Danielle N. Alexander

Perinatal Nutritional Iron Deficiency Impairs Noradrenergic-Mediated Synaptic Efficacy in the CA1 Area of Rat Hippocampus

Many studies have shown that perinatal nutritional iron deficiency (ID) produces learning impairments in children. Research has also shown that catecholamines like epinephrine and norepinephrine play a pivotal role in the consolidation of memories. In this study, we sought to determine if perinatal ID impairs the following: 1) noradrenergic synaptic function in the hippocampus; and 2) several forms of hippocampus-dependent fear learning. Electrophysiological brain slice methods were used to examine noradrenergic-mediated synaptic efficacy in the CA1-hippocampus of rats that were subjected to perinatal ID or control (CN) diets. Rats were fed ID (3 mg Fe/kg) or CN (45 mg Fe/kg) diets on gestational d 14. These diets were maintained until postnatal d (P) 12 after which all rats were switched to the CN diet. Hippocampal slices were prepared between P26 and P30. The noradrenergic agonist isoproterenol (ISO) (1, 2, or 4 micromol) was used to induce modulatory increases in synaptic efficacy in the hippocampal slices. CN slices showed a long-lasting increase in synaptic efficacy as the result of ISO perfusion in the slice bath, whereas ID slices did not show increases in synaptic efficacy as the result of ISO perfusion. ID and CN groups did not differ when ISO was perfused through slices from adult rats (P61). Both young and adult ID rats showed reduced levels of hippocampus-dependent fear learning compared with the young and adult CN rats. Together, these findings suggest that ID may impair early forms of noradrenergic-mediated synaptic plasticity, which may in turn play a role in adult learning deficits.

Bilateral Lesions of the Thalamic Trigeminal Orosensory Area Dissociate Natural from Drug Reward in Contrast Paradigms

Substance abuse and addiction are associated with an apparent devaluation of, and inattention to, natural rewards. This consequence of addiction can be modeled using a reward comparison paradigm where rats avoid intake of a palatable taste cue that comes to predict access to a drug of abuse. Evidence suggests rats avoid intake following such pairings, at least in part, because the taste cue pales in comparison to the highly rewarding drug expected in the near future. In accordance, lesions of the gustatory thalamus or cortex eliminate avoidance of a taste cue when paired with either a drug of abuse or a rewarding sucrose solution, but not when paired with the aversive agent, LiCl. The present study used bilateral ibotenic acid lesions to evaluate the role of a neighboring thalamic structure, the trigeminal orosensory area (TOA), in avoidance of a gustatory cue when paired with sucrose (experiment 1), morphine (experiment 2), cocaine (experiment 3), or LiCl (experiment 4). The results show that the TOA lesion disrupts, but does not eliminate avoidance of a taste cue that predicts access to a preferred sucrose solution and leaves intact the development of a LiCl-induced conditioned taste aversion. The lesion does, however, eliminate the suppression of intake of a taste cue when paired with experimenter-administered morphine or cocaine using our standard parameters. As such, this is the first manipulation found to dissociate avoidance of a taste cue when mediated by a sweet or by a drug of abuse.

Altered eyeblink reflex conditioning in restless legs syndrome patients

BACKGROUND Restless legs syndrome (RLS) is characterized by abnormal leg sensations and an uncontrollable urge to move the lower extremities during rest periods. Evidence suggests that reflex tasks that involve sensory-motor integration may be altered in RLS patients. This led us to determine if RLS patients show alterations in a sensory-motor reflex conditioning task called differential eyeblink conditioning. METHODS RLS subjects were washed out of treatment medication for 7 days prior to testing. Subjects (20 RLS and 19 Control) received 120 discrimination conditioning trials consisting of 60 CS+ trials (i.e., an auditory stimulus paired with the airpuff-US separated by a silent 900 ms trace interval) and 60 CS- trials (i.e., a different auditory stimulus that was NOT paired with the US). RESULTS Control subjects showed normal differential responding to the CS+ and CS-, but the RLS patients showed little or no differential responding. A post-test questionnaire provides evidence that symptomatic interference was not responsible for the eyeblink conditioning deficits in the RLS subjects, and further suggests that neurophysiological factors were responsible for these deficits. CONCLUSIONS Together these results suggest that deficits in eyeblink conditioning are related to the pathophysiology of RLS. The eyeblink conditioning test may also be useful for supporting a clinical diagnosis or treatment strategy for RLS.

Early avoidance of a heroin-paired taste-cue and subsequent addiction-like behavior in rats.

The ability to predict individual vulnerability to substance abuse would allow for a better understanding of the progression of the disease and development of better methods for prevention and/or early intervention. Here we use drug-induced devaluation of a saccharin cue in an effort to predict later addiction-like behavior in a model akin to that used by Deroche-Gamonet et al. (2004) and seek to link such vulnerability to changes in expression of various mu opioid receptor and D2 receptor-interacting proteins in brain. The results show that the greatest heroin-induced suppression of intake of a saccharin cue is associated with the greatest vulnerability to later addiction-like behavior and to differences in the expression of WLS, β-catenin, and NCS-1 in brain compared to rats that exhibited the least suppression of intake of the heroin-paired cue and/or saline controls. Finally, because the self-administration model employed produced no significant differences in drug intake between groups, overall, the resultant changes in protein expression can be more closely linked to individual differences in motivation for drug.

Once is too much: Early development of the opponent process in taste reactivity behavior is associated with later escalation of cocaine self-administration in rats

Evidence suggests that the addiction process may begin immediately in some vulnerable subjects. Specifically, some rats have been shown to exhibit aversive taste reactivity (gapes) following the intraoral delivery of a cocaine-predictive taste cue after as few as 1-2 taste-drug pairings. After only 3-4 trials, the number of gapes becomes a reliable predictor of later cocaine self-administration. Given that escalation of drug-taking behavior over time is recognized as a key feature of substance use disorder (SUD) and addiction, the present study examined the relationship between early aversion to the cocaine-predictive flavor cue and later escalation of cocaine self-administration in an extended-access paradigm. The data show that rats who exhibit the greatest conditioned aversion early in training to the intraorally delivered cocaine-paired cue exhibit the greatest escalation of cocaine self-administration over 15 extended-access trials. This finding suggests that early onset of the conditioned opponent process (i.e., the near immediate shift from ingestion to rejection of the drug-paired cue) is a reliable predictor of future vulnerability and resilience to cocaine addiction-like behavior. Future studies must determine the underlying neural mechanisms associated with this early transition and, hence, with early vulnerability to the later development of SUD and addiction. In so doing, we shall be in position to discover novel diagnostics and novel avenues of prevention and treatment.

Imagery Interference Diminishes in Older Adults: Age-Related Differences in the Magnitude of the Perky Effect

Studies have documented the negative effects of mental imagery on perception (also known as the Perky effect) in younger adults, but imagery-interference effects in older adults have never been assessed. Two experiments examined this issue directly. Experiment 1 demonstrated that visual mental images diminish visual acuity in younger adults (mean age = 19.0) but not older adults (mean age = 73.6). Experiment 2 obtained parallel results, showing that visual imagery interfered with performance on a visual detection task in younger (mean age = 18.7) but not older adults (mean age = 66.7). Processes underlying age-related differences in imagery-interference effects are discussed and implications of these results for changes in cognitive performance in older adults are considered.

Drug-motivated behavior in rats with lesions of the thalamic orosensory area.

Rats suppress intake of a palatable taste cue when paired with a rewarding or an aversive stimulus in appetitive or aversive conditioning, respectively. A similar phenomenon occurs with drugs of abuse, but the nature of this conditioning has been subject for debate. While relatively little is known about the underlying neural circuitry, we recently reported bilateral lesions of the thalamic trigeminal orosensory area isolate drug-induced suppression of intake of a taste cue. The lesion blocks avoidance of the taste cue when paired with experimenter delivered drugs of abuse, yet has no effect on avoidance of the same cue when paired with an aversive agent or when it predicts access to a highly palatable sucrose solution. We hypothesize the lesion may blunt the rewarding properties of the drug. To test this, we used a runway apparatus, as running speed has been shown to increase with increasing reward value. Our hypothesis was supported by failure of the lesioned rats to increase running speed for morphine. Interestingly, lesioned rats did avoid intake of the drug-paired cue when presented in the runway apparatus and displayed naloxone-precipitated withdrawal. Using a partial crossover design, the lesion prevented avoidance of a cocaine-paired cue when presented in the home cage. We conclude that the lesion disrupts avoidance of a taste cue in anticipation of the rewarding properties of a drug but, at least in the presence of contextual cues, allows for avoidance of a taste cue as it elicits the onset of an aversive conditioned state of withdrawal.

Preweaning iron deficiency increases non-contingent responding during cocaine self-administration in rats.

Iron deficiency (ID) is the most prevalent single-nutrient deficiency worldwide. There is evidence that ID early in development (preweaning in rat) causes irreversible neurologic, behavioral, and motor development deficits. Many of these effects have been attributed to damage to dopamine systems, including ID-induced changes in transporter and receptor numbers in the striatum and nucleus accumbens. These mesolimbic dopaminergic neurons are, in part, responsible for mediating reward and thus play a key role in addiction. However, there has been relatively little investigation into the behavioral effects of ID on drug addiction. In 2002, we found that rats made ID from weaning (postnatal day 21) and throughout the experiment acquired cocaine self-administration significantly more slowly than controls and failed to increase responding when the dose of the drug was decreased. In the present study, we assessed addiction for self-administered cocaine in rats with a history of preweaning ID only during postnatal days 4 through 21, and iron replete thereafter. The results showed that while ID did not affect the number of cocaine infusions or the overall addiction-like behavior score, ID rats scored higher on a measure of continued responding for drug than did iron replete controls. This increase in responding, however, was less goal-directed as ID rats also responded more quickly to the non-rewarded manipulandum than did control rats. Thus, while ID early in infancy did not significantly increase addiction-like behaviors for cocaine in this small study, the pattern of data suggests a possible underlying learning or performance impairment. Future studies will be needed to elucidate the exact neuro-behavioral deficits that lead to the increase in indiscriminate responding for drug in rats with a history of perinatal ID.