ROLE OF DOPAMINE OF NUCLEUS ACCUMBENS IN BEHAVIORAL SENSITIZATION TO METHYLPHENIDATE

Behavioral sensitization is defined as the subsequent augmentation of the locomotor response to a drug following repeated administrations of the drug. It is believed to occur due to alterations in the motive circuit in the brain by stressors, central nervous system stimulants, and similar stimuli. The motive circuit (or mesocorticolimbic system) consists of several interconnected nuclei that determine the behavioral response to significant biological stimuli. A final target of the mesocorticolimbic system is the nucleus accumbens (NAc), which is a key structure linking motivation and action. In particular, the dopaminergic innervations of the Nac are considered to be essential in regulating motivated states of behavior such as goal-directed actions, stimulus-reward associations and reinforcement by addictive substances. Therefore, the objective of this study was to investigate the role of dopaminergic afferents of the NAc in the behavioral sensitization elicited by chronic treatment with methylphenidate (MPD), a psychostimulant that is widely used to treat attention deficit hyperactivity disorder. The dopaminergic afferents can be selectively destroyed using catecholamine neurotoxin 6-hydroxydopamine (6-OHDA). In order to determine whether destruction of dopaminergic afferents of the NAc prevents sensitization, I compared locomotor activity in rats that had received infusions of 6-hydroxydopamine (6-OHDA) into the NAc with that of control and sham-operated animals. All groups of rats received six days of single daily MPD injections after measuring their pre and post surgery locomotor baseline. Following the consecutive MPD injections, there was a washout period of 4 days, where no injections were given. Then, a rechallenge injection of MPD was given. Behavioral responses after repeated MPD were compared to those after acute MPD to assess behavioral sensitization. Expression of sensitization to MPD was not prevented by 6-OHDA infusion into the NAc. Moreover, two distinct responses were seen to the acute injection of MPD: one group of rats had essentially no response to acute MPD, while the other had an augmented (‘sensitized’-like) acute response. Among rats with 6-OHDA infusions, the animals with diminished acute response to MPD had intact behavioral sensitization to repeated MPD, while the animals with increased acute response to MPD did not exhibit further sensitization to it. This suggests that the acute and chronic effects of MPD have distinct underlying neural circuitries.

Behavioral responses to methylphenidate: correlations with neuronal activity in the caudate nucleus

Methylphenidate is currently a drug of abuse and readily prescribed to both adolescents and adults. Chronic methylphenidate (MPH) exposure results in an increase in DA in the motive circuit, including the caudate nucleus (CN), similar to other drugs of abuse. This study focuses on research aimed to elucidate if there are intrinsic underlying differences in the CN electrophysiological activity of animals exhibiting different chronic responses to the same dose of MPH. Behavioral and caudate nucleus (CN) neuronal activity following acute and chronic doses of MPH was assessed by simultaneously recording the behavioral and neuronal activity. The experimental protocol lasted for 10 days using four groups; saline, 0.6, 2.5 and 10.0mg/kg MPH. Initially, the study determined that animals exposed to the same dose of MPH exhibited either behavioral sensitization or behavioral tolerance. Therefore animals were classified into two groups (behaviorally sensitized/tolerant) and their neuronal activity was evaluated. Four hundred and fifty one units were evaluated. Overall, a mixture of increases and decreases in CN neuronal populations was observed at initial MPH exposure, and at ED10 baseline and ED10 rechallenge. When separated based on their behavioral response (sensitized/tolerant), significant differences in neuronal response patterns was revealed. Animals exhibiting sensitization were more likely to increase their neuronal activity at ED1 and ED10 baseline, expressing the opposite response at ED10 rechallenge. Furthermore, when neuronal populations recorded from those animals exhibiting behavioral sensitization were statistically compared to those from animals exhibiting behavioral tolerance significant differences were observed. Collectively, these findings tell us that animals exposed to the same dose of MPH can respond oppositely and moreover that there is in fact some intrinsic difference in the two population’s neuronal activity. This study offers new insight into the electrophysiological differences between sensitized and tolerant animals.

GENETIC ANALYSIS OF THE FUNCTION OF THE DROSOPHILA DOUBLESEX-RELATED FACTOR dmrt93B

DMRT (Doublesex and Mab-3 related transcription factor) proteins generally associated with sexual differentiation in many organisms share a common DNA binding domain and are often expressed in reproductive tissues. Aside from doublesex, which is a central factor in the regulation of sex determination, Drosophila possesses three different dmrt genes that are of unknown function. Because the association with sexual differentiation and reproduction is not universal and some DMRT proteins have been found to play other developmental roles we chose to further characterize one of these Drosophila genes. We carried out genetic analysis of dmrt93B, which was previously found to be expressed sex-specifically in the developing somatic gonad and to affect testis morphogenesis in RNAi knockdowns. In order to disrupt this gene, the GAL4 yeast transcriptional activator followed by a polyadenylation signal was inserted after the dmrt93B start codon and introduced into the genome by homologous recombination. Analysis of the knock-in mutation as well as a small deletion removing all dmrt93B sequence demonstrate that loss of function causes partial lethality at the late pupal stage. Surprisingly, these mutations have no significant effect on gonad formation or male fertility. Analysis of GAL4-driven GFP reporter expression indicates that the dmrt93B promoter activity is highly specific to neurons in the suboesophageal and proventricular ganglion in larva and adult of both sexes suggesting a possible role in digestive tract function. Using the Capillary Feeder (CAFÉ) assay to measure daily food intake we find that reduction in this gene’s function leads to an increase in food consumption. These results suggest dmrt93 plays an important role in the formation or maintenance of neurons that affect feeding and support the idea that dmrt genes may not be restricted to roles in sexual differentiation.

Tracking the Flow of Information through the Hippocampal Formation in the Rat

The hippocampus receives input from upper levels of the association cortex and is implicated in many mnemonic processes, but the exact mechanisms by which it codes and stores information is an unresolved topic. This work examines the flow of information through the hippocampal formation while attempting to determine the computations that each of the hippocampal subfields performs in learning and memory. The formation, storage, and recall of hippocampal-dependent memories theoretically utilize an autoassociative attractor network that functions by implementing two competitive, yet complementary, processes. Pattern separation, hypothesized to occur in the dentate gyrus (DG), refers to the ability to decrease the similarity among incoming information by producing output patterns that overlap less than the inputs. In contrast, pattern completion, hypothesized to occur in the CA3 region, refers to the ability to reproduce a previously stored output pattern from a partial or degraded input pattern. Prior to addressing the functional role of the DG and CA3 subfields, the spatial firing properties of neurons in the dentate gyrus were examined. The principal cell of the dentate gyrus, the granule cell, has spatially selective place fields; however, the behavioral correlates of another excitatory cell, the mossy cell of the dentate polymorphic layer, are unknown. This report shows that putative mossy cells have spatially selective firing that consists of multiple fields similar to previously reported properties of granule cells. Other cells recorded from the DG had single place fields. Compared to cells with multiple fields, cells with single fields fired at a lower rate during sleep, were less likely to burst, and were more likely to be recorded simultaneously with a large population of neurons that were active during sleep and silent during behavior. These data suggest that single-field and multiple-field cells constitute at least two distinct cell classes in the DG. Based on these characteristics, we propose that putative mossy cells tend to fire in multiple, distinct locations in an environment, whereas putative granule cells tend to fire in single locations, similar to place fields of the CA1 and CA3 regions. Experimental evidence supporting the theories of pattern separation and pattern completion comes from both behavioral and electrophysiological tests. These studies specifically focused on the function of each subregion and made implicit assumptions about how environmental manipulations changed the representations encoded by the hippocampal inputs. However, the cell populations that provided these inputs were in most cases not directly examined. We conducted a series of studies to investigate the neural activity in the entorhinal cortex, dentate gyrus, and CA3 in the same experimental conditions, which allowed a direct comparison between the input and output representations. The results show that the dentate gyrus representation changes between the familiar and cue altered environments more than its input representations, whereas the CA3 representation changes less than its input representations. These findings are consistent with longstanding computational models proposing that (1) CA3 is an associative memory system performing pattern completion in order to recall previous memories from partial inputs, and (2) the dentate gyrus performs pattern separation to help store different memories in ways that reduce interference when the memories are subsequently recalled.

CHARACTERIZING AND TREATING THE NEUROPATHOLOGY OF TUBEROUS SCLEROSIS COMPLEX IN THE MOUSE

Tuberous sclerosis complex (TSC) is a multisystem, autosomal dominant disorder affecting approximately 1 in 6000 births. Developmental brain abnormalities cause substantial morbidity and mortality and often lead to neurological disease including epilepsy, cognitive disabilities, and autism. TSC is caused by inactivating mutations in either TSC1 or TSC2, whose protein products are known inhibitors of mTORC1, an important kinase regulating translation and cell growth. Nonetheless, neither the pathophysiology of the neurological manifestations of TSC nor the extent of mTORC1 involvement in the development of these lesions is known. Murine models would greatly advance the study of this debilitating disorder. This thesis will describe the generation and characterization of a novel brain-specific mouse model of TSC, Tsc2flox/ko;hGFAP-Cre. In this model, the Tsc2 gene has been removed from most neurons and glia of the cortex and hippocampus by targeted Cre-mediated deletion in radial glial neuroprogenitor cells. The Tsc2flox/ko;hGFAP-Cre mice fail to thrive beginning postnatal day 8 and die from seizures around 23 days. Further characterization of these mice demonstrated megalencephaly, enlarged neurons, abnormal neuronal migration, altered progenitor pools, hypomyelination, and an astrogliosis. The similarity of these defects to those of TSC patients establishes this mouse as an excellent model for the study of the neuropathology of TSC and testing novel therapies. We further describe the use of this mouse model to assess the therapeutic potential of the macrolide rapamycin, an inhibitor of mTORC1. We demonstrate that rapamycin administered from postnatal day 10 can extend the life of the mutant animals 5 fold. Since TSC is a neurodevelopmental disorder, we also assessed in utero and/or immediate postnatal treatment of the animals with rapamycin. Amazingly, combined in utero and postnatal rapamycin effected a histologic rescue that was almost indistinguishable from control animals, indicating that dysregulation of mTORC1 plays a large role in TSC neuropathology. In spite of the almost complete histologic rescue, behavioral studies demonstrated that combined treatment resulted in poorer learning and memory than postnatal treatment alone. Postnatally-treated animals behaved similarly to treated controls, suggesting that immediate human treatment in the newborn period might provide the most opportune developmental timepoint for rapamycin administration.

COCAINE DEPENDENCE: THE ROLE OF SEROTONIN GENES IN

Animal studies have shown that behavioral responses to cocaine-related cues are altered by serotonergic medications. The effects of pharmacological agents on serotonin receptors 2a (5-HT2A) and 2c (5-HT2C), have yielded results suggesting that selective 5-HT2A antagonists and 5-HT2C agonists promote the disruption of cocaine-associated memories. One measure of cocaine related cues in humans is attentional bias, in which cocaine dependent individuals show greater response latency for cocaine related words than neutral words. Data from our laboratory shows that cocaine dependent subjects have altered attentional bias compared to controls. The purpose of this thesis was to investigate the role of the serotonin system in attentional bias and impulsivity in cocaine dependent individuals. We focused on the serotonin transporter, serotonin receptors 2A and 2C and tryptophan hydroxylase 1 and 2 (TPH1 and TPH2). We predicted that attentional bias and impulsivity would be higher in cocaine dependent individuals who had lower serotonin function. In the current study, we found a significant association between TPH2 genotype and attentional bias for the second block of the cocaine Stroop task. There was also a significant association between average attentional bias and HTTLPR genotype in the cocaine dependent individuals. The HT2C receptor genotype and attentional bias in our study sample also showed a significant difference. We did not find a significant difference between the serotonin 2A receptor variants or the TPH1 variants and attentional bias in the cocaine dependent group. In conclusion, the current study suggests that serotonergic medications should be utilized as pharmacotherapeutic treatment for cocaine addiction. Our results indicate that TPH2, the serotonin transporter and 2C receptor should be targeted in such a way as to modulate both, leading to increased synaptic serotonin function.

The Dissociation of Location and Object Working Memory using fMRI and MEG

Visual working memory (VWM) involves maintaining and processing visual information, often for the purpose of making immediate decisions. Neuroimaging experiments of VWM provide evidence in support of a neural system mainly involving a fronto-parietal neuronal network, but the role of specific brain areas is less clear. A proposal that has recently generated considerable debate suggests that a dissociation of object and location VWM occurs within the prefrontal cortex, in dorsal and ventral regions, respectively. However, re-examination of the relevant literature presents a more robust distribution suggestive of a general caudal-rostral dissociation from occipital and parietal structures, caudally, to prefrontal regions, rostrally, corresponding to location and object memory, respectively. The purpose of the present study was to identify a dissociation of location and object VWM across two imaging methods (magnetoencephalography, MEG, and functional magnetic imaging, fMRI). These two techniques provide complimentary results due the high temporal resolution of MEG and the high spatial resolution of fMRI. The use of identical location and object change detection tasks was employed across techniques and reported for the first time. Moreover, this study is the first to use matched stimulus displays across location and object VWM conditions. The results from these two imaging methods provided convergent evidence of a location and object VWM dissociation favoring a general caudal-rostral rather than the more common prefrontal dorsal-ventral view. Moreover, neural activity across techniques was correlated with behavioral performance for the first time and provided convergent results. This novel approach of combining imaging tools to study memory resulted in robust evidence suggesting a novel interpretation of location and object memory. Accordingly, this study presents a novel context within which to explore the neural substrates of WM across imaging techniques and populations.

Extending in vitro conditioning in Aplysia to analyze operant and classical processes in the same preparation.

Operant and classical conditioning are major processes shaping behavioral responses in all animals. Although the understanding of the mechanisms of classical conditioning has expanded significantly, the understanding of the mechanisms of operant conditioning is more limited. Recent developments in Aplysia are helping to narrow the gap in the level of understanding between operant and classical conditioning, and have raised the possibility of studying the neuronal processes underlying the interaction of operant and classical components in a relatively complex learning task. In the present study, we describe a first step toward realizing this goal, by developing a single in vitro preparation in which both operant and classical conditioning can be studied concurrently. The new paradigm reproduced previously published results, even under more conservative and homogenous selection criteria and tonic stimulation regime. Moreover, the observed learning was resistant to delay, shortening, and signaling of reinforcement.

Chronic exposure to MDMA (Ecstasy) elicits behavioral sensitization in rats but fails to induce cross-sensitization to other psychostimulants.

BACKGROUND: The recreational use of 3,4-methylenedioxymethamphetamine (MDMA, ecstasy) among adolescents and young adults has become increasingly prevalent in recent years. While evidence suggests that the long-term consequences of MDMA use include neurodegeneration to serotonergic and, possibly, dopaminergic pathways, little is known about susceptibility, such as behavioral sensitization, to MDMA. METHODS: The objectives of this study were to examine the dose-response characteristics of acute and chronic MDMA administration in rats and to determine whether MDMA elicits behavioral sensitization and whether it cross-sensitizes with amphetamine and methylphenidate. Adult male Sprague-Dawley rats were randomly divided into three MDMA dosage groups (2.5 mg/kg, 5.0 mg/kg, and 10.0 mg/kg) and a saline control group (N = 9/group). All three MDMA groups were treated for six consecutive days, followed by a 5-day washout, and subsequently re-challenged with their respective doses of MDMA (day 13). Rats were then given an additional 25-day washout period, and re-challenged (day 38) with similar MDMA doses as before followed by either 0.6 mg/kg amphetamine or 2.5 mg/kg methylphenidate on the next day (day 39). Open-field locomotor activity was recorded using a computerized automated activity monitoring system. RESULTS: Acute injection of 2.5 mg/kg MDMA showed no significant difference in locomotor activity from rats given saline (control group), while animals receiving acute 5.0 mg/kg or 10.0 mg/kg MDMA showed significant increases in locomotor activity. Rats treated chronically with 5.0 mg/kg and 10.0 mg/kg MDMA doses exhibited an augmented response, i.e., behavioral sensitization, on experimental day 13 in at least one locomotor index. On experimental day 38, all three MDMA groups demonstrated sensitization to MDMA in at least one locomotor index. Amphetamine and methylphenidate administration to MDMA-sensitized animals did not elicit any significant change in locomotor activity compared to control animals. CONCLUSION: MDMA sensitized to its own locomotor activating effects but did not elicit any cross-sensitization with amphetamine or methylphenidate.

Chronic administration of methylphenidate produces neurophysiological and behavioral sensitization.

The electrophysiological properties of acute and chronic methylphenidate (MPD) on neurons of the prefrontal cortex (PFC) and caudate nucleus (CN) have not been studied in awake, freely behaving animals. The present study was designed to investigate the dose-response effects of MPD on sensory evoked potentials recorded from the PFC and CN in freely behaving rats previously implanted with permanent electrodes, as well as their behavioral (locomotor) activities. On experimental day 1, locomotor behavior of rats was recorded for 2 h post-saline injection, and sensory evoked field potentials were recorded before and after saline and 0.6, 2.5, and 10 mg/kg, i.p., MPD administration. Animals were injected for the next five days with daily 2.5 mg/kg MPD to elicit behavioral sensitization. Locomotor recording was resumed on experimental days 2 and 6 after the MPD maintenance dose followed by 3 days of washout. On experimental day 10, rats were connected again to the electrophysiological recording system and rechallenged with saline and the identical MPD doses as on experimental day 1. On experimental day 11, rat's locomotor recording was resumed before and after 2.5 mg/kg MPD administration. Behavioral results showed that repeated administration of MPD induced behavioral sensitization. Challenge doses (0.6, 2.5, and 10.0 mg/kg) of MPD on experimental day 1 elicited dose-response attenuation in the response amplitude of the average sensory evoked field potential components recorded from the PFC and CN. Chronic MPD administration resulted in attenuation of the PFC's baseline recorded on experimental day 10, while the same treatment did not modulate the baseline recorded from the CN. Treatment of MPD on experimental day 10 resulted in further decrease of the average sensory evoked response compared to that obtained on experimental day 1. This observation of further decrease in the electrophysiological responses after chronic administration of MPD suggests that the sensory evoked responses on experimental day 10 represent neurophysiological sensitization. Moreover, two different response patterns were obtained from PFC and CN following chronic methylphenidate administration. In PFC, the baseline and effect of methylphenidate expressed electrophysiological sensitization on experimental day 10, while recording from CN did not exhibit any electrophysiological sensitization.

Family Stability and Childhood Behavioral Outcomes: A Critical Review of the Literature

As the definition of what is considered a family changes in our society, the family unit itself continues to undergo changes. These changes can sometimes lead to decreased stability within the family unit. One of the greatest challenges facing those researching this phenomenon is the lack of consistency within the existing body of research surrounding what familial instability actually is (the definition). This critical review of the literature examines the current body of literature in order to identify what is known about family stability and its impact on adolescent behavior, as well as what gaps currently exist. This review focuses on definitions of family stability, current factors surrounding the stability of the family unit, and addresses the implications that the current body of literature presents.

Behavioral Outcomes of Home-Based Services for Children and Adolescents with Serious Emotional Disorders

The current study evaluates the effectiveness of an intensive home-based treatment program, Families First, on the behaviors of children and adolescents suffering from mental disorders and being at risk for out-ofi home placement. The sample included 85 youngsters and their families from a semi-rural community. The Diagnostic Interview for Children and Adolescents-Revised (DICA-R) was administered to the children, and the Child Behavior Checklist (CBCL) was completed by a parent at pretreatment and posttreatment. The families participated in a 4-6 week, intensive home intervention where crisis intervention, social support services, and needed psychological services were offered. The results indicated that both externalizing and internalizing behavior problems in youngsters with different diagnoses of mental disorders were significantly reduced at posttreatment as indicated by their CBCL scores. Furthermore, youngsters with a diagnosis of Oppositional Defiant Disorder seemed to benefit the most, as evidenced by the improved scores on most subscales of the CBCL. Youngsters with mood disorders and conduct disorders seemed to benefit in their most deficient areas, internalizing behavior problems and delinquent behaviors, respectively. Finally, after participating in Families First, more than half of the youngsters in the sample were able to stay home with their families

Food Insecurity and the Behavioral and Intellectual Development of Children: A Review of the Evidence

Background: Given that an alarming 1 in 5 children in the USA are at risk of hunger (1 in 3 among black and Latino children), and that 3.9 million households with children are food insecure, it is crucial to understand how household food insecurity (HFI) affects the present and future well-being of our children. Purpose: The objectives of this review article are to: (i) examine the association between HFI and child intellectual, behavioral and psycho-emotional development, controlling for socio-economic indicators; (ii) review the hypothesis that HFI is indeed a mediator of the relationship between poverty and poor child development outcomes; (iii) examine if the potential impact of HFI on caregivers’ mental health well-being mediates the relationship between HFI and child development outcomes. Methods: Pubmed search using the key words “food insecurity children.” For articles to be included they had to: (i) be based on studies measuring HFI using an experience-based scale, (ii) be peer reviewed, and (iii) include child intellectual, behavioral and/or socio-emotional development outcomes. Studies were also selected based on backward and forward Pubmed searches, and from the authors’ files. After reviewing the abstracts based on inclusion criteria a total of 26 studies were selected. Results: HFI represents not only a biological but also a psycho-emotional and developmental challenge to children exposed to it. Children exposed to HFI are more likely to internalize or externalize problems, as compared to children not exposed to HFI. This in turn is likely to translate into poor academic/cognitive performance and intellectual achievement later on in life. A pathway through which HFI may affect child development is possibly mediated by caregivers’ mental health status, especially parental stress and depression. Thus, HFI is likely to foster dysfunctional family environments. Conclusion: Findings indicate that food insecure households may require continued food assistance and psycho-emotional support until they transition to a “stable” food secure situation. This approach will require a much better integration of social policies and access to programs offering food assistance and mental health services to those in need. Findings also fully justify increased access of vulnerable children to programs that promote early in life improved nutrition as well as early psycho-social and cognitive stimulation opportunities.

The role of the bed nucleus of the stria terminalis in stress: A behavioral, neurophysiological and neuropharmacological study

During the fifty-five years since the origin of the modern concept of stress, a variety of neurochemical, physiological, behavioral and pathological data have been collected in order to define stress and catalogue the components of the stress response. Over the last twenty-five years, as interest in the neural mechanisms underlying the stress response grew, most of the studies have focused on the hypothalamus and major limbic structures such as the amygdala or on nuclei involved in neurochemical changes observed during stress. There are other CNS sites, such as the bed nucleus of the stria terminalis (BNST), that neuroanatomical and neurochemical studies suggest may be involved in stress, but these sites have rarely been studied. Four experiments were performed for this dissertation, the goal of which was to examine the BNST to determine its role in the regulation of the stress response. The first experiment demonstrated that electrical stimulation of BNST was sufficient to produce stress-like behaviors. The second experiment demonstrated that single BNST neurons altered their firing rate in response to both a noxious somatosensory stimulus such as tail pinch and electrical stimulation of the amygdala (AmygS). The third experiment showed that the opioid, cholinergic, and noradrenergic systems, three neurotransmitter systems implicated in the control of the stress response, were effective in altering the firing rate of BNST neurons. The fourth experiment demonstrated that the cholinergic effects were mediated via muscarinic receptors and showed that the effects of AmygS were not mediated via cholinergic pathways. Collectively, these findings provide a possible explanation for the nonspecificity in causation of stress and the invariability of the stress response and suggest a neurochemical basis for its pharmacological control. ^

Modulatory effects of bag cell peptides in {\it Aplysia}: Behavioral and electrophysiological studies

Reproductive hormones have effects on the nervous system not directly related to reproductive function. In the rat, for example, luteinizing hormone releasing hormone has dramatic effects on learning and memory. The present work attempts to examine the effects of reproductive hormones on non-reproductive behaviors and the neural loci and mechanisms underlying these effects in Aplysia, an animal whose behaviors, reproductive hormones and neural circuitry have been well characterized.^ In Aplysia, the neurosecretory bag cells release several peptides that are responsible for eliciting egg laying. The effects of these peptides on the defensive tail-siphon withdrawal reflex, as well as sensitization of this reflex, were examined. Sensitization, a simple form of nonassociative learning, refers to the behavioral enhancement of a response to a test stimulus after the presentation of a strong stimulus, that may last minutes (short-term) or days (long-term). An extract of the bag cells (BCE) inhibited the baseline siphon component of the tail-siphon withdrawal reflex and suppressed long-term, but not short-term, sensitization of the reflex. Preliminary experiments suggest that BCE also affects the tail component of the tail-siphon withdrawal reflex.^ To determine the neural mechanisms underlying the inhibition of the baseline reflex, electrophysiological studies were performed using an in vitro analogue of the tail-siphon withdrawal reflex to examine the ability of BCE, as well as the individual bag cell peptides (BCPs), to modulate the circuitry of the reflex. Bag cell extract attenuated the synaptic strength of the monosynaptic connections between tail sensory neurons and tail motor neurons. When individually applied only $\beta$-BCP produced a similar attenuation. This effect of $\beta$-BCP was not dependent on changes in duration of the presynaptic action potential.^ An in vitro analogue of long-term sensitization training was developed to examine the mechanisms by which the BCPs may affect long-term sensitization of the tail-siphon withdrawal reflex. This analogue exhibited both short- and long-term facilitation of the connections between the tail sensory and motor neurons.^ The results of these behavioral and electrophysiological experiments suggest that the BCPs inhibit the tail-siphon withdrawal reflex, at least in part, by modulating the synaptic strength of the connections between the sensory neurons and motor neurons underlying the reflex. One candidate for this effect is $\beta$-BCP. Thus, the peptides which elicit egg laying may also serve other functions such as the inhibition of defensive reflexes. In addition, these experiments raise the possibility that BCPs may exert a long lasting effect ($>$24 hr), suppressing long-term sensitization of the tail-siphon withdrawal reflex. ^