Inhibition from ventral tegmental area of nucleus accumbens neurons in the rat

The role of the ventral tegmental area (VTA), which is rich in dopamine-containing cell bodies, on nucleus accumbens (Acc) neurons was examined. In Acc neurons receiving input from parafascicular nucleus (Pf) of thalamus, VTA conditioning stimulation produced an inhibition of spike generation with Pf stimulation. In contrast, VTA conditioning stimulation did not affect Acc neurons receiving input from limbic structures such as the amygdala nucleus and hippocampus.     

Electrophysiological characteristic of corticoaccumbens synapses in rat mesolimbic system reconstructed using organotypic slice cultures

The nucleus accumbens (NAc) is a component of the mesolimbic system involved in drug dependence. Activity of nucleus accumbens neurons is modulated by glutamatergic afferents from the prefrontal cortex and by dopaminergic afferents from the ventral tegmental area (VTA). In the present study, we reconstructed the mesolimbic system using organotypic slice cultures and examined the effects of dopaminergic agents on synaptic activity in the prefrontal cortex-nucleus accumbens synapses. A slice of each of the prefrontal cortex, nucleus accumbens and ventral tegmental area in newborn rat, was arranged on a multi-electrode dish (MED) filled with culture medium so that they contacted each other, termed a 'triple culture'. Extracellular recording using microelectrodes on the multi-electrode dish showed that a single electrical stimulation of the prefrontal cortex slice evoked field excitatory postsynaptic potential, and that population spikes occurred spontaneously in the nucleus accumbens area of the triple culture. The amplitude of evoked field excitatory postsynaptic potentials and the frequency of spontaneous population spikes were decreased by glutamatergic antagonists, D(-)-2-amino-5-phosphonovaleric acid and 6-cyano-7-nitroquinoxaline-2,3-dione. The D1-like receptor agonist SKF38393, but not the D2-like receptor agonist quinpirole, reduced both the amplitude of field excitatory postsynaptic potential and frequency of spontaneous population spikes. Cocaine depressed field excitatory postsynaptic potential and this depression was reversed by D1-like receptor antagonist SCH23390, but not by D2-like receptor antagonist sulpiride. These results suggest that evoked field excitatory postsynaptic potentials and spontaneous population spikes were driven by glutamatergic neurons and were subject to exogenous and endogenous dopaminergic modulation in the triple culture that was similar to that shown in in vivo.     

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)     

Differential effects of SCH 23390 on the apomorphine subsensitivity in the substantia nigra and ventral tegmental area 1 day following withdrawal from continuous or intermittent cocaine pretreatment

Using extracellular single-unit recordings in rats, the effects of chronic intermittent injections and continuous infusion of cocaine on single dopamine neurons were directly compared in the substantia nigra and ventral tegmental area. After 1-day withdrawal we determined: (1) the neuronal sensitivity to the mixed D₁/D₂ agonist apomorphine and (2) its modulation by the D₁ antagonist SCH 23390. The nigral dopamine neurons exhibited subsensitivity to the impulse-inhibiting effects of apomorphine following both intermittent and continuous regimens. SCH 23390 selectively reversed the apomorphine subsensitivity in the intermittent group, while having minimal effects in the other group. Dopamine neurons in the ventral tegmental area, on the other hand, were sub- and normosensitive to apomorphine following intermittent and continuous dosing regimens, respectively. In contrast to the substantia nigra, SCH 23390 failed to alter the apomorphine sensitivity in either of the pretreatment groups. Possible mechanisms underlying these distinctive changes in the substantia nigra and ventral tegmental area following intermittent and continuous cocaine pretreatment regimens are discussed.     

D1 dopamine receptor stimulation enables the postsynaptic, but not autoreceptor, effects of D2 dopamine agonists in nigrostriatal and mesoaccumbens dopamine systems

Possible functional interactions between D1 and D2 dopamine (DA) receptors were examined using extracellular single-cell recording with microiontophoretic application of selective D1 and D2 receptor agonists both postsynaptically, in the rat nucleus accumbens (NAc) and caudate-putamen (CPu), and presynaptically, at impulse-regulating somatodendritic DA autoreceptors in the ventral tegmental area (A10) and substantia nigra pars compacta (A9). In addition, synthesis-modulating nerve terminal DA autoreceptors were studied in both the CPu and NAc using the gamma-butyrolactone (GBL) neurochemical model of isolated nerve terminal autoreceptor function in vivo. In both the NAc and CPu, the inhibition of neurons produced by iontophoresis of the D2 receptor agonists quinpirole or RU-24213 was attenuated by acute DA depletion via the tyrosine hydroxylase inhibitor alpha-methyl-p-tyrosine (AMPT). However, during iontophoresis of the selective D1 DA receptor agonist SKF 38393, the inhibitory effects of the D2 agonists were again evident, suggesting that the attenuation of D2 agonist-induced inhibition was due to decreased D1 receptor activation. In contrast, the inhibitory effects produced by the non-selective D1/D2 agonist apomorphine or by SKF 38393 were unaffected by AMPT pretreatment. Thus, D1 receptor activation appears necessary for D2 receptor-mediated inhibition of NAc and CPu neurons, whereas D2 receptor activation is not required for the inhibition produced by D1 receptor stimulation. In contrast to postsynaptic D2 receptors, the ability of DA agonists to stimulate D2 DA autoreceptors was not altered by manipulations of D1 receptor occupation. Enhancing D1 receptor stimulation with SKF 38393 or reducing D1 receptor occupation with either the selective D1 receptor antagonist SCH 23390 or AMPT failed to alter the rate-inhibitory effect of i.v. quinpirole on A9 or A10 DA neurons. Similarly, iontophoresis of SKF 38393 failed to alter the inhibitory effects of iontophoretic quinpirole. SKF 38393 also failed to affect the inhibition of GBL-induced increases in DOPA accumulation (tyrosine hydroxylase activity) produced by quinpirole in either the NAc or CPu. Furthermore, reversal of GBL-induced increases in DOPA accumulation by apomorphine or quinpirole was unaffected by pretreatment with SCH 23390. Therefore, D1 receptor occupation appears to be necessary for the expression of the functional effects of postsynaptic D2 receptor stimulation but not presynaptic D2 DA autoreceptor stimulation.     

Inhibition from locus coeruleus of nucleus accumbens neurons activated by hippocampal stimulation

Electrophysiological studies using rats were performed to examine the influence of locus coeruleus (LC) on nucleus accumbens (Acc) neurons. Spike generation by hippocampal stimulation was inhibited by both LC conditioning stimulation and iontophoretic application of noradrenaline, but spikes elicited by stimulation of parafascicular nucleus of thalamus were rarely affected by LC conditioning stimulation or noradrenaline. The LC-induced inhibition was antagonized by iontophoretic sotatol, but not by phentolamine, suggesting that noradrenaline derived from the LC inhibits the Acc neurons receiving input from the hippocampus, probably acting on a β-adrenergic receptor.     

Effects of the dopamine D-1 antagonist SCH 23390 microinjected into the accumbens, amygdala or striatum on cocaine self-administration in the rat

This study tested the hypothesis that blockade of D-1 dopamine receptors in the nucleus accumbens shell, central nucleus of the amygdala or dorsal striatum by intracerebral microinjection of the dopamine antagonist SCH 23390 produces an attenuation of the effects of self-administered cocaine. Microinjection of SCH 23390 (0–4.0 μg total dose) into any of the three brain regions dose-dependently increased the rate of cocaine self-administration, consistent with a partial attenuation of the effects of cocaine under these conditions (0.25 mg cocaine i.v.; fixed-ratio 5 timeout 20 s). The regional rank order potency of SCH 23390 was accumbens > amygdala > striatum, striatal injections being equipotent with subcutaneous administration. Moreover, SCH 23390 produced rapid effects on cocaine self-administration only when injected into the accumbens or amygdala. The time course of this regional selectivity was consistent with the rate of diffusion of SCH 23390 from the site of injection as measured by quantitative autoradiography, demonstrating that the regional selectivity of intracerebral injections of SCH 23390 is time-dependent. These results support a role for D-1 dopamine receptors in the nucleus accumbens and amygdala in the effects of self-administered cocaine, and suggest that D-1 receptors in certain portions of the ‘extended amygdala’ may be an important substrate for the reinforcing actions of cocaine.     

Dopamine enhances terminal excitability of hippocampal-accumbens neurons via D2 receptor: role of dopamine in presynaptic inhibition

The effects of dopamine on the axonal terminals of hippocampal-nucleus accumbens (HIPP-ACC) neurons were investigated in urethane-anesthetized rats using extracellular single-unit recording techniques. Antidromic responses recorded in the ventral subiculum of the hippocampus were evoked by stimulation of the medial accumbens. Baseline terminal excitability of these neurons, established by threshold stimulation of the accumbens, was markedly enhanced by conditioning stimulation (10 Hz) of the ventral tegmental area (VTA), the origin of the mesolimbic dopaminergic neurons. Iontophoretic application of sulpiride, a selective D2 antagonist, onto the HIPP-ACC terminals attenuated the increased terminal excitability of these neurons produced by conditioning VTA stimulation, while intraperitoneal injection of SCH23390, a selective D1 antagonist, failed to attenuate this effect. Iontophoretic application of dopamine or its selective D2 agonist, LY171555, onto the terminals of the HIPP-ACC neurons mimicked the prolonged enhancement of the terminal excitability produced by VTA stimulation, whereas SKF38393, a D1 agonist, had no effect. The effects of VTA stimulation, dopamine and LY171555 application were similar after the accumbens had been pretreated with ibotenic acid, suggesting a direct action of dopamine on the axonal terminals of HIPP-ACC neurons, and that changes in terminal excitability were not mediated via interneurons or feedback pathways from the accumbens to the hippocampus. Since iontophoretic application of potassium, a depolarizing agent, also enhanced the terminal excitability of the HIPP-ACC neurons, it appears that dopamine depolarized, via D2 receptors, the axonal terminals of HIPP-ACC neurons.(ABSTRACT TRUNCATED AT 250 WORDS)     

Oxytocin injected into the ventral tegmental area induces penile erection and increases extracellular dopamine in the nucleus accumbens and paraventricular nucleus of the hypothalamus of male rats

The neuropeptide oxytocin (20-100 ng), induces penile erection when injected unilaterally into the caudal but not rostral mesencephalic ventral tegmental area (VTA) of male Sprague-Dawley rats. Such pro-erectile effect started 30 min after treatment and was abolished by the prior injection of d(CH2)5Tyr(Me)(2)-Orn(8)-vasotocin (1 microg), an oxytocin receptor antagonist injected into the same caudal ventral tegmental area or of haloperidol (1 microg), a dopamine receptor antagonist, injected either into the nucleus accumbens shell (NAs) or into the paraventricular nucleus of the hypothalamus (PVN) ipsilateral to the injected ventral tegmental area. Penile erection was seen 15 min after the occurrence of, or concomitantly to, an increase in extracellular dopamine and its metabolite 3,4-dihydroxyphenylacetic acid (DOPAC) in the dialysate obtained from the nucleus accumbens or the paraventricular nucleus, which was also abolished by d(CH2)5Tyr(Me)(2)-Orn(8)-vasotocin (1 microg), injected into the ventral tegmental area before oxytocin. In the caudal ventral tegmental area oxytocin-containing axons/fibres (originating from the paraventricular nucleus) appeared to closely contact cell bodies of mesolimbic dopaminergic neurons retrogradely labelled with Fluorogold injected into the nucleus accumbens shell, suggesting that oxytocin effects are mediated by the activation of mesolimbic dopaminergic neurons, followed in turn by that of incerto-hypothalamic dopaminergic neurons impinging on oxytocinergic neurons mediating penile erection. As the stimulation of paraventricular dopamine receptors not only induces penile erection, but also increases mesolimbic dopamine neurotransmission by activating oxytocinergic neurons, these results provide further support for the existence of a neural circuit in which dopamine and oxytocin influence both the consummatory and motivational/rewarding aspects of sexual behaviour.     

Electrophysiological responses of neurones in the nucleus accumbens to hippocampal stimulation and the attenuation of the excitatory responses by the mesolimbic dopaminergic system

Extracellular single unit recordings were obtained from neurones in the nucleus accumbens of urethane anaesthetized rats. Single pulse stimulation (300-800 microA, 0.15 ms, 0.5-1.5 Hz) of the ventral subiculum of the hippocampus strongly excited silent and spontaneously active (3-6 spikes/s) medial accumbens neurones. The majority of neurones excited by hippocampal stimulation were quiescent and identified only by the elicited action potentials. Neurones on the dorso-medial border of the nucleus accumbens and adjacent lateral septum, with a faster spontaneous discharge rate (8-12 spikes/s), were inhibited by hippocampal stimulation. In the ventral border of the accumbens and the olfactory tubercle, hippocampal stimulation also inhibited the fast-firing (greater than 20 spikes/s) neurones. When trains of 10 conditioning pulses (300-800 microA, 0.15 ms, 10 Hz) were delivered to the ventral tegmental area (VTA) 100 ms before each single-pulse stimulation of the hippocampus, the excitatory responses of the silent and spontaneously active accumbens neurones were attenuated. The possibility of this relatively prolonged attenuation effect being dopamine-mediated was supported by several lines of evidence. Dopamine, applied iontophoretically, reduced markedly the excitatory response of accumbens neurones to hippocampal stimulation. Iontophoretically applied dopamine mimicked the attenuating effect produced by VTA conditioning stimulation in the same neurone. The attenuating effects of VTA conditioning stimulation on the activation of accumbens neurones by hippocampal stimulation was reduced by: (1) administration of 6-hydroxydopamine to the VTA 2 days and 7-9 days prior to the recording session, (2) the intraperitoneal injection of haloperidol 1 h before the recording session, and (3) the iontophoretic application of trifluoperazine to accumbens neurones. These observations support the hypothesis that the attenuating effects of the mesolimbic dopamine system on limbic inputs to the nucleus accumbens may have a role in limbic-motor integration.     

Neonatal medial prefrontal cortex lesion enhances the sensitivity of the mesoaccumbal dopamine system

Neurodevelopmental models of schizophrenia posit that early brain damage leads to dys- or misconnection effects possibly altering synaptic transmission in brain sites distal of the lesion. We tested the hypothesis that neonatal medial prefrontal cortex (mPFC) lesions affect the sensitivity of the mesoaccumbal dopamine (DA) system. Using extracellular single-unit recordings combined with systemic application of the DA agonist apomorphine, followed by the D2 receptor antagonist haloperidol or the D1 receptor antagonist SCH23390, we compared electrophysiological properties of nucleus accumbens core and shell neurons after bilateral excitotoxic lesions of mPFC induced at postnatal day 7 or in adult rats. Whereas animals with adult mPFC lesions showed an altered discharge pattern within the core region, neonatal mPFC lesions altered the discharge pattern within the shell region. Subcutaneous administration of apomorphine (4 mg/kg) reduced accumbal firing rate in 77% of all neurons. Onset and magnitude of apomorphine-induced inhibition of neuronal activity was faster and stronger in rats with neonatal but not adult mPFC lesions in both core and shell regions. Apomorphine-induced inhibition was partially reversed by 0.1 mg/kg haloperidol only in core region of neonatal lesioned rats. Apomorphine-induced excitation of neuronal activity (in 21% of all neurons) was reversed by the D1 receptor antagonist SCH23390 (0.1 mg/kg) in all excited neurons. These data support the hypothesis that neonatal but not adult lesions of mPFC alter cortico-striatal networks and suggest that disturbance of mPFC development leads to neurodevelopmental changes in mesoaccumbal DA system during adulthood.     

Depression of retinogeniculate synaptic transmission by presynaptic D(2)-like dopamine receptors in rat lateral geniculate nucleus

Extraretinal projections onto neurons in the dorsal lateral geniculate nucleus (dLGN) play an important role in modifying sensory information as it is relayed from the visual thalamus to neocortex. The dLGN receives dopaminergic innervation from the ventral tegmental area; however, the role of dopamine in synaptic transmission in dLGN has not been explored. In the present study, whole cell recordings were obtained to examine the actions of dopamine on glutamatergic synaptic transmission. Dopamine (2-100 microm) strongly suppressed excitatory synaptic transmission in dLGN relay neurons that was evoked by optic tract stimulation and mediated by both N-methyl-d-aspartate and non-N-methyl-d-aspartate glutamate receptors. In contrast, dopamine did not alter inhibitory synaptic transmission arising from either dLGN interneurons or thalamic reticular nucleus neurons. The suppressive action of dopamine on excitatory synaptic transmission was mimicked by the D(2)-like dopamine receptor agonist bromocriptine (2-25 microm) but not by the D(1)-like receptor agonist SKF38393 (10-25 microm). In addition, the dopamine-mediated suppression was antagonized by the D(2)-like receptor antagonist sulpiride (10-20 microm) but not by the D(1)-like receptor antagonist SCH23390 (5-25 microm). The dopamine-mediated decrease in evoked excitatory postsynaptic current amplitude was accompanied by an increase in the magnitude of paired-pulse depression. Furthermore, dopamine also reduced the frequency but not the amplitude of miniature excitatory postsynaptic currents. Taken together, these data suggest that dopamine may act presynaptically to regulate the release of glutamate at the retinogeniculate synapse and modify transmission of visual information in the dLGN.     

Autoradiographic localization of D1 dopamine receptors in the rat brain with [3H]SCH 23390

The regional distribution of D1 dopamine (DA) receptors in the rat brain has been studied by quantitative autoradiography using the specific D1 antagonist [3H]SCH 23390 as a ligand. The binding of [3H]SCH 23390 to striatal sections was saturable, stereospecific, reversible and of high affinity (Kd = 2.05 nM); it occurred at a single population of sites and possessed the pharmacological features of the D1 DA receptor. The highest densities of [3H]SCH 23390 binding sites were found in the caudate-putamen, olfactory tubercle, nucleus accumbens and substantia nigra (especially in the pars compacta). High densities were also observed in the nucleus interstitialis striae terminalis, the anterior olfactory nucleus, the entopeduncular nucleus, the subthalamic nucleus, the claustrum and the amygdalohippocampal area. An intermediate labelling was found in the anteromedial and suprarhinal DA terminal fields of the cerebral cortex, the basolateral, medial and lateral amygdaloid nuclei, the endopiriform nucleus, the primary olfactory cortex, the globus pallidus, the superior colliculus (especially the superficial layer), the nucleus amygdaloideus corticalis and the dorsal hippocampus (molecular layer of the CA1 and dentate gyrus). In the anteromedial and suprarhinal cortices, [3H]SCH 23390 binding was more concentrated in layers V and VI. Moderate levels of [3H]SCH 23390 were found in the thalamus, hypothalamus, the habenula, the ventral tegmental area, the posterior cingulate and entorhinal cortices, the supragenual dopamine terminal system and the cerebellum (molecular layer). This regional distribution of [3H]SCH 23390 closely correlated (except for the cerebellum) with the reported distribution of dopaminergic terminals. The topographical distribution of [3H]SCH 23390 has also been studied in detail in striatal subregions. The density of D1 receptors was much greater in the ventrolateral sector and medial margin of the striatum than in the ventromedial and dorsolateral sectors. A rostrocaudal decrease in the densities of D1 sites was also found along the rostrocaudal axis of the caudate-putamen. These lateral to medial and anteroposterior gradients overlapped with the density of the dopaminergic afferents.     

Role of projections from ventral medial prefrontal cortex to nucleus accumbens shell in context-induced reinstatement of heroin seeking

In humans, exposure to contexts previously associated with heroin use can provoke relapse. In rats, exposure to heroin-paired contexts after extinction of drug-reinforced responding in different contexts reinstates heroin seeking. This effect is attenuated by inhibition of glutamate or dopamine transmission in nucleus accumbens shell, or inactivation of ventral medial prefrontal cortex (mPFC). Here, we used an anatomical asymmetrical disconnection procedure to demonstrate that an interaction between glutamatergic projections from ventral mPFC to accumbens shell and local dopamine D(1) postsynaptic receptors contributes to context-induced reinstatement of heroin seeking. We also combined the marker of neuronal activity, Fos, with the retrograde tracer Fluoro-Gold to assess activation in this pathway during context-induced reinstatement. Rats were trained to self-administer heroin for 12 d; drug infusions were paired with a discrete tone-light cue. Lever pressing was subsequently extinguished in a nondrug-associated context in the presence of the discrete cue. Rats were then tested in the heroin- or extinction-associated contexts under extinction conditions. Injections of muscimol + baclofen into ventral mPFC in one hemisphere and D(1)-family receptor antagonist SCH 23390 into the contralateral or ipsilateral accumbens shell decreased context-induced reinstatement. Unilateral injections of muscimol + baclofen into ventral mPFC or SCH 23390 into the accumbens shell had no effect. Context-induced reinstatement was associated with increased Fos expression in ventral mPFC neurons, including those projecting to accumbens shell, with higher double-labeling in the ipsilateral projection than in the contralateral projection. Our results demonstrate that activation of glutamatergic projections from ventral mPFC to accumbens shell, previously implicated in inhibition of cocaine relapse, promotes heroin relapse.     

D1 receptor activation enhances sciatic nerve stimulation-induced inhibition of nigrostriatal dopamine neurons

Nigrostriatal dopamine (NSDA) neurons have been hypothesized to play an important regulatory role in neostriatal sensorimotor integration. In order to provide further information on the nature of sensory modulation of NSDA cells, we have examined the pharmacology of the responsiveness of these neurons to peripheral nerve stimulation. The selective D1 dopamine receptor agonist SKF 38393 enhanced the normal inhibition of NSDA neurons produced by electrical stimulation of the sciatic nerve. The SKF 38393-induced enhancement, but not the basal stimulation-induced inhibition itself, was blocked by prior hemitransection of the forebrain and was reversed by the selective D1 antagonist SCH 23390 but not by the selective D2 antagonist 1-sulpiride. SCH 23390 alone, however, exerted no effect on this inhibition. The selective D1 receptor agonist fenoldopam, which does not cross the blood-brain barrier, also failed to alter the response to sciatic nerve stimulation (i.v. administration). Thus, central D1 receptors (rostral to the midbrain) appear to be involved in a system which mediates phasic control over sensory modulation of NSDA neuronal activity.     

Mesolimbic dopamine projection modulates amygdala-evoked EPSP in nucleus accumbens neurons: an in vivo study

In urethane anesthetized rats, excitatory postsynaptic potential (EPSP) recorded intracellularly from nucleus accumbens neurons following stimulation of the amygdala was attenuated by repetitive stimulation of the ventral tegmental area (VTA). VTA stimulation also depolarized the resting membrane potential of accumbens neurons. Attenuation of the EPSP and membrane depolarization were frequently dissociated but both were blocked by haloperidol, a dopamine antagonist.     

Effects of acute administration of SCH 23390 on dopamine and serotonin turnover in major dopaminergic areas and mesencephalic raphe nuclei — Comparison with ritanserin

1. The effects of acute administration of SCH 23390 (0.05 and 0.25 mg/kg s.c.), a dopamirie D-1 receptor antagonist having also a moderate serotonin-S₂ (5-HT-2) receptor blocking activity, and ritanserin (0.5 mg/kg), a specific 5-HT-2 antagonist, on dopamine (DA) and serotonin (5-HT) turnover were investigated in dopaminergic (nucleus caudatus, nucleus accumbens, substantia nigra, A10 area) and serotonergic (nucleus raphe dorsalis and nucleus raphe medialis) rat brain nuclei.

2. Acute SCH 23390 (both doses) increased the metabolism of DA and tended to augment the rate of DA synthesis (accumulation of DOPA after inhibition of aromatic acid decarboxylase) in the nucleus accumbens, but not in the nucleus caudatus. In addition, SCH 23390 had a moderate effect on DA metabolism in substantia nigra. SCH 23390 did not alter the turnover of 5-HT in any of the nuclei studied.

3. Acute administration of ritanserin did not modify 5-HT or DA turnover in any of the nuclei studied.

4. In conclusion, these results suggest that acute SCH 23390 administration preferentially activates the mesolimbic DA system. The lack of effect of ritanserin on DA or 5-HT turnover in nigrostriatal and mesolimbic DAergic areas suggests that under basal conditions the blockade of 5-HT₂ receptors do not change monoamine metabolism in these areas. The role of 5-HT-2 blockade in the actions of SCH 23390 on DA turnover appears thus to be of a minor importance.     

The nucleus accumbens and inhibition in the ventral tegmental area play a causal role in the Kamin blocking effect

The discovery of Kamin blocking led to the idea that associative learning occurs only when there is a mismatch between actual and predicted outcomes, or prediction error. The neural substrates involved in regulating this prediction error during behavioral learning are still not fully elucidated. We investigated in rats the role of the ventral tegmental area and the nucleus accumbens in Kamin blocking. Our blocking paradigm involved three phases: appetitive classical conditioning of a lever cue, conditioning of a compound of the lever cue plus an auditory cue, and testing response to the auditory cue in extinction. We found that disruption of inhibition in the ventral tegmental area by bicuculline, or designer receptor mediated inactivation of the nucleus accumbens, during compound cue conditioning, attenuated Kamin blocking. These results suggest that inhibition in the ventral tegmental area and inhibitory output from the nucleus accumbens are necessary for blocking and make behaviorally significant contributions to the computation of reward prediction error. In addition, we found that inactivating the neurons in the nucleus accumbens during classical conditioning of the lever cue also attenuated blocking, without affecting classical conditioning of the lever. This indicates that learning in the nucleus accumbens is necessary for blocking and reward estimation. Our results reveal a causal role for nucleus accumbens modulated inhibitory inputs to the ventral tegmental area in the blocking effect and suggest that they contribute to computation of reward prediction error during associative learning.     

Self-stimulation of the nucleus accumbens and ventral tegmental area of tsai attenuated by microinjections of spiroperidol into the nucleus accumbens

The contribution of dopaminergic neurons to self-stimulation of the ventral tegmental area, nucleus accumbens and prefrontal cortex was investigated. The ventral tegmental area is the site of non-striatal dopaminergic neurons and their axons project to the nucleus accumbens and prefrontal cortex. Injections of spiroperidol, a dopamine antagonist, into the nucleus accumbens significantly reduced self-stimulation of the ipsilateral ventral tegmental area but did not influence self-stimulation of the contralateral ventral tegmental area. Injections of spiroperidol into the prefrontal cortex did not reduce self-stimulation of the ipsilateral or contralateral ventral tegmental area. Electrical stimulation of sites in the nucleus accumbens positive for self-stimulation antidromically activated neurons of the ventral tegmental area, and a reduction of discharge of these neurons following administration of apomorphine suggested that they were dopaminergic neurons. These observations provide additional evidence implicating dopaminergic neurons in brain-stimulation reward and suggest that dopaminergic neurons contribute to self-stimulation of the nucleus accumbens but not the prefrontal cortex.     

In vivo receptor binding,neurochemical and functional studies with the dopamine D-1 receptor antagonist SCH 23390

Summary A series of in vivo experiments were undertaken, relating functional (motor activity, body temperature), dopamine (DA) receptor binding and neurochemical (catecholamine synthesis and utilization, DA release) aspects of the pharmacology of SCH 23390 in the rat.The compound inhibited the locomotor hyperactivity, but not the hypothermia, induced by the potent DA stimulant DP-5,6-ADTN. Interstingly, SCH 23390 simultaneously failed to displace DP-5,6-ADTN from its binding sites in the rat striatum—used as a direct in vivo biochemical index of DA (D-2) receptor interaction. The spontaneous locomotion in non-pretreated rats was likewise inhibited by SCH 23390. The locomotor-suppressive action, but not the DP-5,6-ADTN-displacing capcity of the D-2 blocker haloperidol was significantly enhanced by SCH 23390, suggesting that motility can be suppressed by either enhanced D-1 or D-2 (postsynaptic) receptor blockade, but also that the D-1 and D-2 sites involved may be physically distinct.SCH 23390 only slightly altered in vivo neurochemical of DA synthesis, release and nerve-impulse flow, indicating that, while similar in suppressing dopaminergic behaviour, the D-1 antagonist is less effective than traditional neuroleptics as an activator of DA neuronal feedback mechanisms. The weak increases of DA synthesis and release nonetheless obtained were equal in magnitude (30–40%) in the limbic vs. striatal brain areas; also in this respect, SCH 23390 thus differs from classical neuroleptics, which generally display more marked effects in the striatum than in limbic tissue.No major changes in the in vivo indices of NA synthesis and utilization (or in 5-HT synthesis) were found after SCH 23390 administration, by and large supporting the DA receptor specificity of the compound.In summary, the studies demonstrated that SCH 23390 can offset and accentuate, respectively, behavioural consequences of D-2 receptor stimulation and blockade. Importantly, at the same time no direct interaction at the level of D-2 DA receptor sites in the striatum was detected. Only slight, D-2 antagonist-like, changes in neurochemical indices of dopaminergic activity were observed after D-1 receptor blockade by means of SCH 23390. With regard to DA agonist hypothermia, SCH 23390 was without effect per se, but (at a high dose) attenuated the action of the D-2 antagonist haloperidol. The observations may indicate that the complex interactions between central D-1 and D-2 receptor-controlled mechanisms that influence behaviour, neurochemistry, and possibly autonomic nervous expression, are not identical.