The effects of prenatal cocaine exposure and gender on inhibitory control and attention

Children exposed prenatally to cocaine show deficits in emotion regulation and inhibitory control. While controlling for the measures of medical complication in the perinatal period, environmental risk, and prenatal polydrug exposure (alcohol, tobacco, and marijuana), we examined the effects of prenatal cocaine exposure and gender on attention and inhibitory control in 203 children at ages 6, 9, and 11. Cocaine exposure affected the performance of males, but not females. Heavily exposed males showed deficits in the attention and the inhibition tasks. In addition, a significantly greater proportion of heavily exposed males (21%) than unexposed males (7%) or heavily exposed females (7%) failed to complete the task (p < 0.01). Even without those poorest performing subjects, the overall accuracy for heavily exposed males (81%) was significantly reduced (p < 0.05) compared to lightly exposed males (87%) and unexposed males (89%). The findings highlight the importance of considering gender specificity in cocaine exposure effects. Processes by which cocaine effects may be specific to males are discussed.     

Effect of intranasally administered cholecystokinin on encoding of controlled and automatic memory processes

RATIONALE: The neuropeptide cholecystokinin (CCK) is present in abundance in the central nervous system, where it is involved in the regulation of a wide range of functions. It also takes part in the modulation of memory processes, but its effect on human memory systems and processes is not yet well understood. OBJECTIVE: The present experiment was conducted to examine the influence of CCK when present during encoding on later controlled and automatic recognition memory processes in humans. MATERIALS AND METHODS: A version of the process dissociation procedure was used to separate the contributions of controlled and automatic memory processes to participants' recognition memory performance. Data were analyzed within a multinomial modeling framework. Participants (N = 64) received either 40 mug CCK-8S or placebo intranasally. The learning and test phases began 30 min after substance application. Behavioral, physiological, and self-report control variables were measured at three points of time during the experiment. RESULTS: Compared to placebo, CCK increased the automatic, familiarity-based recognition memory component, while the parameter representing controlled, retrieval-based processes did not differ between groups. Also, in the exclusion condition of the test phase, the guessing parameter was reduced by CCK. None of the control variables were affected by the peptide. CONCLUSIONS: This result-the enhancement of the automatic recognition memory component when CCK is applied before encoding (and thus present during encoding and retrieval)-complements earlier results indicating that CCK decreases controlled, recollection-based recognition memory when applied during consolidation. The possible neuronal systems and processes mediating these effects are discussed.     

Compensating for alcohol-induced impairment of control: effects on inhibition and activation of behavior

Rationale Studies have shown that expectations of alcohol-induced impairment can produce adaptive responses to alcohol that reduce the degree of behavioral impairment displayed. However, compensatory effects have been variable for cognitive and psychomotor tasks. Objectives Using a model-driven approach to understanding behavioral control, the present study examined compensatory and impairment effects following the expectation and actual administration of alcohol on the ability to inhibit and activate behavior. Methods Social drinkers (N=17) performed a cued go/no-go task that required quick responses to go targets and inhibition of responses to no-go targets under four conditions: no treatment, alcohol expectancy (placebo), 0.45 g/kg alcohol, and 0.65 g/kg alcohol. Results Inhibitory and activational aspects of behavioral control were impaired by both active doses of alcohol. Alcohol slowed response activation and increased failures to inhibit responses in a dose-dependent manner. Subjects also displayed a small, but statistically significant, compensatory improvement in inhibitory control in response to the expectation of alcohol. Moreover, individual differences in the compensatory response were related to differences in alcohol impairment. Those who displayed greater compensatory responses to placebo displayed the least impairment in response to alcohol. Conclusions By modeling behavioral control as the net effect of countervailing activational and inhibitory influences, the study suggests that fundamental mechanisms of control might not display uniform compensatory reactions to alcohol-related cues. Greater consideration of how alcohol-related expectancies shape behaviors under the drug should lead to a better understanding of individual differences with respect to risk for alcohol abuse.     

Disruptive effects of muscimol infused into the basal forebrain on conditional discrimination and visual attention: differential interactions with cholinergic mechanisms

The behavioural effects of GABAergic manipulation of the basal forebrain were investigated using two behavioural tasks, which previous studies have shown to yield dissociable effects following quisqualate-induced lesions of the basal forebrain: a five-choice serial reaction time task, involving approaching the location of a brief visual stimulus that is associated with reward; and a conditional visual discrimination task, requiring retrieval of information about a discriminative stimulus that stays constant over time. Following acquisition of the tasks, chronic guide cannulae were stereotaxically implanted into the basal forebrain. Those animals trained on the conditional visual discrimination task showed a dose-dependent reduction in choice accuracy and a lengthening of latency to respond correctly to the visual stimulus following administration of the GABA-A agonist, muscimol (1, 2, 3 ng/µl/hem). While certain of these deficits, for example response latency, could be restored to control levels by co-administration of the GABA-A antagonist, bicuculline, none of the behavioural impairments could be significantly attenuated by systemic co-administration of the cholinesterase inhibitor, physostigmine (0.05, 0.1, 0.2 mg/kg, IP). Similarly, a dose dependent effect of muscimol (1, 1.5, 2 ng/µl/hem) on choice accuracy and correct response latency was observed on performance of the five-choice attentional task. However, in contrast to the conditional task, significant attenuation of the impairment in choice accuracy was obtained following administration of physostigmine (0.05 and 0.1 mg/kg). Attenuation of muscimol-induced deficits by administration of bicuculline was also observed. It is therefore evident that although manipulation of GABAergic activity in the region of the basal forebrain produces profound deficits in different tasks of cognitive function, only some of these may be due to modulation of the magnocellular cholinergic projection to the neocortex.     

Alcohol-induced impairment of behavioral control: differential effects on engaging vs. disengaging responses

Rationale Model-based assessments of behavioral control have been used to study the acute effects of alcohol on the ability to execute and inhibit behavioral responses. Response inhibition appears more vulnerable to the impairing effects of alcohol than response execution. Current information processing models have yet to account for this observation. Objectives The present study used a reductionist approach to determine if the particular vulnerability of response inhibition to the effects of alcohol occurs at the level of the action (motor program). The study examined the effects of alcohol on the ability to execute and inhibit behavior in a context in which preliminary information signaled the likelihood that a response should be executed or suppressed. The engagement and disengagement of responses were directly compared under alcohol. Methods Adults (N=24) performed a cued go/no-go task that required quick responses to go targets and suppression of responses to no-go targets. Response requirements were manipulated by varying the nature of the action required whereby half of the participants made key press responses (response engagement) and the other half released ongoing key presses (response disengagement). Performance was tested under three doses of alcohol: 0.00, 0.45, and 0.65 g/kg. Results Dose-dependent increases in commission errors were only observed with response engagement and not with response disengagement. Reaction times were faster for response engagement than response disengagement. Conclusions Response disengagement affords some protection against alcohol-induced impairment of inhibition, indicating that not all aspects of motor processing requiring inhibition are equally impaired by alcohol.     

Specific inhibitory effects of myricetin on human proton-coupled folate transporter: Comparison with its effects on rat proton-coupled folate transporter and human riboflavin transporter 3

Myricetin is a flavonoid that inhibits human proton-coupled folate transporter (hPCFT) in a transient manner, in which inhibition is manifested in its presence, and also in a sustained manner, in which inhibition induced in its presence persists after its removal. In an effort to elucidate the mechanisms involved in those, we examined if myricetin might or might not act similarly on some other transporters. Transporters examined for that, in comparison with hPCFT, were its rat ortholog (rPCFT) and human riboflavin transporter 3 (hRFVT3). Experiments were conducted, using human embryonic kidney 293 cells transiently expressing the transporter to be examined, to assess the effects of myricetin (100 μM) on the uptake of folate by the PCFTs and riboflavin by hRFVT3. For hPCFT, myricetin was confirmed to induce a transient inhibition and also a sustained inhibition. However, myricetin induced neither transient nor sustained type of rPCFT inhibition. hRFVT3 was inhibited by myricetin in a transient manner, but not in a sustained manner. These results suggest the involvement of a hPCFT-specific mechanism in the sustained inhibition. The transient inhibition may be induced by a mechanism specific to hPCFT and also hRFVT3.     

Detection of visual signals by rats: effects of chlordiazepoxide and cholinergic and adrenergic drugs on sustained attention

Central cholinergic and adrenergic pathways support the attentional processes necessary for detecting and reporting temporally unpredictable stimuli. To assess the functional effects of pharmacological manipulations of these pathways, male Long-Evans rats performed a two-choice, discrete-trial signal-detection task in which food was provided for pressing one lever after presentation of a signal (a 300-ms light flash), and for pressing a second lever at the end of a trial lacking a signal. Seven signal intensities were presented during each 1-h session in a pseudo-random order across three 100-trial blocks. After acquisition of a stable performance baseline, the acute effects of chlordiazepoxide (0, 3, 5, 8 mg/kg IP), pilocarpine (0, 1.0, 1.8, 3.0 mg/kg SC), scopolamine 0, 0.030, 0.056, 0.100 mg/kg SC), nicotine (0, 0.08, 0.25, 0.75 mg/kg SC), mecamylamine (0, 1.8, 3.0, 5.6 mg/kg IP), clonidine (0, 0.003, 0.010, 0.030 mg/kg SC), and idazoxan (0, 1, 3, 10 mg/kg SC) were assessed. Five measures of performance were analyzed: response failures; the proportion of “hits” [P(hit): the proportion of correct responses on signal trials]; the proportion of “false alarms” [P(fa): the proportion of incorrect responses on non-signal trials]; and response times (RT) for hits and for correct rejections. All drugs which slowed responding affected RT for hits and correct rejections equivalently, suggesting little or no influence of motor slowing on choice accuracy. Chlordiazepoxide reduced P(hit) at low signal intensities only, without affecting P(fa) or RT, consistent with sensory impairment (reduced visual sensitivity). All other drugs except nicotine reduced P(hit) at high signal intensities preferentially, suggesting a non-visual source of the impairment. Scopolamine, mecamylamine and clonidine affected both P(hit) and P(fa); pilocarpine and idazoxan reduced P(hit) without affecting P(fa). Nicotine at 0.75 mg/kg decreased P(hit) in the first block of trials; at 0.08 mg/kg it increased P(hit) in the second block; no dose affected P(fa). RTs were increased by pilocarpine, scopolamine, mecamylamine and clonidine, but not by nicotine or idazoxan. The data suggest that drugs which reduce cholinergic or adrenergic tone (scopolamine, mecamylamine and clonidine) impair sustained attention by decreasing the detection of signals and by increasing the false alarm rate, whereas drugs which elevate cholinergic or adrenergic tone (pilocarpine, nicotine and idazoxan) decrease attention by impairing detection of signals without affecting the false alarm rate. In contrast, the GABA-facilitating drug chlordiazepoxide appeared to affect visual thresholds rather than attention. Received: 16 October 1996 /Final version: 16 May 1997     

The effects of chronic postweaning amphetamine on rats exposed to alcohol in utero: Weight gain and behavior

Offspring of rats fed alcohol, pair-fed, or fed ad lib control diets during pregnancy were administered a dose of amphetamine (0, 2 or 10 mg/kg) daily from postnatal day 22 (PN22) to PN42. Body weight was measured regularly from PN22 to PN60, and behavior was measured on PN22, PN28, PN36 and PN42. Rats exposed to alcohol in utero weighed less than controls at birth and throughout most of the experiment, despite a significantly accelerated weight gain relative to controls. By PN60, prenatal alcohol-exposed rats weighed the same as pair-fed controls. There were dose-dependent reductions in the rate of weight gain during amphetamine administration. After the daily injections stopped, the high-dose (10-mg/kg) amphetamine groups showed a higher growth rate than the 0-mg/kg and 2-mg/kg groups. There were no interactions between prenatal treatment and dose of amphetamine on body weight gain. Rats exposed to alcohol in utero showed a greater locomotor activation than controls given 2 mg/kg amphetamine. The magnitude of the locomotor activation to this dose of amphetamine decreased equivalently over the four test days for all prenatal treatment groups. Male but not female rats exposed prenatally to alcohol showed an apparent sensitization to 10 mg/kg amphetamine not seen in control rats between PN28 and PN42. There were no group differences in amphetamine-induced stereotypy or SCH-23390-induced catalepsy. The results implied that children with Fetal Alcohol Syndrome who may be treated for attentional dysfunction would show different dose-responses for some behavioral effects of CNS stimulants, but not for growth-retarding “side effects.”     

Differential effects of vasopressinergic and oxytocinergic pre-autonomic neurons on circulatory control: reflex mechanisms and changes during exercise

1. The role of vasopressinergic and oxytocinergic (VPergic and OTergic, respectively) projections to the brain stem in the modulation of heart rate control is discussed on the basis of both changes in the peptide content of the dorsal brain stem (DBS) and functional effects following reflex- and exercise-induced activation in the presence and/or absence of receptor blockade within the nucleus tractus solitarius (NTS) and/or peripheral autonomic block. 2. Experimental data showed a dual effect of NTS VPergic projections on reflex control: (i) to maintain tonically the reflex sensitivity; and (ii) to reset reflex bradycardia towards higher heart rate values when transiently activated. The VPergic drive causes less sympathetic inhibition during pressure increases, mainly by reducing peripheral information going to NTS second-order neurons. Treadmill running increases the vasopressin content within the DBS. This activates NTS V(1) receptors to cause a significant improvement of exercise tachycardia in both sedentary and trained rats. 3. The OTergic drive to DBS areas (NTS/dorsal motor nucleus of the vagus) is also tonic for baroreceptor reflex control: it improves reflex bradycardia by facilitating vagal outflow to the heart. An acute bout of exercise increases DBS oxytocin (OT) content in trained rats, causing a significant blunting of exercise tachycardia only in this group. In both sedentary and trained groups, basal heart rate varies inversely with DBS OT content, the resting bradycardia of trained rats being associated with higher OT content. 4. Specific coordinated activation of VPergic and OTergic suprabulbar pathways is essential to adjust heart rate and cardiac output to circulatory demand at rest and during exercise in both sedentary and trained individuals.     

Phencyclidine-induced impairment in attention and response control depends on the background genotype of mice: reversal by the mGLU<Subscript>2/3</Subscript> receptor agonist LY379268

Rationale Converging evidence implicates glutamate neurotransmission in attention and inhibitory response control.Objective To investigate how the background genotype contributes to glutamates effects on attention and response control, we examined how phencyclidine (PCP) affected the performance of a five-choice serial reaction time (5-CSRT) task in two inbred mouse strains, C57BL/6N and DBA/2N. We also tested a potent mGlu_2/3 receptor agonist, LY379268, against PCPs effects.Methods Mice were trained on a 5-CSRT task, which measures visual attention and response control until they reached asymptotic performance. Both strains of mice were then injected intraperitoneally with 0.5, 1.5 or 3.0 mg/kg PCP. Doses of 1.0 and 3.0 mg/kg of LY379268 were injected subcutaneously to vehicle or PCP-treated mice.Results At asymptotic performance DBA/2N mice were less accurate and made more anticipatory responses than C57BL/6N. PCP impaired accuracy (% correct) and increased perseverative responses of DBA/2N mice at 1.5 mg/kg. However, at doses up to 3.0 mg/kg it had no effect on these measures in C57BL/6N. In DBA/2N mice 1.5 mg/kg PCP increased anticipatory responses far more than 3.0 mg/kg in C57BL/6N mice. No dose of LY379268 prevented the PCP-induced accuracy deficit of DBA/2N mice. The PCP-induced anticipatory and perseverative responding of DBA/2N mice was reduced by 3.0 mg/kg LY379268, while 1.0 and 3.0 mg/kg reduced anticipatory responding in C57BL/6N.Conclusions The background genotype may determine the effects of PCP on attentional performance and the results confirm the importance of glutamate transmission in some aspects of this performance.     

The receptor mechanisms underlying the disruptive effects of haloperidol and clozapine on rat maternal behavior: A double dissociation between dopamine D2 and 5-HT2A/2C receptors

Many antipsychotic drugs disrupt active components of maternal behavior such as pup approach, pup retrieval and nest building at clinically relevant doses in postpartum female rats. However, the neurochemical mechanisms underlying such a disruptive effect remain to be determined. This study examined the neurochemical mechanisms that mediate the disruptive effects of haloperidol (a typical antipsychotic) and clozapine (an atypical antipsychotic) on rat maternal behavior. Postpartum rats were administered with haloperidol (0.2 mg/kg, sc) or clozapine (10.0 mg/kg, sc) together with either vehicle (saline or water), quinpirole (a selective dopamine D₂/D₃ agonist, 0.5 or 1.0 mg/kg, sc), or 2,5-dimethoxy-4-iodo-amphetamine (DOI, a selective 5-HT_2A/2C agonist, 1.0 or 2.5 mg/kg, sc), and their maternal behaviors were tested at different time points before and after drug administration. Haloperidol and clozapine treatment disrupted pup approach, pup retrieval, pup licking and nest building. Pretreatment of quinpirole, but not DOI, dose-dependently reversed the haloperidol-induced disruptions. In contrast, pretreatment of DOI, but not quinpirole, dose-dependently reversed the clozapine-induced disruptions. Quinpirole pretreatment even exacerbated the clozapine-induced disruption of pup retrieval and nest building. These findings suggest a double dissociation mechanism underlying the disruption of haloperidol and clozapine on rat maternal behavior. Specifically, haloperidol disrupts maternal behavior primarily by blocking dopamine D₂ receptors, whereas clozapine exerts its disruptive effect primarily by blocking the 5-HT_2A/2C receptors. Our findings also suggest that 5-HT receptors are involved in the mediation of rat maternal behavior.