Dose-dependent effects of estrogen on prediction error related neural activity in the nucleus accumbens of healthy young women.

RATIONALE: Whereas the effect of the sex steroid 17-beta-estradiol (E2) on dopaminergic (DA) transmission in the nucleus accumbens (NAc) is well evidenced in female rats, studies in humans are inconsistent. Moreover, linear and inverted u-shaped dose response curves have been observed for E2's effects on hippocampal plasticity, but the shape of dose response curves for E2's effects on the NAc is much less characterized. OBJECTIVES: Investigation of dose response curves for E2's effects on DA-related neural activity in the human NAc. METHODS: Placebo or E2 valerate in doses of 2, 4, 6 or 12 mg was orally administered to 125 naturally cycling young women during the low-hormone menstruation phase on two consecutive days using a randomized, double-blinded design. The E2 treatment regimen induced a wide range of E2 levels, from physiological (2- and 4-mg groups; equivalent to cycle peak) to supraphysiological levels (6- and 12-mg groups; equivalent to early pregnancy). This made it possible to study different dose response functions for E2's effects on NAc activity. During E2 peak, participants performed a well-established reversal learning paradigm. We used trial-wise prediction errors (PE) estimated via a computational reinforcement learning model as a proxy for dopaminergic activity. Linear and quadratic regression analyses predicting PE-related NAc activity from salivary E2 levels were calculated. RESULTS: There was a positive linear relationship between PE-associated NAc activity and salivary E2 increases. CONCLUSIONS: The randomized, placebo-controlled elevation of E2 levels stimulates NAc activity in the human brain, likely mediated by dopaminergic processes.

Interactions of benzodiazepines with heroin: Respiratory depression, temperature effects, and behavior.

Benzodiazepines are important therapeutic drugs, but they are often abused and co-abused with opioids. Clinical evidence suggests that benzodiazepines can inhibit respiration, and when combined with the respiratory-depressive effects of opioids, may increase likelihood of death. In this study we used oxygen sensors coupled with high-speed amperometry and multi-site thermorecording to examine how intravenous (iv) midazolam, a potent benzodiazepine, modulates the brain hypoxic and temperature effects of iv heroin in freely-moving rats. Oxygen levels and brain temperature were assessed with high temporal resolution in the nucleus accumbens (NAc), an important structure in the motivational-reinforcement circuit. When administered alone, midazolam (2 mg/kg) modestly decreased NAc temperature but had no evident effects on oxygen levels in this structure. In contrast, heroin (0.4 mg/kg) induced a strong decrease in NAc oxygen that was followed by a weaker, rebound-like oxygen increase. Midazolam pretreatment did not affect heroin-induced brain hypoxia but potentiated the initial hypothermia induced by heroin. However, co-administration of these drugs potentiated the heroin-induced oxygen decrease and enhanced heroin-induced brain hypothermia. Co-administration of heroin and midazolam also resulted in enhanced locomotor inhibition and loss of motor control. This effect caused some rats to collapse, resulting in nose and mouth occlusion, which caused a secondary hypoxic phase. These results could have important implications for human drug users, as the combined use of benzodiazepines with potent opioids not only results in sustained brain hypoxia but creates conditions of loss of motor control which could result in asphyxia and death. This article is part of the Special Issue entitled 'New Vistas in Opioid Pharmacology'.

Role of GABA(A) receptors in the retrorubral field and ventral pallidum in rat jaw movements elicited by dopaminergic stimulation of the nucleus accumbens shell.

The role of gamma-aminobutyric acid (GABA)(A) receptors in the retrorubral field in the production of rat repetitive jaw movements was examined, as this nucleus receives a GABAergic, inhibitory input from the nucleus accumbens and is connected with the parvicellular reticular formation, a region that is directly connected with the orofacial motor nuclei. The GABA(A) receptor antagonist bicuculline (150 ng/0.2 microl per side) significantly produced repetitive jaw movements when injected bilaterally into the retrorubral field, but not the ventral pallidum. The effects of bicuculline were GABA(A) receptor specific, because the effects were abolished by muscimol, a GABA(A) receptor agonist, given into the same site. The bicuculline-induced jaw movements differed qualitatively from those elicited by injection of a mixture of (+/-)-6-chloro-7,8-dihydroxy-3-allyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine-7,8-diol (SKF 82958; 5 microg) and quinpirole (10 microg), agonist at dopamine D1 and D2 receptors respectively, into the nucleus accumbens shell. Nevertheless, bilateral injections of muscimol (10 ng, 25 ng and 50 ng/0.2 microl per side) into the retrorubral field significantly inhibited jaw movements evoked by the dopamine D1/D2 receptor stimulation in the nucleus accumbens shell. Bilateral injections of bicuculline (50 ng and 150 ng/0.2 microl per side) also reduced the dopamine D1/D2 receptor-mediated jaw movements. Essentially similar effects were obtained when muscimol and bicuculline were given into the ventral pallidum, a region that is also known to receive GABAergic inhibitory inputs from the nucleus accumbens. In conclusion, GABA(A) receptor blockade in the retrorubral field elicits characteristic repetitive jaw movements, and the GABA(A) receptors in that region as well as in the ventral pallidum modulate the accumbens-specific, dopamine D1/D2 receptor-mediated jaw movements.

Behavioral expression of opiate withdrawal is altered after prefrontocortical dopamine depletion in rats: monoaminergic correlates.

The objective of this study was to establish the effects of prefrontocortical dopamine depletion on opiate withdrawal and prefrontocortical neurochemical changes elicited by morphine dependence and withdrawal. The dopaminergic content was also measured in the nucleus accumbens during withdrawal, in order to detect reactive changes induced by prefrontocortical lesion. Withdrawal was induced by naloxone in morphine-dependent rats. Monoamine levels were analyzed post-mortem by high performance liquid cromatography. The results showed that chronic morphine dependence did not modify basal levels of monoamines in sham rats, revealing neuroadaptation of prefrontocortical dopamine, noradrenaline and serotonin systems to chronic morphine. The neuroadaptive phenomenon remained after prefrontocortical lesion (> 79% dopamine depletion). On the other hand, a strong increase of dopamine, noradrenaline, and serotonin contents in the medial prefrontal cortex of sham rats was detected during opiate withdrawal. However, in lesioned rats, the increase of prefrontocortical dopamine and serotonin content, but not that of noradrenaline, was much lower. In the nucleus accumbens, prefrontocortical lesion reactively enhanced the dopaminergic tone and, although opiate withdrawal reduced dopaminergic activity in both sham and lesioned rats, this reduction was less intense in the latter group. At a behavioral level, some symptoms of physical opiate withdrawal were exacerbated in lesioned rats (writhing, mastication, teeth-chattering, global score) and exploration was reduced. The findings hence indicate that: (i) prefrontocortical monoaminergic changes play a role in the behavioral expression of opiate withdrawal; (ii) the severity of some withdrawal signs are related to the dopaminergic and serotonergic tone of the medial prefrontal cortex rather than to the noradrenergic one, and (iii) an inverse relationship between mesocortical and mesolimbic dopaminergic systems exists.

Behavioral and biochemical manifestations of mecamylamine-precipitated nicotine withdrawal in the rat: role of nicotinic receptors in the ventral tegmental area.

Brain mesolimbic dopamine (DA) neurons are considered critical for the dependence-producing action of nicotine, and its stimulatory effect on behavior and DA neurotransmission appears largely mediated via nicotinic receptors (nAChRs) in the ventral tegmental area (VTA). The nAChR antagonist mecamylamine administered systemically in chronically nicotine-treated rats elicits a behavioral withdrawal syndrome concomitant with a reduced DA output in the nucleus accumbens (NAC). Here, we investigated the behavioral and biochemical consequences of intrategmental administration of mecamylamine in rats chronically infused with nicotine by means of minipumps for 14 days (9 mg/kg/day). Bilateral, intrategmental mecamylamine injections (1, 3 or 9 micrograms/0.5 microliter/side) dose-dependently increased abstinence signs such as gasps, teeth chatter, and reduced locomotor activity in nicotine-treated, but not in control animals. Moreover, a unilateral intrategmental injection of 9 micrograms mecamylamine reduced DA output in the ipsilateral NAC of chronically nicotine-treated rats, but not in control animals. Consequently, nAChRs in the VTA may be involved not only in the stimulatory effects of acute nicotine administration, but also in the withdrawal reaction following cessation of chronic nicotine treatment.

Nicotine withdrawal hyperalgesia and opioid-mediated analgesia depend on nicotine receptors in nucleus accumbens.

The nucleus accumbens, as part of the mesolimbic dopaminergic reward pathway, mediates both addiction to and withdrawal from substances of abuse. In addition, activity of substances of abuse such as opioids in the nucleus accumbens has been implicated in pain modulation. Because nucleus accumbens nicotinic receptors are important in nicotine addiction and because nicotinic activity can interact with opioid action, we investigated the contribution of nucleus accumbens nicotinic receptors to opioid-mediated analgesia/antinociception. The response of the nociceptive jaw-opening reflex to opioids was studied in the rat, both before and during chronic nicotine exposure. In nicotine-naive rats, intra-accumbens injection of the nicotinic receptor antagonist mecamylamine blocked antinociception produced by either systemic morphine, intra-accumbens co-administration of a mu- and a delta-opioid receptor agonist, or noxious stimulation (i.e., subdermal capsaicin in the hindpaw); intra-accumbens mecamylamine alone had no effect. The antinociceptive effect of either morphine or noxious stimulation was unchanged during nicotine tolerance; however, intra-accumbens mecamylamine lost its ability to block antinociception produced by either treatment. Intra-accumbens mecamylamine by itself precipitated significant hyperalgesia in nicotine-tolerant rats which could be suppressed by noxious stimulation as well as by morphine. These results indicate that nucleus accumbens nicotinic receptors play an important role in both opioid- and noxious stimulus-induced antinociception in nicotine-naive rats. This role was attenuated in the nicotine-dependent state. The suppression of withdrawal hyperalgesia by noxious stimulation suggests that pain can ameliorate the symptoms of withdrawal, thus suggesting a possible mechanism for pain-seeking behavior.

Effects of nicotine and mecamylamine-induced withdrawal on extracellular dopamine and acetylcholine in the rat nucleus accumbens.

RATIONALE: Prior research suggests that high levels of acetylcholine (ACh) in the nucleus accumbens (NAc) are associated with aversive states such as morphine withdrawal, but this has not been tested for nicotine withdrawal. OBJECTIVES: The goal was to test the hypothesis that acute nicotine decreases extracellular ACh and increases extracellular dopamine (DA) in the NAc, while withdrawal from nicotine causes an opposite neurochemical imbalance with high extracellular ACh and low DA. METHODS: Rats were prepared with a microdialysis probe in the NAc (primarily the shell region). They received one injection of nicotine (0.5 mg/kg, s.c.) or chronic nicotine (9 mg/kg per day via osmotic minipump). RESULTS: Naive animals receiving acute nicotine showed a mild, significant increase in both ACh (122% of baseline) and DA (124%). After chronic nicotine administration for 7 days, the nicotinic antagonist mecamylamine (1.0 mg/kg, s.c.) precipitated withdrawal with the appearance of somatic signs (teeth chattering and shakes/tremors) and a significant increase in extracellular ACh to 125% of baseline, while extracellular DA decreased to 65%. Control groups receiving saline in place of nicotine or mecamylamine did not show these effects. CONCLUSIONS: Earlier work suggests that the observed release of accumbens ACh and DA in response to acute nicotine administration may be a factor in nicotine-induced suppression of appetite. ACh release during withdrawal, coupled with the decrease in extracellular DA may play a role in the aversive aspects of nicotine withdrawal that contribute to dependency.

Effect of cocaine, nomifensine, GBR 12909 and WIN 35428 on carbon fiber microelectrode sensitivity for voltammetric recording of dopamine.

Electrochemical measurements using voltammetry or amperometry at carbon-fiber microelectrodes have been used in vitro and in vivo to examine regulatory mechanisms for the central dopamine system. In many of these experiments, dopamine efflux concentrations under control conditions are determined followed by their alterations in response to a drug treatment. The present study demonstrates that some drugs can affect dopamine measurements, not only by their expected pharmacological action but also by directly altering the microelectrode responsivity. The commonly used reuptake inhibitors GBR 12909 (10 microM) and nomifensine (5 microM) drastically reduce electrode sensitivity and, in the case of nomifensine, increase the time to reach a plateau in response to dopamine boluses (i.e. reduced 'frequency response'). Cocaine (10 microM) and WIN 35428 (2 microM) have negligible effect on these indices. This decrease in sensitivity was found in both nafion and non-nafion coated electrodes. Further, the reduction in sensitivity seen in non-nafion coated electrodes was not prevented by increasing the reversal potential (from +1.0 to +1.3 V) and voltage scan rate (from 350 to 450 V/s). These data suggest that care must be taken when interpreting data from voltammetric or amporometric experiments using carbon electrodes where GBR 12909 or nomifensine are used, especially at high concentrations. Furthermore, wherever possible, direct effects of a drug on electrode sensitivity and frequency response should be determined.

Dopamine microdialysis in the nucleus accumbens during acute and chronic morphine, naloxone-precipitated withdrawal and clonidine treatment.

This study shows the effect of opiate withdrawal on dopamine (DA) in the nucleus accumbens (NAC). Microdialysis was used to detect variations in extracellular DA, dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) in the NAC of freely moving rats during acute and chronic morphine treatment followed by naloxone-precipitated withdrawal with and without clonidine. Basal levels of extracellular DA did not change between sessions, but morphine (20 mg/kg, i.p.) caused a significant and identical increase in extracellular DA and metabolites in both the acute phase (day 1) and the chronic phase (day 7). On day 8, naloxone (20 mg/kg i.p.) caused a significant decrease in DA levels accompanied by typical withdrawal symptoms such as wet dog shakes and teeth-chattering. Clonidine pretreatment (200 micrograms/kg, i.p.) eliminated both the withdrawal symptoms and the DA decrease. These results support the view that morphine increases extracellular DA at times when the drug is rewarding and also suggest that the converse may be true; morphine withdrawal decreases DA release in association with the aversive state.

Microdialysis evidence that acetylcholine in the nucleus accumbens is involved in morphine withdrawal and its treatment with clonidine.

This study used microdialysis to measure changes in extracellular acetylcholine (ACh) content in the nucleus accumbens (NAC) of freely moving rats during acute and chronic morphine treatment, and following naloxone-precipitated withdrawal. Morphine injection (20 mg/kg, i.p.) caused a significant decrease in extracellular ACh which was not apparent after repeated exposure to the opiate for 7 days. Basal recovery of ACh was not altered by chronic morphine treatment. On day 8, after morphine dependence had been established, naloxone caused a large increase in ACh levels accompanied by withdrawal symptoms such as wet dog shakes, diarrhea and teeth-chattering. Pretreatment with clonidine (200 micrograms/kg, i.p.) reduced these withdrawal symptoms and eliminated the ACh response. These results suggest that accumbens ACh is involved in some of the aversive aspects of opiate withdrawal.

Role of dopamine D1 and D2 receptors in the nucleus accumbens in jaw movements of rats: a critical role of the shell.

Given the differences in the dopamine neurotransmission between the shell and the core of the nucleus accumbens, as well as the differential involvement of these two domains in oral behaviour of rats, it was decided to determine whether or not dopamine D1 and/or dopamine D2 receptors differentially direct oral behaviour in these two domains in rats. Intra-accumbens injections of the dopamine D1 receptor agonist (+/-)-6-chloro-7,8-dihydroxy-3-allyl-1-phenyl-2,3,4,5-tetrahydro-1H-3- benzazepine (SKF 82958: 5 micrograms/0.2 microliters), the dopamine D2 receptor agonist quinpirole (10 micrograms/0.2 microliters) and their combination were used to assess the role of these accumbens domains in jaw movements of rats. The present study shows that the combined administration of SKF 82958 and quinpirole into the shell, but not the core, of the nucleus accumbens produced a highly significant increase in jaw movements, when doses which per se were nearly ineffective, were injected. This effect was fully inhibited by prior administration of either the dopamine D1 receptor antagonist R-(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine (SCH 23390: 0.5 microgram/0.2 micrograms) or the dopamine D2 receptor antagonist (-)-sulpiride (25 ng/0.5 microliter) into the same region. It is concluded that dopamine D1 and D2 receptors in the shell, but not the core, of the nucleus accumbens are involved in jaw movements of the rat, providing the first piece of evidence that dopamine D1 and D2 receptors in the shell of the nucleus accumbens mediate a particular behaviour.

Behavioural effects of 7-OH-DPAT are solely due to stimulation of dopamine D2 receptors in the shell of the nucleus accumbens; jaw movements.

The goal of this study was to determine whether the dopamine D3 receptor in limbic structures plays a role in the shell-specific and dopamine-dependent display of jaw movements in rats. When combined with the dopamine D1 receptor agonist (+/-)-6-chloro-7,8-dihydroxy-3-allyl-1- phenyl-2,3,4,5-tetrahydro-1 H-3-benzazepine (SKF 82958, 5 micrograms), the putative dopamine D3 receptor agonist (+/-)-7-hydroxy-N, N-di-n-propyl-2-aminotetralin (7-OH-DPAT, 10 micrograms) produced repetitive jaw movements following injection into the shell, but not the core, of the nucleus accumbens. This behaviour was only partially inhibited by local blockade of dopamine D1 receptors (R(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1 H-3-benzazepine, SCH 23390, 500 ng), dopamine D2 receptors (domperidone, 50 and 100 ng) or dopamine D2/3 receptors (l-sulpiride, 25 ng). Combined blockade of both dopamine D1 and D2 receptors in the shell completely antagonized the jaw movements elicited by the cocktail of SKF 82958 and 7-OH-DPAT. Replacing 7-OH-DPAT by another putative dopamine D3 receptor agonist, S(+)-(4aR, 10bR)-3,4,4a,10b-tetrahydro-4-propyl-2H,5H-[I]benzopyrano[4, 3-b]-1, 4-oxazin-9-ol (PD 128,907, 10 micrograms), in the cocktail did not produce jaw movements, when administered into the shell. Injection of the cocktail of SKF 82958 and 7-OH-DPAT into the ventrolateral striatum, which contains nearly no dopamine D3 receptors, also elicited jaw movements. It is concluded that mesolimbic dopamine D3 receptors play no role in the dopamine-dependent and shell-specific jaw movements: the contribution of 7-OH-DPAT in the cocktail of SKF 82958 and 7-OH-DPAT to the display of jaw movements is solely due to its ability to activate dopamine D2 receptors.

Clozapine injected into the nucleus accumbens potentiates apomorphine-induced jaw movements.

The effects of clozapine injected into the nucleus accumbens on apomorphine-induced jaw movements were studied. Jaw movements induced by apomorphine (0.5 mg/kg i.v.) were potentiated by clozapine (10 micrograms/0.2 microliters) injected into the nucleus accumbens 10 min before apomorphine. Enhancement of the apomorphine-induced jaw movements was also found with the muscarinic acetylcholine receptor antagonist, methylscopolamine (2.5 micrograms), whereas the acetylcholine receptor agonist, carbachol (2.5 micrograms), inhibited the effects of apomorphine. Injection of a smaller dose of carbachol (0.1 microgram) alone into the nucleus accumbens 10 min before failed to alter the effects of apomorphine but prevented the potentiation induced by clozapine. Both the 5-hydroxytryptamine(5-HT)2A receptor antagonist, 2-(2-dimethylaminoethylthio)-3-phenylquinoline hydrochloride (ICI 169,369, 0.1 and 0.2 microgram), and the alpha 1-adrenoceptor antagonist, prazosin (0.05 and 0.2 microgram), failed to affect the effects of apomorphine(0.5 mg/kg i.v.). In contrast, clozapine (1, 5 and 10 micrograms), ICI 169,369 (0.1 and 0.2 microgram) or prazosin (0.05 and 0.2 microgram) given into the ventral striatum inhibited the effects of apomorphine (0.5 mg/kg i.v.). It is suggested that the clozapine-induced potentiation in the nucleus accumbens might be due to its antimuscarinic properties.

Ventral striatal vs. accumbal (shell) mechanisms and non-cyclase-coupled dopamine D(1)-like receptors in jaw movements.

This study compared the effects of intracerebral injections of the dopamine D(1)-like receptor agents 3-methyl-6-chloro-7,8-dihydroxy-1-[3-methylphenyl]-2,3,4,5-tetrahydro-1H-3-benzazepine (SK&F 83959) and [R]-3-methyl-7-chloro-8-hydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine (SCH 23390) into the ventrolateral striatum or the shell of the nucleus accumbens on the synergistic induction of jaw movements by intravenous (i.v.) co-administration of [R]-7,8-dihydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine (SK&F 38393) or SK&F 83959 with the dopamine D(2)-like receptor agonist, quinpirole. In the ventrolateral striatum, SCH 23390 and SK&F 83959 each blocked jaw movements induced by i.v. SK&F 38393 with quinpirole, while only SCH 23390 blocked i.v. SK&F 83959 with quinpirole. SCH 23390 was less effective in the accumbens shell than in the ventrolateral striatum, and SK&F 83959 was ineffective to block i.v. SK&F 38393 with quinpirole, while neither SCH 23390 nor SK&F 83959 blocked i.v. SK&F 83959 with quinpirole. As SK&F 83959 inhibits the stimulation of adenylyl cyclase via dopamine D(1A) receptors but acts as an agonist at a putative dopamine D(1)-like receptor site not linked to cyclase, an important role is indicated for non-cyclase-coupled dopamine D(1)-like receptor sites as well as dopamine D(1A) receptors in the regulation of jaw movements via dopamine D(1)-like/D(2)-like receptor synergism, particularly in the ventrolateral striatum.

Cholecystokinin octapeptide and caerulein injection into the dorsomedial nucleus accumbens potentiate apomorphine-induced jaw movements in rats.

The effects of bilateral intra-accumbal and intrastriatal injections of CCK-8 sulphate and its analogue, caerulein, on apomorphine-induced jaw movements were studied in ketamine-anaesthetized rats after C1 spinal transection. Jaw movements were detected by a photo-transducer attached to the mandible. CCK-8 (5, 10 and 20 ng) and its analogue, caerulein (1 and 5 ng), injected into the dorsomedial nucleus accumbens increased the frequency of apomorphine (0.2 mg/kg i.v.)-induced jaw movements. The potentiation was prevented by administration of a CCK-A receptor antagonist, lorglumide (5 ng), together with CCK-8 (20 ng) or caerulein (5 ng). Injection of lorglumide alone into the dorsomedial nucleus accumbens did not alter apomorphine (0.5 mg/kg i.v.)-induced jaw movements. Injections of CCK-8 (20 ng) and caerulein (5 ng) into adjacent sites (the ventrolateral nucleus accumbens, dorsal striatum and ventral striatum) did not affect the responses elicited by apomorphine (0.2 mg/kg i.v.). These results demonstrate that CCK-8 modulates responses elicited by a dopamine receptor agonist, apomorphine, in a region of the brain where CCK-8 is known to co-exist with dopamine.

Prefrontal, accumbal [shell] and ventral striatal mechanisms in jaw movements and non-cyclase-coupled dopamine D1-like receptors.

The effect on jaw movements of intracerebral injections of the dopamine D1-like receptor agents SK&F 83959 (3-methyl-6-chloro-7,8-dihydroxy-1-[3-methylphenyl]-2,3,4,5-tetrahydro-1H-3-benzazepine), SK&F 38393 ([R]-7,8-dihydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine) and SCH 23390 ([R]-3-methyl-7-chloro-8-hydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine) and of injections of the dopamine D2-like receptor agonist quinpirole into the ventrolateral striatum, accumbens shell or prefrontal cortex were studied. SK&F 38393 and SK&F 83959 injected into the ventrolateral striatum synergised with i.v. quinpirole; in the shell of accumbens, SK&F 38393 evidenced weaker synergism with quinpirole, while SK&F 83959 did not synergise with it; neither agent synergised with quinpirole in the prefrontal cortex. Co-injection of SCH 23390 or SK&F 83959 into the prefrontal cortex antagonised jaw movements induced by injection of SK&F 83959 into the ventrolateral striatum in combination with i.v. quinpirole. Injection of SK&F 83959 + quinpirole into the ventrolateral striatum, but not into the accumbens shell, resulted in synergism. These findings indicate a primary, but not exclusive, role for ventral striatal, non-cyclase-coupled dopamine D1-like receptors in the induction of jaw movements. These processes appear to require tonic activity of prefrontal cyclase-linked dopamine D1A [and/or D1B] receptors.

YM-14673, a thyrotropin-releasing hormone analogue, injected into the nucleus accumbens and the striatum produces repetitive jaw movements in rats.

Bilateral injections of the thyrotropin-releasing hormone (TRH) analogue, N alpha-[((S)-4-oxo-2-azetidinyl)-carbonyl]-L-histidyl-L-prolinamide dihydrate (YM-14673, 0.1 microgram and 1 microgram/0.2 microliters), into the nucleus accumbens, the dorsal and ventrolateral striatum produced repetitive jaw movements in a dose-dependent manner. The effects were greatest in the nucleus accumbens and smallest in the ventrolateral striatum. Pattern of the movements differed from that produced by injections of a mixture of SKF 38393 (5 micrograms) and quinpirole (10 micrograms); frequent tongue protrusions were evident in rats treated with the mixture but those were not seen in YM-14673-treated rats. TRH (1 microgram, 10 micrograms and 30 micrograms/0.2 microliters) did not evoke jaw movements from any of the sites. The non-selective dopamine receptor antagonist, cis-(Z)-flupentixol (10 micrograms), significantly reduced the response to administration of YM-14673 (1 microgram) into the nucleus accumbens or dorsal striatum, while the 5-hydroxytryptamine (5-HT)2A receptor antagonist, 2-(2-dimethylaminoethylthio)-3-phenylquinoline hydrochloride (ICI 169,369, 0.2 micrograms), did not affect the response to YM-14673 (1 microgram). Given intrathecally (0.5 microgram/5 microliters), both YM-14673 and TRH produced wet-dog shakes. Although the mechanisms giving rise to the display of jaw movements after intrastriatal injections of YM-14673 remain unknown, stimulation of the dopamine D1/D2 receptors may at least partly contribute to these effects. Anyhow, these mechanisms differ from that underlying the ability of YM-14673 and TRH to elicit wet-dog shakes, a mechanism that is known to involve serotonergic processes.

Effects of cabergoline and rotigotine on tacrine-induced tremulous jaw movements in rats.

OBJECTIVES: We examined the effects of two dopamine agonists, cabergoline and rotigotine, on tacrine-induced tremor and c-Fos expression in rats. METHODS: Rats received intraperitoneal injection of cabergoline (0.5, 1.0, or 5.0mg/kg), rotigotine (1.0, 2.5, or 10.0mg/kg), or vehicle 30min before intraperitoneal injection of tacrine (5.0mg/kg). The number of tremulous jaw movements (TJMs) after tacrine administration was counted for 5min. Animals were sacrificed 2h later under deep anesthesia, and the brain sections were immunostained in order to evaluate the c-Fos expression. RESULTS: Induction of TJMs by tacrine was dose-dependently reduced by pretreatment with cabergoline and rotigotine. The number of c-Fos-positive cells was significantly enhanced in the medial striatum, nucleus accumbens core, and nucleus accumbens shell after tacrine administration, and the enhanced expression of c-Fos in these three regions was significantly attenuated by cabergoline, while rotigotine suppressed c-Fos expression in two regions except the nucleus accumbens core. CONCLUSIONS: These results suggest that tacrine-induced TJMs would be relieved by either cabergoline or rotigotine and that anticholinesterase-induced TJMs and the ameliorating effects of dopamine agonists would relate to neuronal activation in the striatum and nucleus accumbens.

Nucleus accumbens facilitates nociception.

We have previously demonstrated an opioid link in nucleus accumbens (NAc) that mediates antinociception produced by a novel ascending pain modulation pathway. For example, noxious stimulation induces heterosegmental antinociception that is mediated by both mu- and delta-opioid receptors in NAc. However, spinal intrathecal administration of the mu-receptor agonist [D-Ala(2), N-Me-Phe(4),Gly(5)-ol]-enkephalin (DAMGO) also induces heterosegmental antinociception. The aim of the present study in the rat was to identify the intra-NAc opioid receptors that mediate the antinociceptive effects of spinally administered DAMGO and also to determine the effect of NAc efferent activity on nociception. Intra-NAc administration of either the mu-opioid receptor antagonist Cys(2),Tyr(3), Orn(5),Pen(7)amide (CTOP) or the delta-opioid receptor antagonist naltrindole blocked the antinociceptive effect of spinally administered DAMGO on the jaw-opening reflex (JOR). Injection of quaternary lidocaine (QX-314) attenuated the JOR, suggesting that the output of NAc is pronociceptive. In support of this, intra-NAc injection of the excitatory amino acid agonist kainate enhanced the JOR. Thus, it is possible to modulate activity in NAc to bidirectionally attenuate or enhance nociception, suggesting a potential role for NAc in setting nociceptive sensitivity.

Prodynorphin gene deficiency potentiates nalbuphine-induced behavioral sensitization and withdrawal syndrome in mice.

Dynorphin is the presumed endogenous ligand for the kappa-opioid receptor. The dynorphin gene may play a role in psychotropic agent-mediated behavioral changes via dopaminergic modulation. Therefore, in this study, possible involvement of the dynorphin gene in nalbuphine-mediated behavioral responses was examined using prodynorphin (Pdyn) gene knock-out (-/-) mice. Pdyn gene deficiency potentiates nalbuphine-induced behavioral sensitization of locomotor activity and accumbal c-Fos expression. Administration of nalbuphine induced a significant increase in the dialysate dopamine level in the nucleus accumbens. This increase was more pronounced in the Pdyn (-/-) mice than in the wild-type (WT) mice. In addition, Pdyn (-/-) mice were more vulnerable to the naloxone-precipitated withdrawal syndrome (i.e., teeth chattering, wet dog shakes, forepaw tremors, jumping, weight loss, and global withdrawal score) after repeated treatment with nalbuphine than the WT mice. Consistently, nor-binaltorphimine, a kappa-opioid receptor antagonist, significantly potentiated nalbuphine-induced behavioral effects in WT mice, whereas U-50488H, a kappa-opioid receptor agonist, significantly attenuated these changes in Pdyn (-/-) mice in a dose-dependent manner. Our data suggest that the kappa-opioid receptor/dynorphin system is specifically modulated in response to behavioral sensitization and withdrawal signs induced by nalbuphine.