Nobuyoshi Suto

Previous exposure to psychostimulants enhances the reinstatement of cocaine seeking by nucleus accumbens AMPA.

The effect of previous exposure to psychostimulants on the subsequent self-administration of cocaine as well as reinstatement of this behavior by priming infusions of AMPA into the nucleus accumbens (NAcc) was examined. Rats were exposed to five injections, one injection every third day, of either saline or amphetamine (AMPH: 1.5 mg/kg, i.p.). Starting 10 days later, they were trained to self-administer cocaine (0.3 mg/kg/infusion, i.v.) and subsequently tested under a progressive ratio (PR) schedule for 4 consecutive days. As expected, rats exposed to AMPH worked more and obtained more cocaine infusions than saline exposed controls on the PR test sessions. Following daily extinction sessions during which saline was substituted for cocaine, the effect of priming infusions of AMPA (0.0, 0.08, or 0.8 nmol/0.5 μl/side) into the NAcc was then examined on two tests: one conducted 4 days after the last cocaine PR test session (2–3 weeks after the last AMPH exposure injection) and the next 4 weeks later. Consistent with previous reports, NAcc AMPA dose-dependently reinstated cocaine seeking on both tests regardless of exposure condition. Importantly, this priming effect of NAcc AMPA was significantly enhanced in AMPH compared to saline exposed rats on the first test conducted 2–3 weeks after AMPH. On the second test, conducted 4 weeks after cocaine, reinstatement was similarly enhanced in both groups to levels observed on the first test in AMPH exposed rats. These results indicate that both noncontingent (AMPH) and contingent (cocaine) exposure to psychostimulants enhances the reinstatement of cocaine seeking by NAcc AMPA and appears to do so in a time-dependent manner.

Previous exposure to VTA amphetamine enhances cocaine self-administration under a progressive ratio schedule in a D1 dopamine receptor dependent manner.

The effect of previous exposure to amphetamine (AMPH) in the ventral tegmental area (VTA) on the subsequent self-administration of cocaine was assessed. Rats in different groups were pre-exposed to three injections into the VTA of either saline (0.5μl/side) or AMPH (2.5μg/0.5μl/side). Injections were given once every third day. Starting 7–10 days after the last pre-exposure injection, rats were trained to self-administer cocaine (0.3 mg/kg/infusion) under fixed ratio 1 and 2 (FR1 and FR2) schedules and then tested under a progressive ratio (PR) schedule of reinforcement for six consecutive days. No differences between groups were observed during self-administration training under the FR schedules of reinforcement. However, when tested under the PR schedule, VTA AMPH pre-exposed rats worked more and, as a result, obtained more infusions of cocaine than saline pre-exposed rats. Rats in a separate group pre-exposed to VTA AMPH but co-infused with the D1-like dopamine (DA) receptor antagonist SCH23390 (0.25 μg/0.5μl/side) did not show enhanced cocaine self-administration. These rats, as well as others pre-exposed to VTA SCH23390 alone showed levels of cocaine self-administration similar to saline pre-exposed rats. Thus, in a manner paralleling the sensitization of AMPH-induced locomotion and nucleus accumbens DA overflow, previous exposure to AMPH in the VTA leads to enhanced intravenous self-administration of cocaine and activation of D1 DA receptors in this site during pre-exposure is necessary for the production of this effect.

Previous exposure to VTA amphetamine enhances cocaine self-administration under a progressive ratio schedule in an NMDA, AMPA/kainate, and metabotropic glutamate receptor-dependent manner.

Previous exposure to amphetamine (AMPH) in the ventral tegmental area (VTA) enhances cocaine self-administration in a D1 dopamine receptor-dependent manner. The present study examined the contribution of VTA NMDA, AMPA/kainate, and metabotropic glutamate (mGlu) receptors to this effect. Rats in different groups received three intra-VTA injections, one every third day, of either saline (0.5 μl/side), AMPH (2.5 μg/0.5 μl/side), AMPH+CPP (NMDA receptor antagonist; 10 μM or 100 μM/0.5 μl/side), AMPH+CNQX (AMPA/kainate receptor antagonist; 0.3 mM or 1 mM/0.5 μl/side), AMPH+MCPG (mGlu receptor antagonist; 0.5 mM or 50 mM/0.5 μl/side), or the glutamate receptor antagonists alone. Starting 7–10 days after the last pre-exposure injection, rats were trained to self-administer cocaine (0.3 mg/kg/infusion) and then tested under a progressive ratio (PR) schedule of reinforcement for 6 consecutive days. As reported previously, VTA AMPH pre-exposed rats worked more and obtained more infusions of cocaine than saline pre-exposed animals. Coadministration of CPP, CNQX, or MCPG with AMPH during pre-exposure dose-dependently blocked this enhancement of cocaine self-administration. Rats pre-exposed to the glutamate receptor antagonists alone did not differ on the test days from the saline pre-exposed controls. These results indicate that, in a manner paralleling the induction of sensitization of the locomotor stimulating effects of AMPH, activation of NMDA, AMPA/kainate, and mGlu receptors during pre-exposure to AMPH in the VTA is necessary for the enhancement of cocaine self-administration to develop.

Blockade of D2 dopamine receptors in the VTA induces a long-lasting enhancement of the locomotor activating effects of amphetamine

The present study examined the effects of pre-exposure to eticlopride, a D2 dopamine receptor antagonist, in the ventral tegmental area (VTA) on the subsequent locomotor activating effects of amphetamine (AMPH). Rats were pre-exposed to one of three doses of eticlopride (0.75, 3.0 or 12.0 μg/0.5 μl per side) or saline (0.5 μl/side) in the VTA, once every third day, for a total of three infusions. Locomotor activity was recorded for 2 h following each pre-exposure injection. The low and intermediate doses of eticlopride produced no effects, while the high dose decreased locomotor activity compared to saline controls. 10–14 days following the last pre-exposure injection, all rats were challenged with AMPH (1.0 mg/kg, ip) and locomotor activity was recorded. Rats pre-exposed to the low dose of eticlopride exhibited enhanced locomotor activity whereas those pre-exposed to the intermediate or high doses did not differ from saline pre-exposed controls, suggesting that blockade of D2 dopamine receptors in the VTA can lead to sensitized locomotor responding to AMPH. To investigate the possible mechanism by which the low dose of eticlopride induced sensitization, extracellular levels of dopamine were measured as increasing concentrations of eticlopride (0.1, 1.0, 10.0 and 100.0 μmol/l) were perfused through a microdialysis probe implanted in the VTA. Only the lowest eticlopride concentration elevated extracellular dopamine levels. Therefore, as in the case of AMPH-induced sensitization, the induction by eticlopride of sensitization to AMPH may be initiated by the ability of eticlopride to increase extracellular levels of dopamine in the VTA.

Satiating Effects of Cocaine Are Controlled by Dopamine Actions in the Nucleus Accumbens Core

Intravenous cocaine intake in laboratory animals is characterized by periods of apparent drug satiety between regularly spaced earned injections. The reinforcing properties of cocaine are linked primarily to dopaminergic neurotransmission in the shell and not the core of nucleus accumbens. To determine whether the satiating effects of cocaine are similarly mediated, we perfused dopamine receptor agonists into the core or the shell during intravenous cocaine self-administrations by rats. Neither D1-type (SKF38393) nor D2-type (quinpirole) agonist was effective when given alone. However, a combination of the two agonists perfused into the core but not the shell significantly increased the time between cocaine self-injections, decreasing the amount of earned intake. Together with previous findings, the current data suggest that the satiating and reinforcing effects of cocaine are mediated by different ventral striatal output neurons.

Dorsal as well as ventral striatal lesions affect levels of intravenous cocaine and morphine self-administration in rats

While the ventral striatum has long been implicated in the rewarding properties of psychomotor stimulants and opiates, little attention has been paid to the possible contribution of more dorsal regions of the striatum. We have thus examined the effects of lesions in three different striatal subregions on cocaine and morphine self-administration. Different groups of rats were trained to self-administer intravenous cocaine (1.0mg/kg/infusion) or morphine (0.5mg/kg/infusion) first under fixed ratio (FR) and then under progressive ratio (PR) schedules of reinforcement. Upon completion of the training, independent groups received bilateral electrolytic or sham lesions of the dorsal portion of the caudate-putamen (dCPu), the ventral portion of the caudate-putamen (vCPu) or the more ventral nucleus accumbens (NAS). Following recovery, they were tested for self-administration of cocaine (0.25, 0.5, 1.0 and 1.5mg/kg/infusion) or morphine (0.125, 0.25, 0.5 and 0.75mg/kg/infusion) under the PR schedule. The PR responding for each drug was significantly reduced in a dose-dependent manner following lesions of dCPu, vCPu and NAS. While the relative effectiveness of these lesions is likely to be specific to the conditions of this experiment, NAS lesions reduced self-administration of each drug to a greater extent than did dCPu or vCPu lesions.

Distinct memory engrams in the infralimbic cortex of rats control opposing environmental actions on a learned behavior

Conflicting evidence exists regarding the role of infralimbic cortex (IL) in the environmental control of appetitive behavior. Inhibition of IL, irrespective of its intrinsic neural activity, attenuates not only the ability of environmental cues predictive of reward availability to promote reward seeking, but also the ability of environmental cues predictive of reward omission to suppress this behavior. Here we report that such bidirectional behavioral modulation in rats is mediated by functionally distinct units of neurons (neural ensembles) that are concurrently localized within the same IL brain area but selectively reactive to different environmental cues. Ensemble-specific neural activity is thought to function as a memory engram representing a learned association between environment and behavior. Our findings establish the causal evidence for the concurrent existence of two distinct engrams within a single brain site, each mediating opposing environmental actions on a learned behavior. DOI: http://dx.doi.org/10.7554/eLife.21920.001

Cocaine self-administration is not dependent upon mesocortical α1 noradrenergic signaling

The rewarding properties of psychomotor stimulants are traditionally thought to be independent of norepinephrine. Recent findings, however, suggest that local noradrenergic signaling through &agr;1 receptors in the medial prefrontal cortex and the ventral tegmental area – brain regions critically important in natural and drug rewards – is in a position to influence stimulant reward. Despite this controversy, the contribution of this targeted signaling to stimulant self-administration has not been directly assessed. We have thus examined whether pharmacological blockade of &agr;1 receptors in the medial prefrontal cortex and ventral tegmental area alters cocaine self-administration. Rats were trained to lever-press for cocaine (1.0 mg/kg/infusion) under a fixed ratio 1 schedule of reinforcement for 10 days. After training, the rats received a bilateral microinjection of an &agr;1 noradrenergic antagonist (terazosin: 1.0, 5.0, or 10 mM/side), a D1 dopaminergic antagonist (SCH23390: 12.3 mM/side), or saline into either the medial prefrontal cortex or ventral tegmental area immediately before a cocaine self-administration session. Although SCH23390 significantly increased cocaine self-administration when injected into either brain region, terazosin, at all doses and sites tested, failed to alter this behavior. Thus, the maintenance of cocaine self-administration appears to be under the influence of D1 dopaminergic, rather than &agr;1 noradrenergic, signaling at these mesocortical sites.

Bidirectional Modulation of Cocaine Expectancy by Phasic Glutamate Fluctuations in the Nucleus Accumbens

While glutamate in the nucleus accumbens (NAS) contributes to the promotion of drug-seeking by drug-predictive cues, it also appears to play a role in the inhibition of drug-seeking following extinction procedures. Thus we measured extracellular fluctuations of NAS glutamate in response to discriminative stimuli that signaled either cocaine availability or cocaine omission. We trained rats to self-administer intravenous cocaine and then to recognize discriminative odor cues that predicted either sessions where cocaine was available or alternating sessions where it was not (saline substituted for cocaine). Whereas responding in cocaine availability sessions remained stable, responding in cocaine omission sessions progressively declined to chance levels. We then determined the effects of each odor cue on extracellular glutamate in the core and shell subregions of NAS preceding and accompanying lever pressing under an extinction condition. Glutamate levels were elevated in both core and shell by the availability odor and depressed in the core but not the shell by the omission odor. Infusion of kynurenic acid (an antagonist for ionotropic glutamate receptors) into core but not shell suppressed responding associated with the availability odor, but had no effect on the suppression associated with the omission odor. Thus cocaine-predictive cues appear to promote cocaine seeking in part by elevating glutamatergic neurotransmission in the core of NAS, whereas cocaine-omission cues appear to suppress cocaine seeking in part by depressing glutamatergic receptor activation in the same region.

Glutamate and the Self-Administration of Psychomotor-Stimulant Drugs

Psychomotor-stimulant drugs such as the amphetamines and cocaine are self-administered by humans and laboratory animals and produce locomotor activation. Repeated exposure to these drugs produces long-term enhancements in their ability to elicit these locomotor responses so that subsequent re-exposure to the drug, weeks to months later, produces greater behavioral activation than seen initially. Most importantly, previous exposure to such sensitizing regimens of amphetamine injections has also been reported to produce long-lasting enhancements in animals’ predisposition to self-administer the drug. The long-term neurobiological changes associated with these enhancements may also figure importantly in the reinstatement of drug taking in individuals that have been drug-free for some time.