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.

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 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.