Differential modulation of the D1-like- and D2-like dopamine receptor-induced locomotor responses by group II metabotropic glutamate receptors in the rat nucleus accumbens.

There is strong evidence for the existence of functional interactions between metabotropic glutamate receptors and dopamine transmission in the nucleus accumbens. In the present study, we investigated the interactions between group II mGlu receptors and D1-like- and D2-like receptors in the rat nucleus accumbens. Administration of the selective group II metabotropic glutamate receptor agonist APDC, which had no effect when injected alone, potentiated the locomotor response produced by the selective D1-like receptor agonist SKF 38393 but had no effect on those induced by the selective D2-like receptor agonist quinpirole (also known as LY 171555)--a compound believed to act only at D2-like presynaptic receptors when injected alone--or co-administration of SKF 38393+quinpirole--a pharmacological condition thought to stimulate both D1-like receptors and presynaptic and postsynaptic D2-like receptors. In contrast, the selective group II mGlu receptor antagonist LY 341495, which induced an increase in basal locomotor activity, showed no effect on the SKF 38393-induced locomotor response, but abolished that produced by quinpirole or SKF 38393+quinpirole. The present findings demonstrate that stimulation of group II mGlu receptors has a cooperative and potentiating action on the locomotor response induced by D1-like receptor activation, whereas blockade of group II mGlu receptors has an antagonist action on the locomotor responses induced by activation of D2-like receptors. Although these data are consistent from a pharmacological point of view, as the effects of the group II mGlu receptor antagonist LY 341495 were blocked by the group II mGlu receptor agonist APDC and conversely, the subtle neurochemical crosstalks underlying such a differential effect of group II mGlu receptors on D1-like- and D2-like DA receptors remain to be elucidated.     

Striatal and nucleus accumbens D1/D2 dopamine receptors in neuroleptic catalepsy

Haloperidol (2.5-10 micrograms) injected bilaterally into the ventro-rostral striatum or into the nucleus accumbens induced dose-dependent catalepsy whereas its injection into the dorso-rostral striatum (2.5 micrograms) was ineffective. Similarly, the specific antagonist of D1 receptors, SCH 23390 (1-5 micrograms), injected into the ventro-rostral striatum or nucleus accumbens, as well as the specific antagonist of D2 receptors, sulpiride, injected into the ventro-rostral striatum (0.02-15 micrograms) or nucleus accumbens (1-15 micrograms), induced a dose-dependent catalepsy. Both drugs (SCH 23390 2 micrograms, sulpiride 0.5 micrograms) were ineffective when injected into the dorso-rostral striatum. Doses of sulpiride about 100 times lower than those injected into the nucleus accumbens were sufficient to evoke an equipotent catalepsy when injected into the ventro-rostral striatum. However, similar doses of haloperidol and SCH 23390, injected into the ventro-rostral striatum and nucleus accumbens, evoked a similar catalepsy. It is concluded that (1) the catalepsy induced by systemic administration of haloperidol seems to result from the action of this drug on both the ventro-rostral striatum and the nucleus accumbens, (2) both D1 and D2 dopamine receptors in the ventro-rostral striatum are involved in the cataleptogenic action of neuroleptics, and (3) in the nucleus accumbens, only D1 dopamine receptors seem to play an important role in this phenomenon.     

Interaction between accumbens D1 and D2 receptors regulating rat locomotor activity

The effect of intra-accumbens injections of various dopaminergic agonists and antagonists on the rat locomotor activity has been evaluated in automated open fields. Locomotor stimulation has been observed after local administration ofd-amphetamine (10 g), apomorphine (10 g), as well as of solution containing the D₁ agonist SKF 38 393 and D₂ receptor agonist LY 171 555 (quinpirole) in doses (10 and 4 g, respectively) which were inactive when both drugs were administered separately. On the other hand separate injections of metoclopramide (0.1 g) and SCH 23 390 (0.5 g) (D₂ and D₁ receptor antagonists) very potently inhibited animals' locomotor activity. The data indicate that concomitant stimulation of both accumbens D₁- and D₂-receptor related mechanisms is a necessary condition to increase rat motility. Moreover, it seems that accumbens D₁ receptors may be differently involved in the control of facilitatory versus inhibitory motor processes.     

Group II, but not group I, metabotropic glutamate receptors in the rat nucleus accumbens contribute to amphetamine-induced locomotion

Recently, it was reported that blocking metabotropic glutamate receptors (mGluRs) in the rat nucleus accumbens (NAcc) prevents the generation of locomotion by amphetamine (AMPH) in this site. In these studies, the non-selective group I/group II mGluR antagonist (R,S)-alpha-methyl-4-carboxyphenylglycine [(R,S)-MCPG] was used. The present study used more selective receptor antagonists to examine the specific contribution of group I and group II mGluRs to this effect. When co-injected bilaterally with AMPH into the NAcc, the group II selective mGluR antagonist (2S)-alpha-ethylglutamic acid [EGLU; 0.5-5.0 nmole/side] dose-dependently blocked the locomotion and rearing produced by AMPH. Equimolar concentrations of the group I selective antagonist (R,S)-1-aminoindan-1,5-dicarboxylic acid [AIDA; 0.5-5.0 nmole/side] were without effect. As previously reported for (R,S)-MCPG, neither of these receptor antagonists produced locomotor effects when injected alone in these concentrations into the NAcc. These results suggest that group II, but not group I, mGluRs in the rat NAcc contribute importantly to the ability of AMPH to produce locomotor activation.     

Regulation of CART mRNA in the rat nucleus accumbens via D3 dopamine receptors

A variety of studies indicate that CART in the nucleus accumbens (NAcc) is involved in the action of psychostimulants. In order to understand in more detail if and how dopamine is involved in the regulation of CART mRNA in the NAcc, the present studies of individual receptors were performed. The D1 agonist, dihydrexidine, and the D1 antagonist, SCH23,390, were administered separately and in combination to adult male rats; however, no changes were found in CART mRNA as measured by in situ hybridization. The D2/3 agonist, quinpirole, was administered either separately or in combination with the D2 selective antagonist, L741,626, or the D3 selective antagonist, GR103,691. Quinpirole produced a decrease in CART mRNA of up to 43%. This effect was blocked by pretreatment with the D3 antagonist GR103, 691, but not by the D2 antagonist, L741,626. CART peptide levels showed a similar decrement after acute quinpirole. CART mRNA levels in the NAcc of D3 mutant mice were found to be higher than that in wild-type animals, but treating the mutants with quinpirole failed to produce a decrease in CART expression like that observed in wild-type rodents. These findings demonstrate that CART is regulated by dopamine in the NAcc, at least partly by D3 dopamine receptors.     

Electroconvulsive shock increases dopamine D1 and D2 receptor mRNA in the nucleus accumbens of the rat

The present study examined the effects of acute and repeated administration of electroconvulsive shock (ECS) on levels of D₁ and D₂ receptor mRNAs in the nucleus accumbens and striatum (caudate-putamen) of the rat. Quantitative in situ hybridisation with³⁵S-labelled oligonucleotide probes specific for D₁ and D₂ receptor mRNAs was utilised. Compared to controls, rats receiving a single ECS showed higher levels of both D₁ and D₂ receptor mRNAs in the nucleus accumbens 4 h, but not 24 h, after treatment. Similarly, rats receiving ECS repeatedly (five ECS in 10 days) also exhibited higher levels of D₁ and D₂ receptor mRNAs in the nucleus accumbens 4 h, but not 24 h, after the last treatment. The effects of single and repeated ECS treatment on dopamine receptor mRNA levels were localised to the caudal region of the nucleus accumbens. No statistically significant changes in mRNA levels were detected in the striatum of rats treated with either acute or repeated ECS. We discuss the possibility that increased expression of D₁ and D₂ receptors in the nucleus accumbens may be involved in the dopamine-enhancing properties of ECS detected in behavioural studies.     

Discriminative stimulus properties of cocaine: modulation by dopamine D1 receptors in the nucleus accumbens

Dopamine (DA) D₁ and D₂ receptors are involved in mediating the behavioral effects of cocaine, including its discriminative stimulus properties. The purpose of the present study was to investigate the role of the nucleus accumbens and, in particular, accum bens DA D₁ receptors in modulating the stimulus effects of cocaine. Thus, rats were trained to discriminate cocaine (10 mg/kg, IP) from saline using a two-lever, water-reinforced FR 20 drug discrimination task. In substitution tests, systemic (IP) administration of cocaine (0.625–20 mg/kg) produced a dose-related increase in cocaine-appropriate responding. Microinjections of cocaine (2.5–40 µg) into the nucleus accumbens also engendered dose-dependent and complete substitutions (> 80% drug-lever responding) for the systemic training dose of cocaine, whereas intra-accumbens artificial cerebrospinal fluid (1 µl/side) produced primarily saline-appropriate responding. In antagonism tests, pretreatment with the DA D₁ antagonist SCH 23390 (3–12 µg/kg) completely antagonized (<20% drug-lever responding) a dose of cocaine (5 mg/kg) that produced greater than 90% cocaine-lever responding when given alone. Additionally, intra-accumbens injections of SCH 23390 (0.025–0.4 µg) prior to systemic cocaine (5 mg/kg) also significantly blocked the cocaine stimulus. The present results confirm the importance of the nucleus accumbens in mediating the discriminative stimulus properties of cocaine and suggest a primary role of accumbens DA D₁ receptors in modulating this behavior.Some of these data were presented at the annual FASEB Experimental Biology meeting in New Orleans (1993)     

Role of nucleus accumbens dopamine D1 and D2 receptors in instrumental and Pavlovian paradigms of conditioned reward

RATIONALE: This study investigated the role of nucleus accumbens dopamine D1 and D2 receptors in two different paradigms of conditioned reward. OBJECTIVE: We addressed the question whether accumbal dopamine is important for the motor or for the motivational components of reward. METHODS: We compared the effects of intra-accumbal infusion of the dopamine D1 receptor antagonist SCH23390 (0.3, 1.0, 3.0 microg) and the D2 receptor antagonist sulpiride (0.3, 1.0, 3.0 microg) on conditioned lever pressing for food, with the effects on the inhibition of the startle response by a conditioned reward signal. RESULTS: Both the D1 and the D2 antagonist dose-dependently attenuated conditioned lever pressing for reward under a fixed-ratio of responding and increased the consumption of freely available lab chow. However, the preference for freely available pellets, and the attenuation of the startle response in the presence of a conditioned stimulus predicting reward were not impaired by blockade of accumbal dopamine receptors. CONCLUSIONS: Our data support the idea that dopamine in the nucleus accumbens is necessary for instrumental response selection in the context of reward rather than for the mere motor performance of behavior or for the evaluation of the hedonic properties of rewarding stimuli.     

Psychomotor-activating effects mediated by dopamine D(2) and D(3) receptors in the nucleus accumbens

The contribution made by specific dopamine receptor subtypes to the induction of motor behaviors has not been firmly established. Here, we first characterized the behavioral effects induced by a D(2)-class receptor agonist, bromocriptine, following injections into the nucleus accumbens (Acb). Bromocriptine showed an atypical D(2)-class receptor agonist profile, having no observable effect on a range of motor behaviors. However, when coadministered with the D(1)-class receptor agonist SKF 38393, bromocriptine showed a typical D(2)-class receptor agonist profile, enhancing locomotor activity and suppressing spontaneous yawning. We then administered the dopamine receptor antagonists L-741626 and nafadotride, which possess relative selectivity for D(2) and D(3) receptors, respectively, prior to injections of dopamine agonists into the Acb. Nafadotride significantly reduced the locomotor-enhancing effects elicited by the coadministration of SKF 38393 and the D(2)-class receptor agonist (+)-PD 128907 into the Acb, and also attenuated the effects induced by the combination of SKF 38393 and bromocriptine, although not significantly so. L-741626 mildly attenuated the locomotor effects elicited by both drug combinations. Taken together, these results suggest that both D(2) and D(3) receptors in the Acb contribute to the expression of heightened psychomotor activation.     

Dopamine D1 receptors and group I metabotropic glutamate receptors contribute to the induction of long-term potentiation in the nucleus accumbens

Long-term changes in the efficacy of glutamatergic synaptic transmission in the striatal complex are proposed to underlie motor learning and neuroadaptations leading to addiction. Dopamine and glutamate play key roles in the induction of long-term potentiation (LTP) and long-term depression (LTD) in the dorsal striatum, but their contribution to synaptic plasticity in the ventral striatum (nucleus accumbens, NAc) has been less extensively studied. We have examined the role of dopamine, glutamate and GABA in the induction of LTP in mouse brain slices containing the NAc. High-frequency stimulation of glutamatergic inputs elicited LTP of field excitatory postsynaptic potentials/population spikes (fEPSP/PSs) in the core region of the NAc. GABA did not seem to participate in LTP induction because LTP was not altered in the presence of either a GABA(A)- (bicuculline) or a GABA(B)- (CGP 55845) receptor antagonist. However, the dopamine D1 receptor antagonist SCH 23390, but not the dopamine D2 receptor antagonist sulpiride, impaired LTP. The dopamine reuptake blocker nomifensine also inhibited LTP induction. We found that group I metabotropic glutamate receptors (mGluRs) contribute to LTP induction because the mGluR1 antagonist LY 367385, or the mGluR5 antagonist MPEP, blocked LTP induction. Furthermore, the glutamate reuptake blocker DL-TBOA also impaired LTP. The present results demonstrate that dopamine and glutamate play critical roles in the mechanisms of induction of LTP in the NAc through the activation of dopamine D1 receptors and group I mGluRs. However, LTP is negatively regulated when endogenous levels of dopamine or glutamate are elevated.     

Modulation of the locomotor responses induced by D1-like and D2-like dopamine receptor agonists and D-amphetamine by NMDA and non-NMDA glutamate receptor agonists and antagonists in the core of the rat nucleus accumbens

Dopamine and glutamate interactions in the nucleus accumbens (NAcc) play a crucial role in both the development of a motor response suitable for the environment and in the mechanisms underlying the motor-activating properties of psychostimulant drugs such as amphetamine. We investigated the effects of the infusion in the NAcc of NMDA and non-NMDA receptor agonists and antagonists on the locomotor responses induced by the selective D(1)-like receptor agonist SKF 38393, the selective D(2)-like receptor agonist quinpirole, alone or in combination, and D-amphetamine. Infusion of either the NMDA receptor agonist NMDA, the NMDA receptor antagonist D-AP5, the non-NMDA receptor antagonist CNQX, or the non-NMDA receptor agonist AMPA resulted in an increase in basal motor activity. Conversely, all of these ionotropic glutamate (iGlu) receptor ligands reduced the increase in locomotor activity induced by focal infusion of D-amphetamine. Interactions with dopamine receptor activation were not so clear: (i). infusion of NMDA and D-AP5 respectively enhanced and reduced the increase in locomotor activity induced by the infusion of the D(1)-like receptor agonist of SKF 38393, while AMPA or CNQX decreased it; (ii). infusion of NMDA, D-AP5, and CNQX reduced the increase in locomotor activity induced by co-injection of SKF 38393+quinpirole--a pharmacological condition thought to activate both D(1)-like and D(2)-like presynaptic and postsynaptic receptors, while infusion of AMPA potentiated it; (iii). infusion of either NMDA, D-AP5 or CNQX, but not of AMPA, potentiated the decrease in motor activity induced by the D(2)-like receptor agonist quinpirole, a compound believed to act only at presynaptic D(2)-like receptors when injected by itself. Our results show that NMDA receptors have an agonist action with D(1)-like receptors and an antagonist action with D(2)-like receptors, while non-NMDA receptors have the opposite action. This is discussed from a anatamo-functional point of view.     

Effect of antidepressant drugs on dopamine D1 and D2 receptor expression and dopamine release in the nucleus accumbens of the rat

This study examined the effect of repeated treatment with the antidepressant drugs, fluoxetine, desipramine and tranylcypromine, on dopamine receptor expression (mRNA and binding site density) in sub-regions of the nucleus accumbens and striatum of the rat. The effect of these treatments on extracellular levels of dopamine in the nucleus accumbens was also measured. Experiments using in situ hybridisation showed that the antidepressants caused a region-specific increase in D₂ mRNA, this effect being most prominent in the nucleus accumbens shell. In contrast, none of the treatments increased D₁ mRNA in any of the regions examined. Measurement of D₂-like binding by receptor autoradiography, using the ligand [³H]YM-09151-2, revealed that both fluoxetine and desipramine increased D₂-like binding in the nucleus accumbens shell; fluoxetine had a similar effect in the nucleus accumbens core. Tranylcypromine, however, had no effect on D₂-like binding in the nucleus accumbens but decreased binding in the striatum. In microdialysis experiments, our data showed that levels of extracellular dopamine in the nucleus accumbens were not altered in rats treated with either fluoxetine or desipramine, but increased by tranylcypromine. From our findings, we propose that the antidepressant drugs tested enhance dopamine function in the nucleus accumbens through either increased expression of postsynaptic D₂ receptors (fluoxetine and desipramine) or increased dopamine release (tranylcypromine). Received: 5 January 1998/Final version: 6 April 1998     

Acetylcholine release in rat nucleus accumbens is regulated through dopamine D2-receptors

Summary Experiments in slices of rat nucleus accumbens were carried out in order to investigate whether the release of acetylcholine in this tissue is modulated through dopamine receptors. The slices were preincubated with ³H-choline and then superfused and stimulated electrically twice for 2 min each at a frequency of 3 Hz.The electrically evoked overflow of tritium averaged 2.9–3.9% of the tritium content of the tissue in the various groups. The D₂-selective agonist quinpirole (0.01–1 mol/l) reduced the evoked overflow of tritium by maximally 56%, an effect antagonized by the D₂-selective antagonist (–)-sulpiride (1 mol/l). The D₁-selective agonist 2,3,4,5-tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine (SKF 38393) caused a slight decrease only at the high concentration of 10 mol/l. (–)-Sulpiride (0.1–10 mol/l) moderately increased the evoked overflow of tritium when given alone. The dopamine uptake inhibitor nomifensine (10 mol/l) caused a decrease, and in its presence the increase produced by (–)-sulpiride became much more marked, amounting to maximally 149%. (+)-Sulpiride (0.1–1 mol/l) failed to change the evoked overflow of tritium in the presence of nomifensine. The dopamine-releasing agent (±)-amphetamine (1 mol/l) also reduced the evoked overflow, an effect abolished by (–)-sulpiride. Finally, bretylium (1 mmol/l), which blocks the release of dopamine, increased the evoked overflow. (–)-Sulpiride (1 mol/l) lost its facilitatory effect in slices treated with bretylium.We conclude that the release of acetylcholine in rat nucleus accumbens, like its release in the nucleus caudatusputamen, is modulated through dopamine D₂-receptors. The receptors are activated by endogenous dopamine under the conditions of these experiments. Send offprint requests to K. Starke at the above address     

Transient depletion of nucleus accumbens dopamine content may contribute to initial akinesia induced by MPTP in common marmosets

Acute treatment of common marmosets with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) caused an initial profound akinesia and other motor deficits. However, over the following months akinesia gradually disappeared although the animals remained clumsy and poorly coordinated. At 10 days following MPTP treatment there was a profound decrease in the dopamine, HVA and DOPAC content of the caudate nucleus, putamen and nucleus accumbens. By 3-4 months following MPTP treatment the animals had largely recovered from their akinesia, but the caudate nucleus and putamen dopamine, HVA and DOPAC content remained low. In contrast, the dopamine content of the nucleus accumbens had returned towards normal and the metabolite levels were higher than at 10 days. No overall alterations in 5HT or 5HIAA levels were observed at either time point. The transient and reversible nature of dopamine loss in the nucleus accumbens may contribute to the initial profound akinesia exhibited by common marmosets treated with MPTP. The restoration of dopamine levels in the nucleus accumbens may be partially responsible for the subsequent recovery of motor function that occurs in MPTP-treated marmosets.     

Cooperation between D1- and D2-dopamine receptors in the nucleus accumbens.

Apomorphine, used in small doses (20-50 micrograms/kg), induced an increase in the activity of an endogenous inhibitor of cAMP dependent protein kinases (Walsh inhibitor, type I inhibitor) in nucleus accumbens of the rat. The action of apomorphine was blocked by sulpiride and aminophylline and enhanced by SCH-23390. Pretreatment with 6-OH-dopamine resulted in a shift of the dose-response curve for apomorphine to the left, suggesting supersensitivity of D2 receptors. Moreover, stimulation of D2 receptors induced a decrease in phosphorylation of DARPP-32, a specific protein, located in neurones containing D1 receptors. Large doses of apomorphine (over 0.5 mg/kg) provoked a decrease in type I inhibitor activity, blocked by SCH-23390 and enhanced by sulpiride and aminophylline. Moreover, SCH-23390 blocked a decrease in type I inhibitor activity induced by large doses of sulpiride and sulpiride blocked an increase in type I inhibitor activity produced by large doses of SCH-23390. The results suggest that D1 and D2 receptors in the nucleus accumbens could cooperate with the same adenylate cyclase and could be located on the same neurones.     

Ontogeny of locomotor activity and grooming in the young rat: role of dopamine D1 and D2 receptors

Locomotor activity and grooming were assessed in 11- and 17-day-old rat pups after treatment with selective dopamine (DA) D-1 and D-2 agonists (SKF 38393 and quinpirole, respectively) and antagonists (SCH 23390 and sulpiride, respectively). Quinpirole enhanced the locomotor activity of both the 11- and 17-day-olds, effects antagonized by either SCH 23390 or sulpiride. Drug-induced increases in grooming were apparent only after high doses (30.0 mg/kg i.p.) of SKF 38393 (11- and 17-day-olds) or when SKF 38393 (15.0 mg/kg i.p.) was given in conjunction with sulpiride (11-day-olds). In general, these results suggest that challenge with selective DA agonists and antagonists induces patterns of responding which are similar to those typically observed in adult rats. Moreover, these results indicate that rat pups, like adults, require a functioning DA D-1 receptor system for the expression of DA D-2-mediated activity.     

Drug-induced modulation of locomotor hyperactivity induced by picrotoxin in nucleus accumbens

Locomotor hyperactivity was induced in rats by bilateral injection of picrotoxin (PIC) into the nucleus accumbens (NAC) followed by intraperitoneal (IP) or intra-accumbens (IA) injection of agents affecting dopamine (DA), acetylcholine, serotonin, or GABA receptors. IP injection of haloperidol and diazepam attenuated PIC-induced hypermotility in a dose-dependent manner. Low (sedative) doses of the DA agonists apomorphine (APO) and lisuride, or pretreatment with reserpine abolished PIC-induced hypermotility. Independent of a preceding IA injection of PIC, higher IP doses of APO produced the well-known locomotor effect. LSD, and the atypical neuroleptic, sulpiride, potentiated PIC-induced hypermotility strongly whereas clozapine was ineffective. IA injection of carbachol or haloperidol, in doses which antagonized hypermotility induced by APO IP, did not influence PIC-induced hypermotility. The atypical neuroleptics, clozapine and sulpiride, and the benzodiazepine, diazepam, inhibited PIC-induced hypermotility. The results suggest that there is a complex involvement of GABA, DA and serotonin functions in the effectuation of PIC-induced hypermotility and that PIC-induced hypermotility may be affected by DA-sensitive structures situated outside the NAC.     

ERbeta mediates the estradiol increase of D2 receptors in rat striatum and nucleus accumbens

Estradiol was previously reported to increase striatal D(2) receptor density. The following experiments investigated the contribution of each estrogen receptor in estradiol modulation of D(2) receptors. Ovariectomized Sprague-Dawley rats were treated for 2 weeks with an agonist for ERalpha, 4,4',4'-(4-propyl-[1H]-pyrazole-1,3,5-triyl)trisphenol (PPT), an agonist for ERbeta, 2,3-bis(4-hydroxyphenyl)-propionitrile (DPN) and compared to estradiol treatment. Ovariectomy decreased D(2) agonist and antagonist striatal binding sites, specific binding was measured using [(3)H]quinpirole and [(3)H]spiperone. Estradiol prevented this decrease, while DPN but not PPT mimicked the estradiol increase of D(2) receptor specific binding. In the nucleus accumbens, ovariectomy decreased [(3)H]quinpirole specific binding in the core and left the shell unchanged. Similarly, estradiol and DPN but not PPT prevented this decrease. Neither ovariectomy nor treatments affected [(3)H]spiperone specific binding in this area. In the olfactory tubercle, neither ovariectomy nor treatments changed D(2) receptor binding. Finally, both ovariectomy and treatments did not affect D(2L), D(2S) mRNA and D(2L)/D(2S) ratios measured by semi-quantitative RT-PCR. The present results show, for the first time, that an ERbeta agonist treatment modulates D(2) receptors and suggest that ERbeta is involved in the estradiol modulation of D(2) receptors.     

Lithium and bupropion antagonise the phasic changes in locomotor activity caused by dopamine infused into the rat nucleus accumbens

Dopamine infused persistently (25 g/24 h for 13 days) into the nucleus accumbens of rat brain caused phasic increases in spontaneous locomotor activity during the period of infusion. This phasic responding was prevented by lithium administered throughout the infusion period in divided doses (3×daily administrations of 2.5 mg/kg IP) or as a continuous IP infusion (7.5 mg/kg/24 h), and by bupropion treatment (5–20 mg/kg 3 × daily). In contrast, imipramine, amitriptyline and nomifensine failed to prevent the phasic locomotor response to dopamine at doses which did not by themselves cause marked motor changes. Locomotor activity was measured using individual photocell cages, and rats preselected to (–)NPA were those initially showing a modest locomotor activity. Fourteen to twenty-eight days after discontinuing the dopamine infusion rats showed increased responsiveness to (–)NPA which persisted throughout the remainder of the 70-day withdrawal period. This long-term change was prevented when lithium was given continuously throughout the period of dopamine infusion, but not when lithium was given in divided doses, showing the importance of the mode of drug delivery. The long-term change caused by the dopamine infusion could also be prevented by bupropion but not by imipramine, amitriptyline or nomifensine to show again that the actions of classical antidepressant drugs may be differentiated from those of lithium and bupropion. Therefore, it is suggested that the model of phasic hyperactivity described may provide a means for more closely analysing, both behaviourally and biochemically, the site and mechanism of action of lithium (and bupropion) in the control of the short- and long-term consequences of an enhanced mesolimbic dopamine activity. Offprint requests: B. Costall