Changes In Dopamine Receptor Sensitivity Research Articles

Levodopa-Induced Response Fluctuations in Patients with Parkinson???s Disease

Fluctuations in response to levodopa in patients in the advanced stages of idiopathic Parkinson's disease occur frequently and are a difficult problem to treat. Patients who are treated with levodopa have an additional 10% risk of experiencing response fluctuations with each year of treatment: 50% of patients have this problem after 5 years of receiving levodopa therapy and almost 100% of patients after 10 years. The mechanisms by which response fluctuations occur are only partially understood and can be divided into three main types: (i) presynaptic neuronal degeneration leading to a lack of buffering of released levodopa, which is mainly related to wearing-off phenomena; (ii) postsynaptic changes in dopamine receptor sensitivity and number, partially caused by the presynaptic changes, which are clinically related to at-random response fluctuations; and (iii) pharmacokinetic and pharmacodynamic influences of exogenously administered dopaminergic agents. Several oral and parenteral treatment strategies are recommended to manage response fluctuations, such as optimisation of dopamine receptor agonist therapy in combination with a reduction of the levodopa load; use of slow-release levodopa formulations; use of catechol-O-methyltransferase inhibitors; an increase of levodopa dose frequency; use of high-dose amantadine; and intermittent or continuous use of apomorphine and/or levodopa. Continuous stimulation of dopamine receptors with dopaminergic agents is one of the crucial basic steps in the treatment of patients at an advanced stage of Parkinson's disease, and the preferential use of dopamine receptor agonists has proven to be successful in the prevention and treatment of response fluctuations.

Sensitization of amphetamine-induced stereotyped behaviors during the acute response: role of D 1 and D 2 dopamine receptors

During the response to an injection of amphetamine, rapid changes occur in the ability of the drug to induce stereotyped behaviors. This enhanced responsivity does not involve changes in the caudate–putamen or nucleus accumbens extracellular dopamine response, but appears to require activation of dopamine receptors. In the present studies we examined the role that D 1 and D 2 dopamine receptors might play in the development and expression of the enhanced stereotypy response. In one series of experiments we used the dopamine agonists, SKF 82958 and quinpirole as relatively selective probes at D 1 and D 2 dopamine receptors, respectively, to test for changes in dopamine receptor sensitivity following a pretreatment (`priming') with 4.0 mg/kg amphetamine. Doses of both SKF 82958 and quinpirole which were sub-threshold to induce perseverative behaviors in control animals, promoted stereotyped behaviors in amphetamine-primed animals, suggesting an enhanced sensitivity of both D 1 and D 2 receptors. In a second series of experiments, we sought to determine whether priming with these relatively selective dopamine receptor agonists, as well as the mixed D 1/D 2 agonist, apomorphine, would result in an enhanced stereotypy response to the subsequent administration of non-stereotypy producing doses of amphetamine (0.5–1.5 mg/kg). Priming with the dopamine receptor agonists each resulted in an enhanced amphetamine-induced stereotypy response. These results indicate that both D 1 and D 2 dopamine receptors contribute to both the development and the expression of the altered stereotypy responsivity, though several dose- and time-related observations suggest that other mechanisms likely contribute as well. Because these changes are apparent during the amphetamine response, they may have important implications for the evolving behavioral alterations which result when stimulants are administered in a binge pattern of drug abuse.

Increased dopamine receptor sensitivity in the rat following acute administration of sufentanil, U50,488H and d-Ala2-d-Leu5-enkephalin

The effects of acutely administered opioid receptor agonists sufentanil, U50,488H and [D-Ala2,D-Leu5]-enkephalin (DADL) were observed upon dopamine D1 and D2 binding site density in the striatum of the rat. In addition, the functional implications of opioid-induced changes in dopamine receptor sensitivity were studied using the behavioural profile elicited by apomorphine in the rat. The mu-agonist sufentanil (1 or 20 micrograms/kg, i.p.), the kappa-agonist U50,488H (10 mg/kg, i.p.) and DADL (1 microgram/animal, i.c.v.) all significantly elevated D2 but not D1 binding site density in rat striatum. Pretreatment with sufentanil (1 microgram/kg, i.p.) induced an elevation in apomorphine-induced stereotyped behaviour, but attenuated locomotor activity. Following administration of U50,488H (10 mg/kg, i.p.), both the degree of stereotypy and the intensity of the locomotor activity were enhanced. Contralateral rotation was observed in animals pretreated with DADL (1 microgram/animal, i.c.v.) following challenge with apomorphine. It is concluded that the opioid agonists studied induce a significant elevation in functional D2 sites to the exclusion of D1 sites. However, the precise mechanism by which this effect is elicited remains to be established.

Effects of hemivibrissotomy in the rat: Time-dependent asymmetries in turning and biogenic amines induced by apomorphine

Behavioral and neurochemical changes accompanying unilateral removal of vibrissae were investigated in the rat. Rats were tested either 4 hours or 10 days after hemivibrissotomy. A systemic injection of apomorphine (0.5 mg/kg) induced turning behavior towards the intact vibrissae side in rats tested 4 hours after hemivibrissotomy. Compared to these animals, apomorphine induced more turning towards the side of vibrassae removal and less turning towards the intact side in animals tested 10 days after vibrissae removal. This reversal is suggestive of time-dependent changes in dopamine receptor sensitivity. Analysis of biogenic amines (dopamine, norepinephrine, serotonin) in the hemispheres ipsi- and contralateral to the side of vibrissae removal revealed evidence for neurochemical changes in apomorphine- and amphetamine-treated rats. Lateralized and bilateral differences were found in the neostriatum, septum and ventral mesencephalon, which were dependent on the side and duration of hemivibrissotomy. These results are discussed with respect to the behavioral and neural analogy between hemivibrissotomy and unilateral 6-hydroxydopamine lesions of the nigrostriatal system.

Selective involvement of dopamine in the nucleus accumbens in the feeding response elicited by muscimol injection in the nucleus raphe dorsalis of sated rats

Muscimol injection (100 ng) in the nucleus raphe dorsalis (NRD) caused intense eating in non-food-deprived rats. At a dose (10 μg) blocking dopamine mediated responses (examined by increased locomotion or stereotypy caused by systemically injected d-amphetamine), fluphenazine injected in the n. accumbens, but not in the striatum, significantly reduced the eating response elicited by muscimol in the NRD while food intake of deprived rats was not significantly modified by fluphenazine injected in either area. Fluphenazine (20 μg) in the striatum reduced eating in both conditions, but the animals showed marked sedation which obviously interfered with the feeding response. Dopamine release and synthesis, measured respectively by 3-methoxytryramine and accumulation of dihydroxyphenylalanine after aromatic amino acid decarboxylase inhibition, were significantly reduced in the n. accumbens, but not in the striatum, of muscimol treated animals. The metabolism of serotonin was reduced in both areas of muscimol treated rats. It is suggested that changes in dopamine receptor sensitivity, together with changes in serotonin function, might be involved in the feeding response caused by muscimol injection in the NRD.

Changes in dopamine receptor sensitivity in humans after heavy alcohol intake.

Dopamine (DA) sensitivity, assessed through maximal growth hormone (GH) response to stimulation by apomorphine (APO) (0.18-0.24 mg iv) was studied in 16 chronic alcoholics newly admitted after a period of heavy alcohol intake. Repeated hormonal tests were thereafter performed during a 2-month period under strictly controlled conditions to avoid relapse into alcohol consumption. Eight healthy volunteers with alcohol consumption slightly less than that of the general population were used as controls. It was found that DA sensitivity in the early abstinence phase was higher than later in the 2-month recovery period but not significantly different from control values. The relatively higher DA sensitivity in the early abstinence phase might be responsible for a lower threshold for psychotic symptoms and neuroleptic-induced extrapyramidal side effects. The results of this study give further evidence of a prolonged recovery phase after heavy alcohol intake.

Striatal dopamine metabolism in response to apomorphine: the effects of repeated amphetamine pretreatment

The dose-dependent decrease in striatal dopamine (DA) metabolites following apomorphine (APO) administration was utilized as an index of changes in DA receptor sensitivity following the repeated administration of amphetamine (AMPH). The results suggest that: (a) repeated AMPH pretreatment does not alter DA autoreceptor sensitivity; and (b) interpretations of the decline in striatal DA metabolites at high doses of APO (> 50 μg/kg), in terms of activation of postsynaptic DA receptors, may require re-evaluation.

Apomorphine-induced stereotypic cage climbing in mice as a model for studying changes in dopamine receptor sensitivity

We have previously confirmed in mice that apomorphine (APO) induces dopamine specific stereotypic cage climbing. Apparent changes in dopamine receptor sensitivity induced by chronic drug administration appear to be measurable by this technique. In the present experiments, murine stereotypic cage climbing was evaluated as a model system for assessing the dopamine receptor supersensitivity induced by chronic administration of the potent butyrophenone neuroleptic spiroperidol. Spiroperidol induced a significantly enhanced response induced by APO (about a 7-fold increase) manifest by 48 hr (but not 24 hr) following cessation of the last chronic injection. Time-response analyses demonstrated that the action of test doses of APO (1.0 or 4.5 mg/kg, IP) was significantly prolonged in the chronic-spiroperidol animals relative to controls. The supersensitivity in the spiroperidol-treated animals lasted more than three weeks for each dose of the neuroleptic and the APO dose-response curve was shifted to the left in spiroperidol-treated animals. Results are discussed in terms of the utility of the model for establishing dose-response, time-course, and duration of effect data within the same group of animals.

Blockage of narcotic-induced dopamine receptor supersensitivity by cyclo(Leu-Gly).

We have previously reported that the administration of cyclo(Leu-Gly) to mice prior to morphinization blocked the development of tolerance to the analgesic effects of morphine as well as the development of some signs of physical dependence. In the present series of experiments, the effect of the same peptide treatment on changes in dopamine receptor sensitivity induced by chronic morphine treatment were determined. Changes in dopamine receptor sensitivity were determined by measuring (i) the effect of the dopamine agonist apomorphine on locomotor activity and (ii) the hypothermic response to another dopamine agonist, piribedil. Mice that had received the chronic morphine treatment were found to require significantly less apomorphine to produce an increase in locomotor activity, and they exhibited a significantly greater hypothermic response to piribedil than did morphine-naive mice. The injection of 0.2 mumol of cyclo(Leu-Gly) per mouse 2 hr prio to morphine treatment prevented this increased response to both dopamine agonists. Administration of the peptide after the tolerance and dependence had developed did not alter morphine tolerant and dependent states states or the enhanced response to apomorphine or piribedil. It is concluded that dopamine receptor supersensitivity may be involved in the development of narcotic tolerance and physical dependence.

The effect of chronic administration and withdrawal of amphetamine on cerebral dopamine receptor sensitivity

Mice with a 6-hydroxydopamine induced unilateral nigro-striatal lesion received (+)-amphetamine sulphate (2.5-20 mg/kg) over a 3-month period by daily incorporation into the drinking water. Druing this period the circling response to apomorphine hydrochloride (0.01-0.5 mg/kg, s.c.) was increasingly suppressed in comparison to control animals, while spontaneous locomotor activity increased. Following drug withdrawal the circling response to apomorphine remained suppressed two months later. However, spontaneous locomotor activity was also reduced up to 1 month following drug removal. The dopamine content of the lesioned side of the forebrain was 25% of the intact side in control animals and was not further reduced by amphetamine administration. The dopamine content of the intact forebrain was reduced by 43% during amphetamine administration and remained 18% depressed 1 month following drug withdrawal. No changes in 5-hydroxytryptamine or noradrenaline concentrations were observed in either the intact or lesioned side. This data, while showing that chronic amphetamine treatment can induce persistent changes in dopamine receptor sensitivity, can be interpreted in terms of increased striatal receptor sensitivity or as a decreased response of dopamine receptors in the nucleus accumbens.