Gaba(A) receptors in the pedunculopontine tegmental nucleus play a crucial role in rat shell-specific dopamine-mediated, but not shell-specific acetylcholine-mediated, turning behaviour

The role of GABA(A) receptors in the pedunculopontine tegmental nucleus in turning behaviour of rats was studied. Unilateral injection of the GABA(A) receptor agonist, muscimol (25-100 ng), into the pedunculopontine tegmental nucleus dose-dependently produced contraversive pivoting, namely tight head-to-tail turning marked by abnormal hindlimb backward stepping. This effect was GABA(A) receptor specific, since it was prevented by the GABA(A) receptor antagonist, bicuculline (50 ng), which alone did not elicit turning behaviour. Unilateral injection of a mixture of dopamine D(1) ((+/-)-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine-7,8-diol [SKF 38393], 5 microg) and D(2) (quinpirole, 10 microg) receptor agonists into the nucleus accumbens shell has been found to elicit contraversive pivoting, whilst unilateral injection of the acetylcholine receptor agonist (carbachol, 5 microg) into the same site is known to elicit contraversive circling, namely turning marked by normal stepping. The pivoting induced by a mixture of SKF 38393 (5 microg) and quinpirole (10 microg) injected into the nucleus accumbens shell was significantly inhibited by bicuculline (50 ng) injected into the pedunculopontine tegmental nucleus, whereas muscimol (25 ng) had no effect. Neither muscimol (25 ng) nor bicuculline (50 ng) modulated the contraversive circling induced by carbachol (5 microg) injected into the nucleus accumbens shell. It is therefore concluded that unilateral stimulation of GABA(A) receptors in the pedunculopontine tegmental nucleus can elicit contraversive pivoting and that the pedunculopontine tegmental nucleus is one of the output stations of the accumbens region that mediates shell-specific, dopaminergic pivoting, but not of the accumbens region that mediates shell-specific, cholinergic circling.     

GABAA receptors in the mediodorsal thalamus play a crucial role in rat shell-specific acetylcholine-mediated,but not dopamine-mediated,turning behaviour

The role of GABA_A receptors in the mediodorsal thalamus (mdT) in turning behaviour of rats was studied. Neither the GABA_A receptor agonist muscimol (50 ng) nor the antagonist bicuculline (200 ng) unilaterally injected into the mdT elicited any behavioural change. Unilateral injection of the acetylcholine receptor agonist (carbachol, 5 μg) into the nucleus accumbens shell has been found to elicit contraversive circling while unilateral injection of a mixture of dopamine D₁ ((±)-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine-7,8-diol [SKF 38393], 5 μg) and D₂ (quinpirole, 10 μg) receptor agonists into the same site is known to elicit contraversive pivoting. The contraversive circling induced by unilateral injection of carbachol (5 μg) into the nucleus accumbens shell was dose-dependently inhibited by muscimol (25 and 50 ng) injected into the mdT. This inhibitory effect of muscimol (50 ng) was antagonised by co-administration of bicuculline (200 ng), which alone did not modify the contraversive circling induced by carbachol (5 μg). The contraversive pivoting induced by unilateral injection of a mixture of SKF 38393 (5 μg) and quinpirole (10 μg) into the nucleus accumbens shell was inhibited by muscimol (25 and 50 ng) injected into the mdT, whereas bicuculline (200 ng) injected into the mdT did not significantly modify the pivoting. The inhibitory effect of muscimol (50 ng) on the pivoting induced by a mixture of SKF 38393 (5 μg) and quinpirole (10 μg) was not dose-dependent and not antagonised by bicuculline (200 ng). The present study suggests that GABA_A receptors in the mdT play a limited role in spontaneously occurring locomotor activity. Secondly, this study demonstrates that GABA_A receptors in the mdT transmit accumbens-dependent cholinergic circling, but not accumbens-dependent dopaminergic pivoting, to other brain structures. Finally, the present study shows that muscimol-sensitive, non-GABA_A receptors in the mdT influence the accumbens-dependent dopaminergic pivoting. To what extent GABA_B receptors in the mdT mediate the muscimol-induced effects upon the dopaminergic pivoting behaviour requires additional research.     

Somatostatin receptors in the nucleus accumbens modulate dopamine-dependent but not acetylcholine-dependent turning behaviour of rats

The role of somatostatin receptors in the nucleus accumbens shell in rat turning behaviour was studied. Unilateral injection of neither the somatostatin receptor agonist somatostatin (1.0 μg) nor the somatostatin receptor antagonist cyclosomatostatin (100.0 ng) into the nucleus accumbens shell elicited turning behaviour. Unilateral injection of a mixture of dopamine D₁ ((±)-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine-7,8-diol, SKF 38393) and D_2/3 (quinpirole) receptor agonists into the nucleus accumbens shell has been found to elicit contraversive pivoting. Somatostatin (0.5 and 1.0 μg) dose-dependently potentiated the contraversive pivoting induced by a mixture of SKF 38393 (1.0 μg) and quinpirole (10.0 μg) injected into the nucleus accumbens shell. This potentiating effect of somatostatin (1.0 μg) on the dopaminergic pivoting was dose-dependently inhibited by cyclosomatostatin (10.0 and 100.0 ng) injected into the nucleus accumbens shell. Unilateral injection of acetylcholine receptor agonist carbachol into the nucleus accumbens shell has been found to elicit contraversive circling. Neither somatostatin (1.0 μg) nor cyclosomatostatin (100.0 ng) significantly affected the contraversive circling induced by carbachol (5.0 μg) injected into the nucleus accumbens shell. These results suggest that somatostatin receptors in the nucleus accumbens shell play a modulatory role in rat dopaminergic pivoting, but not in rat cholinergic circling.     

Effects of GABA compounds injected into the subpallidal regions of rat brain on nucleus accumbens evoked hyperactivity

The effects of administration of gamma-aminobutyric acid (GABA) compounds into the ventral pallidum and substantia innominata on the locomotor hyperactivity induced by the dopamine agonist 2-amino-6,7-dihydroxy-1,2,3,4-tetrahydronaphthalene (ADTN) in the nucleus accumbens were investigated in rats. Hyperactivity induced by ADTN was antagonized by the GABA receptor agonists muscimol, isoguvacine, and baclofen. The compounds were equally effective in both subpallidal regions. In contrast, the GABA antagonists picrotoxin and bicuculline injected into subpallidal sites had no effects on accumbens-evoked hyperactivity, although by themselves both antagonists caused a mild and transient locomotor stimulation. It is suggested that GABA receptors in the subpallidal areas are involved in locomotor stimulation elicited from the nucleus accumbens.     

Enhanced GABA function in the angular complex (lateral periaqueductal grey matter and adjacent reticular formation) alters the postural component of striatal- or nigral-derived circling

Summary Unilateral injection of muscimol into the angular complex (lateral periaqueductal grey matter and adjacent reticular formation) caused ipsiversive rotation. Focal injection of picrotoxin into the same site produced contraversive rotation. Administration of apomorphine to animals with a unilateral 6OHDA lesion of the left medial forebrain bundle caused contraversive rotation. Focal injection of muscimol into the angular complex reversed the direction of rotation such that apomorphine administration now produced ipsiversive circling. Unilateral injection of muscimol into substantia nigra zona reticulata caused contraversive rotation. Focal injection of picrotoxin into the same site produced ipsiversive rotation. The prior injection of muscimol into the ipsilateral angular complex prevented the contraversive rotation induced by intranigral administration of muscimol such that animals now showed ipsiversive circling. In both 6-OHDA-lesioned animals and animals receiving intranigral muscimol, focal injection of muscimol into the angular complex caused a reversal in the direction of circling through loss of the postural component with no obvious change in locomotor activity. Bilateral electrolytic lesions of the angular complex overall had no effect on amphetamine-induced locomotion. Manipulation of GABA function in the angular complex alters circling behaviour initiated from the striatum or substantia nigra by altering the postural component without affecting the locomotor response of the animals. The data suggest a critical role for the angular complex as an outflow station from basal ganglia.     

Forebrain circuitry involved in effort-related choice: Injections of the GABAA agonist muscimol into ventral pallidum alter response allocation in food-seeking behavior

Organisms often make effort-related choices based upon assessments of motivational value and work requirements. Nucleus accumbens dopamine is a critical component of the brain circuitry regulating work output in reinforcement-seeking behavior. Rats with accumbens dopamine depletions reallocate their instrumental behavior away from food-reinforced tasks that have high response requirements, and instead they select a less-effortful type of food-seeking behavior. The ventral pallidum is a brain area that receives substantial GABAergic input from nucleus accumbens. It was hypothesized that stimulation of GABA(A) receptors in the ventral pallidum would result in behavioral effects that resemble those produced by interference with accumbens dopamine transmission. The present studies employed a concurrent choice lever pressing/chow intake procedure; with this task, interference with accumbens dopamine transmission shifts choice behavior such that lever pressing for food is decreased but chow intake is increased. In the present experiments, infusions of the GABA(A) agonist muscimol (5.0-10.0 ng) into the ventral pallidum decreased lever pressing for preferred food, but increased consumption of the less preferred chow. In contrast, ventral pallidal infusions of muscimol (10.0 ng) had no significant effect on preference for the palatable food in free-feeding choice tests. Furthermore, injections of muscimol into a control site dorsal to the ventral pallidum produced no significant effects on lever pressing and chow intake. These data indicate that stimulation of GABA receptors in ventral pallidum produces behavioral effects similar to those produced by accumbens dopamine depletions. Ventral pallidum appears to be a component of the brain circuitry regulating response allocation and effort-related choice behavior, and may act to convey information from nucleus accumbens to other parts of this circuitry. This research may have implications for understanding the brain mechanisms involved in energy-related psychiatric dysfunctions such as psychomotor retardation in depression, anergia, and apathy.     

Evidence for the participation of nigrotectal γ-aminobutyrate-containing neurones in striatal and nigral-derived circling in the rat

The γ-aminobutyrate-containing nature of nigrotectal neurones and the possible involvement of the tectum in circling behaviour were investigated in the rat. Electrolytic or kainic acid lesions of the substantia nigra reduced γ-aminobutyrate levels on average by 19–29% in intermediate and deep, but not superficial superior colliculus. Placement of lesions or injection of muscimol (40 ng) into these γ-aminobutyrate-innervated layers of superior colliculus gave only weak ipsilateral posturing or circling that was intensified by apomorphine, but which strongly antagonized contraversive apomorphine-induced circling in 6-hydroxydopamine pretreated rats (lateral > medial sites). Contraversive circling to unilateral intranigral muscimol (40 ng) was significantly attenuated by lesions or muscimol injections placed in the ipsi- or contralateral superior colliculus. Picrotoxin (40 ng) and tetanus toxin (30 mouse LD₅₀ doses) evoked explosive motor behaviour from medial colliculus and vigorous contraversive circling when injected into the lateral colliculus. The latter offset ipsiversive asymmetries to kainate (0.8 μg) in the corresponding substantia nigra. Bilateral intratectal picrotoxin produced hyperactivity that reversed haloperidol catalepsy. Similar bilateral administration of muscimol did not produce catalepsy but a state of frozen immobility. Kainic acid introduced into the superior colliculus gave mixed excitatory-inhibitory responses initially followed by ipsiversive circling only and loss of tectal perikarya. None of these drug effects occurred from the overlying cerebral cortex or subjacent tegmentum.We propose that separate medial ‘non-postural’ and lateral ‘postural’ tectal locomotor regions may exist in the superior colliculus that are situated within a striato-nigrotectal outflow system capable of influencing the animal's motor activity and posture.     

Opposite locomotor asymmetries elicited from the medial and lateral substantia nigra: role of the superior colliculus

The present study investigated the role of the superior colliculus (SC) in the expression of opposing locomotor asymmetries elicited from the medial and lateral substantia nigra pars compacta (SNC). In experiment one it was found that amphetamine stimulated ipsiversive circling produced by unilateral SC lesions was additive with the ipsiversive circling produced by alpha-flupenthixol microinjections into the lateral SNC but was not additive with the contraversive circling produced by such injections into the medial SNC. Experiment two showed that the amphetamine stimulated ipsiversive circling produced by unilateral SC lesions was additive with the contraversive circling produced by lateral SNC lesions but was not additive with the ipsiversive circling produced by medial SNC lesions. Both experiments were taken to suggest that the striato-nigral-colliculus system is an output path for medial SNC derived circling but is not an output path for the opposing circling behavior derived from the lateral SNC.     

Lack of intersite GABA receptor subtype antagonist effects upon mu opioid receptor agonist-induced feeding elicited from either the ventral tegmental area or nucleus accumbens shell in rats

Pretreatment with the GABA(A) receptor antagonist, bicuculline or the GABA(B) receptor antagonist, saclofen, into the nucleus accumbens (Nacc) shell, respectively, potentiates and reduces feeding elicited by the mu opioid agonist, [D-Ala(2), Nme(4), Gly-ol(5)]-enkephalin (DAMGO), administered into the same site. DAMGO-induced feeding elicited from the ventral tegmental area (VTA) region is significantly reduced by pretreatment with saclofen into the same site indicating local GABA mediation of opioid-induced feeding in each site. Given the neuroanatomical and functional connections between the two sites, the present study evaluated the dose-dependent actions of bicuculline and saclofen pretreatment in one site upon DAMGO-induced feeding elicited from the second site. Pretreatment of either bicuculline (7.5-75 ng) or saclofen (1.5-10 microg) into the Nacc shell failed to alter the time course or magnitude of DAMGO-induced feeding elicited from the VTA region. DAMGO-induced feeding elicited from the Nacc shell was unaffected by VTA region pretreatment with either bicuculline (7.5-75 ng) or saclofen (1.5-5 microg). A higher (10 microg) saclofen dose prevented significant DAMGO-induced feeding after 1 and 4 h. Thus, although GABA receptor subtype antagonists are capable of differentially modulating DAMGO-induced feeding when both drugs are applied locally in either the VTA region or the Nacc shell, it appears that any effects between the VTA region and the Nacc shell in modulating DAMGO-induced feeding do not depend upon a GABAergic synapse in the other site.     

The glutamatergic projection from the prefrontal cortex to the nucleus accumbens core is required for cocaine-induced decreases in ventral pallidal GABA

Cocaine-primed reinstatement of drug seeking is associated with a decrease in extracellular GABA in the ventral pallidum (VP). The present study investigated the neural mechanism of this cocaine-induced decrease in VP GABA by determining if activity of the glutamatergic projection from the medial prefrontal cortex (PFC) to the nucleus accumbens is required for the effect. Microdialysis was performed to measure extracellular GABA in the VP while simultaneously, either a combination of the GABA agonists baclofen and muscimol was microinjected into the PFC, or the AMPA/kainate glutamate receptor antagonist CNQX was microinjected into the accumbens core. Inhibition of the PFC with GABA agonists and blockade of AMPA glutamate receptors in the accumbens core were both sufficient to prevent the cocaine-induced decrease in VP GABA, further implicating increased activity of the cortico-striato-pallidal circuit in relapse to drug seeking.     

Differential role of GABAA and GABAB receptors in two distinct output stations of the rat striatum: studies on the substantia nigra pars reticulata and the globus pallidus

The role of GABA_A and GABA_B receptors in the substantia nigra pars reticulata and the globus pallidus in turning behaviour of rats was studied. Unilateral injection of the GABA_A receptor agonist muscimol (25 and 50 ng) into the substantia nigra pars reticulata elicited contralateral pivoting, namely tight head-to-tail turning marked by abnormal hindlimb backward stepping. This effect was GABA_A receptor specific, since it was dose-dependent and prevented by co-administration of the GABA_A receptor antagonist bicuculline (100 and 200 ng) which alone did not elicit turning behaviour. Unilateral injection of the GABA_B receptor agonist baclofen (100 and 200 ng) into the substantia nigra pars reticulata also produced contralateral pivoting. This effect was GABA_B receptor specific, since it was dose-dependent and inhibited by the GABA_B receptor antagonist CGP 55845 (200 ng) which alone did not elicit turning behaviour. In contrast, unilateral injection of bicuculline (100 and 200 ng) into the globus pallidus produced contralateral circling, namely turning marked by normal stepping. This effect was GABA_A receptor specific, since it was dose-dependent and prevented by muscimol (50 ng), which alone did not elicit turning behaviour. Unilateral injection of baclofen (100 and 200 ng) into the globus pallidus dose-dependently produced ipsilateral pivoting; this effect was inhibited by CGP 55845 (200 ng), which alone did not elicit turning behaviour. The present study demonstrates that GABA_A and GABA_B receptors in the globus pallidus and the substantina nigra pars reticulata play differential roles in the production of turning behaviour. This study underlines the notion that the two types of turning, namely pivoting and circling, are valid tools to map out the information flow across the basal ganglia.     

Hyperphagia induced by GABAA receptor-mediated inhibition of the nucleus accumbens shell: dependence on intact neural output from the central amygdaloid region

To investigate the role of corticolimbic input in modulating feeding-related nucleus accumbens (Acb) circuitry, researchers temporarily deactivated sites within the basolateral amygdaloid complex (BLA) or central amygdaloid region (CeA) via GABA(A) agonist (muscimol) infusions and measured feeding responses following muscimol infusions into the Acb shell. Hyperphagia elicited by intra-Acb shell muscimol was not altered by coinfusions of intra-BLA muscimol. In contrast, muscimol infusions into the CeA dose-dependently reduced feeding elicited either by intra-Acb shell GABA(A) receptor stimulation or by food deprivation and produced a syndrome of forepaw treading. Intra-CeA tetrodotoxin infusions also blocked intra-Acb shell muscimol-induced hyperphagia. Hence, feeding elicited by intra-Acb shell GABA(A) receptor stimulation requires intact neural output from the CeA but not the BLA.     

Alterations in food intake elicited by GABA and opioid agonists and antagonists administered into the ventral tegmental area region of rats

Food intake is significantly increased following administration of mu-selective opioid agonists into the ventral tegmental area (VTA) region acting through multiple local opioid receptor subtypes. Since GABA receptor agonists in the VTA region are capable of eliciting feeding, the present study investigated whether feeding elicited by the mu-selective opioid agonist [D-Ala(2), NMe(4), Gly-ol(5)]-enkephalin (DAMGO) in the VTA region was altered by pretreatment into the same site with equimolar doses of either GABA(A) (bicuculline) or GABA(B) (saclofen) antagonists, and further, whether pretreatment with either general opioid or selective GABA receptor antagonists decreased feeding elicited by GABA(A) (muscimol) or GABA(B) (baclofen) agonists in the VTA region. DAMGO-induced feeding in the VTA region was dose-dependently decreased following pretreatment with either GABA(A) or GABA(B) antagonists in the absence of significant alterations in food intake by the antagonists per se. However, the presence of short-lived seizures following bicuculline in the VTA region suggests that this ingestive effect was caused by nonspecific actions. In contrast, GABA(B) receptors are involved in the full expression of mu-opioid agonist-induced feeding in this region since saclofen failed to elicit either seizure activity or a conditioned taste aversion. Pretreatment with naltrexone in the VTA region reduced intake elicited by baclofen, but not muscimol. Finally, baclofen-induced feeding was significantly reduced by saclofen, but not bicuculline, pretreatment in the VTA region. Therefore, possible coregulation between GABA(B) and opioid receptors in the VTA region, as suggested by immunocytochemical evidence, is supported by these behavioral effects upon ingestion.     

Dopamine D1/D2 agonists injected into nucleus accumbens and ventral pallidum differentially affect locomotor activity depending on site.

Ventral pallidal dopamine has been recently shown to play an important role in psychostimulant reward and locomotor activation. The aim of the present study was to compare the roles of ventral pallidal D1 and D2 receptors in evoking locomotor activity with those in the nucleus accumbens. The D1 agonist SKF 38393 and the D2 agonist quinpirole hydrochloride (0.3-3 microg/ 0.5 microl) were bilaterally injected into ventral pallidum or nucleus accumbens through pre-implanted cannulae. In the ventral pallidum, 0.3-1 microg SKF 38393 increased locomotor activity while 3 microg had no effect; 3 microg quinpirole suppressed locomotion while 0.3-1 microg had no effect. Locomotor activity induced by an equigram (0.3 microg) mixture of SKF 38393 and quinpirole, while significantly higher than that induced by 0.3 microg quinpirole was not significantly higher than that induced by 0.3 microg SKF 38393 alone. At the 3 microg dose, SKF 38393 injections into anterior ventral pallidum increased activity; injections into posterior ventral pallidum decreased activity. In the nucleus accumbens, 0.3-3 microg SKF 38393 dramatically increased locomotor activity while quinpirole moderately increased locomotion. In the group that had previously received the full quinpirole dose range, injection of the equigram (0.3 microg) mixture of SKF 38393 and quinpirole induced locomotor activation which was higher than that induced by either drug alone or by the addition of the effect of each drug alone, i.e. synergy occurred. Moreover, rats that had previously received SKF 38393 developed a sensitized locomotor response to subsequent SKF 38393, quinpirole or the mixture of these two drugs. The difference in locomotor response to dopamine agonists between the ventral pallidum and nucleus accumbens is consistent with electrophysiological evidence collected at these two sites. These findings suggest that, unlike the nucleus accumbens, where D1 and D2 receptor activation may facilitate each other to induce a synergistic effect on locomotor activity, ventral pallidal D1 and D2 receptors may be located on different neurons and coupled with different, if not opposite, behavioral output.     

Motor activity and the GABAA-receptor in the ventral pallidum/substantia innominata complex.

The present study deals with the role of the gamma-aminobutyric acid-A (GABAA) receptor in motor activity in the rostral part of the ventral pallidum/substantia innominata complex. Both the specific GABAA antagonist bicuculline (25-100 ng/0.5 microliter) and the GABAA agonist muscimol (25 ng/0.5 microliter) enhanced motor activity. It was moreover found that bicuculline (50-100 ng) dose-dependently attenuated the activity induced by muscimol (25 ng). Conversely, muscimol (25 ng) attenuated the bicuculline (25-50 ng) induced activity. These data thus show that both stimulation and blockade of GABAA receptors within the area under study enhance motor activity.     

Mapping of contraversive and ipsiversive circling responses to ventral tegmental and substantia nigra electrical stimulation

Circling responses to ventral mesencephalic electrical stimulation were studied over a range of stimulation sites and a range of stimulation frequencies. Contraversive circling was seen with 62% of the sites stimulated; positive sites were found in the ventral tegmental area, the medial lemniscus, and the zona compacta and zona reticulata of the substantia nigra; frequency thresholds were in the range of 15-60 Hz. Ipsiversive circling was seen with 30% of the sites stimulated; these sites tended to be in the region of nigral dopamine cell bodies, but this correlation was not perfect; some ipsiversive circling sites were found in zona reticulata, and some were found dorsal to zona compacta. Ipsiversive circling had high frequency thresholds, in the range of 100-150 Hz, and generally had longer latencies than those for contraversive circling. In one-third of the cases where ipsiversive circling was seen with high frequency stimulation, contraversive circling was obtained with lower frequency stimulation at the same site. In these cases contraversive circling was seen first, with short latency at low frequencies. As stimulation frequency was raised, the period of contraversive circling became shorter and the animals then stopped and reversed direction. The dispersion of positive sites rules out the suggestion that there are simple medial-lateral differences in the direction of circling elicited by nigral stimulation, and the dispersion of sites and the frequency response of the effects suggest that neither direction of circling results from direct depolarization of the dopaminergic cells themselves.     

Feeding induced by GABA(A) receptor stimulation within the nucleus accumbens shell: regional mapping and characterization of macronutrient and taste preference.

This study investigated the areas of the nucleus accumbens shell involved in the modulation of feeding behavior by GABAergic stimulation and characterized this response using macronutrient diets as well as saline, sucrose, and saccharin solutions. The GABA agonist muscimol induced a pronounced feeding response when infused in the medial nucleus accumbens shell but not in the ventral or lateral accumbens shell. In the macronutrient preference study, muscimol increased the intake of both high fat and high carbohydrate diets when presented separately. When both diets were available simultaneously, muscimol stimulated feeding of both diets to the same degree. Muscimol elicited a robust increase in the consumption of sucrose solution. However, no effect of muscimol was demonstrated for water, saline, or saccharin intake. These findings provide evidence for a selective role for GABA-sensitive neurons in the medial accumbens shell in the regulation of ingestive behavior and further suggest that GABA(A) receptors in this region do not modulate palatability, macronutrient selection, or rewarding properties of food.     

Topography and functional role of dopaminergic projections from the ventral mesencephalic tegmentum to the ventral pallidum.

A dopaminergic projection from the ventral tegmental area to the ventral pallidum was identified in the rat using anterograde tract tracing and combined retrograde tracing-immunocytochemistry. The projection was found to be topographically organized such that fibers innervating the ventromedial ventral pallidum arose from neurons located along the midline nuclei of the ventral mesencephalon, including the nucleus interfascicularis and nucleus linearis caudalis. Ventral tegmental neurons situated more laterally, in the nucleus parabrachialis pigmentosus and nucleus paranigralis, projected to the ventromedial and dorsolateral ventral pallidum. The substantia nigra did not supply a major contribution to this projection. The proportion of ventral tegmental area dopaminergic neurons projecting to the ventral pallidum ranged from approximately 30% to 60%. The functional significance of the projection is indicated since intra-ventral pallidum microinjections of dopamine elicited a dose-dependent increase in locomotor activity. Furthermore, whereas pretreatment of the ventral pallidum with the GABAA agonist muscimol has been shown to attenuate opioid-induced locomotor activity elicited from the ventral pallidum, it did not attenuate the dopamine-induced motor response. Thus, while mu-opioids in the ventral pallidum may presynaptically regulate GABAergic efferents from the nucleus accumbens, it appears that the dopaminergic input directly influences the ventral pallidal output neuron which is involved in locomotion.     

GABA transmission in the ventral pallidum is not involved in the control of latent inhibition in the rat

Latent inhibition describes a process of learning to ignore stimuli of no consequence, and is disrupted in acute, positive-symptomatic schizophrenia. Understanding the neural basis of latent inhibition in animals may help to elucidate the neural dysfunction underlying positive schizophrenic symptoms in man. Evidence suggests a crucial role for dopamine transmission in the nucleus accumbens in the control of latent inhibition. The present studies investigated the role of the GABA-ergic efferent from the nucleus accumbens to the ventral pallidum in latent inhibition. The GABA(A) agonist muscimol (4.56 ng/microl), and antagonist picrotoxin (0.2 microg/microl), were infused into the ventral pallidum, and effects on latent inhibition were assessed using a conditioned suppression procedure. Neither drug produced specific effects on latent inhibition when given alone and, in the case of muscimol, failed to reverse the disruption of latent inhibition induced by systemic amphetamine. In addition to significant non-specific drug effects, a positive control experiment revealed that intra-pallidal picrotoxin significantly enhanced locomotion, suggesting that our manipulations of ventral pallidal GABA function were behaviourally effective. We conclude that modulating ventral pallidal GABA transmission does not affect latent inhibition. The implications of this finding for theories of the neural circuitry mediating latent inhibition and for understanding the functional role of ventral pallidal GABA transmission are discussed.     

Behavioural effects mediated by unilateral nigral dopamine receptor stimulation in the rat

Summary Unilateral intranigral injections of dopamine in conscious rats pretreated with nialamide resulted in either ipsiversive or contraversive rotation depending upon the site of injection. Injection of dopamine (50 g) into the zona compacta of the substantia nigra induced weak ipsiversive or mixed ipsiversive and contraversive rotation. Injection of dopamine (12.5–50.0 g) into zona reticulata of substantia nigra induced only contraversive circling. Destruction of the ipsilateral medial forebrain bundle (MFB) using 6-hydroxydopamine (6-OHDA) abolished ipsiversive circling but enhanced contraversive circling produced by dopamine or apomorphine. The combination of a unilateral 6-OHDA lesion of MFB with a kainic acid or electrolesion of the ipsilateral strio-nigral and pallido-nigral pathways reduced contraversive circling to intranigral apomorphine (10 g). Ipsiversive circling produced following intranigral injection of dopamine is dependent upon the integrity of ascending dopamine neurones. Contraversive rotation is independent of ascending dopamine pathways but is reliant upon afferent input to the substantia nigra from the striatum and/or globus pallidus.