Effects Of Dopamine Depletion Research Articles

Dopamine Control of Gene Expression in Basal Ganglia Nuclei: Striatal and Nonstriatal Mechanisms

Although the effects of dopamine depletion and dopamine receptor blockade on gene expression, have been studied not only in the striatum, but also in other regions of the basal ganglia and the brain, most of the attention has been devoted to the effects of dopamine on gene regulation in the striatum. In an effort to examine changes in gene expression caused by alterations in dopaminergic transmission in regions of the basal ganglia that received striatal inputs, the effects of nigrostriatal lesions and haloperidol administration on the expression of glutamic acid decarboxylase (Mr 67,000: GAD 67) mRNA in the globus pallidus have been examined. Measuring GAD mRNA offers a distinct opportunity to obtain information on the GABAergic efferent neurons of this region, because, in contrast to GAD or GABA, the mRNA is contained in their cell bodies, not in the terminals of striatal neurons projecting to the pallidus. Although there is evidence that GABA and N-methyl-D-aspartate receptors decrease in the globus pallidus after prolonged alteration in dopamine transmission, less is known about other molecules that are likely to play a role in changes in neuronal activity. One intriguing possibility is that prolonged changes in neuronal firing are associated with changes in expression of ion channels, in particular, potassium channels, which are known to influence the pattern of neuronal firing.

Effects of dopamine depletion in the medial prefrontal cortex on the stress-induced increase in extracellular dopamine in the nucleus accumbens core and shell

In the present study we examined whether depletion of dopamine in the medial prefrontal cortex alters the neurochemical activity of mesoaccumbens dopamine neurons and/or their behavioral correlate, motor behavior. Infusion of 6-hydroxydopamine (1 μg) into the medial prefrontal cortex of rats pretreated with a norepinephrine uptake blocker produced a 70% loss of tissue dopamine, with relative sparing of the norepinephrine content (−23%) in that region. Using in vivo microdialysis, we monitored basal and evoked extracellular dopamine in the nucleus accumbens core and shell of control and lesioned rats. The concentration of basal extracellular dopamine in the nucleus accumbens core was similar in control and lesioned rats; however, basal dopamine efflux in the nucleus accumbens shell was approximately 30% higher in lesioned rats than in controls. Lesions did not alter the ability of systemic d-amphetamine (1.5 mg/kg, i.p.) to increase extracellular dopamine in the nucleus accumbens shell. In contrast, the dopamine depletion in the medial prefrontal cortex attenuated the amphetamine-induced increase in extracellular dopamine in the nucleus accumbens core, as well as the amphetamine-induced increase in locomotor activity. Lesions did not significantly alter the effects of tail pressure (30 min) on extracellular dopamine in the nucleus accumbens core. However, the depletion of dopamine in the medial prefrontal cortex potentiated the stress-induced increase in extracellular dopamine in the nucleus accumbens shell. These data demonstrate that mesocortical dopamine neurons influence (i) amphetamine-induced dopamine efflux in the nucleus accumbens core and (ii) stress-evoked dopamine efflux in the nucleus accumbens shell. It has been proposed that a disruption in the interaction between cortical and subcortical dopamine neurons is involved in the pathophysiology of schizophrenia. The present data raise the possibility that a disruption in the interaction between mesocortical dopamine neurons and dopamine neurons projecting to the nucleus accumbens shell is involved in those symptoms of schizophrenia that are influenced by stress.

Interactions between D1 and muscarinic receptors in the induction of striatal c- fos in rats depleted of dopamine as neonates

The contributions of striatal D1 receptors to the expression of sensorimotor behavior are qualitatively different in rats depleted of dopamine (DA) as neonates vs. as adults. In an effort to reveal neuronal mechanisms underlying these behavioral differences we determined the effects of the partial D1 agonist SKF 38393, the muscarinic antagonist scopolamine, and the combination of the two drugs on the induction of c- fos in the striatum and its projection sites, the globus pallidus and substantia nigra. Adult rats, given intracerebroventricular injections of 6-hydroxydopamine (6-OHDA, 50 μg/5 μl/hemisphere) or its vehicle on postnatal day 3, were treated with SKF 38393 (1.5 mg/kg, i.p.), scopolamine (5.0 mg/kg, i.p.) or the combination of the two drugs. There was no significant induction of c- fos in vehicle-treated controls, regardless of drug administration. In DA-depleted rats, scopolamine also did not induce c- fos whereas SKF 38393 produced a significant increase in the number of FOS-positive cells in the dorsal, but not ventral, striatum. The combined administration of scopolamine and SKF 38393 resulted in a potent synergism in the number of FOS-positive cells in DA-depleted rats. These interactions between lesion condition and drugs on c- fos induction were not secondary to differences in drug-induced behavioral activity. Activity levels were no different in vehicle vs. DA-depleted rats following the combined administration of scopolamine + SKF 38393, yet the two groups of rats exhibited marked differences in the density of FOS-positive striatal neurons. The effects of scopolamine and SKF 38393 on c- fos induction in striatum are qualitatively similar to those reported in rats DA-depleted as adults and suggest that, at this single-label level of analysis, the ability of D1 and muscarinic receptors to influence striatal activity does not contribute to the marked age-related differences in the behavioral effects of DA depletions.

Prenatal cocaine exposure and postnatal hypoxia independently decrease carotid body dopamine in neonatal rats

The effects of prenatal cocaine exposure on the levels of carotid body dopamine (DA) and its metabolites 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) were investigated in 5-day-old rat pups exposed to normoxic and hypoxic conditions. Timed-pregnant Sprague-Dawley rats were injected b.i.d. with either cocaine HCl (30 mg/kg) or isotonic saline (1 ml/kg) from gestational days 7–21. On the fifth postnatal day, pups were subjected to either 20 min of 0.21 or 0.08 fractional inspired oxygen (F[O 2). Under a strictly timed protocol, both carotid bodies were removed from each pup, placed in an antioxidant solution to prevent DA breakdown, and subsequently analyzed via HPLC with electrochemical detection to determine carotid body DA and DOPAC content. Two-way ANOVA revealed decreases in DA in cocaine-exposed pups. No HVA was detectable in any of the samples. The 0.08 F 1O 2 condition decreased DA compared to 0.21 F 1O 2. The additive consequences of DA depletion resulting from the combination of prenatal cocaine and postnatal hypoxia decreased carotid body DA to 14% of control levels, with several animals exhibiting DA content below detection limits. Considering the role of the carotid body in the ventilatory response to hypoxia, these data suggest that prenatal cocaine exposure may adversely affect the normal chemoreceptive function of the carotid body.

Human Ventromesencephalic Grafts Restore Dopamine Release and Clearance in Hemiparkinsonian Rats

We and others reported previously that transplantation of fetal ventromesencephalic homograft restores the apomorphine-induced rotational behavior and electrochemical indices of dopamine (DA) depletion in the 6-hydroxydopamine (6-OHDA)-lesioned rat. We found that regeneration of KCl-evoked DA release and tyrosine hydroxylase (TH) immunoreactivity was limited to the graft area even 4 months after transplantation. In the present experiments, we transplanted human fetal ventromesencephalic tissue to the 6-OHDA-lesioned rats. After transplantation, rats received chronic cyclosporin and vibramycin treatment. We found that human fetal grafts from the substantia nigra can restore the effects of DA depletion in 6-OHDA-lesioned rats; these fetal grafts were found to reduce the apomorphine-induced rotational behavior and restore K +-evoked DA release as well as DA clearance in the striatum. The area with active DA release is far beyond the transplantation site, unlike that seen in the homografted rats. These electrochemical responses correspond to the extended outgrowth of TH-positive neuronal fibers distal to the graft area. Taken together, our data suggest that rats that received human mesencephalic graft had much greater DA innervation and more complete restoration of function than those that received homografts.

Effects of dopamine depletion on the morphology of medium spiny neurons in the shell and core of the rat nucleus accumbens

Nucleus accumbens receives a dense dopaminergic innervation which is important in regulating motivated states of behavior such as goal-directed actions, stimulus-reward associations and reinforcement of addictive substances. The shell and core territories of this nucleus each receive functionally and morphologically distinct dopaminergic inputs and lesions of the ascending pathways totally deprive the core but not the shell of dopaminergic fibers. Medium spiny neurons are the principal targets of dopaminergic terminals. The present study explored whether the loss of dopamine inputs can affect these neurons and whether cells in the shell and core would be equally susceptible to such a loss. Intracellular injection in fixed slices and neuronal reconstruction were used to analyze the dendritic trees of 62 neurons in the shell and core of animals that received a unilateral, chronic 6-hydroxydopamine lesion of the medial forebrain bundle. In the dopamine-depleted core, dendrites are significantly shorter (16% decrease) than in the intact core and in both the dopamine-depleted core and lateral shell, dendrites are less spiny than in respective control regions. Dopamine loss in the medial shell is associated with significantly more tortuous dendrites that are lower in spine density. However, the number of spines is not reduced which may mean that the increase recorded for segment length, although insignificant in tests, could be responsible for the change in spine density. These data suggest that the loss of dopamine can affect accumbal neuronal morphology and, moreover, can affect neuronal structures differentially in the shell and core.

The effects of nucleus accumbens dopamine depletions on continuously reinforced operant responding: Contrasts with the effects of extinction

Two experiments were undertaken to study the role of nucleus accumbens dopamine (DA) in instrumental lever pressing on a continuous reinforcement schedule (CRF). In the first experiment, the neurotoxic agent 6-hydroxydopamine was infused directly into the nucleus accumbens to investigate the effects of DA depletion on lever pressing performance. DA depletion had only a modest effect on the total number of lever presses, and there was a significant effect on total lever presses only on the first test day (third day postsurgery). Analyses also were performed on responding across the 45-min session by breaking down the session into three 15-min periods. During the test session on day 3 postsurgery, there was a significant group × time interaction, with DA-depleted rats showing a significant reduction in the numbers of responses in the first 15-min period, but no significant effects over the second or third 15-min period within the session. Although control rats showed a within-session decline in responding, the DA-depleted rats did not. In addition, analysis of interresponse times (IRTs) indicated that accumbens DA depletions produced a slowing of the local rate of responding as indicated by a significant decrease in high rate (i.e., short-duration IRT) responses and an increase in low rate (i.e., long-duration IRT) responses. In a second experiment, the effects of extinction on CRF performance were investigated. Unlike the effects of nucleus accumbens DA depletion, extinction produced lower levels of responding throughout the entire test session. In contrast to the effects of accumbens DA depletions, analysis of IRTs indicated that extinction produced a significant increase in high-rate responses (low IRTs), which is probably indicative of an extinction “burst.” These results indicate that accumbens DA depletions produce a response slowing that does not closely resemble the effects of extinction.

The role of nucleus accumbens dopamine in responding on a continuous reinforcement operant schedule: A neurochemical and behavioral study

Two experiments were undertaken to investigate the role of nucleus accumbens dopamine (DA) in instrumental lever pressing on a continuous reinforcement (CRF) schedule. Rats trained to press a lever for food reinforcement on a CRF schedule, and food-deprived control rats, were implanted with dialysis probes in the nucleus accumbens. The day after implantation, rats were tested and dialysis samples were assayed for DA and the DA metabolite 3,4-dihydroxyphenylacetic acid (DOPAC). Performance of the lever-pressing task resulted in significant increases in extracellular levels of DA and DOPAC relative to control rats. The increases in extracellular DA were significantly correlated (r = 0.92) with the number of lever press responses committed. In the second experiment, the neurotoxic agent 6-hydroxydopamine was infused directly into the nucleus accumbens to investigate the effects of DA depletion on lever-pressing performance. DA depletion had only a modest effect on the total number of lever presses, and there was a significant effect on total lever presses only on the first test day (third day postsurgery). Analyses also were performed on responding across the 45-min session by breaking down the session into three 15-min periods. There was a significant group x time interaction, with DA-depleted rats showing a significant reduction in the numbers of responses in the first 15-min period, but no significant effects over the second or third 15 min in the session. This initial slowing of response rate was present across all 5 test days. These results indicate that DA release and metabolism increases in rats performing on a CRF schedule, and that DA depletion produces a slowing of initial response rate.

Phenylalanine in the caudate nucleus of dopamine depleted rats.

Dopamine depleting lesions of the substantia nigra result in a reduction of the striatal accumulation of 2-phenylethylamine following monoamine oxidase inhibition. It is established that this effect may not be due to a change in availability of aromatic L-amino acid decarboxylase in striatum. Nevertheless, the possibility remains that striatal concentrations of phenylalanine (the precursor of 2-phenylethylamine) may be altered by dopamine-depleting lesions. The present experiments assessed the effects of dopamine depletion induced by 6-OHDA (7 days following 8 micrograms/4 microliters unilateral substantia nigra injection) on striatal concentrations of phenylalanine, dopamine, 5-hydroxytryptamine and their metabolites. In addition, the effects of reserpine-induced (10 mg kg-1, 2h, sc) amine depletion on these striatal levels were also assessed. Under equivalent conditions reserpine is reported to increase striatal accumulation of 2-phenylethylamine. 6-OHDA induced a significant unilateral depletion of dopamine, DOPAC and HVA and increased 5-HIAA but had no significant effect on phenylalanine levels. Reserpine decreased dopamine and 5-hydroxytryptamine and increased DOPAC, HVA and 5-HIAA levels, no changes in phenylalanine were observed. This pattern of results was also observed when lesioned animals or reserpine-treated animals were pretreated with (-)-deprenyl (2 mg kg-1, 2 hr, sc), the treatment previously used to induce accumulation of 2-phenylethylamine. These data indicate that changes in 2-phenylethylamine previously observed under these conditions may not simply be secondary to a change in striatal phenylalanine concentrations.

Involvement of nucleus accumbens dopamine in the motor activity induced by periodic food presentation: a microdialysis and behavioral study

Two experiments were undertaken to investigate the role of accumbens dopamine (DA) in food-related motor activities. Although presentation of large amounts of food elicits feeding behavior, periodic food presentation (PFP; e.g. a 45-mg pellet every 45 s) induces considerable locomotion, rearing and other motor activities in food-deprived rats. In the first experiment, in vivo microdialysis methods were used to study DA release and metabolism in the nucleus accumbens of behaving rats exposed to periodic food presentation. Four behavioral conditions were used: high rate of PFP (one pellet per 45 s), low rate of PFP (one pellet per 4 min), massed food presentation and food deprivation control. The rats that received a high rate of PFP showed substantial increases in locomotor activity, and also showed significant increases in extracellular DA and DA metabolites. Rats that received massed presentation of food pellets consumed large quantities of food, but showed no significant increases in locomotor activity or DA release. Although the group that received the high rate of PFP showed the highest motor activity and the largest increase in DA release, there was only a modest correlation ( r = 0.34) between motor activity and increased DA release. In the second experiment, the neurotoxic agent 6-hydroxydopamine (6-OHDA) was injected into the nucleus accumbens in order to assess the effects of DA depletion on PFP-induced motor activity. DA depletion significantly reduced PFP-induced motor activity in the first week after surgery, but by the second week DA-depleted rats had recovered normal levels of motor activity. DA levels in the nucleus accumbens of 6-OHDA-treated rats were highly correlated with the initial deficit in PFP-induced activity. These studies demonstrate that PFP increases motor activity through a mechanism that depends upon DA in nucleus accumbens. Accumbens DA could be acting to modulate or facilitate aspects of locomotor function, but the relatively low correlation between DA release and motor activity suggests that accumbens DA release may not directly control the motor output.

The effect of dopamine depletion on light-evoked and circadian retinomotor movements in the teleost retina.

The retinae of lower vertebrates undergo a number of structural changes during light adaptation, including the photomechanical contraction of cone myoids and the dispersion of melanin granules within the epithelial pigment. Since the application of dopamine to dark-adapted retinae is known to produce morphological changes that are characteristic of light adaptation, dopamine is accepted as a casual mechanism for such retinomotor movements. However, we report here that in the teleost fish, Aequidens pulcher, the intraocular injection of 6-hydroxydopamine (6-OHDA), a substance known to destroy dopaminergic retinal cells, has no effect on the triggering of light-adaptive retinomotor movements of the cones and epithelial pigment and only slightly depresses the final level of light adaptation reached. Furthermore, the retina continues to show circadian retinomotor changes even after 48 h in continual darkness that are similar in both control and 6-OHDA injected fish. Biochemical assay and microscopic examination showed that 6-OHDA had destroyed dopaminergic retinal cells. We conclude, therefore, that although a dopaminergic mechanism is probably involved in the control of light-induced retinomotor movements, it cannot be the only control mechanism, nor can it be the cause of circadian retinomotor migrations. Interestingly, 6-OHDA injected eyes never reached full retinomotor dark adaptation, suggesting that dopamine has a role to play in the retina's response to darkness.

Regulation by dopaminergic neurotransmission of dopamine D 2 mRNA and receptor levels in the striatum and nucleus accumbens of the rat

The effect of dopamine depletion or pharmacological blockade of dopamine receptors on striatal and accumbens dopamine D 2 mRNA and receptor levels was assessed by in situ hybridization histochemistry and receptor autoradiography. The time course of pharmacological blockade with haloperidol demonstrates a complex mode of regulation of dopamine D 2 mRNA and receptor levels. By day 8 of haloperidol treatment, D 2 mRNA and receptor levels were decreased (up to 20%) in the medial and anterior aspects of the caudate-putamen (mCPU and aCPU) and the nucleus accumbens (NAc). However, by day 21 of haloperidol treatment, D 2 mRNA and receptor were increased relative to vehicle-injected controls. Likewise, unilateral dopamine depletion due to 6-hydroxydopamine (6-OHDA) lesions of mesencephalic dopaminergic neurons resulted in decreased levels of D 2 receptor mRNA by day 8 post-lesion in the ipsilateral mCPU, aCPU and the NAc. However, at days 14 or 21 post-lesion, there was a reversal of the effect with increases of up to 22% in all brain regions ipsilateral to the lesion. Although no decreases in receptor level were observed at day 8, significant increases in receptor level in all three brain regions were detected at days 14 and 21 post-lesion. The results demonstrate that midbrain dopaminergic innervation exerts tonic effects on the levels of dopamine D 2 receptor and mRNA in the caudate-putamen and the nucleus accumbens of the rat. Changes in receptor level are frequently accompanied by comparable changes in mRNA level, indicating a mass action relationship between receptor level and receptor biosynthesis in these forebrain regions in the rat.

6‐Hydroxydopamine Lesion of Ventral Tegmental Area Dopaminergic Cell Bodies does not Impair Neuroendocrine Responses to Environmental Stimuli

Abstract To evaluate the influence of dopamine neurons in neuroendocrine responses to environmental stimulations, rats received bilateral injections of the neurotoxin 6-hydroxydopamine in the ventral tegmental area. Six weeks after the lesion, forebrain areas lost up to 88% of their dopamine content, and the areas innervated by the noradrenergic bundle, which passes through the ventral tegmental area, were also depleted of noradrenaline. Despite these profound changes of catecholamine content, we show that the responses of major neuroendocrine systems to environmental stimuli were not modified. Basal levels of circulating adrenocorticotropin, corticosterone, prolactin and catecholamines, as well as their increase by novel environment exposure, handling and/or electric footshock, were not modified by the lesion. These results favor the hypothesis that the effect of dopamine depletion is more on behavioral response initiation and/or performance than on the cognitive functions or emotional processes. They also question the importance of the ventral noradrenergic bundle in the activation of the hypothalamo-pituitary-adrenal axis by stressful stimuli.

Effect of dopamine depletion upon the K +-evoked release of CCK from superfused striatal slices

The effect of a lack of dopamine (DA) in the striatum upon the K +-evoked release of cholecystokinin (CCK) from superfused rat striatal slices has been studied. Two pharmacological tools were used to deplete the nigrostriatal DA system: administration of α-methyl- p-tyrosine which competitively inhibits DA synthesis and lesions with 6-hydroxydopamine of the medial forebrain bundle. In both cases there was a significant inhibition of the K +-evoked release of CCK. The observed effects might be relevant on pathological conditions implying depletion of the DA system.

Effects of dopamine depletion on the spontaneous activity of type I striatal neurons: relation to local dopamine concentration and motor behavior.

The relation between the electrophysiological activity of Type I striatal neurons, local dopamine (DA) concentration, and motor behavior in rats was investigated using intraventricular administration of the neurotoxin 6-hydroxydopamine (6-HDA) and extracellular single-unit recording. Results are compared with findings of past experiments in which the activity of Type II striatal neurons was examined after comparable 6-HDA-induced lesions. Several differences between the present observations and the earlier results were found. First, although large depletions (greater than 50%) of DA local to the site of the recording were required before the spontaneous firing rate of either cell type was increased, the levels necessary for this effect were found to be less for Type I cells than for Type II neurons. Second, although DA depletions of greater than 50% always were associated with increased Type I cell activity, depletions of greater than 95% resulted in spontaneous firing rates that were lower than those observed after depletions of approximately 90%. Thus, the relation between extent of dopaminergic depletion and Type I cell firing rate was biphasic, whereas that relation previously was found to be monophasic for Type II neurons. Finally, whereas increased Type I cell activity in the lateral striatum was associated with the aphagia, adipsia, and akinesia induced by large DA-depleting brain lesions, increased Type II cell activity in the medial striatum was found to be associated with these impairments. Because accumulating evidence suggests that the functioning of the lateral striatum is more critical for these behaviors, however, it is proposed that the substrate of the behavioral dysfunctions resulting from DA depletion is the Type I cell population in lateral striatum.

Amphetamine and LSD as discriminative stimuli: Alterations following neonatal monoamine reductions

Male adult Sprague-Dawley rats (70 days of age), neonatally depleted of either 5-hydroxytryptamine (5HT) via 5,7-dihydroxytryptamine (5,7-DHT; ICS) + desmethylimipramine (DMI; IP) at 3 days of age or dopamine (DA) via 6-hydroxydopamine (6-OHDA; ICS) + DMI at 14 days of age, were trained to discriminate either d-LSD-tartrate (80 μg/kg; IP) or d-amphetamine ( d-AMPH sulfate (0.90 mg/kg; IP) from saline utilizing a two lever drug discrimination paradigm. A neurochemical analysis at the termination of these studies revealed the following in terms of %DA or %5HT (presented in that order) depleted with respect to the appropriate vehicle control group; telencephalon; 96 and 96%, diencephalon; 51 and 31%, and brain stem; 76 and 80%. Rats learned to discriminate either d-AMPH or LSD regardless of amine depleted. In addition, the depletion of 5HT had little effects on dose or drug generalizations, or the ability of known antagonists to antagonize the discrimination stimulus (DS) effects of either LSD or d-AMPH. The effect of DA depletion, on the other hand, was to increase the sensitivity of the LSD DS at low doses, while decreasing the sensitivity of the d-amphetamine DS. DA depletion alsp had the effect of reducing the effectiveness of the LSD-antagonists, pizotifen maleate (BC 105), while the opposite was observed for the d-AMPH antagonist, trifluoperazine HCl. These data suggest that: (1) LSD and d-amphetamine discrimination stimuli are not mediated and/or influenced via the compromised aspects of the 5HT systems (other central mechanisms may have compromised for these 5HT deficits); (2) the LSD DS is mediated or influenced both by serotonergic and dopaminergic mechanisms; and (3) the d-amphetamine DS is mediated by certain aspects of the dopaminergic system with little evidence for the involvement of 5HT systems.

Effects of dopamine depletion on rotational behavior to dopamine agonists

The contralateral rotation to various dopamine agonists was determined in rats with unilateral lesions of the left nigrostriatal pathway both with and without dopamine depletion caused by dopamine synthesis inhibition. The rotation to drugs possessing D-2 dopamine agonist activity alone was greatly diminished by dopamine depletion. In contrast, the rotation induced by drugs possessing D-1 dopamine agonist activity (either D-1 alone or D-1 plus D-2) was affected to a much lesser extent by dopamine depletion.