonstrate that reduced DCC during development results in a behavioural phenotype opposite to that observed in developmental models of schizophrenia and identify DCC as a critical factor in the development of DA function.     

Sparing of behavior and basal extracellular dopamine after 6-hydroxydopamine lesions of the nigrostriatal pathway in rats exposed to a prelesion sensitizing regimen of amphetamine

Repeated administration of amphetamine leads to enduring augmentation of its behavioral-activating effects, enhanced dopamine (DA) release in striatal regions, and morphological changes in DA target neurons. Here we show that exposure to a 2-week escalating-dose regimen of amphetamine prevents behavioral asymmetries of forelimb use and spontaneous (drug-independent) turning behavior following unilateral 6-hydroxydopamine (6-OHDA) lesions of the nigrostriatal pathway made 7-14 days after termination of amphetamine treatment (Experiments 1-3). Exposure to three nonescalating injections of amphetamine 7 days before 6-OHDA lesions had no effect (Experiment 2). Prelesion amphetamine treatment led to normalization of basal extracellular levels of striatal DA as measured by microdialysis on days 11-14 and 25-28 after lesioning (Experiment 3). However, there were no significant differences between treatment groups in postmortem tissue levels of DA and its metabolites, indicating a dissociation between the DA depletion and the extracellular levels of DA as measured by microdialysis. Finally, rats exposed to the escalating amphetamine regimen had reduced lesion-induced loss of TH-IR cells in the ipsilateral DA cell body regions (Experiment 3). Thus, prelesion exposure to the escalating doses of amphetamine may render the cells resistant to the consequences of damage after subsequent 6-OHDA lesions, possibly by accelerating the development of compensatory changes in the DA neurons that typically accompany behavioral recovery. The potential role of amphetamine-induced endogenous neurotrophic factors in the behavioral sparing and normalization of basal extracellular DA levels observed after subsequent 6-OHDA lesions is discussed.     

Acetylcholine from the mesopontine tegmental nuclei differentially affects methamphetamine induced locomotor activity and neurotransmitter levels in the mesolimbic pathway

Methamphetamine (MA) increases dopamine (DA) levels within the mesolimbic pathway and acetylcholine (ACh), a neurotransmitter known to increase DA cell firing and release and mediate reinforcement, within the ventral tegmental area (VTA). The laterodorsal tegmental (LDT) and pedunculopontine tegmental (PPT) nuclei provide cholinergic input to the VTA; however, the contribution of LDT- and PPT-derived ACh to MA-induced DA and ACh levels and locomotor activation remains unknown. The first experiment examined the role of LDT-derived ACh in MA locomotor activation by reversibly inhibiting these neurons with bilateral intra-LDT microinjections of the M2 receptor agonist oxotremorine (OXO). Male C57BL/6 J mice were given a bilateral 0.1 μl OXO (0, 1, or 10 nM/side) microinjection immediately prior to IP saline or MA (2 mg/kg). The highest OXO concentration significantly inhibited both saline- and MA-primed locomotor activity. In a second set of experiments we characterized the individual contributions of ACh originating in the LDT or pedunculopontine tegmental nucleus (PPT) to MA-induced levels of ACh and DA by administering intra-LDT or PPT OXO and performing in vivo microdialysis in the VTA and NAc. Intra-LDT OXO dose-dependently attenuated the MA-induced increase in ACh within the VTA but had no effect on DA in NAc. Intra-PPT OXO had no effect on ACh or DA levels within the VTA or NAc, respectively. We conclude that LDT, but not PPT, ACh is important in locomotor behavior and the cholinergic, but not dopaminergic, response to systemic MA.     

Heightened locomotor-activating effects of amphetamine administered into the nucleus accumbens in adolescent rats

There is a shift in sensitivity to systemically administered psychostimulants in adolescence, as evidenced by less amphetamine-induced locomotor activity in adolescent compared to adult rodents. Locomotor activating effects of amphetamine are dependent on drug actions in the core of the nucleus accumbens (NAc), but the contribution of this region to age differences in amphetamine sensitivity has not been studied directly. In the present study, we investigated the development of the NAc using targeted injections of amphetamine (0, 3, or 6 μg/side) directly into the NAc core in early (postnatal day 30; P30) or late (P45) adolescence, or in adulthood (P75). Locomotor activity was recorded during two 1 h sessions, 48 h apart. Amphetamine increased locomotor activity at all ages. P45 rats were more active than adults only at the 3 μg/side dose, but this difference was not significant when baseline activity was taken into account. In contrast, P30 rats were more active than adults at the 6 μg/side dose, indicating that the magnitude of the locomotor response is highest in early adolescence. Results of the present study are the first to directly show a developmental difference in the sensitivity of the NAc to amphetamine under conditions in which the influence of pharmacokinetic factors and regulatory brain regions is minimized.