Serotonin receptor HTR6-mediated mTORC1 signaling regulates dietary restriction-induced memory enhancement.

Dietary restriction (DR; sometimes called calorie restriction) has profound beneficial effects on physiological, psychological, and behavioral outcomes in animals and in humans. We have explored the molecular mechanism of DR-induced memory enhancement and demonstrate that dietary tryptophan-a precursor amino acid for serotonin biosynthesis in the brain-and serotonin receptor 5-hydroxytryptamine receptor 6 (HTR6) are crucial in mediating this process. We show that HTR6 inactivation diminishes DR-induced neurological alterations, including reduced dendritic complexity, increased spine density, and enhanced long-term potentiation (LTP) in hippocampal neurons. Moreover, we find that HTR6-mediated mechanistic target of rapamycin complex 1 (mTORC1) signaling is involved in DR-induced memory improvement. Our results suggest that the HTR6-mediated mTORC1 pathway may function as a nutrient sensor in hippocampal neurons to couple memory performance to dietary intake.

Neurobiological changes in striatal glutamate are associated with trait impulsivity of differential reinforcement of low-rate-response behavior in male rats.

Impulsive action can be measured using rat's responses on a differential reinforcement of low-rate-response (DRL) task in which performance may be varied between rats. Nevertheless, neurobiological profiles underlying the trait impulsivity of DRL behavior remain largely unknown. Here, in vivo non-invasive proton magnetic resonance spectroscopy (1H-MRS) and Western blot assay were performed to assess neurobiological changes in the dorsal striatum (DS) and nucleus accumbens (NAc) in relation to individual differences in DRL behavior. A cohort of rats was subjected to acquire a DRL task over 14 daily sessions. High impulsive (HI) and low impulsive (LI) rats were screened by behavioral measures displaying a lower response efficiency and performing more nonreinforced responses in HI rats and vice versa. MRS measurements indicated that the HI group had a lower NAc glutamate (Glu) level than did the LI group, whereas no such difference was found in the other five metabolites in this area. Moreover, no intergroup difference was observed in any metabolite in the DS. The results of Western blot assay revealed that protein expressions of GluN1 (but not GluN2B) subunit of N-methyl-D-aspartate receptors in the DS and NAc were higher in the HI group than in the LI group. This inherent timing impulsivity was not attributed to risky behavioral propensity because both Hl and LI rats could acquire a risk-dependent choice. The findings of this study, supported by certain correlations among behavioral, brain imaging, and neuroreceptor indices, provide evidence of the neurobiological changes of striatal Glu underlying trait impulsive action of DRL behavior.

Task-Dependent Effects of SKF83959 on Operant Behaviors Associated With Distinct Changes of CaMKII Signaling in Striatal Subareas.

BACKGROUND: SKF83959, an atypical dopamine (DA) D1 receptor agonist, has been used to test the functions of DA-related receptor complexes in vitro, but little is known about its impact on conditioned behavior. The present study examined the effects of SKF83959 on operant behaviors and assayed the neurochemical mechanisms involved. METHODS: Male rats were trained and maintained on either a fixed-interval 30-second (FI30) schedule or a differential reinforcement of low-rate response 10-second (DRL10) schedule of reinforcement. After drug treatment tests, western blotting assayed the protein expressions of the calcium-/calmodulin-dependent protein kinase II (CaMKII) and the transcription factor cyclic AMP response element binding protein (CREB) in tissues collected from 4 selected DA-related areas. RESULTS: SKF83959 disrupted the performance of FI30 and DRL10 behaviors in a dose-dependent manner by reducing the total number of responses in varying magnitudes. Moreover, the distinct profiles of the behavior altered by the drug were manifested by analyzing qualitative and quantitative measures on both tasks. Western-blot results showed that phospho-CaMKII levels decreased in the nucleus accumbens and the dorsal striatum of the drug-treated FI30 and DRL10 subjects, respectively, compared with their vehicle controls. The phospho-CREB levels decreased in the nucleus accumbens and the hippocampus of drug-treated FI30 subjects but increased in the nucleus accumbens of drug-treated DRL10 subjects. CONCLUSIONS: Our results provide important insight into the neuropsychopharmacology of SKF83959, indicating that the drug-altered operant behavior is task dependent and related to regional-dependent changes of CaMKII-CREB signaling in the mesocorticolimbic DA systems.

Lack of effect of dopamine receptor blockade on SKF83959-altered operant behavior in male rats.

Dopamine (DA) is important for the performance of operant behavior as revealed by psychopharmacological studies that manipulate the activity of DA subtype receptors. However, the effects of SKF83959, an atypical DA D1 receptor agonist, on operant behavior and the underlying pharmacological mechanisms remain unclear. The present study sought to determine whether blockade of DA D1- and D2-subtyped receptors would reverse the operant behavior altered by SKF83959. Male rats were trained to respond on either a fixed-interval 30 s (FI30) schedule or a differential reinforcement of low-rate response 10 s (DRL10) schedule, two timing-relevant tasks but with distinct reinforcement contingencies. Pharmacological evaluation was conducted with injection of a selective D1 (or D2) receptor antagonist alone or in combined with SKF83959 (1.0 mg/kg) following a stable baseline of behavioral performance. The results showed that SKF83959 treatment alone significantly disrupted the performance of FI30 and DRL10 behaviors mainly by showing the decreases of the response-related measures, and the distinct profiles of the behavior altered by the drug were manifested by the qualitative analysis of inter-response time data on both tasks. The effects of SKF83959 were not significantly affected/reversed by the pretreatment of either SCH23390 or eticlopride injected at the doses of 0.02 and 0.06 mg/kg; however, a subtle reversal effect was observed in the treatment of low-dose eticlopride. Despite that these results confirm the FI30 and DRL10 behaviors changed by SKF83959, the absence of pharmacological reversal effect by DA receptor antagonist suggests that either D1- or D2-subtyped receptors may not play a critical role in the alteration of timing-relevant operant behavior produced by SKF83959.

Delayed extinction and stronger drug-primed reinstatement of methamphetamine seeking in rats prenatally exposed to morphine.

Prenatal morphine (PM) affects the development of brain reward system and cognitive function. The present study aimed to determine whether PM exposure increases the vulnerability to MA addiction. Pregnant Sprague-Dawley rats were administered saline or morphine during embryonic days 3-20. The acquisition, extinction and reinstatement of methamphetamine (MA) conditioned place preference (CPP) and intravenous self-administration (SA) paradigms were assessed in the male adult offspring. There was no difference in the acquisition and expression of MA CPP between saline- and PM-exposed rats, whereas PM-exposed rats exhibited slower extinction and greater MA priming-induced reinstatement of drug-seeking behavior than controls. Similarly, MA SA under progressive ratio and fixed ratio schedules was not affected by PM exposure, but PM-exposed rats required more extinction sessions to reach the extinction criteria and displayed more severe MA priming-, but not cue-induced, reinstatement. Such alterations in extinction and reinstatement were not present when PM-exposed rats were tested in an equivalent paradigm assessing operant responding for food pellets. Our results demonstrate that PM exposure did not affect the association memory formation during acquisition of MA CPP or SA, but impaired extinction learning and increased MA-primed reinstatement in both tasks. These findings suggest that the offspring of women using morphine or heroin during pregnancy might predict persistent MA seeking during extinction and enhanced propensity to MA relapse although they might not be more susceptible to the reinforcing effect of MA during initiation of drug use.

Dissociable contribution of nucleus accumbens and dorsolateral striatum to the acquisition of risk choice behavior in the rat.

While a growing body of research has suggested that the mesocorticolimbic dopamine systems play a key role in decision making under risk, how the nucleus accumbens (NAC) is involved in the acquisition of risk choice behavior remains unclear. This study used a T-maze task to assess risk-based decision making in which the rat was required to assess the risk by choosing to enter either a small and certain reward arm or a large but uncertain reward arm of the maze. The latter option, when chosen, resulted in provision of 2, 4, or 8 sweeten pellets with a probability (p) of 0.5, 0.25, or 0.125, respectively. Thus the latter arm provided three different conditions of reward ratio, compared to the choice of former arm, which always provided 1 pellet with p=1. This risk choice task was then run with the expected value being equality between the binary choice options. The experimental rats first received an excitoneurotoxic lesion affecting either the NAC or the dorsolateral striatum (DLS) and this was followed by post-lesion behavioral examination. The sham lesion control rats acquired a stable risk choice with regard to each reward ratio over a 10-day test. The pattern of choice behavior appeared in risk-seeking when p=0.5 to obtain 2 pellets, and was risk-averse when larger reward resulted in lower p. The NAC lesion significantly disrupted the acquisition of the aforementioned risk choice behavior and apparently shifted the choice into a risk-averse style for all three reward ratios. No such effect was observed in the rats with DLS lesions. Neither the gross motor action nor the discrimination of different reward magnitudes was impaired by the lesions affecting either the NAC or DLS as assessed by an additional experiment. These findings suggest that firstly there is heterogeneity between NAC and DLS with respect to risk-based decision making, and that secondly the NAC is involved and critical to the acquisition of behavioral choice under risk, specially when the expected value of the reward under the two choice options is equal.

Interval timing relative to response inhibition in the differential reinforcement of low-rate responding in normally developing young adults.

With recent proposal suggesting the multifaceted nature of impulsivity, researchers have been intrigued by the question of whether the impulsive behaviour measured in the traditionally psychological paradigms is unitary. One such paradigm, the differential reinforcement of low-rate responding (DRL), has been used to assess response inhibition, but its underlying mechanism has still been debated. In present research, we examined and differentiated the effects of both response inhibition and interval timing on a multisession DRL-10 s (DRL-10 s) in a large sample of normally developing young adults, as well as with three other measures including the stop-signal reaction task (SSRT), time production task-10 s (TPT-10 s), and the Barrett impulsivity scale-11 (BIS-11). The results showed that behavioural changes existed in DRL. As the task sessions progressed, there was an increase in both reinforcement probability and peak time, but a decrease in burst responses. Most importantly, both principal component analysis and generalized multilevel modeling yielded consistent results that as the task progressed, there was an increasing involvement of the TPT in the late sessions of DRL. However, none of the effect of SSRT was found. In sum, the differential degrees of involvement of the timing process, relative to response inhibition, were observed in DRL.

Neural basis of operant behaviors maintained on the differential-reinforcement-of-low-rate (DRL) schedule in rodents.

Various schedules of reinforcement have long been used in experimental psychology to establish and maintain operant behaviors. These reinforcement contingencies have also been widely applied in preclinical psycho- and neurobiology research. However, the differential reinforcement of low-rate response (DRL) schedule has received less attention than other schedules based on response ratios or different types of intervals. Hence, little is known about the neural basis of DRL schedule-controlled behavior. Herein, we review early and recent reports of rodent experiments utilizing brain lesions and intracranial drug infusions to respectively elucidate the neural substrates and neuropharmacological basis of DRL behavior. Overall, the available evidence implies that 1) certain cortical and subcortical areas are differentially involved in the DRL behavior and 2) disruption of dopamine or serotonin neurotransmission alters DRL behavior. We further identify remaining challenges in the field and suggest future work that will be helpful for understanding the neurobehavioral mechanisms of the DRL schedule of reinforcement.

Comparative effects of cannabinoid CB1 receptor agonist and antagonist on timing impulsivity induced by d-amphetamine in a differential reinforcement of low-rate response task in male rats.

RATIONALE: In human beings and experimental animals, maladaptive impulsivity is manifested by the acute injection of psychostimulants, such as amphetamine. Cannabinoid CB1 receptors have been implicated in the regulation of stimulant-induced impulsive action, but the role of CB1 receptors in timing-related impulsive action by amphetamine remains unknown. METHODS: Male rats were used in evaluating the effects of CB1 receptor antagonist and agonist (SR141716A and WIN55,212-2, respectively) systemically administered individually and combined with d-amphetamine on a differential reinforcement of low-rate response (DRL) task, an operant behavioral test of timing and behavioral inhibition characterized as a type of timing impulsive action. RESULTS: A distinct pattern of DRL behavioral changes was produced by acute d-amphetamine (0, 0.5, 1.0, and 1.5 mg/kg) treatment in a dose-dependent fashion, whereas no significant dose effect was detected for acute SR141716A (0, 0.3, 1, and 3 mg/kg) or WIN55,212-2 (0, 0.5, 1, and 2 mg/kg) treatment. Furthermore, DRL behavior altered by 1.5 mg/kg d-amphetamine was reversed by a noneffective dose of SR141716A (3 mg/kg) pretreatment. The minimally influenced DRL behavior by 0.5 mg/kg d-amphetamine was affected by pretreatment with a noneffective dose of WIN55,212-2 (1 mg/kg). CONCLUSION: These findings reveal that the activation and blockade of CB1 receptors can differentially modulate the timing impulsive action of DRL behavior induced by acute amphetamine treatment. Characterizing how CB1 receptors modulate impulsive behavior will deepen our understanding of the cannabinoid psychopharmacology of impulsivity and may be helpful in developing an optimal pharmacotherapy for reducing maladaptive impulsivity in patients with some psychiatric disorders.

Dopamine receptor antagonists impair place conditioning after acute stress in rats.

An immediate and robust release of dopamine appears in the brain under an acute stressor, but the functional role of dopamine under stress remains elusive. We recently showed conditioned place preference (CPP) induced by the acute application of a stressor such as being placed on an elevated stand or immobilized in a restraint holder. This study tested whether dopamine is involved in such CPP. The selective dopamine D1 and D2 receptor antagonists, SCH23390 and raclopride, respectively, were injected before stressor manipulation. The doses of SCH23390 (0.025 and 0.05 mg/kg) and raclopride (0.05 and 0.1 mg/kg) used to test for stressor-induced CPP were verified to be ineffective on spontaneous locomotor activity. The results showed that both drugs attenuated the development of stressor-induced CPP. Such a CPP blocking effect by pretreatment of dopamine receptor antagonist was true for either kind of stressor manipulated. These findings indicate that an acute stressor can facilitate a follow-up place conditioning, and that dopamine is involved in the present type of CPP formation.

Examination of the effects of SCH23390 and raclopride infused in the dorsal striatum on amphetamine-induced timing impulsivity measured on a differential reinforcement of low-rate responding (DRL) task in rats.

Although the striatal dopamine (DA) is reportedly involved in impulsive action, little is known about the DA subtype receptors of dorsal striatum (dSTR) in the impulsive control involved in differential reinforcement of low-rate-responding (DRL) behavior. We examined the receptor-specific dopaminergic modulation of d-amphetamine (AMP)-altered DRL 10 s (DRL-10 s) performance by locally infusing SCH23390 (SCH) and raclopride (RAC), DA D1 and D2 receptor antagonists, respectively, into the rat's dSTR. Systemic injection of AMP significantly affected DRL-10 s behavior by increasing total, non-reinforced, and bust responses, as well as by decreasing reinforced responses, which correspondingly caused a leftward shift of the inter-response-time distribution curve as confirmed by a profound decrease in peak time (i.e., <10 s). Neither SCH nor RAC into dSTR pharmacologically reversed the timing impulsivity produced by AMP as measured by non-reinforced responses and peak time. However, the increase in total responses and the decrease in reinforced responses by AMP were reversed by intra-dSTR SCH or RAC. These results suggest that the D1 and D2 receptors of the dSTR may be involved in behavioral components apart from the timing impulsivity produced by AMP on a DRL task, which components are distinctly different from those in other terminal areas of midbrain DA systems.

Task-Dependent Differences in Operant Behaviors of Rats With Acute Exposure to High Ambient Temperature: A Potential Role of Hippocampal Dopamine Reuptake Transporters.

Behavioral or cognitive functions are known to be influenced by thermal stress from the change in ambient temperature (Ta). However, little is known about how increased Ta (i.e., when the weather becomes warm or hot) may affect operant conditioned behavior and the neural substrates involved. The present study thus investigated the effects of high Ta on operant behaviors maintained on a fixed-ratio 1 (FR1) and a differential reinforcement for low-rate responding 10 s (DRL 10-s) schedule of reinforcement. The rats were randomly assigned to three groups receiving acute exposure to Ta of 23°C, 28°C, and 35°C, respectively, for evaluating the effects of high Ta exposure on four behavioral tests. Behavioral responses in an elevated T-maze and locomotor activity were not affected by Ta treatment. Regarding operant tests, while the total responses of FR1 behavior were decreased only under 35°C when compared with the control group of 23°C, those of DRL 10-s behavior were significantly reduced in both groups of 28°C and 35°C. Distinct patterns of inter-response time (IRT) distribution of DRL behavior appeared among the three groups; between-group differences of behavioral changes produced by high Ta exposure were confirmed by quantitative analyses of IRT data. Western blot assays of dopamine (DA) D1 and D2 receptor, DA transporter (DAT) and brain-derived neurotrophic factor (BDNF) were conducted for the sample tissues collected in six brain areas from all the subjects after acute high Ta exposure. Significant Ta-related effects were only revealed in the dorsal hippocampus (dHIP). In which, the DAT levels were increased in a Ta-dependent fashion that was associated with operant behavior changes under high Ta exposure. And, there as an increased level of D1 receptors in the 28°C group. In summary, these data indicate that the performance of operant behavior affected by the present high Ta exposure is task-dependent, and these changes of operant behaviors cannot be attributed to gross motor function or anxiety being affected. The regulation of dHIP DAT may be involved in this operant behavioral change under high Ta exposure.

Development of conditioned place preference induced by intra-accumbens infusion of amphetamine is attenuated by co-infusion of dopamine D1 and D2 receptor antagonists.

The present study investigated the role of dopamine receptors within the nucleus accumbens in place conditioning induced by D-amphetamine. Previous work has shown that conditioned place preference can be established by intra-accumbens infusion of amphetamine. The present study further examined whether bilateral co-infusion of the selective dopamine receptor antagonists with D-amphetamine into this region would disrupt the development of conditioned place preference induced by intra-accumbens amphetamine treatment. Bilateral infusions of D-amphetamine into the nucleus accumbens at the dose of 10 microg per side significantly induced conditioned place preference. At the tested doses of 1 microg and 10 microg, either the selective D1 dopamine receptor antagonist (SCH23390) or the selective D2 dopamine receptor antagonist (raclopride) infused with the high dose into the nucleus accumbens significantly blocked the development of conditioned place preference induced by intra-accumbens amphetamine treatment. Furthermore, the sole infusion of SCH23390 or raclopride into the nucleus accumbens produced little or no place conditioning effect. It is concluded that the dopamine D1 and D2 receptors in the nucleus accumbens are critically involved in the development of amphetamine induced conditioned place preference.

Differential effects of lesions in the subareas of medial prefrontal cortex on the development of behavioral sensitization to amphetamine: the role of environmental context.

Based on the notion of the heterogeneity of the medial prefrontal cortex (mPFC), the effects of lesions of the dorsal and ventral subareas of mPFC were examined on the development of behavioral sensitization induced by d-amphetamine (AMP). The first part of this study determined behavioral sensitization to AMP by the use of the rat with intermittent repeated AMP administrations in three types of environmental context including an infrared locomotor activity test-box, the home cage, and a novel third place. In experimental groups, each subject was initially injected with AMP of 0.5 mg/kg as the pretest treatment and then received seven injections of AMP (1 mg/kg) every other day in the context where it was assigned. Following two days of withdrawal, the subject was challenged by AMP of 0.5 mg/kg as the post-test treatment. Behavioral sensitization to AMP on the locomotor activity was determined by the difference between pre- and post-test. The results showed that the most profound locomotor sensitization to AMP appeared in the test box group. A less but significant degree of locomotor sensitization to AMP was observed for the home cage group. A trend of locomotor sensitization to AMP observed in the novel third place group was not statistically confirmed. In the second part of experiment, we then investigated the effects of lesions in the dorsal and ventral mPFC subareas on the development of locomotor sensitization to AMP in the test box and home cage. Results showed that locomotor sensitization was significantly appeared in every sham-operated control group tested in either test box or home cage. Lesions of ventral mPFC significantly inhibited the development of locomotor sensitization to AMP in test box, but not in home cage. Lesions of dorsal mPFC failed to affect AMP locomotor sensitization developed in either test box or home cage. These data indicate that the heterogeneous functions of mPFC subareas involved in the development of behavioral sensitization to AMP are dependent on different contexts applied for repeated intermittent drug administration.

Effects of d-amphetamine on risk choice in rats depend on the manner in which the expected reward value is varied.

Decision making related to risks and rewards has been studied in the rodent by using several behavioral tests including the use of probability discounting tasks. However, it still remains unclear how long-term values and the different levels of risk are involved in decisions with reward uncertainty. In this study, we used a T-maze choice task to investigate the role of expected reward values in decision making under risk in the rat. The task was specifically set up to run with the expected value (EV) being equal to 1 between binary choice options (small-and-certain vs. large-but-risky rewards). The tests were carried out by providing three reward ratios that represented different levels of riskiness. Moreover, by varying the reward probabilities, the EV of the large-but-risky choice option that was set at either 0.5 or 2 was manipulated to determine whether choice could be influenced by the contrast between unequal EVs. Results demonstrated that the rats were able to distinguish different EVs because they clearly chose the option with a relatively larger EV (2 > 1 and 1 > 0.5). By way of contrast, risk-dependent choice appeared when the EVs were equal; in particular, risk-prone choice was made in a low-risk state, whereas risk-averse choice was made in a high-risk state. The systemic injection of d-amphetamine slightly increased the large-but-risky choices only under the high-risk condition in which the EVs were set to be equal; d-amphetamine did not affect the risk choices in the other two EVs set unequal. Overall, the present results implicate that the contrasts for unequal EVs and the different levels of risk are decision parameters critically involved in the rat's choice. And, relatively low doses of d-amphetamine did not have much of an effect on the present model of risk choice.

Dopamine receptor antagonists reverse amphetamine-induced behavioral alteration on a differential reinforcement for low-rate (DRL) operant task in the rat.

Previous studies have shown that amphetamine significantly alters operant responding on the behavior maintained on a schedule of differential reinforcement of low-rate (DRL). As such, behavioral deficiency of DRL responding has been observed by the drug-induced increase of non-reinforced responses and a leftward shift of inter-response time (IRT) curve on DRL responding in the rat. However, the neurochemical basis for amphetamine-induced DRL behavioral alternations remain to be elucidated. The present study was then designed to examine whether the effects of amphetamine were dependent on dopamine-subtyped receptors, this was carried out by the co-administration of the selective D1 and D2 receptor antagonists, SCH23390 and raclopride respectively. Rats were first trained to perform on DRL 10-sec task and then divided into four groups, which received separate types of double injections before the behavioral session. The four groups were the saline control group, the amphetamine alone group, the dopamine antagonist alone group, and the combination of [corrected] amphetamine and dopamine antagonist group. The saline control group performed DRL responding in an efficient manner with a major index for the peak time of the IRT curve, which was fairly localized within the 10-sec bin throughout the test phase. The subjects injected with amphetamine (1 mg/kg) significantly shortened IRT that led to a leftward shift of IRT curve, which was further revealed by a decreased peak time without significant effectiveness on the peak rate and burst response. Even though the group given SCH23390 or raclopride alone showed profound disruption on DRL behavior by flattening the IRT curve, the co-administration of amphetamine with SCH23390 or raclopride reversed the aforementioned amphetamine-induced behavioral deficiency on DRL task. Together, these results suggest that the dopamine D1 and D2 receptors are involved and important to the temporal regulation of DRL response under psychostimulant drug treatment. Furthermore, this highlights the involvement of the brain dopamine systems in the temporal regulation of DRL behavior performance.

Regional differences in dopamine receptor blockade affect timing impulsivity that is altered by d-amphetamine on differential reinforcement of low-rate responding (DRL) behavior in rats.

The ability to control when to start an action and when to stop is crucial in human and animal behavior. A failure to suppress premature behavior or to carry out an action in a timely manner is commonly seen in several neuropsychological disorders. Despite the phenomenon, the exact neural mechanisms underlying this timing impulsivity remain to be elucidated. Systemic injection of d-amphetamine (AMP) has been shown to disrupt rat's performance in the differential reinforcement of low-rate (DRL) task that requires both optimal timing and proper impulsive control as measured by peak time and non-reinforced responses, respectively. By directly infusing selective D1 or D2 receptor antagonists (SCH23390 and raclopride, respectively) into three brain areas, we aimed to uncover which brain regions and which dopamine receptor subtypes are involved in counteracting the rat's deficit of DRL performance induced by the systemic injection of AMP. We found that D1, but not D2 receptors in the dorsal hippocampus (dHIP) and nucleus accumbens (NAC) played an important role in impulsive control as well as in timing. In the medial prefrontal cortex (mPFC), both D1 and D2 receptors played an equal role in impulsive control, but only mPFC D1 was critical in the control of timing. Together, our data revealed a regional-dependent and dopamine receptor subtype specific effect across each region tested in the mesocorticolimbic circuits on the deleterious effect of AMP in the DRL task. The current findings further advance our understanding of the neurobehavioral mechanisms involved in timing impulsivity.

Acute effects of d-amphetamine on the differential reinforcement of low-rate (DRL) schedule behavior in the rat: comparison with selective dopamine receptor antagonists.

Amphetamine and it analogs have been shown to affect operant behavior maintained on the differential reinforcement of a low-rate (DRL) schedule. The aim of the present study was to investigate what specific component of the DRL response is affected by d-amphetamine. The acute effects of d-amphetamine on a DRL task were compared with those of the selective dopamine D1 and D2 receptor antagonists, SCH23390 and raclopride, respectively. Pentylenetetrazole and ketamine were also used as two reference drugs for comparison with d-amphetamine as a psychostimulant. Rats were trained to press a lever for water reinforcement on a DRL 10-s schedule. Acute treatment of d-amphetamine (0, 0.5, and 1.0 mg/kg) significantly increased the response rate and decreased the reinforcement in a dose-related fashion. It also caused a horizontal leftward shift in the inter-response time (IRT) distribution at the doses tested. Such a shifting effect was confirmed by a significant decrease in the peak time, while the mean peak rate and burse response remained unaffected. In contrast, both SCH23390 (0, 0.05, and 0.10 mg/kg) and raclopride (0, 0.2, and 0.4 mg/kg) significantly decreased the total, non-reinforced, and burst responses. The de-burst IRT distributions were flattened out as shown by the dose-related decreases in the mean peak rate for both dopamine antagonists, but no dramatic shift in peak time was detected. Interestingly, neither pentylenetetrazole (0, 5, and 10 mg/kg) nor ketamine (0, 1, and 10 mg/kg) disrupted the DRL behavioral performance. It is then conceivable that d-amphetamine at the doses tested affects the temporal regulation of DRL behavior. The effectiveness of d-amphetamine is derived from its drug action as a psychostimulant. Taken together, these data suggest that different behavioral components of DRL task are differentially sensitive to pharmacological manipulation.

Differential effects of dopamine receptor subtype-specific agonists with respect to operant behavior maintained on a differential reinforcement of low-rate responding (DRL) schedule.

Previous studies have shown that d-amphetamine, a dopamine (DA) indirect agonist, alters operant responding with respect to the behavior maintained on a differential reinforcement of low-rate (DRL) schedule of reinforcement. These behavioral changes have been presumed to result from drug-induced hyperdopaminergia that leads to activation of DA receptors. This study investigated the acute dose effects of DA receptor subtype-selective agonists on the performance of DRL 10-sec behavior by rats. SKF38393 (a D1 receptor agonist) and quinpirole (a D2/D3 receptor agonist) were able to dose-dependently disrupt DRL 10-sec behavior by decreasing the total responses, the non-reinforced responses, and the peak rate of response. Bromocriptine (a D2/D3 receptor agonist) produced a significantly different pattern of behavioral changes when examined during two distinct time phases (15 min and 3 hr after the drug injection). DRL responding was only altered at higher doses of bromocriptine in the second phase as indicated by decreasing reinforced responses and peak rate, together with an increase of burst responses. In contrast to the D1 and D2/D3 receptor agonists, PD168077 (a D4 receptor agonist) did not affect DRL 10-sec behavior. None of these tested drugs affected DRL 10-sec behavior in a manner similar to that of d-amphetamine. These findings show that there are differential effects on the performance of DRL 10-sec behavior when drugs are able to preferentially activate D1, D2/D3 and D4 receptors, supporting the assertion that there is functional heterogeneity of the DA receptor subtypes.

Differential effects of diazepam infused into the amygdala and hippocampus on negative contrast.

Behavioral suppression is observed when animals shift from a high to a lower magnitude of reward in comparison to animals that continuously receive the lower magnitude reward. As previously reported, systemic administration of benzodiazepines promotes recovery from this negative contrast. This study aimed to assess where the neural substrate(s) located in the limbic areas for diazepam to induce such recovery effects on negative contrast. With food-deprived rats, the negative contrast procedure was conducted by comparing a group consuming a 32% sucrose solution which was shifted to 4% with a group consuming only 4% sucrose throughout the experiment. Represented mainly by a decreased number of licks, the negative contrast effects were clearly shown in the control groups receiving the vehicle. Systemic injection of diazepam dose-dependently reduced this contrast. Further, this negative contrast effect was significantly attenuated by local infusion of diazepam (30 microg) into the amygdala, but no such effect was confirmed when diazepam was infused into the hippocampus. Together, the present study shows that a reliable anti-contrast effect can be induced by diazepam administration peripherally or locally infused into the amygdala. These data indicate that the amygdala is involved in the recovery effects of benzodiazepines on consummatory negative contrast.