Infusion Of D-amphetamine Research Articles

Priming threshold: a novel quantitative measure of the reinstatement of cocaine self-administration

The intravenous injection of cocaine has been reported to reliably reinstate (prime) the self-administration of cocaine in animals. We report herein that there is a cocaine priming threshold in rats trained to self-administer cocaine. The cocaine priming threshold is defined as the minimum level of cocaine in the body that will reinstate maintained cocaine self-administration. The mean cocaine priming threshold in rats was calculated to be approximately 186 to 212 μg kg −1. Therefore, any injection, series of injections or continuous infusion that result in a level of cocaine equivalent to that produced by a single intravenous injection of this range of doses, will reinstate cocaine self-administration. The priming threshold was significantly increased by the D 1 dopamine receptor antagonist SCH23390 (10 μg kg −1, i.v.), indicating a role for dopaminergic neurotransmission. The priming threshold, but not the inter-injection interval of maintained self-administration, was increased following withdrawal from a 7-day infusion of d-amphetamine. In addition, there was no correlation between the cocaine priming threshold and the inter-injection intervals of maintained cocaine self-administration. Therefore, the mechanisms underlying the reinstatement of cocaine self-administration are distinct from the mechanisms underlying the maintenance of cocaine self-administration and they are differentially regulated. It is possible that the priming threshold may represent a distinct target for medications development.

Dopamine Fluctuations in the Nucleus Accumbens during Maintenance, Extinction, and Reinstatement of Intravenous d-Amphetamine Self-Administration

Moment-to-moment fluctuations of nucleus accumbens dopamine (DA) were determined in rats self-administering or passively receiving "yoked" intravenous infusions of D-amphetamine. The initial lever presses of each session caused elevations in DA concentration, usually to an initial peak that was not maintained throughout the rest of the session. As the initial ("loading") injections were metabolized, DA levels dropped toward baseline but were sustained at elevated plateaus by subsequent lever pressing that was spaced throughout the remainder of the 3 hr sessions. During this period, DA levels fluctuated phasically, time-locked to the cycle of periodic lever pressing. Consistent with the known pharmacological actions and dynamics of amphetamine, peak DA elevations were seen approximately 10-15 min after each injection, and the mean DA level was at a low point in the phasic cycle at the time of each new lever press. During extinction periods when saline was substituted for amphetamine, DA levels dropped steadily toward baseline levels despite a dramatic increase in (now-unrewarded) lever pressing. Noncontingent injections during extinction reinstated lever-pressing behavior and increased nucleus accumbens DA concentrations. These data are consistent with the hypothesis that under the conditions of this experiment-during periods of amphetamine intoxication in well-trained animals-the timing of amphetamine self-administration comes primarily under the control of extracellular DA concentrations. The probability of lever pressing during the maintenance phase is highest when DA concentrations fall near a characteristic trigger point, a trigger point that is significantly elevated above baseline, and falls as DA concentrations fall below or increase above that trigger point.

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 microg) 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.

Striatal dopamine-glutamate interactions reflected in substantia nigra reticulata firing.

To gain insight into the role of striatal dopamine in basal ganglia functioning, dopaminergic drugs alone and in combination with the glutamate receptor agonist kainic acid were infused in the lateral striatum via a microdialysis probe, while single-unit recordings of substantia nigra reticulata neurons were made in chloral hydrate-anaesthetized rats. Striatal infusion of dopaminergic drugs did not significantly affect the firing rate of substantia nigra reticulata neurons, which was related to the low activity of striatal cells under basal conditions, illustrated by the lack of effect of striatal infusion of TTX on substantia nigra reticulata activity. Under glutamate-stimulated conditions, striatal infusion of d-amphetamine potentiated the inhibition of substantia nigra reticulata neurons induced by striatal kainic acid. Thus, under stimulated but not basal conditions, the modulatory role of dopamine in the striatum could be demonstrated. Dopamine potentiated the inhibitory effect of striatal kainic acid on the firing rate of the basal ganglia output neurons.

Amphetamine-induced neurochemical and locomotor responses are expressed differentially across the anteroposterior axis of the core and shell subterritories of the nucleus accumbens.

The administration of psychostimulants increases dopamine (DA) release within the nucleus accumbens (NAC), a terminal projection site of mesolimbic DA neurons, originating in the ventral tegmental area (VTA). Recent evidence demonstrates that two subdivisions of the NAC, the dorsolateral core and the ventromedial shell, can be distinguished by morphological and immunohistochemical differences, as well as by their distinct anatomical connections. It has been suggested that these two subregions subserve different functions that are related to goal-directed behaviors, stimulus-reward associations, and reinforcement induced by addictive drugs. The shell region, in particular, modulates inputs from the limbic system, whereas the core is preferentially innervated by nuclei that process motor information. In the present study, we sought to investigate if (1) the direct infusion of d-amphetamine (AMPH) by reverse microdialysis into either the core or shell of the NAC across its anteroposterior axis differentially affects dialysate DA and 5-HT levels, and (2) these subterritories also subserve different behavioral functions. Following the determination of basal DA and 5-HT levels, four increasing concentrations of AMPH (0.05, 0.10, 0.50, 1.00 microM) were substituted for the dialysis perfusate for 60 min each. Movement units were detected by an infrared sensor and were transmitted through a motion interface to an activity monitor analyzer. AMPH produced a dose-dependent increase in locomotor activity after microinfusion into either the rostral shell, caudal shell or core of the NAC. The potency of the AMPH-induced locomotor activating effect was significantly higher in the rostral shell of the NAC compared with the caudal shell and the core. The lowest concentrations of AMPH (0.05, 0.1 microM) produced an equipotent decrease in dialysate DA in either the rostral shell, caudal shell, or core. At 1.0 microM, however, AMPH selectively increased DA in the rostral shell, whereas DA reached baseline values both in the caudal shell and core. Basal dialysate DA levels were significantly higher in the core relative to both the rostral and caudal parts of the shell. The highest dose of AMPH significantly increased dialysate 5-HT levels over baseline only in the caudal shell of the NAC. The basal dialysate 5-HT levels did not significantly differ between the three subterritories of the NAC. These results emphasize the heterogeneity and functional compartmentalization within the NAC, the differential regulation of neurochemical and motor responses across the anteroposterior axis of the NAC, and the preferential effect of AMPH in the rostral shell subterritory of the NAC.

Neuroethological assessment of amphetamine-induced behavioral changes and their reversal by neuroleptics: Focus on the amygdala and nucleus accumbens

1. 1. An ethological approach was combined with intracerebral infusions of amphetamine to broaden understanding of how this drug acts on mesolimbic neuronal systems to alter behavior. 2. 2. Rats, tested in sets of three, were allowed to interact with each other or with various novel objects in an open-field arena. Specific behavioral responses were assessed and grouped into several broad categories: motivation (movement directed toward novel objects), social (movement involving contact with other rats), and motor (movement without obvious direction toward environmental stimuli) as well as no movement (quiet rest). 3. 3. Infusion of d-amphetamine (10 μg/μl) into either the amygdala or nucleus accumbens elevated motor behavior relative to control rats in the set, but only amygdaloid infusions also increased the motivation score. Intra-amygdaloid clozapine or haloperidol blocked the increase in this score, but only clozapine also blocked the motor effects of intra-amygdaloid amphetamine. 4. 4. Although neither neuroleptic in the accumbens blocked the amphetamine-induced increase in the motor category, both clozapine and haloperidol lowered the motivation score below the amphetamine level. 5. 5. The results suggest a role for the amygdala in the motivational component of amphetamine-induced behavioral effects. Both neuroleptics, moreover, appear to reverse this component perhaps by acting via either amygdaloid or accumbal mechanisms. Although follow-up studies are warranted, a neuroethological approach is likely to shed new light on the neuronal systems underlying the complex behavioral changes induced by amphetamine and related stimulants.

A Comparison of the Effects of Risperidone, Raclopride, and Ritanserin on Intravenous Self-Administration of d-Amphetamine

These experiments were conducted to examine the effects of simultaneous blockade of dopamine D 2 and 5-hydroxytryptamine 2 (5-HT) receptor function on responding for intravenous infusions of d-amphetamine. Rats were trained to self-administer d-amphetamine intravenously according to a progressive ratio schedule of reinforcement, in which response requirements increased for successive infusions until responding extinguished. In the first experiment it was shown that increases in the unit infusion dose of d-amphetamine resulted in an increase in the number of amphetamine infusions earned. Thus, the strength of responding for d-amphetamine was linked to the dose of drug received. The mixed D 2 and 5-HT 2 receptor antagonist risperidone (0.1, 0.2, and 0.4 mg/kg) reduced responding for d-amphetamine (60 μg/kg infusion). The selective D 2 antagonist raclopride (0.1, 0.2, and 0.4 mg/kg) also reduced responding for d-amphetamine. In contrast, the selective 5-HT 2 antagonist ritanserin (0.63, 1.25, and 2.5 mg/kg) failed to alter amphetamine self-administration. Combined injections of raclopride (0.05 or 0.1 mg/kg) and ritanserin (2.5 mg/kg) were no more effective than injections of raclopride alone in reducing responding for d-amphetamine. Overall, these results suggest that 5-HT 2 receptor blockade plays a negligible role in the rewarding effects of d-amphetamine measured by intravenous self-administration, and does not contribute to the suppressant effects of risperidone on this behavior.

Basal forebrain cholinergic lesions enhance conditioned approach responses to stimuli predictive of food.

This study examined the effects of lesions to different neuronal populations within the basal forebrain on reward-related learning. Rats received bilateral alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) or quinolinate lesions that preferentially destroy the cholinergic nucleus basalis magnocellularis (NBM) or noncholinergic ventral pallidal neurons, respectively. Both lesions enhanced conditioned approach responses to stimuli predictive of food but did not increase the locomotor stimulating effect of d-amphetamine. Although both lesions disrupted the discriminative control over behavior by a conditioned stimulus, they did not impair the subsequent acquisition of instrumental responding with conditioned reinforcement (CR). Indeed, both lesions were associated with an increased responding with CR following intra-accumbens infusions of d-amphetamine (0, 1, 3, 10, and 20 microg). Quinolinate lesions also increased responses on an inactive control lever. Neither lesion altered consummatory responses to food or sucrose. Results suggest that NBM lesions may disrupt the balance between cortical and subcortical dopamine levels, and/or produce a deficit in attentional mechanisms that is manifested as increased responding to specific stimuli.

Amphetamine effects on dopamine release and synthesis rate studied in the Rhesus monkey brain by positron emission tomography.

Positron emission tomography (PET) was used in a multitracer protocol to evaluate D-amphetamine induced effects on dopamine biosynthesis rate and release in propofol anesthetized Rhesus monkeys. L-[beta-11C]DOPA was used as biochemical probe to study the brain dopamine biosynthesis rate whilst dopamine release was followed by the binding displacement of the [11C]-radiolabelled dopamine receptor antagonists, raclopride and N-methylspiperone. Studies were performed with either a constant rate intravenous infusion of D-amphetamine aiming at plasma concentrations of 0.2 to 25 ng/ml or with intravenous bolus doses of 0.1 and 0.4 mg/kg. Decreased binding of the dopamine receptor antagonists was measured in both modes of D-amphetamine administration but notably [11C]N-methylspiperone was less able to sense D-amphetamine induced release of dopamine. At plasma concentrations aimed above 1 ng/ml a levelling off of the binding of [11C]raclopride at 68 +/- 8.1% of the baseline value indicated that displacement was only possible from a fraction of the binding sites. Amphetamine was observed to increase the rate constant for L-[beta-11C]DOPA utilization in the brain. This was most likely due to an acutely induced subsensitivity of presynaptic dopamine receptors. L-[beta-11C]DOPA and [11C]raclopride were found suitable to indicate changes in dopamine synthesis rate and release respectively using PET and can be used to mirror drug-induced changes of brain dopaminergic function.

Effects of Administration Regime on the Psychotomimetic Properties of d-amphetamine in the Squirrel Monkey ( Saimiri sciureus )

Studies have reported that d-amphetamine can induce a schizophreniform psychosis in humans and can induce abnormal behaviour patterns in monkeys that resemble the psychotic symptoms observed in man. The purpose of the present study was to identify a drug administration regime that in squirrel monkeys reliably could induce such behaviours in order to use this as a model of schizophrenia. The behavioural effects of acute, subchronic and continuous administration of d-amphetamine were determined in male and female squirrel monkeys during short term separation from the colony and in the home cage. It was found that abnormal behaviours developed in both male and female subjects and that they were most evident in the home cage. The number of subjects responding was highest during continuous infusion followed by subchronic treatment. The study indicated that prolonged administration of high doses of d-amphetamine is necessary for the development of abnormal behaviours. These findings suggest that animal models of schizophrenia based on d-amphetamine should be based on chronic administration or continuous infusion of d-amphetamine instead of acute injections.

Effects of excitotoxic lesions of the central amygdaloid nucleus on the potentiation of reward-related stimuli by intra-accumbens amphetamine.

The present study examined the effects of lesions of the central nucleus of the amygdala (CeA) on the acquisition of a new response with conditioned reinforcement (CR) and its potentiation by intra-accumbens infusions of d-amphetamine (1, 3, 10, and 20 microg/microl). Rats were trained to associate a light-plus-noise compound stimulus with the availability of a sucrose solution before receiving both bilateral ibotenic acid lesions of the CeA and cannulas implanted above the nucleus accumbens. Lesions of the central nucleus did not impair the performance of positively reinforced discriminated approach, nor did they impair the acquisition of a new response with conditioned reinforcement. However, the potentiation of responding with CR following intra-accumbens amphetamine was blocked in lesioned animals. These results are discussed in terms of the possible interactions between associative mechanisms in the amygdala and the mesolimbic dopamine projection.

Bilateral intra-accumbens self-administration of d-amphetamine: antagonism with intra-accumbens SCH-23390 and sulpiride.

The efficacy of d-amphetamine to support a selective bilateral intra-accumbens self-administration response was examined. Bilateral intra-accumbens infusions of d-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 microgram d-amphetamine; responses upon the second, control lever were recorded but had no programmed consequences. Animals were not 'primed' with non-contingent infusions of d-amphetamine at any time during these experiments. Nonetheless, animals readily acquired a selective response upon the drug lever. Removal of the d-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 of d-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.

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 of d-amphetamine (10 micrograms), the D1 dopamine receptor agonist SKF-38393 (0.1 microgram), the D2 dopamine receptor agonist LY-171555 (quinpirole; 0.1 microgram) or the opiate receptor agonist [D-Ala2]-methionine enkephalinamide (DALA; 1 microgram) selectively increased responding on the CR lever. Infusion with DALA intra-VTA had no effect. However, pretreatment with DALA intra-VTA (10 x 1 microgram/day) subsequently reduced the selectivity of the response to infusions intra-accumbens with d-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 of d-amphetamine, SKF-38393, LY-171555 or DALA again increased responding on the CR lever only. Pretreatment with intra-accumbens d-amphetamine (5 x 1 microgram/day) reduced the selectivity of the response subsequently to d-amphetamine, and blocked the response to SKF-38393, LY-171555 or DALA. In experiment 3, intra-accumbens infusions of the mu-opiate receptor agonist [D-Ala2,N-Me-Phe4,Gly5-ol]-enkephalin (0.003-0.1 microgram), or the delta-opiate receptor agonist [D-Pen2,5]-enkephalin (0.03-1 microgram) 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.

Cholecystokinin-dopamine interactions within the nucleus accumbens in the control over behaviour by conditioned reinforcement

Abstract Cholecystokinin (CCK) is colocalised with dopamine in the postero-medial nucleus accumbens (NAS). We have utilised an acquisition of a new response procedure to investigate the interaction between CCK and dopamine in the control over behaviour by conditioned reinforcers. A conditioned reinforcer (CR) may be defined as an initially neutral stimulus which gains control over behaviour through selective association with a primary reinforcer. Here, rats learned to associate a light/noise compound stimulus with the imminent availability of 10% sucrose reinforcement. Later, in the absence of sucrose, responding on one of two novel levers (the CR lever) was acquired and maintained by contingent presentation of the CR alone, while responding on the second lever had no programmed consequences. In Expt. 1, infusion of 10 μg d-amphetamine within the postero-medial NAS enhanced responding selectively on the CR lever. Infusion of sulphated CCK octapeptide (CCK: 1 or 10 ng) alone within the same area had no effect on response rate. However, infusion of CCK immediately prior to d-amphetamine caused a dose-dependent potentiation of the impact of d-amphetamine upon rates of response on the CR lever. In Expt. 2, infusion of d-amphetamine (10 μg) within the postero-medial NAS again enhanced responding selectively upon the CR lever. Intra-accumbens infusion of CCK (10 ng), or s.c. administration of the CCK A receptor antagonist devazepide had no effect upon response rates. However, CCK again potentiated the d-amphetamine-induced increase in rates of response, and this potentiation was blocked by pretreatment with devazepide. These results are discussed in terms of the co-modulation by CCK and dopamine of the processing of reward-related stimuli within the NAS.

Differential effects of excitotoxic lesions of the basolateral amygdala, ventral subiculum and medial prefrontal cortex on responding with conditioned reinforcement and locomotor activity potentiated by intra-accumbens infusions of d-amphetamine

Abstract The experiments reported here have investigated the impact on reward-related processes of lesioning the basolateral amygdala, ventral subiculum and prelimbic cortex which represent the major limbic sources of afferents to the ventral striatum. The results showed that, while lesions of the prelimbic cortex were without effect on the approach to a CS predictive of sucrose reinforcement and the acquisition of a new response with conditioned reinforcement, lesions of the other two structures significantly impaired both responses. However, there were important differences between the effects of basolateral amygdala and ventral subiculum lesions. Thus, lesions of the ventral subiculum completely abolished the locomotor response to intra-accumbens infusions of d-amphetamine, in addition to blocking the potentiative effect of the same treatment on responding with conditioned reinforcement. Lesions of the basolateral amygdala, by contrast, reduced the control over behaviour by a conditioned reinforcer, but not the potentiation of that control by intra-accumbens d-amphetamine except at the highest dose. Moreover, the locomotor response to d-amphetamine-induced increases in dopamine in the nucleus accumbens was unaffected by amygdala lesions over the dose range blocked by ventral subiculum lesions. The results suggest a rather selective effect of amygdala-ventral striatal interactions on processes subserving conditioned reinforcement and a more fundamental influence of ventral subiculum-ventral striatal interactions in mediating the psychomotor stimulant effects of d-amphetamine.

In vitro extracellular recording from nigral dopamine neurons following continuous d-amphetamine infusion

Single nigral dopamine neurons were extracellularly recorded in vitro after withdrawal from continuous d-amphetamine sulfate infusion (5.0 mg/kg per day for 7 days via subcutaneous osmotic minipumps). Seven days after withdrawal, the dopamine neurons were supersensitive to impulse-inhibition by dopamine. This increased sensitivity suggests a supersensitivity of soma/dendritic autoreceptors on these neurons, as we previously hypothesized based on a supersensitivity to intravenous apomorphine. In contrast to the day 7, the withdrawal day 1 was associated with a normosensitivity to dopamine, suggesting that the apomorphine subsensitivity observed in vivo on this day may be secondary to non-autoreceptor changes.

Interactions between the amygdala and ventral striatum in stimulus-reward associations: Studies using a second-order schedule of sexual reinforcement

Bilateral,N-methyl- d-aspartate-induced lesions of the basolateral region of the amygdaloid complex in male rats resulted in a marked decrease in instrumental responses maintained by a visual conditioned reinforcer in a paradigm in which sexual reinforcement was presented under a second-order schedule. There were no effects of lesions of the amygdala on the unconditioned sexual behaviour of the males, i.e. on behaviour elicited by primary reinforcers. Infusion of d-amphetamine bilaterally into the nucleus accumbens region of the ventral striatum resulted in a dose-dependent amelioration of the decrease in instrumental behaviour maintained by a conditioned reinforcer which followed lesions of the amygdala. This effect of d-amphetamine critically depended upon the presentation of the conditioned reinforcer (a previously neutral light which had gained reinforcing properties through its prior association with sexual interaction). The results indicate that the basolateral region of the amygdala may interact with dopamine-dependent processes in the ventral striatum in mediating the control by conditioned reinforcers over instrumental behaviour.

Involvement of the amygdala in stimulus-reward associations: Interaction with the ventral striatum

The involvement of the amygdala in the potentiation of responding for conditioned reinforcers following intra-accumbens amphetamine injections has been studied. Thirsty rats were trained to associate a light-noise compound stimulus with water and then implanted with guide cannulae in the nucleus accumbens. Half of these rats received excitotoxic lesions of the basolateral region of the amygdala by infusingN-methyl- d-aspartate, whereas the other half received infusions of the vehicle. In the test phase, water was no longer presented but responding on one of two novel levers produced the light-noise compound (the conditioned reinforcer) whereas responding on the other lever had no effect. The two groups received four counterbalanced intra-accumbens infusions of amphetamine (3, 10 and 30 μg/μl) or vehicle over four test days. Intra-accumbens amphetamine infusions dose-dependently increased responding on the lever providing a conditioned reinforcer but had no significant effect on responding on the lever which did not produce the conditioned reinforcer. Compared with controls, the lesioned group exhibited a significant, selective reduction in responding on the lever providing a conditioned reinforcer. with no change on the lever on which responding had no consequence, irrespective of drug or control treatment. Control experiments showed that the amygdala lesioned animals were not hypodipsic and exhibited similar levels of hyperactivity following intra-accumbens infusions of d-amphetamine. Furthermore, the capacity to discriminate the conditioned stimulus as well as to acquire a new motor task was not altered by the lesion. These results indicate a role for the amygdala in mediating the effects of stimulus-reward associations on behaviour, via an action on dopamine-dependent mechanisms of the ventral striatum.

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 microliters 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 micrograms/2 microliters) 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 (greater than 80%) in the nucleus accumbens following intra-accumbens d-amphetamine; however, in subjects with DA depletion of the posterior caudate nucleus (greater than 80%).(ABSTRACT TRUNCATED AT 250 WORDS)

Unilateral, intranigral infusions of amphetamine produce differential, bilateral changes in unit activity and extracellular levels of ascorbate in the neostriatum of the rat

Simultaneous recordings of single-unit activity and oxidation current were obtained bilaterally from the neostriatum of rats in response to unilateral infusion of d-amphetamine (2.0 μl of 10 μg/μl) into the substantia nigra. Whereas neuronal activity increases ipsilaterally and decreases contralaterally, the electrochemical signals, which reflect extracellular ascorbate, increase bilaterally. In each case, changes in unit activity precede the change in ascorbate release. Systemic administration of haloperidol (0.2 mg/kg) blocks the increase in oxidation current bilaterally, but reverses the neuronal activity response only on the ipsilateral side. These results lend further support to the view that intranigral amphetamine facilitates neostriatal ascorbate release, but this effect is not correlated with changes in single-unit activity.