Potentiation of prefrontal cortex dopamine function by the novel cognitive enhancer d-govadine.

Cognitive impairment is a debilitating feature of psychiatric disorders including schizophrenia, mood disorders and substance use disorders for which there is a substantial lack of effective therapies. d-Govadine (d-GOV) is a tetrahydroprotoberberine recently shown to significantly enhance working memory and behavioural flexibility in several prefrontal cortex (PFC)-dependent rodent tasks. d-GOV potentiates dopamine (DA) efflux in the mPFC and not the nucleus accumbens, a unique pharmacology that sets it apart from many dopaminergic drugs and likely contributes to its effects on cognitive function. However, specific mechanisms involved in the preferential effects of d-GOV on mPFC DA function remain to be determined. The present study employs brain dialysis in male rats to deliver d-GOV into the mPFC or ventral tegmental area (VTA), while simultaneously sampling DA and norepinephrine (NE) efflux in the mPFC. Intra-PFC delivery or systemic administration of d-GOV preferentially potentiated medial prefrontal DA vs NE efflux. This differential effect of d-GOV on the primary catecholamines known to affect mPFC function further underscores its specificity for the mPFC DA system. Importantly, the potentiating effect of d-GOV on mPFC DA was disrupted when glutamatergic transmission was blocked in either the mPFC or the VTA. We hypothesize that d-GOV acts in the mPFC to engage the mesocortical feedback loop through which prefrontal glutamatergic projections activate a population of VTA DA neurons that specifically project back to the PFC. The activation of a PFC-VTA feedback loop to elevate PFC DA efflux without affecting mesolimbic DA release represents a novel approach to developing pro-cognitive drugs.

Differential patterns of basal and naloxone-evoked dopamine efflux in the rat dorsal and ventral striatum following prolonged-intermittent exposure to morphine.

Hypodopaminergia in the ventral striatum is a putative neurobiological correlate of withdrawal in opioid-dependent individuals. This perspective stands in contrast to brain imaging studies with chronic opioid users showing that naloxone-enhanced dopamine (DA) release in the dorsal striatum is positively correlated with withdrawal aversion. Here, we examined regional differences in striatal DA function associated with opioid withdrawal in rats exposed to intermittent morphine injections for 31 days. Basal concentrations of DA were reduced (i.e., indicating a hypodopaminergic state) in the ventral striatum on Day 10 of morphine exposure, whereas a more prolonged period of morphine treatment was required to reveal hypodopaminergia in the dorsal striatum on Day 31. The ventral striatum consistently exhibited naloxone-induced transient reductions in DA below the hypodopaminergic basal levels, whereas morphine enhanced DA efflux. In the dorsal striatum, DA responsivity to naloxone shifted from a significant decrease on Day 10 to a notable increase above hypodopaminergic basal levels on Day 31, corroborating the findings in the human dorsal striatum. Unexpectedly, the magnitude of morphine-evoked increases in DA efflux on Day 31 was significantly blunted relative to values on Day 10. These findings indicate that prolonged-intermittent access to morphine results in a sustained hypodopaminergic state as reflected in basal levels in the striatum, which is accompanied by regional differences in DA responsivity to naloxone and morphine. Overall, our findings suggest that prolonging the duration of morphine exposure to 31 days is sufficient to reveal neuroadaptations that may underlie the transition from initial drug exposure to opioid dependence.

Morphine Withdrawal-Induced Hyperalgesia in Models of Acute and Extended Withdrawal Is Attenuated by l-Tetrahydropalmatine.

Effective pain control is an underappreciated aspect of managing opioid withdrawal, and its absence presents a significant barrier to successful opioid detoxification. Accordingly, there is an urgent need for effective non-opioid treatments to facilitate opioid detoxification. l-Tetrahydropalmatine (l-THP) possesses powerful analgesic properties and is an active ingredient in botanical formulations used in Vietnam for the treatment of opioid withdrawal syndrome. In this study, rats receiving morphine (15 mg/kg, i.p.) for 5 days per week displayed a progressive increase in pain thresholds during acute 23 h withdrawal as assessed by an automated Von Frey test. A single dose of l-THP (5 or 7.5 mg/kg, p.o.) administered during the 4th and 5th weeks of morphine treatment significantly improves pain tolerance scores. A 7-day course of l-THP treatment in animals experiencing extended withdrawal significantly attenuates hyperalgesia and reduces the number of days to recovery to baseline pain thresholds by 61% when compared to vehicle-treated controls. This indicates that the efficacy of l-THP on pain perception extends beyond its half-life. As a non-opioid treatment for reversing a significant hyperalgesic state during withdrawal, l-THP may be a valuable addition to the currently limited arsenal of opioid detoxification treatments.

Optogenetic modulation of glutamatergic afferents from the ventral subiculum to the nucleus accumbens: Effects on dopamine function, response vigor and locomotor activity.

Dopamine (DA) signalling in the nucleus accumbens (NAc) motivates behavior in part by adjusting the exerted effort according to the anticipated value of the outcome. Here we examined the effects of optogenetic activation or inhibition of the glutamatergic ventral subiculum (vSub) to NAc pathway on motivation to work for food rewards and locomotor behavior. Using a novel probe that combines optical stimulation with microdialysis, we show that channelrhodopsin2 (ChR2)-mediated activation of these glutamatergic afferents increased DA efflux in the NAc. This protocol also selectively influenced motivation to seek food in a progressive-ratio (PR) task by re-invigorating lever-pressing, but only during a period of reduced motivation following failure to achieve food reward (i.e., after the breakpoint, BP). Importantly, identical ChR2-mediated photostimulation parameters failed to affect the rate of operant responding in the PR segment prior to reaching the BP. In contrast, during the segment of vigorous lever-pressing prior to the BP, halorhodopsin-mediated optogenetic inhibition of glutamatergic vSub-NAc activity caused an immediate and sustained suppression of food-seeking behavior. Based on these results, we conclude that glutamatergic vSub-NAc afferents can modulate food-seeking behavior, including 'response vigor', as a function of present motivational state. In a 'low-motivational state' following failure to achieve an anticipated reward, optogenetic stimulation of this pathway can reinvigorate lever-pressing behavior. In turn, inhibition of this glutamatergic pathway appears to decrease motivated responding. These data may be relevant to dysregulated motivational states common to psychiatric conditions, including depression, schizophrenia, and substance use disorders.

Anticipation: An Essential Feature of Anhedonia.

The following essay addresses the evolution of the term "anhedonia" as a key construct in biological psychiatry, especially as it pertains to positive emotional and motivational states central to mental health and well-being. In its strictest definition, anhedonia was intended to convey an inability to experience "pleasure" derived from ingestion of sweet tastes or the experience of pleasant odors and tactile sensations, among a host of positive sensations. However, this definition has proved to be too restrictive to capture the complexity of key psychological factors linked to major depression, schizophrenia, and substance use disorders it was originally intended to address. Despite the appeal of the elegant simplicity of the term anhedonia, its limitations soon became apparent when used to explain psychological constructs including aspects of learning, memory, and incentive motivation that are major determinants of success in securing the necessities of life. Accordingly, the definition of anhedonia has morphed into a much broader term that includes key roles in the disturbance of motivation in the form of anergia, impaired incentive motivation, along with deficits in associative learning and key aspects of memory, on which the ability to predict the consequences of one's actions are based. Here we argue that it is this latter capacity, namely predicting the likely consequences of motivated behavior, which can be termed "anticipation," that is especially important in the key deficits implied by the general term anhedonia in the context of neuropsychiatric conditions.

Neural bases for attenuation of morphine withdrawal by Heantos-4: role of l-tetrahydropalmatine.

Severe withdrawal symptoms triggered by cessation of long-term opioid use deter many individuals from seeking treatment. Opioid substitution and α2-adrenergic agonists are the current standard of pharmacotherapy for opioid use disorder in western medicine; however, each is associated with significant complications. Heantos-4 is a non-opioid botanical formulation used to facilitate opioid detoxification in Vietnam. While ongoing clinical use continues to validate its safety and effectiveness, a mechanism of action accounting for these promising effects remains to be specified. Here, we assess the effects of Heantos-4 in a rat model of morphine-dependence and present evidence that alleviation of naloxone-precipitated somatic withdrawal signs is related to an upregulation of mesolimbic dopamine activity and a consequent reversal of a hypodopaminergic state in the nucleus accumbens, a brain region implicated in opioid withdrawal. A central dopaminergic mechanism is further supported by the identification of l-tetrahydropalmatine as a key active ingredient in Heantos-4, which crosses the blood-brain barrier and shows a therapeutic efficacy comparable to its parent formulation in attenuating withdrawal signs. The anti-hypodopaminergic effects of l-tetrahydropalmatine may be related to antagonism of the dopamine autoreceptor, thus constituting a plausible mechanism contributing to the effectiveness of Heantos-4 in facilitating opioid detoxification.

Heantos-4, a natural plant extract used in the treatment of drug addiction, modulates T-type calcium channels and thalamocortical burst-firing.

Heantos-4 is a refined combination of plant extracts currently approved to treat opiate addiction in Vietnam. In addition to its beneficial effects on withdrawal and prevention of relapse, reports of sedation during clinical treatment suggest that arousal networks in the brain may be recruited during Heantos administration. T-type calcium channels are implicated in the generation of sleep rhythms and in this study we examined whether a Heantos-4 extraction modulates T-type calcium channel currents generated by the Cav3.1, Cav3.2 and Ca3.3 subtypes. Utilizing whole-cell voltage clamp on exogenously expressed T-type calcium channels we find that Heantos inhibits Cav3.1 and Cav3.3 currents, while selectively potentiating Cav3.2 currents. We further examined the effects of Heantos-4 extract on low-threshold burst-firing in thalamic neurons which contribute to sleep oscillations. Using whole-cell current clamp in acute thalamic brain slices Heantos-4 suppressed rebound burst-firing in ventrobasal thalamocortical neurons, which express primarily Cav3.1 channels. Conversely, Heantos-4 had no significant effect on the burst-firing properties of thalamic reticular neurons, which express a mixed population of Cav3.2 and Cav3.3 channels. Examining Heantos-4 effects following oral administration in a model of absence epilepsy revealed the potential to exacerbate seizure activity. Together, the findings indicate that Heantos-4 has selective effects both on specific T-type calcium channel isoforms and distinct populations of thalamic neurons providing a putative mechanism underlying its effects on sedation and on the thalamocortical network.

Selective effects of D- and L-govadine in preclinical tests of positive, negative, and cognitive symptoms of schizophrenia.

There is a critical need to develop novel pharmacotherapeutics capable of addressing the positive, negative, and cognitive symptoms of schizophrenia. Building on recent studies with a racemic mixture of the synthetic tetrahydroprotoberberine, D,L-Govadine, we isolated the D- and L-stereoisomers and employed a battery of behavioral, neurochemical, and electrophysiological procedures to assess their individual therapeutic potential. Rodent models predictive of antipsychotic efficacy and those that model positive symptoms were employed and we found that L-Govadine, but not D-Govadine, improved these measures. Pretreatment with either stereoisomer during CS pre-exposure prevented the disruption of latent inhibition by amphetamine. Moreover, pretreatment with either stereoisomer also improved deficits in social interaction in the neonatal ventral hippocampal lesioned rat. Improved cognitive performance in two different prefrontal cortex-dependent tasks was observed with D-, but not L-Govadine, which strongly suggests that the D-steroisomer may be an effective cognitive enhancer. Alterations in dopamine efflux were also assessed and L-Govadine increased dopamine efflux in both the prefrontal cortex and nucleus accumbens. However, D-Govadine only increased dopamine efflux in the prefrontal cortex and not in the nucleus accumbens. Electrophysiological studies confirmed that L-Govadine is a DA-D2 antagonist, whereas D-Govadine shows no appreciable physiological effects at this receptor. Collectively these data show that L-Govadine performs well on measures predictive of antipsychotic efficacy and rodent models of positive symptoms through antagonism of DA-D2 receptors, whereas D-Govadine improves impairments in compromised memory function in delayed response tasks possibly through selective increases in DA efflux in the frontal cortex.

Interference with AMPA receptor endocytosis: effects on behavioural and neurochemical correlates of amphetamine sensitization in male rats.

BACKGROUND: Behavioural sensitization has been linked to drug craving in both clinical and preclinical studies of addiction. Increased motor activity is accompanied by enhanced dopamine (DA) release, particularly in the nucleus accumbens (NAcc). The neural bases of sensitization are linked to alterations in synaptic connections that also underlie learning and memory. The present study uses an "interference" peptide, Tat-GluA2(3Y), that blocks long-term depression (LTD) at glutamatergic synapses by disrupting the endocytosis of α- amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptors (AMPARs), to explore the role of this form of synaptic plasticity in the induction and maintenance of sensitization. METHODS: Rats were given 5 injections of d-amphetamine (d-AMPH, 1.0 mg/kg, intraperitoneal) every second day. Tat-GluA2(3Y), was administered by 2 different routes (intravenously and intracerebrally to the ventral tegmental area [VTA] or to the NAcc) before each injection of d-AMPH. After a 14-day drug-free period, expression of behavioural sensitization was evoked by a challenge injection of d-AMPH (0.5 mg/kg, intraperitoneal). Dopamine efflux in the NAcc was measured by high-pressure liquid chromatography with electrochemical detection analyses of brain dialysates on days 1, 9 and 24 of the intravenous peptide experiment. RESULTS: Systemic administration of Tat-GluA2(3Y) during the induction phase blocked maintenance of behavioural sensitization and attenuated the maintenance of neurochemical sensitization. Intra-VTA infusion of Tat-GluA2(3Y) before each administration of d-AMPH did not affect induction, but inhibited maintenance and subsequent expression of sensitization, whereas intra-NAcc infusion of the peptide did not affect induction or maintenance of sensitization. LIMITATIONS: The relevance of behavioural sensitization in rodents is related to the development of craving and does not provide direct measures of drug reinforcement. CONCLUSION: These findings confirm that drug-induced neuroplasticity is labile and may be subject to disruption at a time when long-lasting associations between drug reward and contextual stimuli are formed. Furthermore, the unique ability of Tat-GluA2(3Y) to block maintenance of behavioural sensitization implicates LTD in the consolidation of essential associative memories. Tat-GluA2(3Y) has the unique ability to disrupt functional neuroadaptations triggered by repeated psychostimulant exposure and therefore may protect against the development of craving and drug seeking behaviours.

Daily monitoring of dopamine efflux reveals a short-lasting occlusion of the dopamine agonist properties of d-amphetamine by dopamine transporter blockers GBR 12909 and methylphenidate.

In vivo brain microdialysis was used in conjunction with "reverse-dialysis" of the dopamine-transporter (DAT) blockers GBR 12909 and methylphenidate (MPH) to observe the temporal course of their effects on d-amphetamine (d-AMPH)-induced increases in dopamine (DA) efflux in the rat nucleus accumbens (NAc). Reverse-dialysis of d-AMPH (10 µM) for 30 min resulted in a 2000-2500% increase in DA efflux. Pretreatment with GBR 12909 or MPH (20, 100 µM) for 90 min, which on their own elevated DA levels ∼2000-3000% above baseline values, dose-dependently occluded d-AMPH-evoked DA efflux. In GBR 12909-treated rats, basal levels of DA remained dramatically elevated at 24, 48, and 72 h following treatment, while levels in the MPH group returned back toward pretreatment values. Despite this contrast in basal DA efflux, the magnitudes of DA efflux evoked by a second exposure to d-AMPH were comparable in the two treatment groups. Together, these data support the development of DAT blockers as potential pharmacological interventions for the control of psychostimulant abuse. Furthermore, our data implicate DAT as a common site of action for both GBR 12909 and MPH, as well as d-AMPH.

Dynamic fluctuations in dopamine efflux in the prefrontal cortex and nucleus accumbens during risk-based decision making.

Mesocorticolimbic dopamine (DA) has been implicated in cost/benefit decision making about risks and rewards. The prefrontal cortex (PFC) and nucleus accumbens (NAc) are two DA terminal regions that contribute to decision making in distinct manners. However, how fluctuations of tonic DA levels may relate to different aspects of decision making remains to be determined. The present study measured DA efflux in the PFC and NAc with microdialysis in well trained rats performing a probabilistic discounting task. Selection of a small/certain option always delivered one pellet, whereas another, large/risky option yielded four pellets, with probabilities that decreased (100-12.5%) or increased (12.5-100%) across four blocks of trials. Yoked-reward groups were also included to control for reward delivery. PFC DA efflux during decision making decreased or increased over a session, corresponding to changes in large/risky reward probabilities. Similar profiles were observed from yoked-rewarded rats, suggesting that fluctuations in PFC DA reflect changes in the relative rate of reward received. NAc DA efflux also showed decreasing/increasing trends over the session during both tasks. However, DA efflux was higher during decision making on free- versus forced-choice trials and during periods of greater reward uncertainty. Moreover, changes in NAc DA closely tracked shifts in choice biases. These data reveal dynamic and dissociable fluctuations in PFC and NAc DA transmission associated with different aspects of risk-based decision making. PFC DA may signal changes in reward availability that facilitates modification of choice biases, whereas NAc DA encodes integrated signals about reward rates, uncertainty, and choice, reflecting implementation of decision policies.

Repeated cycles of restricted food intake and binge feeding disrupt sensory-specific satiety in the rat.

The relationship between food restriction and subsequent dysregulation of food intake is complex, variable and long-lasting. The present study investigated in rats whether repeated cycles of food restriction and binge feeding opportunities may alter regulation of food intake by employing a test for sensory-specific satiety. Rats that experienced repeated food restriction-binge cycles maintained heavier body weights compared to rats that remained on continuous food restriction. In contrast to the control subjects, rats that alternated between food restriction and binge feeding failed to display sensory-specific satiety. During the first meal, there was a gradual decrease in the amount of food intake over a 40 min period. When presented with a second meal of the same food, these rats responded to the familiar food in a manner similar as to a novel food (i.e., comparable quantities of both types of food were consumed). Food restriction-binge feeding cycles may be considered as a form of stress, which in turn is associated with cross-sensitization to numerous behavioral responses. Therefore, we propose that stress-induced disruption of sensory-specific satiety reflects a sensitized response to food, in which the interaction between sensory and satiety factors are no longer the key regulators of food choice and meal cessation. Furthermore, a role for sensory-specific satiety in terminating food intake appeared to decline with the progression of the cycles, thereby contributing to a steady increase in body weight of rats that experienced restriction with bouts of binge feeding opportunities.

A preclinical assessment of d.l-govadine as a potential antipsychotic and cognitive enhancer.

Tetrahydroprotoberberines (THPBs) are compounds derived from traditional Chinese medicine and increasing preclinical evidence suggests efficacy in treatment of a wide range of symptoms observed in schizophrenia. A receptor-binding profile of the THPB, d.l-govadine (d.l-Gov), reveals high affinity for dopamine and noradrenaline receptors, efficacy as a D2 receptor antagonist, brain penetrance in the 10-300 ng/g range, and thus motivated an assessment of the antipsychotic and pro-cognitive properties of this compound in the rat. Increased dopamine efflux in the prefrontal cortex and nucleus accumbens, measured by microdialysis, is observed following subcutaneous injection of the drug. d.l-Gov inhibits both conditioned avoidance responding (CAR) and amphetamine-induced locomotion (AIL) at lower doses than clozapine (CAR ED50: d.l-Gov 0.72 vs. clozapine 7.70 mg/kg; AIL ED50: d.l-Gov 1.70 vs. clozapine 4.27 mg/kg). Catalepsy is not detectable at low biologically relevant doses, but is observed at higher doses. Consistent with previous reports, acute d-amphetamine disrupts latent inhibition (LI) while a novel finding of enhanced LI is observed in sensitized animals. Treatment with d.l-Gov prior to conditioned stimulus (CS) pre-exposure restores LI to levels observed in controls in both sensitized animals and those treated acutely with d-amphetamine. Finally, possible pro-cognitive properties of d.l-Gov are assessed with the spatial delayed win-shift task. Subcutaneous injection of 1.0 mg/kg d.l-Gov failed to affect errors at a 30-min delay, but decreased errors observed at a 12-h delay. Collectively, these data provide the first evidence that d.l-Gov may have antipsychotic properties in conjunction with pro-cognitive effects, lending further support to the hypothesis that THPBs are a class of compounds which merit serious consideration as novel treatments for schizophrenia.

Block of voltage-gated calcium channels stimulates dopamine efflux in rat mesocorticolimbic system.

Dopamine (DA) efflux from terminals of the mesocorticolimbic system is linked to incentive motivation, drug dependency and schizophrenia. Strategies for modulating dopaminergic activity have focused on transmitter receptors or the DA transporter, not on DA release, largely due to lack of systemically available drugs acting at this level. Central synapses use two main calcium channels for excitation-secretion coupling, either P/Q-type, N-type, or both. Here we investigate changes in mesocorticolimbic DA efflux following administration of NP078585, a novel orally available calcium channel blocker exhibiting high affinity block of N- and T-types versus P/Q- and L-types. NP078585 was applied either intra peritoneally (i.p.; 2.5-10 mg/kg) or by reverse-dialysis (10-25 microM) into either the Ventral Tegmental Area (VTA) or the Nucleus Accumbens (NAc), and the changes in DA levels in both the VTA and NAc were monitored using microdialysis. We found that both systemic and central administration of NP078585, but not vehicle, enhanced DA efflux in the NAc but not the VTA. The enhancement of DA levels was replicated by local applications of omega-conotoxin GVIA (2.5 microM), a selective peptide N-type channel blocker, to either VTA or NAc, suggesting N-type mediation. Furthermore, application of the GABA(A)-selective antagonist bicuculline (50 microM) to the VTA enhanced DA efflux in both VTA and NAc, and occluded the NP078585-induced enhancement in the latter structure. We propose that the actions of NP078585 and omega-conotoxin largely reflect block of N-type channels in terminals of GABAergic interneurons, leading to reduced GABA release, disinhibition of DA neurons and enhanced DA release in the NAc.

Neural circuits engaged in ventral hippocampal modulation of dopamine function in medial prefrontal cortex and ventral striatum.

Dopamine (DA) transmission in the medial prefrontal cortex (mPFC) and nucleus accumbens (NAc) is crucial for various cognitive processes. However, our understanding of the regulation of DA efflux by glutamatergic afferents to these areas is incomplete. Using microdialysis in freely moving rats, we provide evidence in the present study that brief stimulation (20 Hz, 10 s) of the ventral hippocampus potently increases DA efflux in the mPFC, NAc, and ventral tegmental area for 30-40 min. Subsequent experiments show that the stimulation-evoked increase in DA efflux in the mPFC depends on local activation of alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA)/kainate, but not N-methyl-D-aspartate, receptors in the mPFC. Additionally, neural activity and ionotropic glutamate receptor activation in the ventral tegmental area are necessary for ventral hippocampal stimulation to increase mPFC DA efflux. Blocking neural activity or ionotropic glutamate receptors in the ventral tegmental area also attenuated the stimulation-evoked increase in DA efflux in the NAc. Evidence in support of a role for the mPFC in the stimulation-evoked increase in NAc DA was not obtained. Taken together, these observations highlight the important role of the ventral hippocampus in modulating forebrain DA efflux via separate neural circuits.

A top-down perspective on dopamine, motivation and memory.

Dopamine (DA) activity, in the form of increased neural firing or enhanced release of transmitter from nerve terminals and varicosities, is linked to a number of important psychological processes including: movement; hedonic reactions to positive reward; provision of an error detection signal during the acquisition of new learning; response to novel stimuli; provision of reinforcement signals essential for acquisition of new action patterns; and incentive motivation. This review focuses primarily on our research linking dynamic changes in DA efflux on the timescale of minutes, with incentive motivation, as revealed by brain dialysis experiments in behaving animals. Recent experiments on sensory-specific satiety and successive positive and negative contrast are discussed along with the distinction between preparatory behaviors that precede contact with biologically significant stimuli and subsequent consummatory behaviors. The relationship between DA efflux in the medial prefrontal cortex (mPFC) and foraging for food based on working memory is also discussed in support of the conjecture that DA may serve as a link between motivation and memory functions. Evidence in support of 'top-down' regulation of dopaminergic activity in the mesocorticolimbic DA pathways is reviewed briefly to introduce a mechanism by which activation of ascending DA projections in this manner might optimize dopaminergic modulation of executive function within regions such as the mPFC. Collectively, these processes could ensure coordination between cognitive processes that assess current opportunities and the motivational systems that select and engage patterns of approach behavior that bring organisms into contact with the essentials for survival.

Dopamine efflux in the nucleus accumbens during within-session extinction, outcome-dependent, and habit-based instrumental responding for food reward.

RATIONALE: Dopamine (DA) activity in the nucleus accumbens (NAc) is related to the general motivational effects of rewarding stimuli. Dickinson and colleagues have shown that initial acquisition of instrumental responding reflects action-outcome relationships based on instrumental incentive learning, which establishes the value of an outcome. Given that the sensitivity of responding to outcome devaluation is not affected by NAc lesions, it is unlikely that incentive learning during the action-outcome phase is mediated by DA activity in the NAc. OBJECTIVES: DA efflux in the NAc after limited and extended training was compared on the assumption that comparable changes would be observed during both action-outcome- and habit-based phases of instrumental responding for food. This study also tested the hypothesis that increase in NAc DA activity is correlated with instrumental responding during extinction maintained by a conditioned stimulus paired with food. METHODS: Rats were trained to lever press for food (random-interval 30 s schedule). On the 5th and 16th day of training, microdialysis samples were collected from the NAc or mediodorsal striatum (a control site for generalized activity) during instrumental responding in extinction and then for food reward, and analyzed for DA content using high performance liquid chromatography. RESULTS: Increase in DA efflux in the NAc accompanied responding for food pellets on both days 5 and 16, with the magnitude of increase significantly enhanced on day 16. DA efflux was also significantly elevated during responding in extinction only on day 16. CONCLUSIONS: These results support a role for NAc DA activity in Pavlovian, but not instrumental, incentive learning.

Effects of short-term abstinence from escalating doses of D-amphetamine on drug and sucrose-evoked dopamine efflux in the rat nucleus accumbens.

Abstinence from high doses of psychostimulant drugs, in both humans and rodents, is linked to adverse psychological effects including anhedonia, a core symptom of major depression, manifested behaviorally as decreased responding for rewarding stimuli. The present study used brain microdialysis in freely moving rats to examine the effect of D-amphetamine (D-amph) withdrawal on changes in extracellular dopamine (DA) levels in the nucleus accumbens (NAc) evoked by D-amph or behavior related to sucrose consumption. D-amph was administered intraperitoneally (i.p.) according to an escalating dose (ED) schedule (from 1 to 10 mg/kg, 3 doses/day). We first confirmed the development of tolerance by monitoring DA efflux in the NAc in response to 5 and 10 mg/kg doses of D-amph administered during the ED schedule of drug administration and again in response to the 5 mg/kg dose of D-amph 72 h following the last 10 mg/kg D-amph injection. In a separate study, DA efflux in the NAc was first shown to be increased significantly during both preparatory and consummatory phases of responding for a 4% sucrose solution. Withdrawal from the ED schedule of D-amph caused a selective attenuation of DA efflux only during the preparatory phase of the sucrose test. These results provided convincing evidence of neurochemical adaptation within the mesocorticolimbic DA pathway during and following the administration of an ED schedule of D-amph as well as suppressed neurochemical responses to a psychostimulant drug and cues associated with a natural reward after withdrawal from drug treatment. Accordingly, these findings support the hypothesis that downregulation of mesocorticolimbic DA function maintained during D-amph withdrawal may account for the selective disruption of motivated behavior reported in studies employing psychostimulant drug withdrawal as a model of depression in rodents.

Attenuation of d-amphetamine self-administration by baclofen in the rat: behavioral and neurochemical correlates.

RATIONALE: Recent reports have demonstrated that gamma-aminobutyric acid (GABA)-ergic compounds attenuate the reinforcing effects of cocaine in rats. Baclofen, a GABA(B) receptor agonist, appears to be particularly effective in this respect, suggesting that GABA(B) receptor activation is critically involved in mediating anti-cocaine effects. Amphetamine, like cocaine, is a psychomotor stimulant with high abuse potential in humans. OBJECTIVES: The purpose of the present investigation was to determine whether baclofen may attenuate the reinforcing effects of d-amphetamine (dAMPH) in rats. Dose-response curves were generated to examine the effect of three doses of baclofen (1.8, 3.2 or 5.6 mg/kg, IP) on dAMPH intravenous self-administration (IVSA). Separate groups were trained to self-administer two doses of dAMPH (0.1 mg/kg or 0.2 mg/kg per injection) under either a fixed-ratio (FR) or progressive ratio (PR) schedule of reinforcement. Microdialysis was performed in an additional group of rats to examine the effect of baclofen on dAMPH-induced increases in dopamine (DA) efflux in the nucleus accumbens (NAc). RESULTS: Pretreatment with baclofen produced dose-dependent reductions in responding for dAMPH under both the FR and PR schedules, and attenuated dAMPH-induced increases in DA levels in the NAc. CONCLUSION: These results add to previous findings showing that baclofen attenuates the reinforcing effects of psychostimulant drugs, and suggest that further investigation into the effects of GABA(B) receptor agonists on drug self-administration is warranted.

Attenuated dopamine efflux in the rat nucleus accumbens during successive negative contrast.

Rats shifted from 4% to 32% sucrose displayed successive negative contrast by initiating significantly fewer bouts of licking than control rats maintained on 4% sucrose. No significant increase in dopamine (DA) efflux in the nucleus accumbens (NAc) was observed during consumption of 4% sucrose by rats shifted from 32%. In contrast, consumption of 4% sucrose by control rats was accompanied by a significant increase in DA efflux in the NAc, which remained elevated 10 min postconsumption. These data are consistent with the hypothesis that DA efflux in the NAc reflects the current incentive valence of sucrose reward and its influence on initiation of individual bouts of sucrose consumption.