6-Hydroxydopamine lesions of the nucleus accumbens,but not of the caudate nucleus,attenuate enhanced responding with reward-related stimuli produced by intra-accumbens d-amphetamine

Intra-accumbens d-amphetamine enhances responding for reward-related stimuli (conditioned reinforcers, CRs), whereas intra-caudate d-amphetamine has only weak and variable effects (Taylor and Robbins 1984). The present experiment further examined the involvement of the nucleus accumbens and the role of dopamine (DA) in this effect. Thirsty rats were trained to associate a flash of a light and movement of a dipper (CR) with water. After implantation of permanent guide cannulae aimed at the nucleus accumbens, they were assigned to one of four groups, receiving either bilateral 6-OHDA (4 mg/ml free base in 2 1 0.1% ascorbic acid/0.9% saline) or sham (vehicle) infusions into the nucleus accumbens or the caudate nucleus. In the test phase, two novel levers were available. Responding on one lever (CR lever) produced the light and dipper stimuli without water presentation, whereas responding on the other (NCR lever) had no effect. All four groups received four counterbalanced intra-accumbens infusions of d-amphetamine (3, 10, 20 g/2 l) or vehicle. On the 5th test day, subjects were pretreated subcutaneously with apomorphine (0.1 mg/kg). Intra-accumbens d-amphetamine in both sham-lesioned groups produced a dose-dependent increase in responding on the CR lever, but no significant change on the NCR lever. No selective increases in responding on either lever were found in animals with 6-OHDA-induced depletion of DA (>80%) in the nucleus accumbens following intra-accumbens d-amphetamine; however, in subjects with DA depletion of the posterior caudate nucleus (>80%), increases in responding on the CR lever were observed to be similar in magnitude to those of both the sham-lesioned groups. Following systemic administration of apomorphine, only rats in the nucleus-accumbens-lesioned group continued to respond, preferring the CR lever, thus suggesting the involvement of DA receptors in these effects. These results indicate that enhanced responding for CR following administration of psychomotor stimulant drugs is critically dependent on dopaminergic activation of the nucleus accumbens, rather than the caudate nucleus.     

Injection of 5-HT into the nucleus accumbens reduces the effects ofd-amphetamine on responding for conditioned reward

Injection ofd-amphetamine into the nucleus accumbens potentiates responding for stimuli paired with a primary reward. A previous study showed that this potentiating effect ofd-amphetamine on responding for conditioned reward (CR) was attenuated by peripherally injectedd-fenfluramine, a 5-hydroxytryptamine (5-HT) releaser and re-uptake inhibitor. The present experiments further examined the effects of manipulating 5-HT function within the nucleus accumbens on responding for CR, and on the potentiation of CR responding following intra-accumbens injection ofd-amphetamine. Water deprived rats were trained to associate a compound stimulus with water delivery during a conditioning phase. During a test phase water was not delivered, but the compound stimulus was delivered according to a random ratio 2 schedule following a response on one of two levers. Rats responded at a higher rate on the lever delivering this CR.d-Amphetamine (10 g) injected into the nucleus accumbens enhanced responding on the CR lever. Co-injections of 5-HT (5 and 10 g) into the nucleus accumbens abolished the response-potentiating effect ofd-amphetamine but were without effect on the base-line level of responding for CR. This reduction by 5-HT of the response potentiating effect ofd-amphetamine was prevented by prior treatment with the 5-HT receptor antagonist metergoline (1 mg/kg). Responding for water was not altered by 5-HT and so the effects of 5-HT on responding for CR cannot be due to a change in the motivation to seek the primary reward. Thus, elevating 5-HT activity within the nucleus accumbens antagonises the effects ofd-amphetamine on responding for CR within the nucleus accumbens. These results suggest that 5-HT within the nucleus accumbens may play an important role in mediating incentive motivation by modulating dopaminergic neurotransmission.     

The transport of (+)-amphetamine by the neuronal noradrenaline carrier

Summary PC-12 cells (a clonal line of rat phaeochromocytoma cells) take up noradrenaline by a transport system which is identical with the neuronal amine transport system (uptake₁). The uptake of ³H-noradrenaline into reserpine-pretreated PC-12 cells (monoamine oxidase inhibited) was saturable (K_m=0.6±0.1 mol/l), dependent on sodium and chloride, and competitively inhibited by (+)-amphetamine (K_i=0.18±0.04 mol/l), cocaine (K_i=0.55±0.15 mol/l) and desipramine (K_i=4.3±0.6 nmol/l). The uptake and accumulation of ³H (+)-amphetamine showed characteristics comparable to those of ³H-noradrenaline, since the uptake of ³H (+)-amphetamine (0.1 mol/l) was reduced by omission of sodium or chloride from the incubation medium. The sodium-sensitive component of uptake and accumulation of ³H (+)-amphetamine was fully inhibited by cocaine and desipramine. The IC₅₀ of desipramine for inhibition of the sodium-sensitive component of the 1-min uptake of ³H (+)-amphetamine (20 nmol/l) was about 2 nmol/l, i.e., identical with the K_i for inhibition of uptake of ³H-noradrenaline. At concentrations above 1 mol/l, desipramine additionally caused an inhibition of the sodium-independent permeation of ³H (+)-amphetamine into PC-12 cells.Hence, by using a homogeneous population of cells endowed with uptake₁, it is possible to demonstrate — besides a pronounced lipophilic entry — a carrier-mediated uptake of ³H (+)-amphetamine.Some of the results were communicated to the German Pharmacological Society (Bönisch 1981). This study was supported by the Deutsche Forschungsgemeinschaft (Bo 521)     

Mesoaccumbens dopamine-opiate interactions in the control over behaviour by a conditioned reinforcer

These experiments examined the role of dopamine-opiate interactions in the ventral tegmental area (VTA) and nucleus accumbens in the mediation of reinforcement-related behaviour. It has been shown previously that opiates induce a dopamine-dependent increase in locomotor activity in rats when infused into the VTA, and a dopamine-independent hyperactivity when infused into the nucleus accumbens. The present study investigated the generality and significance of these two findings, by examining dopamine-opiate interactions in the control over behaviour exerted by a conditioned reinforcer (CR), an arbitrary stimulus which gains control by association with primary reinforcement. Rats were trained to associate a light/noise stimulus with sucrose reinforcement, and the efficacy of the CR in controlling behaviour was assessed by measuring its ability to support a new lever pressing response. Responding on one lever (CR lever) produced the CR, responding on the other lever had no programmed consequences. In experiment 1, intra-accumbens infusions ofd-amphetamine (10 µg), the D₁ dopamine receptor agonist SKF-38393 (0.1 µg), the D₂ dopamine receptor agonist LY-171555 (quinpirole; 0.1 µg) or the opiate receptor agonist [d-Ala²]-methionine enkephalinamide (DALA; 1 µg) selectively increased responding on the CR lever. Infusion with DALA intra-VTA had no effect. However, pretreatment with DALA intra-VTA (10 × 1 µg/day) subsequently reduced the selectivity of the response to infusions intra-accumbens withd-amphetamine or SKF-38393, and blocked the response to LY-171555 or DALA. Pretreatment also shifted to the right the dose-response function for DALA intra-accumbens. In experiment 2, intra-accumbens infusions ofd-amphetamine, SKF-38393, LY-171555 or DALA again increased responding on the CR lever only. Pretreatment with intra-accumbensd-amphetamine (5 × 1 µg/day) reduced the selectivity of the response subsequently tod-amphetamine, and blocked the response to SKF-38393, LY-171555 or DALA. In experiment 3, intra-accumbens infusions of the -opiate receptor agonist [d-Ala²,N-Me-Phe⁴,Gly⁵-ol]-enkephalin (0.003–0.1 µg), or the -opiate receptor agonist [d-Pen^2, 5]-enkephalin (0.03–1 µg) enhanced selectively responding on the CR lever. Thus, the dopamine-dependent locomotor-stimulant properties of intra-VTA infusions of opiates are associated with impaired conditioned reinforcer efficacy. Finally, repeated stimulation of the mesoaccumbens dopamine pathway may compromise the dopamine-independence of the opiate system within the nucleus accumbens.     

The effect of amantadine and (+)-amphetamine on motility in rats after inhibition of monoamine synthesis and storage

The effect of amantadine and (+)-amphetamine on motility was investigated by subcutaneous administration to rats. Amantadine 50 and 100 mg/kg induced a moderate increase of motility. (+)-amphetamine 1, 2.5 and 5 mg/kg showed a more potent locomotor stimulant effect. A stereotyped licking was found during the hypermotility induced by (+)-amphetamine 5 mg/kg.Pretreatment with the catecholamine synthesis inhibitor -methyl-p-tyrosine inhibited the effect of (+)-amphetamine but not that of amantadine. Reserpine potentiated the effects of both amantadine and (+)-amphetamine. Tetrabenazine antagonized the hyperactivity produced by (+)-amphetamine but potentiated amantadine induced hyperactivity. The locomotor stimulant effect of amantadine seems to differ in certain respects from that of amphetamine.     

The effects of apomorphine, (+)-amphetamine and L-dopa on maximal electroshock convulsions--a comparative study in the rat and mouse

The anticonvulsant activity of apomorphine, (+)-amphetamine and pargyline + l -dopa was examined in the rat and mouse. Whereas all three treatments produced anticonvulsant effects in the rat, only (+)-amphetamine and l -dopa were anticonvulsant in the mouse. It is suggested that enhanced dopamine-like activity is responsible for the anticonvulsant activity of these three drugs in the rat. The anticonvulsant activity of (+)-amphetamine and l -dopa in the mouse may be unrelated to their pharmacological activity on dopaminergic neurons.     

Bilateral intra-accumbens self-administration ofd-amphetamine: Antagonism with intra-accumbens SCH-23390 and sulpiride

The efficacy ofd-amphetamine to support a selective bilateral intra-accumbens self-administration response was examined. Bilateral intra-accumbens infusions ofd-amphetamine were made contingent upon the acquisition of a lever-pressing response. Two identical levers were available within the operant chamber. Depression of the drug lever resulted in the intra-accumbens delivery of 1 µgd-amphetamine; responses upon the second, control lever were recorded but had no programmed consequences. Animals were not primed with non-contingent infusions ofd-amphetamine at any time during these experiments. Nonetheless, animals readily acquired a selective response upon the drug lever. Removal of thed-amphetamine moiety from the infusate resulted in a large decline in responding, and the abolition of the selectivity of the response for the drug lever. Adulteration of the infusate with either the D₁ dopamine receptor antagonist SCH-23390 or the D₂ dopamine receptor antagonist sulpiride enhanced the rate of response selectively upon the drug lever. Reductions in the dose ofd-amphetamine also increased the rate of response. The effect of co-adulteration of the infusate with both SCH-23390 and sulpiride together was purely additive. The implications of these data for the methodology of intracranial drug self-administration, and the relationship between D₁ and D₂ dopamine receptors within the nucleus accumbens are discussed.     

Amphetamine-type reinforcement by dopaminergic agonists in the rat

Intravenous self-administration of d-amphetamine (0.25 mg/kg/injection) decreased in a dose-related fashion after injections of the dopaminergic agonists apomorphine and piribedil. The dopaminergic agonists appear to suppress amphetamine intake in the same way as do free amphetamine injections, by extending drug satiation in a given interresponse period. Clonidine, an alpha noradrenergic agonist, did not have similar effects. Apomorphine and piribedil did not increase ¹⁴C-amphetamine levels in rat brains, nor did they retard disappearance of ¹⁴C-amphetamine; thus their amphetamine-like effects are not due to alterations of amphetamine metabolism. Rats responding for amphetamine continued to respond for apomorphine or piribedil when the latter drugs were substituted for the former. Rats experienced in amphetamine self-administration readily initiated and maintained responding for apomorphine and piribedil. The dopaminergic blocker (+)-butaclamol disrupted responding for apomorphine and piribedil, although it produced no marked increase in responding for the dopaminergic agonists, as it does for amphetamine. These data add to the evidence that actions in the dopaminergic synapse account for amphetamine's reinforcing properties.     

Inhibition of d-amphetamine-induced locomotor activity by injection of haloperidol into the nucleus accumbens of the rat

The effect of intracerebral administration of antagonists of dopamine and noradrenaline upon the locomotor stimulation induced by intraperitoneal injection of d-amphetamine sulfate in rats was investigated. Injection of low doses of the dopamine antagonist haloperidol (2.5 g and 5 g) bilaterally into the nucleus accumbens antagonized the locomotor stimulation following d-amphetamine. No significant inhibition was observed following administration of the alpha-adrenergic antagonist phentolamine or the beta-adrenergic antagonist propranolol into the nucleus accumbens. Injection of the same doses of haloperidol into the caudate nucleus did not inhibit the d-amphetamine induced locomotor activity, in contrast to the effects seen following injection into the nucleus accumbens.The results confirm the significance of dopaminergic mechanisms for the locomotor stimulant effect of d-amphetamine and indicate that the mesolimbic dopamine system plays an important role in this respect.     

d-Amphetamine and punished responding: The role of catecholamines and anorexia

Rats were trained to press a lever for food on a schedule in which components of variable interval reinforcement (VI2) alternated with conflict components in which every response resulted in food delivery and footshock. Low doses of d-amphetamine selectively suppressed responding in the confliet component in a dose-dependent manner, whereas prefeeding suppressed responding in both components. Pretreatment with noradrenergic blocking agents (propranolol, phentolamine and phenoxybenzamine) did not diminish the suppressant effect of d-amphetamine, but this effect was reduced by pretreatment with alpha-methyl-para-tyrosine methylester and dopamine blockers (spiroperidol, haloperidol and clozapine) indicating that d-amphetamine was exerting its selective suppressant effect via the release of dopamine. It is suggested that the effects of low doses d-amphetamine on behaviour in conflict situations may provide a useful model for investigating the mode of action of neuroleptic drugs.     

Amphetamine induced release of endogenous dopamine in vitro is not reduced following pretreatment with reserpine

Summary The release of endogenous dopamine evoked by electrical stimulation or by exposure to (+)-amphetamine (10 M) was determined in superfused striatal slices of the rat.The spontaneous and the electrically-evoked release of dopamine were significantly increased in the presence of nomifensine (10 M). After reserpine pretreatment (5 mg/kg, s.c., 24 h), the striatal dopamine content was reduced by about 90%. Exposure to 10 M (+)-amphetamine during 2 min released similar amounts of dopamine from striatal slices of untreated or reserpine pretreated rats. Similar results were obtained when monoamine oxidase activity was inhibited in vivo with pargyline.Pretreatment with reserpine does not modify the (+)-amphetamine-induced release of dopamine, in spite of the marked reduction of the striatal dopamine content. These results provide direct evidence for the view that (+)-amphetamine releases dopamine from a special, reserpine-resistant pool of newly synthetized transmitter.Some of the results described in this publication have been presented at the British Pharmacological Society Meeting (Arbilla et al. 1984a)     

Biochemical and behavioural effects of tyrosine hydroxylase inhibition

Summary Selective depletion of the brain catecholamines (CA) was induced in cat and rat by administration of 3, -dimethyl tyrosine methylester-HCl (H 59/64), a specific inhibitor of tyrosine hydroxylase. A concomitant decrease of conditioned avoidance responses (CAR) was observed. The observations give additional support to the view that the brain CA play a role in the maintenance of CAR. The functional significance of the CA synthesis inhibition was further demonstrated in reserpine pretreated cats. In these animals the CAR was restored by (+)-amphetamine but the behavioural restoration failed to appear after the combined reserpine and H 59/64 pretreatment. A small subthreshold dose of l-DOPA given after (+)-amphetamine, restored the activity of amphetamine.     

Behavioural effects of the α2-adrenoceptor antagonists idazoxan and yohimbine in rats: comparisons with amphetamine

Although yohimbine has long been known to increase arousal, reactivity and anxiety in animals and humans, little is known about the behavioural effects of more selective ₂-adrenoceptor antagonists such as idazoxan. In a recent experiment, however, it was found that in rats both yohimbine and idazoxan increased low rates of lever pressing, an effect also produced by amphetamine. The purpose of the present study was to investigate further the effects of yohimbine and idazoxan in comparison with those of d-amphetamine on the operant behaviour of rats. In rats trained to press a lever on a FI 60s schedule to obtain food both yohimbine and idazoxan increased response rates, although the effect of yohimbine was considerably greater than that of idazoxan. Lower doses of d-amphetamine had no consistent effect on overall rates of responding whereas a higher dose suppressed responding. Characteristically, d-amphetamine increased responding during early portions of the intervals and decreased responding during the final portions. Idazoxan and yohimbine tended to increase responding throughout the intervals except immediately after reinforcement. When idazoxan was administered in combination with prazosin FI response rates were markedly decreased. Administration of DSP4 did not alter the response rate-increasing effects of either yohimbine or idazoxan. In rats trained to discriminate d-amphetamine from saline both idazoxan and yohimbine gave rise to responding on the saline associated lever. Combination of idazoxan with d-amphetamine did not antagonise the amphetamine cue but produced substantial reductions in response rates, probably due to toxicity. These results confirm previous findings that both idazoxan and yohimbine have behavioural stimulant effects but do not clarify the mechanisms involved. It is clear, however, that the behavioural actions of these ₂-adrenoceptor antagonists have little in common with those of the psychomotor stimulant amphetamine.     

Isolation rearing impairs the reinforcing efficacy of intravenous cocaine or intra-accumbensd-amphetamine: impaired response to intra-accumbens D1 and D2/D3 dopamine receptor antagonists

Male Lister hooded rats were raised from weaning either alone (isolation reared) or in groups of five (socially reared controls). At 5 months of age, bilateral guide cannulae were implanted within the nucleus accumbens, and experiments began. The effect of isolation rearing upon the reinforcing efficacy of the intravenous self-administration of cocaine (experiment 1), or the bilateral intra-accumbens self-administration ofd-amphetamine (experiment 2) was assessed. Self-administration was made contingent upon the acquisition of a novel lever-pressing response. Two identical levers were available within each operant chamber. Responding on one lever resulted in the delivery of drug (experiment 1: cocaine, 1.5 mg/kg per infusion; experiment 2:d-amphetamine, 0.25 µg/side), responding on the second, control lever was recorded but had no programmed consequences. Animals were not primed with noncontingent infusions at any time. For experiment 1, animals received intra-accumbens infusions of the D1 dopamine receptor antagonist SCH-23390, or the D2 dopamine receptor antagonist sulpiride over two test sessions. Within each session, animals received a cumulative series of doses of each dopamine receptor antagonist. A validation group received doses of each antagonist according to more conventional methods (one dose per session). In either case, intra-accumbens infusions of SCH-23390 or sulpiride enhanced the rate of the self-administration of cocaine in socially reared controls. However, isolation rearing impaired this response to intra-accumbens infusions of the dopamine receptor antagonists. Experiment 2a examined the acquisition of the intra-accumbens self-administration ofd-amphetamine. Socially reared controls acquired readily a selective response upon the drug lever. However, isolation reared animals acquired a selective response at a greatly retarded rate. In experiment 2b, a fulld-amphetamine dose-response function was examined. Isolation rearing impaired the response to a range of doses ofd-amphetamine. In experiment 2c, the infusate (1 µgd-amphetamine per infusion) was adulterated with either SCH-23390 or sulpiride. Adulteration with either dopamine receptor antagonist enhanced the rate of response by socially reared controls. Isolation rearing impaired this response to SCH-23390, and blocked the response to sulpiride. These data are discussed in relation to the functioning of cortico-limbicstriatal systems, with particular reference to the mesoaccumbens dopamine projection.     

Effect of nicotine pretreatment on striatal dopaminergic system in rats

Rats were pretreated with saline or nicotine (1.5 mg/kg/day) by subcutaneously implanting each animal with an Alzet osmotic minipump for 1 or 14 days. Short-term (1-day) administration of nicotine to rats reduced the stimulatory effect of (+)-amphetamine on locomotor activity. This was correlated with an attenuation in the ability of (+)-amphetamine to stimulate [3H]dopamine formation from [3H]tyrosine in rat striatal slices of these nicotine-treated animals. In long-term (14-day) nicotine-pretreated animals, both the apomorphine- and (+)-amphetamine-induced locomotor activity were potentiated. This behavioral potentiation was associated with an increase in the total number of postsynaptic dopaminergic receptor binding sites in the striatum. The development of striatal dopamine receptor supersensitivity may be caused by a decrease in the rate of dopamine turnover in the striatum.     

Enhanced behavioural control by conditioned reinforcers following microinjections of d-amphetamine into the nucleus accumbens

Stimulant drugs have been shown to enhance the control over behaviour exerted by stimuli previously correlated with primary reinforcers, termed conditioned reinforcers (CR). Experiment 1 examined the possible neuroanatomical specificity of the enhancement of conditioned reinforcement following intracerebral injections ofd-amphetamine. Thirsty rats were trained to associate, a light with water. In the test phase, water was no longer presented but the light (CR) was intermittently produced by responding on one of two novel levers. Rats with bilateral guide cannulae aimed at the nucleus accumbens, posterior caudate nucleus, or medio-dorsal nucleus of the thalamus received four counterbalanced microinfusions ofd-amphetamine (10, 20, 30 g/2 l) or vehicle (control) over 4 test days. There was a dose-dependent selective increase in responding on the lever that produced the light (CR) with intra-accumbensd-amphetamine infusions. Quantitatively similar, but much more variable effects were found with intra-caudate infusions and no effects following intra-thalamicd-amphetamine. Experiment 2 provided evidence that the enhanced control over responding by a CR with intra-accumbensd-amphetamine is behaviourally specific. Three groups of rats received a compound tone — plus —light stimulus that was positively, negatively or randomly correlated with water during training. Intra-accumbensd-amphetamine produced selective increases in responding only if the contingent stimulus had been positively correlated. The results suggest that the nucleus accumbens may play an important role ind-amphetamine's enhanced control over behaviour exerted by conditioned reinforcers.     

Effects of intra-amygdala R(+) 7-OH-DPAT on intra-accumbens d-amphetamine-associated learning II. Instrumental conditioning

Rats were trained to associate an initially neutral conditioned stimulus (CS) with a response-independent, intra-accumbens infusion of d-amphetamine (the unconditioned stimulus; US). Elsewhere, we have reported that as a result of this training, presentations of the CS alone elicited a conditioned response consisting of increased locomotor activity and that acquisition of this conditioned response was enhanced by post-session, intra-amygdala infusion of the dopamine D₃ receptor preferring agonist, R(+) 7-OH-DPAT. Here, in this same group of animals, we have examined the conditioned rewarding properties of the drug-associated CS by determining its ability to support the acquisition of a novel instrumental response in the absence of drug reward. Thus, rats were presented with two novel levers. Presentation of the drug-associated CS was made contingent upon depression of one of the levers (CR lever), while responding upon the other lever (NCR lever) had no programmed consequences. Preferential responding upon the lever delivering the drug-associated CS was observed despite a 6-week interval between CS-US training and the conditioned reward test. Intra-accumbens administration of d-amphetamine (0–20?μg) increased the control over behaviour exerted by the CS, increasing CR, but not NCR lever responding. In contrast, rats that received three pairings of an intra-accumbens infusion of d-amphetamine in combination with intra-amygdala infusion of R(+) 7-OH-DPAT, 3 weeks prior to testing, displayed similar rates of response upon both levers and were insensitive to the potentiation of responding for conditioned reward following intra-accumbens d-amphetamine. However, intra-accumbens d-amphetamine stimulated locomotor activity in a similar, dose-related manner in both groups. In this way, rats that had received intra-accumbens infusion of d-amphetamine in combination with intra-amygdala infusion of R(+) 7-OH-DPAT appeared exactly like control group rats, for which the CS had been paired with intra-accumbens d-amphetamine on a negative basis only. A locomotor activity test indicated that one behavioural consequence of intra-amygdala administration of R(+) 7-OH-DPAT was the reduction of the unconditioned locomotor response resulting from intra-accumbens administration of d-amphetamine. Hence, the present data demonstrate that the conditioned rewarding properties of a drug-associated CS are specific to the CS-US association and are relatively insensitive to decay over time. However, the rewarding properties of a drug-associated CS were selectively abolished following activation of amygdala D₃ receptors during presentation of the drug reward. Potential explanations for this effect are discussed, including the possibility that intra-amygdala R(+) 7-OH-DPAT reduced the incentive value of the US.     

Studies in mice on the antagonism of (+)-amphetamine anorexia by alpha-methyl-p-tyrosine methyl ester HCl.

Experiments were carried out in mice to investigate the individual roles of dopamine and noradrenaline in both the production of (+)-amphetamine anorexia and in its antagonism by α-methyl-p-tyrosine methyl ester HCl. The anorexia resulting from (+)-amphetamine pretreatment (2 mg/kg, s.c.) was potentiated by intracerebroventricular injection of dopamine (8 μg) and noradrenaline (8 μg). Neither catecholamine, however, produced any anorectic effects when given alone at these dose levels. The anorexia produced by (+)-amphetamine was antagonised by α-methyl-p-tyrosine methyl ester HC1 (40–160 mg/kg, i.p.) and the submaximal antagonism at 80 mg/kg α-methyl-p-tyrosine was reversed by l-DOPA (40 and 80 mg/kg, i.p.) and by intracerebroventricular dopamine (4 and 8 μg). Noradrenaline, in intracerebroventricular doses of up to 8 μg, failed to produce this reversal. These results indicate that, although a role for both dopamine and noradrenaline may be implicated in the production of (+)-amphetamine anorexia and in its antagonism by α-methyl-p-tyrosme, the noradrenergic component is dependent upon a fully functional dopaminergic system.     

Long-term l-Dopa pretreatment of mice: Central receptor subsensitivity or supersensitivity?

The effect of d-amphetamine added to the drinking water on the rate of conditioned lever pressing by rats was determined using fixed-ratio 30 (FR-30) and fixed-interval 2-min (FI-2) schedules of food presentation. After 32 days of gradual increase in drug concentration the average drug ingestion was 13 mg/kg/day. In tests with various doses of d-amphetamine injected before and after the chronic ingestion regimen, the rate-decreasing effects of d-amphetamine on FR responding were attenuated after chronic treatment, indicating development of a two- to three-fold tolerance. However, the rate-decreasing effect of d-amphetamine on FI responding was not altered by chronic ingestion. Since acute amphetamine treatment reduced the reinforcement frequency under the FR but not the FI schedule, these results are consistent with the hypothesis that a behavioral tolerance will develop most readily to drug effects that decrease the frequency of reinforcement. Upon removal of d-amphetamine from the drinking water there was some increase in the rate of FR responding, but no change in FI responding.     

The effect of quetiapine (Seroquel™) on conditioned place preference and elevated plus maze tests in rats when administered alone and in combination with (+)-amphetamine

Rationale

Recent case reports describe recreational use of quetiapine and drug-seeking behaviour to obtain quetiapine, an atypical antipsychotic.

Objective

We examined the hypothesis that quetiapine (10, 20 or 40 mg/kg) alone or co-administered with (+)-amphetamine (0.25, 0.5, 0.75 or 2.0 mg/kg) will affect reward and/or decrease anxiety in rats, as measured by conditioned place preference (CPP) and elevated plus maze (EPM) test, respectively.

Results

Quetiapine (20 mg/kg) produced greater open arm time and entries in the EPM test compared to 10 and 40 mg/kg, and quetiapine (10 mg/kg) significantly increased open arm entries and time when co-administered with (+)-amphetamine (0.5 mg/kg) compared to (+)-amphetamine (0.5 mg/kg) alone, suggesting decreased anxiety. Quetiapine (10, 20 or 40 mg/kg) produced no CPP when administered alone; the lowest dose of quetiapine (10 mg/kg) reduced CPP produced by a low dose of (+)-amphetamine (0.25 mg/kg), but had no significant effect on CPP produced by a higher dose (0.5 mg/kg).

Discussion

The quetiapine-induced anxiolytic effect in the EPM might explain why humans are misusing quetiapine and combining it with (+)-amphetamine. It is possible that humans experience an anxiolytic effect of the combined drugs and relatively unaltered rewarding effects of (+)-amphetamine. The results shed some light on the question of why humans are abusing and misusing quetiapine, despite its dopamine (DA) D₂ receptor antagonism; it will be the task of future studies to identify the pharmacological mechanism mediating this behaviour.