Bilateral 6-hydroxydopamine Research Articles

Dopamine depletion in the medial prefrontal cortex induces sensitized-like behavioral and neurochemical responses to cocaine

It has been postulated that behavioral sensitization to cocaine is associated with an attenuation of cocaine-induced dopamine (DA) transmission in the medial prefrontal cortex (mPFC). Hence, experiments were designed to examine the effects of chemically-induced cortical DA depletion on the acute behavioral and neurochemical responses to cocaine. One week following two bilateral 6-hydroxydopamine (6-OHDA) injections into the mPFC, animals received injections of cocaine (7.5, 15 or 30 mg/kg, i.p.) or saline (1 ml/kg, i.p.) in a randomized fashion with a minimum 3 day intertrial interval. Cocaine produced a dose-dependent increase in motor activity which was significantly enhanced in animals depleted (mean of 76%) of dopamine in the mPFC. Likewise, 6-OHDA lesions of the mPFC produced a significant enhancement of cocaine-induced DA transmission in the nucleus accumbens (NAC) as estimated by in vivo microdialysis. These data indicate a permissive involvement of cortical DA in mediating behavioral and neurochemical responses to cocaine, as well as confirm the ability of the mPFC to influence subcortical structures in response to an acute injection of cocaine. Collectively, the present findings suggest that alterations in cortical DA transmission may be a neural substrate mediating the development of sensitization to cocaine, and thus, may contribute to the addictive properties of cocaine.

Short and long term plasticity after lesioning of the cell body or terminal field area of the dopaminergic mesocorticolimbic system in the rat

To investigate within one study regenerative capacities of dopaminergic axons and cell bodies, short and long term recovery of behavioral and biochemical impairments following a bilateral 6-hydroxydopamine (6-OHDA) lesion of the ventral tegmental area (VTA)–nucleus accumbens (NAc) pathway was investigated in rats. Novelty-induced motility, presynaptic functions and the levels of dopamine (DA) and its metabolites were reduced when cell bodies in the VTA or axons in the NAc were lesioned. Spontaneous recovery of the behavioral deficit was observed 4 weeks after a lesion of the NAc. Subsequently presynaptic functions recovered as shown by the reappearance of low dose apomorphine (50 mg/kg)-induced hypomotility, normalization of [ 3 H ]dopamine uptake, reinnervation of the NAc and normalization of levels of DA and its metabolites within 24 weeks. In contrast, after a VTA lesion no recovery was observed during 48 weeks, neither from hypomotility and loss of the low dose apomorphine response nor from decreased [ 3 H ]dopamine uptake and levels of DA in the NAc. Short term postsynaptic supersensitivity (hypermotility upon a higher dose of apomorphine (125 mg/kg)) was present 1 and 4 weeks after the lesion but not thereafter. A near total absence of dopaminergic neurons in the VTA and axons in the NAc were found 24 weeks postlesion. Treatment with the ACTH-(4–9) analog ORG 2766 (10 mg/kg s.c., 6 days once daily) facilitated recurrence of presynaptic functions after a lesion of axons but had no short or long term effect when cell bodies were lesioned. These findings substantiate the postulate that the peptide facilitates recovery processes.

Modulation of mesolimbic dopaminergic activity over the rat estrous cycle

Clinical observations have suggested that ovarian steroid hormones modulate the symptomology of psychiatric disorders and this modulation is thought to be due to a protective effect of estrogen on dopaminergic activity. To test this hypothesis, mesolimbic dopamine (DA) activity was examined in relationship to endogenous hormone levels. Using in vivo electrochemical techniques, K +-stimulated DA release was measured in the nucleus accumbens of control, intact cycling female rats and experimental rats which had received bilateral 6-hydroxydopamine (6-OHDA) lesions to the medial prefrontal cortex (PFC) to produce subcortical hyperactivity. DA release and reuptake fluctuated with changes in circulating steroid levels in both control and lesion groups. In non-lesioned control rats, stimulated DA release peaked during diestrus I (DI) and was attenuated during diestrus II (DII) and estrus. DA transport, as measured by a change in T 1/2 time, was significantly potentiated during proestrus. The expression of subcortical hyperactivity following lesions to the medial PFC appeared to be dependent on the steroid environment; during DII an increased responsiveness was observed while a significant decrease in K +-stimulated release was observed during DI. These cyclic changes in DA release were not associated with dramatic changes in DA transport except during proestrus when transport was significantly prolonged. These data suggest that cyclic fluctuation of ovarian steroids may modulate DA activity presynaptically through an alteration in both release and reuptake and that this modulation effectively dampens the expression of subcortical hyperactivity except under specific hormonal conditions.

Effect of 6-hydroxydopamine lesions of the medial prefrontal cortex on intravenous cocaine self-administration under a progressive ratio schedule of reinforcement

Rats were trained to self-administer intravenous cocaine under a progressive ratio (PR) schedule of reinforcement. Under this schedule, an increasing number of lever responses had to be made to obtain each subsequent reinforcement (1.5 mg/kg per injection). Once stable responding was achieved with this schedule, bilateral 6-hydroxydopamine (6-OHDA) or vehicle-only injections were delivered into the medial prefrontal cortex (mPFC). Following recovery from surgery, the animals were given access to cocaine under the PR schedule. The effect of the lesion on self-administration behaviour was examined at various doses of cocaine (0.09–1.5 mg/kg per injection). 6-OHDA lesions of the mPFC had no effect on self-administration behaviour at the higher unit doses of cocaine. However, at the lower doses (0.09 and 0.19 mg/kg per injection), the lesion caused a significant increase in break point (BP), the number of responses made to obtain the last reinforcement of a self-administration session. The neurochemical results showed a significant reduction (57%) in mPFC levels of dopamine (DA) and 3,4-dihydroxyphenylacetic acid (DOPAC) (53%), with no changes in noradrenaline or serotonin levels. In contrast, the lesion caused no changes in DA or DOPAC levels in the nucleus accumbens (NACC) or striatum. These results indicate that the DAergic innervation of the mPFC cortex has a role in cocaine self-administration behaviour; however, whether this role is contingent on NACC DA function remains to be elucidated.

Immunoreactive changes resulting from dopaminergic denervation of the dentate gyrus of the rat hippocampal formation

The hypothesis that dopaminergic denervation is a factor in the development of hippocampal neurofibrillary tangles was tested in the rat with bilateral stereotaxic 6-hydroxydopamine (6-OHDA) lesions of the ventral tegmental area (VTA). This led to the postsynaptic appearance of cytoplasmic immunoreactivity to ubiquitin in neurons of the dentate gyrus. An additional postsynaptic morphologic abnormality was seen when the animals were pretreated with the D 1 dopaminergic antagonist SCH 23390 and the VTA lesions were combined with septal lesions affecting cholinergic and GABAergic neurons projecting to the dentate gyrus. These changes consisted of a loss of dendritic microtubule associated protein (MAP-2) and tau immunoreactivity and a prominence of remaining dendrites in the molecular layer of the dentate gyrus. Additional investigation will be needed to determine if these transynaptic changes in dentate neurons, resulting from denervation, represent a precursor stage to neurofibrillary tangle development.

6-Hydroxydopamine lesion of the rat prefrontal cortex impairs motor initiation but not motor execution

We examined the effects of bilateral 6-hydroxydopamine (6-OHDA) lesions of the medial prefrontal cortex (PFC) in rats on motor initiation and execution in a simple reaction time task. Reaction times (RT) and movement times (MT) were measured in trained rats on four pre- and postoperative days. Animals with 6-OHDA lesions were selectively impaired on motor initiation as measured by a significant increase in RT on each postoperative day. Motor execution was intact postoperatively, since MT was not altered. Neurochemical analysis revealed a significant depletion of prefrontal dopamine (DA) and noradrenaline (NA) in lesioned animals. It was concluded that DA and, to a lesser extent, NA in the rat PFC were involved in monitoring RT performance.

The role of dopamine in the maintenance and breakdown of [formula omitted] synergism

The neurochemical factors involved in the maintenance and breakdown of dopamine D1D2 receptor synergism were investigated by giving rats various pharmacological treatments that diminish the ability of dopamine to interact with its D1 and/or D2 receptors. Following these treatments, rats were observed for the expression of stereotyped motor behavior in response to independent stimulation of D1 or D2 receptors. Independent D2-mediated responses were observed: (a) 2 h after the last of three daily reserpine (1 mg/kg) injections, (b) 48 h after bilateral 6-hydroxydopamine (6-OHDA) lesions of the mesostriatal pathways, (c) 24 h after a concentrated 48-h regimen (one injection/6 h) of eticlopride (0.5 mg/kg) or eticlopride + SCH 23390 (0.5 mg each), and (d) 2 h after a concentrated 48-h regimen (one injection/6 h) of α-methyl-p-tyrosine (αMPT; 100 mg/kg), but not after control treatments or a concentrated regimen of SCH 23390 alone. By contrast, independent D1-mediated responses were observed only after three daily reserpine injections or 48 h after bilateral 6-OHDA lesions. Independent D1-mediated stereotypy was not observed under control conditions or following a concentrated 48-h regimen of (a) SCH 23390 or eticlopride (0.5 mg/kg each) alone or in combination, (b) a high dose of SCH 23390 (1.0 mg/kg), (c) αMPT (100 mg/kg), or (d) αMPT (100 mg/kg)+SCH 23390 (1.0 mg/kg). Reserpine, bilateral 6-OHDA, and αMPT treatments produced striatal dopamine depletions of 96%, 92%, and 71%, respectively. These data indicate that the breakdown in D1D2 synergism consists of two components: (a) D1 independence from the controlling influence of D2 receptors, and (b) D2 independence from the controlling influence of D1 receptors. The interaction of synaptic DA with its D2 receptors plays a major role in determining whether these receptors can function independently of D1 receptors, whereas reduced DA-D1 activity alone appears insufficient to elicit D1 independence.

Regulatory behaviour, exploration and locomotion following NMDA or 6-OHDA lesions in the rat nucleus accumbens

The effects of bilateral, N-methyl-D-aspartate (NMDA)-induced lesions of the nucleus accumbens (N.Acc.) on regulatory and behavioural responding were studied in rats and compared with the effects of bilateral 6-hydroxydopamine (6-OHDA) lesions. After postoperative body weight, food and water intake had been monitored for a period of 4 weeks, rats were tested in an exploration-choice box. Spontaneous locomotion and the locomotor and stereotypy responses to different doses of dopaminergic agonists were measured subsequently. Detailed assessment of NMDA-induced lesion volumes showed that on average 81.53% of total N.Acc. area was damaged, depending on excitotoxin dose. Tyrosine hydroxylase immunohistochemistry was used to confirm loss of mesolimbic dopamine neurones following 6-OHDA. Analysis of the behavioural data showed that NMDA N.Acc. lesions significantly enhanced exploratory behaviour, spontaneous locomotor activity and the locomotor response to a low dose of D-amphetamine. By comparison, 6-OHDA lesions did not affect exploration and spontaneous locomotion but significantly attenuated the locomotor response to a low dose of D-amphetamine. Regulatory responses were unaffected 28 days after surgery, although NMDA-lesioned rats took longer to recover from postoperative hypodipsia. The results suggest that NMDA N.Acc. lesions induce a deficit in the control of general locomotor output and are consistent with the hypothesis that the N.Acc. functions as an interface between sensory input and locomotor output and that it is needed to channel activity levels appropriately.

Opioid binding in the rostral hypothalamus is reduced following lesion of the ventral noradrenergic tract in female rats.

Experiments were undertaken to establish whether opioid receptors exert a direct presynaptic influence on noradrenergic (NA) terminals in the preoptic/anterior hypothalamus (PO/AH) of the female rat. Thus, opioid binding studies were performed in rats with lesions of the ventral NA tract (VNAT; the main NA projection to the hypothalamus) to assess whether a loss of NA terminals may also result in a decrease in opioid binding in the PO/AH. In the first experiment, unilateral electrolytic lesions of the VNAT caused a significant reduction in both the NA content and specific [3H]-diprenorphine binding to membrane homogenates in the ipsilateral PO/AH. In the second experiment bilateral 6-hydroxydopamine (6-OHDA)-induced lesions of the VNAT caused a significant reduction in NA levels in the PO/AH as well as significant decreases in the density of [3H]-diprenorphine binding to tissue sections of the PO/AH when compared to control animals. These results strongly suggest that the NA input to the PO/AH is regulated by endogenous opioid peptides, and provide an anatomical substrate to explain opioid-NA interactions in the control of gonadotrophin releasing hormone (GnRH) and gonadotrophin secretion.

Potentiation of spiperone-induced oral activity in rats after neonatal 6-hydroxydopamine

The influence of central dopaminergic fibers on drug-induced oral activity in rats has not been well studied. Rats were treated 3 days after birth with bilateral intracerebroventricular 6-hydroxydopamine (6-OHDA; 134 ωg total, base form) to destroy dopaminergic fibers in the brain. Control rats received vehicle by the same route. At about 10 weeks of age, a challenge dose of the dopamine D2 receptor antagonist, spiperone (40 ωg/kg, IP), produced an 8-fold increase in the number of oral movements during a 60-minute observation period, vs. the control group. SKF 38393 (3.0 mg/kg, IP), a D1 agonist, produced the same number of oral movements as spiperone in the 6-OHDA group, representing a 2.4-fold increase over the controls. The B max and K d for both D1 and D2 receptors was not changed in rat striatum by neonatal 6-OHDA treatment, even though dopamine content was reduced by 96%. These findings demonstrate that oral activity in rats can be greatly altered, even when there is no change in absolute numbers of D1 and D2 receptors and no change in the ratio of D1:D2 receptors.

Formation of synaptic graft-host connections by noradrenergic locus coeruleus neurons transplanted into the adult rat hippocampus

Transplants of cell suspension obtained from the locus coeruleus region of 13- to 14-day-old rat fetuses were implanted into the hippocampal formation of intact adult rats or rats from which the noradrenergic afferents to the hippocampus had been removed by bilateral 6-hydroxydopamine (6-OHDA) injections into the dorsal tegmental noradrenergic bundle. The growth noradrenergic axons into the host hippocampus from the implant was studied at 4–8 months after surgery by immunohistochemistry using antisera raised against tyrosine hydroxylase or noradrenaline. In the animals with an intact noradrenergic system the host noradrenergic afferents were removed by bilateral dorsal bundle lesions 2 weeks before sacrifice. Fine axon-like fibers (diameter about 0.3 μm) and thick dendrite-like fibers (diameter about 1.3 μm), labeled immunohistochemically, were abundant and spread far from the graft. By electron microscopy, immunolabeled axon-like fibers formed mostly symmetrical synaptic contacts with nonlabeled spines and shafts of dendrites in the host. Labeled dendrite-like fibers of presumed graft origin penetrated deep into the host neuropil and received abundant afferents from nonlabeled axon terminals. The extent of graft-derived noradrenergic axons and the synapses established with the host hippocampal neurons were similar in the chronically denervated animals and in the animals where the intrinsic noradrenergic afferents had been left intact until 2 weeks before sacrifice. The results show that implanted embryonic noradrenergic neurons are able to innervate the hippocampus in both the presence and the absence of an intact intrinsic noradrenergic innervation and that the ingrowing axons form abundant synaptic connections with the host hippocampal neurons under both conditions. Dendritic processes from the grafted noradrenergic neurons that extend deep into the host tissue may receive a reciprocal synaptic host afferent input.

Neuronal sites mediating locomotor hyperactivity following central neurokinin agonist administration

The stable substance P analog, DiMeC7, increases spontaneous locomotor activity after infusion into the lateral ventricles or median raphe nucleus (MRN). The elevated locomotion observed after intracerebroventricular (ICV) infusion of DiMeC7 was attenuated, but not blocked, by bilateral 6-hydroxydopamine (6OHDA) lesions of the ventral tegmental area (VTA). In contrast, bilateral 6OHDA lesions of the nucleus accumbens (NAS) blocked the motor activity induced by ICV administration of DiMeC7. Similar lesions did not affect the increases in moto behavior observed after MRN infusions of DiMeC7. However, the hyperactivity following MRN microinjections of DiMeC7 was attenuated by intraperitoneal administration of the dopamine (DA) antagonist, haloperidol. The results suggest that ICV infusions of DiMeC7 increase locomotor activity by acting directly on neurones in the NAS and in part by influencing, directly or indirectly, the activity of DA cells in the VTA. The increased motor activity seen after MRN administration of DiMeC7 appears to depend on DA neurons but not on projections to the NAS.

Involvement of Dopamine Neurons in the Regulation of β‐Adrenergic Receptor Sensitivity in Rat Prefrontal Cortex

The contribution of dopamine (DA) afferents to the regulation of beta-adrenergic receptor sensitivity (isoproterenol-stimulated adenylate cyclase activity) in the rat prefrontal cortex was investigated by comparing the effects of lesions affecting either both DA and noradrenaline (NA) or NA fibers alone. Bilateral 6-hydroxydopamine (6-OHDA) lesions made in the ventral tegmental area destroyed ascending DA and to a variable extent ascending NA fibers innervating the prefrontal cortex. Two opposite effects were observed depending on the extent of cortical NA denervation: (a) When NA denervation was complete (less than 4% of controls), a marked increase in the isoproterenol-sensitive adenylate cyclase activity (+78%) was found. The amplitude of this denervation supersensitivity was similar to that occurring following complete and selective destruction of NA innervation induced by bilateral 6-OHDA injections made into the pedunculus cerebellaris superior. (b) When 6-OHDA injections into the ventral tegmental area led to a partial destruction of cortical NA afferents (10-40% of control values), a hyposensitivity of the isoproterenol-induced adenylate cyclase activity (-30%) was observed. This effect contrasted with the moderate supersensitivity seen in rats with partial, but selective, destruction of NA innervation (pedunculus cerebellaris superior lesions). The hyposensitivity of beta-adrenergic receptors obtained in rats with partial lesions of cortical NA fibers, but devoid of cortical DA innervation, suggests that DA neurons may regulate, under certain conditions, the denervation supersensitivity of beta-adrenergic receptors.

Effects of B‐HT 920 on nigrostriatal and mesolimbic dopamine systems in normosensitive and supersensitive rats

1. B-HT 920, a D2 dopamine receptor agonist, was tested for its ability to exert presynaptic actions in normosensitive rats, and for possible postsynaptic actions in rats made 'supersensitive' to apomorphine. 2. In normosensitive rats, B-HT 920 (0.01-0.3 mg kg-1, i.p.) increased dopamine concentrations and lowered metabolite levels to a similar extent in all four terminal regions examined (medial prefrontal cortex, olfactory tubercle, nucleus accumbens, caudate-putamen). Analogous effects were seen for 5-hydroxytryptamine and its metabolite 5-hydroxyindoleacetic acid. 3. Rats which received bilateral 6-hydroxydopamine (6-OHDA) infusions into the caudate-putamen showed signs of postsynaptic dopamine receptor activation (stereotyped behaviour) in response to B-HT 920 (0.1 and 1.0 mg kg-1, i.p.) and to apomorphine (0.2 mg kg-1, s.c.). Similarly, B-HT 920 (0.1 mg kg-1) induced contralateral circling in rats that had received unilateral 6-OHDA infusions into the medial forebrain bundle; the rate of circling increased gradually over several weeks. 4. In contrast, bilateral 6-OHDA infusions into the nucleus accumbens resulted in a supersensitive (locomotor stimulant) response to a low dose of apomorphine (0.1 mg kg-1, s.c.), but not to B-HT 920 (0.01 and 0.1 mg kg-1). 5. In intact rats, withdrawal of chronic haloperidol treatment induced behavioural supersensitivity to apomorphine but not to B-HT 920.

Functional recovery after destruction of dopamine systems in the nucleus accumbens of rats. I. Behavioral and biochemical studies

Bilateral 6-hydroxydopamine (6-OHDA) lesions in the nucleus accumbens of rats induced motor hypoactivity 7 days after the lesion. Spontaneous functional recovery of this impaired behavior occurred in 3–4 weeks. Behavioral and biochemical studies suggest that the hypoactivity is due to damage of the dopamine systems in the nucleus accumbens. The 6-OHDA lesions induced a decrease in the nucleus accumbens levels of dopamine and its metabolites of about 30% both 7 and 20 days after the lesion. The in vitro uptake of [ 3H]dopamine in nucleus accumbens tissue of the 6-OHDA-lesioned rats was decreased to the same extent at 7, 14 and 28 days after the lesion. Scatchard analysis of [ 3H]haloperidol binding studies in nucleus accumbens tissue revealed a shift from one type of binding site in tissue of sham-lesioned rats to two types of binding sites in tissue of 6-OHDA-lesioned rats 29 days after the lesion. This shift was not present in nucleus accumbens tissue 8 days after a 6-OHDA lesion. The spontaneously recovered rats showed an enhanced behavioral response upon administration of the dopamine agonist apomorphine. The present data suggest that the spontaneous functional recovery of impaired motor activity is caused by the development of supersensitivity of the dopamine receptor systems in the nucleus accumbens. This supersensitivity may be the result of increased affinity of one type of binding site or an increased number of functional binding sites.

Lesions of the substantia nigra retard Pavlovian eye-blink but not heart rate conditioning in the rabbit.

Bilateral radio-frequency (RF) lesions of the substantia nigra retarded Pavlovian eye-blink (EB) conditioning without affecting concurrent heart rate (HR) conditioning. Dopamine (DA) depletion occurred only in the caudate nucleus, whereas norepinephrine (NE) depletion was limited to the hypothalamus. Bilateral 6-hydroxydopamine (6-OHDA) lesions of substantia nigra retarded acquisition of both EB and HR responses. Six-OHDA lesions produced significant NE depletion in the nucleus acumbens/septi, frontal cortices, and hypothalamus, as well as DA depletion in the caudate nucleus. Trials required to reach EB conditioning criterion was significantly correlated with caudate DA levels. The magnitude of conditioned bradycardia was on the other hand significantly correlated with hypothalamic NE levels. These results suggest that interruption of the nigro-striatal dopaminergic pathway retards Pavlovian somatomotor learning without affecting concurrent autonomic learning, although the latter may depend on an intact ascending NE pathway to the hypothalamus, which passes through the tegmentum and thus is also destroyed in some cases by substantia nigra lesions.

Partial protection by desmethylimipramine of the mesocortical dopamine neurones from the neurotoxic effect of 6-hydroxydopamine injected in ventral mesencephalic tegmentum. The role of noradrenergic innervation

As shown in the rat by estimation of dopamine (DA) and noradrenaline (NA) levels, bilateral 6-hydroxydopamine (6-OHDA, 4 μg/μl) lesions made in the ventral mesencephalic tegmentum (VMT) destroy both ascending DA and NA neurones. Pretreatment of rats with desmethylimipramine (DMI, 30 mg/kg, i.p.), 30 min before microinjection of 6-OHDA into the VMT partially prevented the destruction of the DA neurones innervating the prefrontal and cingulate cortices but not those innervating subcortical structures (nucleus accumbens, olfactory tubercles, septum). Results obtained from the prefrontal cortex of rats with extensive lesions of the ascending NA neurones performed 15 days prior to the 6-OHDA lesions of the VMT in the presence of DMI, imply that NA innervation of the VMT seems to be required for DMI to protect the cortical DA neurones from the neurotoxic effect of 6-OHDA.

Differentiation of dopamine agonists using drug-induced rotation in rats with unilateral or bilateral 6-hydroxydopamine destruction of ascending dopamine pathways

Eighteen compounds with dopamine agonist properties were examined in two rat rotational models. In the classical Ungerstedt model, a unilateral 6-hydroxydopamine (6OHDA) lesion destroyed nigrostriatal and mesolimbic dopamine pathways on one side. Indirectly acting compounds, amphetamine, amantadine, methylphenidate and S1694, produced ipsiversive rotation, which was inhibited by pretreatment with α-methyl- p-tyrosine (AMPT). All other compounds produced contraversive rotation, but the rotation caused by CM 29-712, bromocriptine and ET 495 was reduced by AMPT. In animals with a bilateral 6OHDA lesion removing both dopaminergic inputs to nucleus accumbens and the dopaminergic input into one striatum, indirectly acting drugs caused ipsiversive posturing prevented by AMPT, but little rotation. All other compounds produced contraversive rotation, but the effects of CM 29-712, bromocriptine and ET 495 were reduced by AMPT pretreatment. Inhibition of monooxygenase drug metabolising activity utilising SKF-525A inhibited contraversive turning induced by bromocriptine and ET 495 in the unilateral lesion model, but had no effect on rotation caused by apomorphine or CM 29-712. We conclude that, in addition to indirect pre-synaptically acting agonists and direct post-synaptic receptor agonists, there are a small group of compounds which produce rotation associated with direct receptor activation, which is inhibited by disruption of pre-synaptic dopamine function. The mechanism of action of this latter group is not understood, but cannot be attributed solely to active metabolite formation.

Paradoxical reinforcing properties of apomorphine: Effects of nucleus accumbens and area postrema lesions

Apomorphine (0.01–10.0 mg/kg, subcutaneously) paradoxically produced both dose-dependent aversive and positive reinforcing effects, as measured in conditioned taste aversion and place preference paradigms, respectively. The conditioned taste aversions produced by apomorphine were not modified in rats with bilateral 6-hydroxydopamine (6-OHDA) lesions of the nucleus accumbens (producing 92% depletion of dopamine in the nucleus accumbens) nor in rats with thermal lesions of the area postrema. Both types of lesions were behaviorally verified as effective in other paradigms; the 6-OHDA lesions potentiated the facilitatory effects of apomorphine on locomotor activity in photocell cages, and the area postrema lesions attenuated the conditioned taste aversions to a novel flavor paired with scopolamine methylnitrate (1.0 mg/kg, intraperitoneally). However, 6-OHDA lesions of the nucleus accumbens did clearly potentiate the conditioned place preferences induced by apomorphine. These results suggest that both the positive reinforcing and locomotor effects of apomorphine may partially result from activation of post-synaptic dopamine receptors in the nucleus accumbens. Moreover, the dissociation of apomorphine's aversive and positive reinforcing properties revealed by the 6-OHDA lesions may provide the first step in attempts to pinpoint the different brain sites of action where apomorphine produces its opposite motivational effects.

Apomorphine-induced facilitation of intracranial self-stimulation following dopamine denervation of the nucleus accumbens

Two groups of rats were trained to lever press for intracranial self-stimulation (ICSS) from electrodes aimed at the posterior lateral hypothalamus or at the region of the locus coeruleus. Following stabilization of baseline responding using descending rate/intensity functionsm,bilateral 6-hydroxydopamine (6-OHDA) lesions to the nucleus accumbens (N.Acc.) were performed. Subsequent injections of apomorphine (SC) resulted in significant increases in self-stimulation in both lesion groups and significant decreases in self-stimulation in both groups of sham operated animals. These results indicate that the destruction of the dopaminergic terminals in the nucleus accumbens results in a “supersensitive” enhancement of the ICSS stimulating properties of apomorphine regardless of the electrode placement. Both lesion groups also showed a pronounced increase in locomotor activity in photocell cages following treatment with the same dose of apomorphine. These results complement previous work showing that dopamine destruction affects ICSS regardless of electrode placement and support the hypothesis that the midbrain dopamine systems have a general response enabling role in reinforced behavior.