Injections of -amphetamine into the ventral pallidum increase locomotor activity and responding for conditioned reward: a comparison with injections into the nucleus accumbens

The nucleus accumbens and ventral pallidum receive dopamine (DA) projections from the mesencephalon. Although DA inputs to the nucleus accumbens are implicated in both locomotion and reward processes, little is known of the behavioural significance of DA in the ventral pallidum. These studies examined the effects of -amphetamine injected into the nucleus accumbens or ventral pallidum on locomotor activity and responding for a conditioned reward (CR). In the nucleus accumbens -amphetamine dose dependently (1, 3 and 10 μg) increased locomotion within 5–10 min of injection. Intra-ventral pallidum microinjections of -amphetamine also increased activity in this dose range, but the effect occurred with a longer latency (5–20 min). The magnitude of the response evoked by ventral pallidum injections was lower than that evoked by nucleus accumbens injections. The GABA_A antagonist picrotoxin (0.1 μg) stimulated activity when injected into the ventral pallidum but not the nucleus accumbens, providing a pharmacological dissociation between the two injection sites. In the CR studies, -amphetamine injected into both sites potentiated responding for a CR previously paired with food delivery, without altering responding on an inactive lever. Picrotoxin injected into the ventral pallidum reduced responding and abolished the selectivity of responding for CR. The results show that DA release in the ventral pallidum enhances locomotion and responding for a CR, providing evidence that DA in the ventral pallidum plays a significant role in the mediation of the effects of -amphetamine. The failure of picrotoxin to elevate responding for CR despite increasing locomotor activity indicates that pharmacologically-induced blockade of GABA_A receptors in the ventral pallidum disrupts goal-directed responding.     

Where does damage lead to enhanced food aversion: the ventral pallidum/substantia innominata or lateral hypothalamus?

The purpose of this study was to identify sites where striatopallidal lesions produce two distinct sensory-triggered hyperkinetic syndromes: (1) exaggerated forelimb treading alone to oral taste infusions and (2) sensorimotor exaggerated treading plus enhanced aversive reactions to taste infusions. The behavioral characteristics of these syndromes have been described previously (Berridge, K.C. and Cromwell, H.C.,Behav. Neurosci., 104 (1990) 778–795). Bilateral excitotoxin lesions were made using quinolinic acid (10 μg in 1 μl) in the caudate/putamen, nucleus accumbens, globus pallidus or ventral pallidum/substantia innominata. In order to identify the precise center, borders, severity and size of lesion sites that caused these hyperkinetic treading syndromes, neuron counts (modified fractionator technique) and glial fibrillary acidic protein immunoreactivity (GFAP-IR) densitometry were used in a stereological mapping analysis. The site of lesions that produced the hyperkinetic treading syndrome without enhanced aversion was found to be restricted to the globus pallidus (GP). Damage exceeding 60% neuron loss bilaterally within a0.8 × 1.0 × 1.0 mm subregion of the ventromedial GP produced this syndrome. The site of lesions that produced the combined syndrome of hyperkinetic treading and aversive enhancement was ventral to the globus pallidus, within the ventral pallidum/substantia innominata (VP/SI). Damage exceeding 70% neuron loss bilaterally within a1.0 × 0.5 × 1.0m diameter subregion of the ventromedial ventral pallidum/substantia innominata produced this syndrome. This subterritory was located immediately lateral to the border of the lateral hypothalamus. Bilateral lesions to the caudate/putamen or nucleus accumbens did not produce either hyperkinetic treading syndrome. These results are discussed in terms of the connectivity of the ventral pallidal/substantia innominata and globus pallidus regions and in terms of neuropathological models of hyperkinetic disorders.     

Involvement of the nucleus accumbens–ventral pallidal pathway in postictal behavior induced by a hippocampal afterdischarge in rats

The hypothesis that postictal motor behaviors induced by a hippocampal afterdischarge (AD) are mediated by a pathway through the nucleus accumbens (NAC) and ventral pallidum (VP) was evaluated in freely moving rats. Tetanic stimulation of the hippocampal CA1 evoked an AD of 15–30 s and an increase in number of wet-dog shakes, face washes, rearings and locomotor activity. Bilateral injection of haloperidol (5 μg/side) or the selective dopamine D₂ receptor antagonist, (±)-sulpiride (200 ng/side) before the hippocampal AD, into the NAC selectively reduced rearings and locomotor activity, but not the number of wet-dog shakes and face washes. Injection of R(+)-SCH-23390 (1 μg/side), a D₁ receptor antagonist, or rimcazole (0.4 mg/side), a σ opioid receptor antagonist, into the NAC did not significantly alter postictal behaviors. Bilateral injection of muscimol (1 ng/side), a γ-aminobutyric acid (GABA_A) receptor agonist, into the VP before the AD significantly blocked all postical behaviors. It is concluded that postictal locomotor activity induced by a hippocampal AD is mediated by activation of dopamine D₂ receptors in the NAC and a pathway through the VP.     

Medial preoptic area interactions with the nucleus accumbens-ventral pallidum circuit and maternal behavior in rats

Several experiments explored the roles of nucleus accumbens (NA), ventral pallidum (VP) and medial preoptic area (MPOA) in the regulation of maternal behavior in rats. A preliminary experiment found that bilateral radiofrequency lesions of medial NA did not disrupt maternal behavior. Experiment 1 found that bilateral infusions of muscimol into VP, but not into medial NA, reversibly disrupted maternal behavior. Experiment 2 found that unilateral muscimol injections into VP disrupted maternal behavior to a greater extent when paired with a contralateral N-methyl-d-aspartic acid (NMDA) MPOA lesion than when paired with a sham MPOA lesion. Experiment 3 showed that a unilateral NMDA MPOA lesion paired with a contralateral NMDA VP lesion (Contra group) disrupted maternal behavior to a much greater extent than did sham NMLA lesions or NMDA lesions of MPOA and VP ipsilateral to one another. Experiment 3 focused on the specificity of the maternal behavior disruptions and found that the primary maternal deficit in the Contra females was a severe deficit in retrieval behavior. Importantly, these females showed normal hoarding behavior, home cage activity, and elevated plus maze activity. Experiment 3 used Neu N immunohistochemistry to define the extent of MPOA and VP excitotoxic lesions. It is hypothesized that MPOA acts to facilitate the active components of maternal behavior by inhibiting NA, which then releases VP from GABAergic inhibition, and such disinhibition of VP allows pup stimuli to trigger appropriate maternal responses.     

Patterns of glucose use after bicuculline-induced convulsions in relationship to γ-aminobutyric acid and μ-opioid receptors in the ventral pallidum — functional markers for the ventral pallidum

Bicuculline-induced convulsions increased glucose use throughout the brain and sharply demarcated the ventral pallidum and globus pallidus. Glucose use in the nucleus accumbens also increased after bicuculline-induced convulsions, except for a circumscribed region in the dorsomedial shell. Since the projection from the nucleus accumbens to the ventral pallidum contains γ-aminobutyric acid (GABA) and the opioid peptide, enkephalin, the pattern of increased glucose use in the ventral pallidum and nucleus accumbens after bicuculline-induced convulsions was compared to the topography of GABA_A and μ-opioid receptors. The pattern of glucose use in the nucleus accumbens and ventral pallidum resembled the topography of GABA_A, but differed from that of μ-opioid receptors. Bicuculline may disinhibit GABAergic efferents to the ventral pallidum resulting in a dramatic increase in glucose use within striatopallidal synaptic terminals as well as in local terminals of the pallidal projection neurons.     

DOI disrupts prepulse inhibition of startle in rats via 5-HT2A receptors in the ventral pallidum

Serotonin (5-HT)_2A receptors are known to be involved in prepulse inhibition of the startle response (PPI), a measure of sensorimotor inhibition that is deficient in schizophrenia, Huntington's disease, and obsessive compulsive disorder. In the present studies, the localization of the 5-HT_2A receptors responsible for modulating PPI was investigated using central injections of the hallucinogenic 5-HT₂ agonist DOI and the novel 5-HT_2A antagonist MDL 100,907. 5-HT_2A receptors are densely localized in the nucleus accumbens (NAC) and the ventral pallidum (VP), areas known to be important components of neural circuitry that mediates the ventral forebrain modulation of PPI. In the present studies, it was found that the infusion of DOI (0.0–5.0 μg/0.5 μl) into the VP disrupted PPI without having effects on startle reactivity. In contrast, similar infusions into the NAC had no effect on PPI or startle reactivity. The infusion of MDL 100,907 into the VP was found to increase PPI by itself and to attenuate the PPI-disruptive effects of systemically administered DOI. It is concluded that 5-HT_2A receptors within the VP are important for the modulation of PPI, presumably through interactions at intrinsic GABAergic or cholinergic interneurons.     

Conditioned place preference and locomotor activation produced by injection of psychostimulants into ventral pallidum

The ventral pallidum (VP) is often viewed as an output structure of the nucleus accumbens septi (NAS). However, VP, like NAS, receives a dopaminergic input from the ventral tegmental area. These experiments investigated some behavioral effects of microinjection into VP of drugs which enhance dopaminergic transmission. Injection of 25 μg dopamine or 5–10 μg amphetamine into VP produced hypermotility. In contrast, injection of 12.5–50 μg cocaine initially suppressed, then increased, activity. Injection of 100 μg cocaine only produced hypomotility in the 1-h period examined. The hypomotility following cocaine seemed to be a local anesthetic effect, because it was mimicked by 50–200 μg procaine. Procaine did not, however, produce subsequent hypermotility. Conditioned place preference (CPP) was produced by 10 μg amphetamine and 50 μg cocaine but not 100 μg procaine. We conclude that injection of cocaine into VP, unlike similar injections into NAS, produces CPP. These results support the idea of an involvement of dopamine in VP in reward and locomotor activation, independent of dopamine in NAS. The use of intracerebral injections of cocaine is complicated, however, by an apparent local anesthetic effect of the drug.     

NMDA receptor antagonist-induced dopamine release in the ventral pallidum does not correlate with motor activation

The ventral pallidum is the output structure of the nucleus accumbens in the ventral corticostriato-thalamocortical loop. Information processing in this loop is critically involved in motor behavior and reinforcement. The ventral pallidum receives a direct dopaminergic input from the ventral tegmental area, but also glutamatergic input from cortical and limbic areas. It has been assumed that dopamine release in the VP is indeed modulated by glutamate. The present study investigated the effects of NMDA receptor blockade on motor behavior and dopamine release in the ventral pallidum. In a first experiment, rats were implanted with microdialysis probes in the ventral pallidum and were systemically injected or locally perfused via the microdialysis probe with dizocilpine (0.32 mg/kg, 10 and 100 microM, respectively). Effects on dopamine and on locomotion were simultaneously monitored. In a second experiment, ventral pallidum was lesioned by quinolinic acid and the effects of systemic dizocilpine (0.08 and 0.16 mg/kg) on locomotion and stereotyped sniffing behavior were determined. It was found that systemic and local dizocilpine administration increased dopamine release in the ventral pallidum to a similar extent whereas only systemic treatment was accompanied by locomotor stimulation. Lesion of the ventral pallidum did not affect locomotion and stereotyped sniffing behavior induced by systemic dizocilpine treatment. Thus, DA release in the ventral pallidum that is elevated by blockade of NMDA receptors is not relevant for activation of motor behavior.     

Dopamine depletion in the rostral nucleus accumbens alters the cerebral metabolic response to cocaine in the rat

The functional consequences of dopamine depletion in the rostral nucleus accumbens were examined using the quantitative 2-[¹⁴C]deoxyglucose method for determining rates of local cerebral glucose utilization. Cerebral metabolism was determined in 35 brain structures of Sprague–Dawley rats with unilateral 6-hydroxydopamine or sham lesions of the rostral accumbens. The effect of the lesion was assessed in cocaine-naive animals treated systemically with cocaine or saline. In saline-treated animals, the lesion increased cerebral metabolism in typical basal ganglia regions, such as the globus pallidus and entopeduncular nucleus, as well as portions of the extended amygdala that included the bed nucleus of the stria terminalis and the hypothalamic preoptic area. Cerebral metabolism was affected bilaterally in a subset of all affected structures which demonstrated that the functional consequences of the lesion extended beyond the primary monosynaptic output zones of the rostral accumbens. The lesion also changed the topography of the normal cocaine response such that cocaine effects were blunted in the shell of the nucleus accumbens, globus pallidus and the medial ventral pallidum. Thus, the present study describes functional evidence of the link between the rostral accumbens and the extended amygdala and demonstrates that dopamine in the rostral accumbens plays an important role in the central response to cocaine.© 1997 Elsevier Science B.V. All rights reserved.     

Intrinsic neurons are involved in lateral hypothalamic self-stimulation

The recent technique of using ibotenic acid to lesion selectively local neurons while sparing fibers of passage permitted us to answer a long-standing question: is lateral hypothalamic self-stimulation supported by fibers of passage or are the intrinsic hypothalamic neurons involved? Three groups of adult male Sprague-Dawley rats were used. In a normal group, electrodes were bilaterally implanted in the lateral hypothalamus and self-stimulation (ICSS) was obtained separately with the right and left electrodes, at various current intensities, using a nose-poke response. In the experimental group, the intrinsic neurons of the lateral hypothalamus were destroyed unilaterally by local injection of ibotenic acid (4 or 6 μg in 0.5 μl); the other side served as the sham-lesion control. Ten days later ICSS electrodes were implanted bilaterally, one in the lesioned area, the other in the contralateral hypothalamus. As in the case of the normal animals, the rate of nose-poking (ICSS) was then determined separately for each electrode. In the normal rats, ICSS rates were the same with stimulation on either side and the increase in ICSS rate as a function of the increase in current intensity was the same on each side. In the experimental rats, ICSS of the lesioned side was decreased in all cases; moreover, after lesion with the 6 μg dose, ICSS was totally suppressed. Self-stimulation of the sham-lesioned side was not significantly different from that observed in the normal rats. In 6 rats sampled from the lesioned groups as well as in 3 additional unimplanted animals, biochemical assays compared dopamine and serotonin contents of the two striata and noradrenaline and serotonin contents of the two hippocampi. No difference was observed for these two structures between the side ipsilateral to the lesion and the contralateral side. Moreover, none of these monoamine levels differed from those seen in the unimplanted rats. These results, taken together, suggest that intrinsic lateral hypothalamic neurons are involved in ICSS.     

Effect of morphine applied by intrapallidal microdialysis on the release of dopamine in the nucleus accumbens

The effect of morphine, administered intrapallidally, on extracellular concentrations of DA, DOPAC, and HVA in the nucleus accumbens and striatum was studied in the behaving rat using the in vivo microdialysis technique. Unilateral application of morphine hydrochloride was perfomed through microdialysis probes into the rat ventral pallidum (10 μ1 of 0 2.6 4.0, 13.0, and 26.0 mM) or globus pallidus (10 μ1 of 0 and 26.0 mM). The levels of DA, DOPAC, and HVA were measured using the HPLC with EC detection in dialysates collected from the nucleus accumbens, anteromedial, and anterolateral striatum. Samples were taken every 45 min over 3 h before and over 5 h after morphine or vehicle administration. Administration of morphine into the ventral pallidum resulted in increased DOPAC and HVA concentrations in the nucleus accumbens. Pretreatment with naloxone (1 mg/kg, SC) abolished this effect of morphine. Administration of morphine into the globus pallidus resulted in increased DA, DOPAC, and HVA concentrations in the nucleus accumbens and DA in the anteromedial striatum. The levels of DA and metabolites in anterolateral striatum remained rather unchanged following morphine administered into the ventral pallidum or the globus pallidus. The changes in DA neurotransmission into the nucleus accumbens induced by morphine application into the ventral pallidum and globus pallidus are reminiscent of a phasic and tonic release of DA respectively. The results show that intrapallidal morphine increases DA neurotransmission in nucleus accumbens and suggest that the effect of morphine is mediated by ventral pallidum/mesolimbic and globus pallidus/thalamocortical pathways, depending on the site of injection.     

Changes in γ-aminobutyric acid, μ-opioid and neurotensin receptors in the accumbens-pallidal projection after discrete quinolinic acid lesions in the nucleus accumbens

Discrete quinolinic acid lesions in the nucleus accumbens altered [³H]muscimol binding to γ-aminobutyric acid receptors, [¹²⁵I]neurotensin binding to neurotensin receptors, [¹²⁵I]Tyr-d-Ala-Gly-NMePhe-Gly-OH binding to μ-opioid receptors, and [³H]quinuclidinyl benzilate binding to muscarinic receptors. Within lesions of the lateral accumbens core, [³H]muscimol binding increased and [¹²⁵I]Tyr-d-Ala-Gly-NMePhe-Gly-OH, [¹²⁵I]eurotensin and [³H]quinuclidinyl benzilate binding decreased. Lesions of the medial nucleus accumbens resulted in decreased [¹²⁵I]Tyr-d-Ala-Gly-NMePhe-Gly-OH and [³H]quinuclidinyl benzilate binding while no alterations were observed for [³H]muscimol or [¹²⁵I]neurotensin binding. These data support anatomical distinctions between medial and lateral nucleus accumbens. Destruction of intrinsic neurons in the dorsomedial nucleus accumbens core increased [³H]muscimol binding in the dorsal rim of the ventral pallidum and the rostral globus pallidus without altering [¹²⁵I]Tyr-d-Ala-Gly-NMePhe-Gly-OH binding. Destruction of neurons in the lateral nucleus accumbens core or medial shell did not alter [³H]muscimol binding in the ventral pallidum. The lack of upregulation in γ-aminobutyric acid receptors suggests that the γ-aminobutyric acid-containing projection from the dorsomedial core to the dorsal rim of the ventral pallidum differs from the projection from the lateral accumbens core and medial shell to the more ventral regions of the pallidum. Fluoro-gold retrogade tracer histochemistry confirmed the specific projection from the dorsomedial core to the dorsal ventral pallidum; and from the shell of the nucleus accumbens to more ventral regions of the ventral pallidum.     

6-Hydroxydopamine lesion of ventral pallidum blocks acquisition of place preference conditioning to cocaine

In parallel with nucleus accumbens (NAS), ventral pallidum (VP) also receives a dopaminergic projection from the ventral tegmental area (VTA). The present study examined the involvement of this mesopallidal dopaminergic system in the action of cocaine. In the first experiment, the effect of cocaine injections on VP dopamine was examined by microdialysis. Intraperitoneal (i.p.) injections of cocaine 5–20 mg/kg dose-dependently increased the extracellular dopamine level in VP 2.5–4.5-fold. In addition, intra-VP perfusion of 20 μM cocaine induced a 12-fold increase of dopamine locally. The second experiment examined the role of VP dopamine in cocaine-induced conditioned place preference (CPP) and locomotor activation. Rats received bilateral intra-VP injections of 3–4 μg 6-OHDA or ascorbic acid vehicle in 0.5 μl volume. Tissue assays indicated that the 6-OHDA-lesioned rats had significantly lowered dopamine concentration in VP, but not in NAS or striatum. As a group, 6-OHDA lesions blocked the development of CPP to 5 mg/kg cocaine but not to 10 mg/kg cocaine. However, rats with more than 60% depletion in VP dopamine did not develop CPP to cocaine at either dose. Preference for the cocaine-paired side correlated significantly with dopamine concentration in VP, but not in NAS or striatum. It was concluded that VP dopamine may play a critical role in the initial rewarding effect of cocaine. 6-OHDA lesions also blocked locomotor activation induced by 5 mg/kg cocaine but had no effect on 10 mg/kg cocaine-induced locomotion. Dopamine concentration in VP did not correlate with the locomotor activation response to cocaine at either dose. These findings further establish the involvement of the mesopallidal dopaminergic system in the action of cocaine.     

The effects of ventral tegmental administration of GABA(A), GABA(B), NMDA and AMPA receptor agonists on ventral pallidum self-stimulation

The ventral pallidum (VP) is a basal forebrain structure that is interconnected with motor and limbic structures and may be considered as an interface between motivational and effector neural signals. Results from a considerable number of studies suggest that this structure is critically involved in reward-related behavior. The VP shares reciprocal connections with other reward-implicated regions, such as the ventral tegmental area (VTA). This anatomy predicts that drug-induced neuronal alterations in the VTA could profoundly alter the function of the VP. Here, using the curve-shift intracranial self-stimulation method, we studied the effects of muscimol (GABA(A) agonist), baclofen (GABA(B) agonist), NMDA and AMPA, microinjected bilaterally into the VTA on the rewarding efficacy of VP self-stimulation. Central injections of the highest dose of muscimol (0.128 microg) resulted in significant elevations in VP self-stimulation thresholds, indicating a reduction in the rewarding efficacy of the stimulation. Elevations in VP self-stimulation thresholds were also evident after intrategmental injections of higher doses of baclofen (0.12, 0.48 microg). By contrast, intrategmental activation of NMDA and AMPA receptors did not affect reward thresholds. These findings suggest that GABAergic and glutamatergic transmission in the VTA activate different circuits that may mediate different functions. Thus, the VTA--VP projection activated by GABA modulates VP stimulation reward, while the projection activated by glutamate may be involved in reward-unrelated effects, rather than in the processing of reward. The decreased rewarding efficacy of VP self-stimulation following intrategmental injections of muscimol and baclofen may be due to GABAergic modulation of ventral tegmental dopaminergic and nondopaminergic neurons projecting to the VP.     

Excessive disgust caused by brain lesions or temporary inactivations: mapping hotspots of the nucleus accumbens and ventral pallidum

Disgust is a prototypical type of negative affect. In animal models of excessive disgust, only a few brain sites are known in which localized dysfunction (lesions or neural inactivations) can induce intense ‘disgust reactions’ (e.g. gapes) to a normally pleasant sensation such as sweetness. Here, we aimed to map forebrain candidates more precisely, to identify where either local neuronal damage (excitotoxin lesions) or local pharmacological inactivation (muscimol/baclofen microinjections) caused rats to show excessive sensory disgust reactions to sucrose. Our study compared subregions of the nucleus accumbens shell, ventral pallidum, lateral hypothalamus, and adjacent extended amygdala. The results indicated that the posterior half of the ventral pallidum was the only forebrain site where intense sensory disgust gapes in response to sucrose were induced by both lesions and temporary inactivations (this site was previously identified as a hedonic hotspot for enhancements of sweetness ‘liking’). By comparison, for the nucleus accumbens, temporary GABA inactivations in the caudal half of the medial shell also generated sensory disgust, but lesions never did at any site. Furthermore, even inactivations failed to induce disgust in the rostral half of the accumbens shell (which also contains a hedonic hotspot). In other structures, neither lesions nor inactivations induced disgust as long as the posterior ventral pallidum remained spared. We conclude that the posterior ventral pallidum is an especially crucial hotspot for producing excessive sensory disgust by local pharmacological/lesion dysfunction. By comparison, the nucleus accumbens appears to segregate sites for pharmacological disgust induction and hedonic enhancement into separate posterior and rostral halves of the medial shell.     

GABAA receptors containing alpha 1 and beta 2 subunits are mainly localized on neurons in the ventral pallidum.

The gamma-aminobutyric acid (GABA) projection from the nucleus accumbens to the ventral pallidum (VP) is important in the regulation of locomotion. Thus, stimulation and inhibition of GABAA receptors in the VP can alter locomotor activity. To determine whether the GABAA receptors are located presynaptically on accumbens efferents to the VP or postsynaptically on neurons intrinsic to the VP two experiments were performed. In the first, quinolinic acid lesions of the nucleus accumbens did not alter [3H]muscimol binding in the VP, while lesions in the VP significantly reduced (60-80%) binding as measured by light microscopic receptor autoradiography. In the second experiment, in situ hybridization with oligonucleotide probes for mRNAs of the alpha 1 and beta 2 subunits of the GABAA receptor was examined in the nucleus accumbens and VP. No mRNA for either subunit was observed in the nucleus accumbens, although many positively labeled neurons were present within the VP. By contrast, a moderate to high density of cells in both the nucleus accumbens and VP contained mRNA for glutamic acid decarboxylase. These data argue that the majority of GABAA receptors in the VP are not located presynaptically on axonal terminals originating from neurons in the nucleus accumbens.     

Brain reward circuitry beyond the mesolimbic dopamine system: A neurobiological theory

Reductionist attempts to dissect complex mechanisms into simpler elements are necessary, but not sufficient for understanding how biological properties like reward emerge out of neuronal activity. Recent studies on intracranial self-administration of neurochemicals (drugs) found that rats learn to self-administer various drugs into the mesolimbic dopamine structures—the posterior ventral tegmental area, medial shell nucleus accumbens and medial olfactory tubercle. In addition, studies found roles of non-dopaminergic mechanisms of the supramammillary, rostromedial tegmental and midbrain raphe nuclei in reward.To explain intracranial self-administration and related effects of various drug manipulations, I outlined a neurobiological theory claiming that there is an intrinsic central process that coordinates various selective functions (including perceptual, visceral, and reinforcement processes) into a global function of approach. Further, this coordinating process for approach arises from interactions between brain structures including those structures mentioned above and their closely linked regions: the medial prefrontal cortex, septal area, ventral pallidum, bed nucleus of stria terminalis, preoptic area, lateral hypothalamic areas, lateral habenula, periaqueductal gray, laterodorsal tegmental nucleus and parabrachical area.     

Efferent connections of the ventral pallidum: evidence of a dual striato pallidofugal pathway

Previous histological and histochemical studies have provided evidence that the globus pallidus (external pallidal segment) as conventionally delineated in the rat extends ventrally and rostrally beneath the transverse limb of the anterior commissure, invading the olfactory tubercle with its most ventral ramifications. This infracommissural subdivision of the globus pallidus or ventral pallidum (VP) is most selectively identified by being pervaded by a dense plexus of substance-P-positive striatofugal fibers; the extent of this plexus indicates that the VP behind the anterior commissure continues dorsally over some distance into the anteroventromedial part of the generally recognized (supracommissural) globus pallidus; the adjoining anterodorsolateral pallidal region, here named dorsal pallidum (DP), receives only few substance-P-positive fibers, but contains a dense plexus of enkephalin-positive striatal afferents that also pervades VP. Available autoradiographic data indicate that VP and DP receive their striatal innervation from two different subdivisions of the striatum: whereas VP is innervated by a large, anteroventromedial striatal region receiving substantial inputs from a variety of limbic and limbic-system-associated structures (and therefore called "limbic striatum"), DP receives its striatal input from an anterodorsolateral striatal sector receiving only sparse limbic afferents ("nonlimbic" striatum) but instead heavily innervated by the sensorimotor cortex. The present autoradiographic study has produced evidence that this dichotomy in the striatopallidal projection is to a large extent continued beyond the globus pallidus: whereas the efferents of DP were traced to the subthalamic nucleus and substantia nigra, those of VP were found to involve not only the subthalamic nucleus and substantia nigra but also the frontocingulate (and adjoining medial sensorimotor) cortex, the amygdala, lateral habenular and mediodorsal thalamic nucleus, hypothalamus, ventral tegmental area, and tegmental regions farther caudal and dorsal in the midbrain. These findings indicate that the ventral pallidum can convey striatopallidal outflow of limbic antecedents not only into extrapyramidal circuits but also back into the circuitry of the limbic system.     

Localization of brain reinforcement mechanisms: intracranial self-administration and intracranial place-conditioning studies.

Intracranial self-administration (ICSA) and intracranial place conditioning (ICPC) methodologies have been mainly used to study drug reward mechanisms, but they have also been applied toward examining brain reward mechanisms. ICSA studies in rodents have established that the ventral tegmental area (VTA) is a site supporting morphine and ethanol reinforcement. ICPC studies confirmed that injection of morphine into the VTA produces conditioned place preference (CPP). Further confirmation that activation of opioid receptors within the VTA is reinforcing comes from the findings that the endogenous opioid peptide met-enkephalin injected into the VTA produces CPP, and that the mu- and delta-opioid agonists, DAMGO and DPDPE, are self-infused into the VTA. Activation of the VTA dopamine (DA) system may produce reinforcing effects in general because (a) neurotensin is self-administered into the VTA, and injection of neurotensin into the VTA produces CPP and enhances DA release in the nucleus accumbens (NAC), and (b) GABA(A) antagonists are self-administered into the anterior VTA and injections of GABA(A) antagonists into the anterior VTA enhance DA release in the NAC. The NAC also appears to have a major role in brain reward mechanisms, whereas most data from ICSA and ICPC studies do not support an involvement of the caudate-putamen in reinforcement processes. Rodents will self-infuse a variety of drugs of abuse (e.g. amphetamine, morphine, phencyclidine and cocaine) into the NAC, and this occurs primarily in the shell region. ICPC studies also indicate that injection of amphetamine into the shell portion of the NAC produces CPP. Activation of the DA system within the shell subregion of the NAC appears to play a key role in brain reward mechanisms. Rats will ICSA the DA uptake blocker, nomifensine, into the NAC shell; co-infusion with a D2 antagonist can block this behavior. In addition, rats will self-administer a mixture of a D1 plus a D2 agonist into the shell, but not the core, region of the NAC. The ICSA of this mixture can be blocked with the co-infusion of either a D1 or a D2 antagonist. However, the interactions of other transmitter systems within the NAC may also play key roles because NMDA antagonists and the muscarinic agonist carbachol are self-infused into the NAC. The medial prefrontal (MPF) cortex supports the ICSA of cocaine and phencyclidine. The DA system also seems to play a role in this behavior since cocaine self-infusion into the MPF cortex can be blocked by co-infusing a D2 antagonist, or with 6-OHDA lesions of the MPF cortex. Limited studies have been conducted on other CNS regions to elucidate their role in brain and drug reward mechanisms using ICSA or ICPC procedures. Among these regions, ICPC findings suggest that cocaine and amphetamine are rewarding in the rostral ventral pallidum (VP); ICSA and ICPC studies indicate that morphine is rewarding in the dorsal hippocampus, central gray and lateral hypothalamus. Finally, substance P mediated systems within the caudal VP (nucleus basalis magnocellularis) and serotonin systems of the dorsal and median raphe nuclei may also be important anatomical components involved in brain reward mechanisms. Overall, the ICSA and ICPC studies indicate that there are a number of receptors, neuronal pathways, and discrete CNS sites involved in brain reward mechanisms.