Cynthia Crawford - Academia.edu (original) (raw)

Papers by Cynthia Crawford

Psychopharmacology, Jan 5, 2015

The SSRI antidepressant fluoxetine is one of the few drugs that is effective at treating depressi... more The SSRI antidepressant fluoxetine is one of the few drugs that is effective at treating depression in adolescent humans. In contrast, the SSRI paroxetine has limited efficacy and is more at risk for inducing suicidal behavior. The purpose of the present study was to more fully characterize the differential actions of paroxetine and fluoxetine. In experiment 1, male and female rats were injected with paroxetine (2.5 or 10 mg/kg), fluoxetine (10 mg/kg), or vehicle for 10 days starting on postnatal day (PD) 35, and affective behaviors were assessed using sucrose preference and elevated plus maze tasks. A separate set of rats were used to examine monoamine levels. In experiment 2, rats were injected with paroxetine (2.5, 5, or 10 mg/kg), fluoxetine (5, 10, or 20 mg/kg), or vehicle during the same time frame as experiment 1, and anxiety-like behaviors were measured using elevated plus maze, light/dark box, and acoustic startle. Repeated SSRI treatment failed to alter sucrose preference,...

Neurotoxicology and Teratology, 2000

The purpose of the present study was to determine whether exposure to amphetamine during the prew... more The purpose of the present study was to determine whether exposure to amphetamine during the preweanling period would alter dopaminergic functioning in the dorsal striatum of adult rats. In three experiments, we assessed the effects of repeated amphetamine treatment on striatal protein kinase A (PKA) activity, dopamine (DA) D 1-like and D 2-like binding sites, and DA content. Rats were pretreated with saline or amphetamine (2.5 mg/kg, ip) for 7 consecutive days starting on postnatal day (PD) 11. At PD 90, rats were killed and their dorsal striata (i.e., caudate ± putamen) were removed and frozen until time of assay. Amphetamine pretreatment produced long-term reductions in both striatal PKA activity and DA content. Early amphetamine exposure also resulted in an upregulation of D 2-like binding sites, while leaving D 1-like binding sites unaffected. It is likely that the upregulation of D 2-like binding sites was stimulated by the persistent decline in striatal DA levels. Although speculative, it is possible that excess striatal D 2-like receptors were responsible for inhibiting PKA activity through actions on the cAMP signal transduction pathway. The behavioral relevance of these amphetamine-induced neurochemical changes has not yet be determined.

Psychopharmacology, 2008

Unlike adult rats, young rats exhibit context-dependent and context-independent behavioral sensit... more Unlike adult rats, young rats exhibit context-dependent and context-independent behavioral sensitization when assessed after a single pretreatment injection of cocaine. The purpose of this study was to determine whether: (1) the context-dependent and context-independent sensitization of young rats can be dissociated based on the persistence of the sensitized response and (2) the expression of behavioral sensitization is associated with region-specific increases in Fos immunoreactivity (Fos-IR). On postnatal day (PD) 19, rats were injected with either saline or cocaine (30 mg/kg) in a novel test chamber or the home cage. After 1, 3, 5, 7, 14, or 61 abstinence days, rats were challenged with 20 mg/kg cocaine and locomotor activity was measured for 60 min. In a separate experiment, rats pretreated on PD 19 were challenged with cocaine (10-30 mg/kg) on PD 80. The sensitized responding of young rats persisted for the same length of time (5 days) regardless of whether cocaine pretreatment occurred in a novel environment or the home cage. Behavioral sensitization did not reemerge in adulthood. When assessed after three abstinence days (i.e., on PD 22), acute treatment with cocaine increased Fos-IR in various brain regions, but sensitized responding was associated with elevated Fos expression in only the caudate-putamen (CP) and prefrontal cortex (PFC). Persistence of the sensitized response cannot be used to dissociate the one-trial context-dependent and context-independent sensitization of young rats. Fos data indicate that the CP and PFC may be involved in the mediation of short-term behavioral sensitization on PD 22.

Neuroscience, 2010

κ-Opioid receptor stimulation attenuates psychostimulant-induced increases in extracellular dopam... more κ-Opioid receptor stimulation attenuates psychostimulant-induced increases in extracellular dopamine in the caudate-putamen (CPu) and nucleus accumbens of adult rats, while reducing cocaine-induced locomotor activity and stereotyped behaviors. Because κ-opioid receptor agonists (e.g., U50,488 or U69,593) often affect the behavior of preweanling rats in a paradoxical manner, the purpose of the present study was to determine whether κ-opioid receptor stimulation differentially affects dopaminergic functioning in the CPu depending on age. In vivo microdialysis was used to determine whether U50,488 (5 mg/kg) attenuates cocaine-induced dopamine overflow in the dorsal CPu on postnatal day (PD) 17 and PD 85. In the microinjection experiment, cocaineinduced stereotyped behaviors were assessed in adult and preweanling rats after bilateral infusions of vehicle or U50,488 (1.6 or 6.4 µg per side) into the CPu. Results showed that U50,488 attenuated the cocaine-induced increases in CPu dopamine overflow on PD 85, while the same dose of U50,488 did not alter dopamine dialysate levels on PD 17. Cocaine also increased stereotyped behaviors (repetitive motor movements, behavioral intensity scores, and discrete behaviors) at both ages, but adult rats appeared to exhibit more intense stereotypic responses than the younger animals. Consistent with the microdialysis findings, bilateral infusions of U50,488 into the dorsal CPu decreased the cocaine-induced stereotypies of adult rats, while leaving the behaviors of preweanling rats unaffected. These results suggest that the neural mechanisms underlying κ-opioid/dopamine interactions in the CPu are not fully mature during the preweanling period. This lack of functional maturity may explain why κ-opioid receptor agonists frequently induce different behavioral effects in young and adult rats.

Journal of Neural Transmission, 2007

The purpose of this study was to determine whether aripiprazole, a D2-like partial agonist increa... more The purpose of this study was to determine whether aripiprazole, a D2-like partial agonist increasingly prescribed to children, alters DA synthesis via actions at autoreceptors in the dorsal striatum and medial prefrontal cortex (mPFC) of preweanling rats. The ability of dopaminergic agents to alter DOPA accumulation in the striatum and mPFC was measured after NSD-1015 on postnatal day (PD) 20. Dopaminergic tone was manipulated by administering reserpine, g-butyrolactone (GBL), or through amphetamine withdrawal. Results showed that the partial agonists aripiprazole and terguride increased striatal DOPA accumulation under normosensitive conditions, but decreased DOPA accumulation in states of low dopaminergic tone. A different pattern of results was observed in the mPFC, because terguride and haloperidol, but not aripiprazole, increased DOPA accumulation under normosensitive conditions. In conclusion, the present data show that aripiprazole affects striatal synthesis modulating autoreceptors in an adult-typical manner during the late preweanling period. Unlike in adult rats, however, the mPFC of preweanling rats appears to contain transitory synthesis modulating autoreceptors that are sensitive to drug manipulation.

Psychopharmacology, 1994

In the present study, the abilities of NPA (a direct DA receptor agonist) and amphetamine (an ind... more In the present study, the abilities of NPA (a direct DA receptor agonist) and amphetamine (an indirect DA receptor agonist) to induce short-and long-term behavioral sensitization were assessed in 11-and t7-day-old rats (age at initial injection). Rats were injected on 4 consecutive days with amphetamine (1.0, 2.5, or 5.0 mg/kg), NPA (1.0 mg/kg), or saline. A final test day occurred either 2 days (experiment 1) or 8 days (experiment 2) later. On the test day, rats given successive agonist injections received a single injection of the same agonist again; whereas rats given successive saline injections received either amphetamine or NPA for the first time. Five minutes after injection, locomotor activity (line-crosses), stereotyped sniffing, and vertical activity were measured during a 30-min testing session. The results showed that 11-and 17-day-old rats exhibited behavioral sensitization when tested with NPA or amphetamine after a 2-day interval. In contrast, neither NPA nor amphetamine was able to sensitize the behaviors of preweanling rats when measured 8 days after initial drug treatments. Therefore, these results show that both direct and indirect DA agonists are able to induce short-term behavioral sensitization in preweanling rats, but that the mechanisms responsible for mediating long-term behavioral sensitization have not yet matured.

The Journal of Neuroscience, 1996

The role of D 1 dopamine (DA) receptors in mediating the ability of DA to modulate responses attr... more The role of D 1 dopamine (DA) receptors in mediating the ability of DA to modulate responses attributable to activation of NMDA receptors was examined in mice lacking D 1A dopamine receptors. Specifically, experiments were designed to test the hypothesis that the ability of DA to potentiate responses mediated by activation of NMDA receptors was attributable to activation of D 1 receptors. Based on this hypothesis, we would predict that in the D 1A mutant mouse, either DA would not induce enhancement of NMDA-mediated responses, or the enhancement would be severely attenuated. The results provided evidence to support the hypothesis. In mutant mice, DA and D 1 receptor agonists did not potentiate responses mediated by activation of NMDA receptors. In contrast, in control mice, both DA and D 1 receptor agonists markedly potentiated responses mediated by activation of NMDA receptors. The effects of DA in attenuating responses mediated by activation of non-NMDA receptors also were altered in the mutant, suggesting that this action of DA may require coupling or interactions between D 1 and D 2 receptors. The present studies also provided an opportunity to assess some of the basic electrophysiological and morphological properties of neostriatal neurons in mice lacking D 1A DA receptors. Resting membrane potential, action potential parameters, input resistance, excitability, somatic size, dendritic extent, and estimates of spine density in mutants and controls were similar, suggesting that these basic neurophysiological and structural properties have not been changed by the loss of the D 1A DA receptor.

Developmental Neuroscience, 1999

The present study examined the electrophysiological effects produced by activation of specific do... more The present study examined the electrophysiological effects produced by activation of specific dopamine (DA) receptors and the distribution of DA receptor subtypes and glutamate receptor subunits [N-methyl-D-aspartate (NMDAR1) and GluR1] in cortical tissue samples obtained from children (ages 3 months to 16 years) undergoing epilepsy surgery. DA receptor activation produced differential effects depending on the receptor subtype that was activated. D1 receptor family agonists generally enhanced cortical excitability and favored the emergence of epileptogenic activity. In contrast, D2 receptor family agonists had more variable effects on cortical excitability and the expression of epileptiform discharges. Activation of D1 or D2 receptors decreased the amplitude of non-NMDA-mediated excitatory postsynaptic potentials. In contrast, DA and D1 agonists increased the amplitude of NMDA-mediated potentials. Immunohistochemical analysis showed that the DA receptor subtypes and glutamate recep...

Early methylphenidate exposure enhances cocaine self-

Journal of Neuroscience Research

The Journal of pharmacology and experimental therapeutics, Jan 19, 2018

Abnormality of dopamine D2 receptor (D2R) function, often observed as D2R supersensitivity (D2RSS... more Abnormality of dopamine D2 receptor (D2R) function, often observed as D2R supersensitivity (D2RSS), is a commonality of schizophrenia and related psychiatric disorders in humans. Moreover, virtually all psychotherapeutic agents for schizophrenia target D2R in brain. Permanent D2RSS as a feature of a new animal model of schizophrenia was first reported in 1991, then behaviorally and biochemically characterized over the next 15-20 years. In this model of schizophrenia characterized by production of D2RSS in ontogeny, there are demonstrated alterations of signaling processes; as well as functional links between the biologic template of the animal model; and ability of pharmacotherapeutics to modulate or reverse biological and behavioral modalities towards normality. Another such animal model, featuring knockout of Trace Amine-Associated Receptor 1 (TAAR1), demonstrates D2RSS with an increase of the proportion of D2R in the high affinity state. Currently, TAAR1 agonists are being explor...

Psychopharmacology, Jan 18, 2018

Ontogenetic differences in the behavioral responsiveness to cocaine have often been attributed to... more Ontogenetic differences in the behavioral responsiveness to cocaine have often been attributed to the maturation of dopaminergic elements (e.g., dopamine transporters, D2 receptors, receptor coupling, etc.). The purpose of this study was to determine whether ontogenetic changes in cocaine pharmacokinetics might contribute to age-dependent differences in behavioral responsiveness. Male and female neonatal (PD 5), preweanling (PD 10 and PD 20), and adult (PD 70) rats were injected (IP) with cocaine or saline and various behaviors (e.g., locomotor activity, forelimb paddle, vertical activity, head-down sniffing, etc.) were measured for 90 min. In a separate experiment, the dorsal striata of young and adult rats were removed at 10 time points (0-210 min) after IP cocaine administration. Peak cocaine values, cocaine half-life, and dopamine levels were determined using HPLC. When converted to percent of saline controls, PD 5 and PD 10 rats were generally more sensitive to cocaine than old...

Brain Research, Mar 16, 2001

We investigated whether tetanic-stimulation and activation of metabotropic glutamate receptors (m... more We investigated whether tetanic-stimulation and activation of metabotropic glutamate receptors (mGluRs) can modify field-synaptic-potentials and protein kinase activity in rat auditory cortex, specifically protein kinase A (PKA) and protein kinase C (PKC). Tetanic stimulation (50 Hz, 1 s) increases PKA and PKC activity only if the CNQX-sensitive field-EPSP (f-EPSP) is also potentiated. If the f-EPSP is unchanged, then PKA and PKC activity remains unchanged. Tetanic stimulation decreases a bicuculline-sensitive field-IPSP (f-IPSP), and this occurs whether the f-EPSP is potentiated or not. Potentiation of the f-EPSP is blocked by antagonists of mGluRs (MCPG) and PKC (calphostin-C, tamoxifen), suggesting that the potentiation of the f-EPSP is dependent on mGluRs and PKC. PKC antagonists block the rise in PKC and PKA activity, which suggests that these may be coupled. In contrast, ACPD (agonist at mGluRs) decreases both the f-EPSP and the f-IPSP, but increases PKC and PKA activity. Quisqualate (group I mGluR agonist), decreases the f-IPSP, and increases PKA activity, suggesting that the increase in PKA activity is a result of activation of group I mGluRs. Additionally, the increase in PKC and PKA activity appears to be independent of the decrease of the f-EPSP and f-IPSP, because PKC antagonists block the increase in PKC and PKA activity levels but do not block ACPD&amp;#39;s effect on the f-EPSP or f-IPSP. These data suggest that group I mGluRs are involved in potentiating the f-EPSP by a PKC and possibly PKA dependent mechanism which is separate from the mechanism that decreases the f-EPSP and f-IPSP.

Neuroreport, Aug 1, 1997

The role of dopamine D1A receptors in mediating amphetamine-induced sensitization was investigate... more The role of dopamine D1A receptors in mediating amphetamine-induced sensitization was investigated using the D1A-deficient mouse. During the drug pre-exposure phase, D1A-deficient and control mice were injected for five consecutive days with saline or amphetamine (2 mg/kg, i.p.). Locomotor activity was measured on the first and fifth pre-exposure day. After three abstinence days, mice were given either amphetamine or saline and locomotor activity was again assessed. Mice were then sacrificed and protein kinase A (PKA) activity was measured. In contrast to control mice, D1A-deficient mice did not show a progressive increase in locomotor activity across days. Importantly, both control and mutant mice did exhibit behavioral sensitization, because mice pre-exposed and tested with amphetamine were more active than mice acutely tested with the drug. Even so, the amphetamine-induced locomotor activity of the mutant mice was significantly reduced when compared with similarly treated control mice, indicating that the sensitized response was less pronounced in the D1A-deficient mouse. PKA activity also varied depending on genotype, since amphetamine decreased PKA activity in control but not D1A-deficient mice.

Psychopharmacology, 1993

In general, preweanting and adult rats respond similarly when challenged with competitive dopamin... more In general, preweanting and adult rats respond similarly when challenged with competitive dopamine (DA) agonists or antagonists. In contrast, results using a noncompetitive antagonist suggest that the Dt and D2 receptor systems of preweanling and adult rats differ in some critical way. To further assess this phenomenon, the behavioral effects of irreversible receptor blockade were assessed across 8 days in NPA (a nonselective DA agonist), quinpirole (a D 2 agonist), or SKF 38393 (a D1 agonist) treated 17-day-old rat pups. The irreversible antagonist N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ) did not block the locomotor activity and rearing of NPA-or quinpirole-treated rat pups, nor did EEDQ reduce SKF 38393-induced grooming. Moreover, pretreatment with EEDQ appeared to potentiate the normal increases in locomotor activity and rearing produced by NPA, but only when D2 receptors were not protected by a previous injection of sulpiride (a D 2 antagonist). Taken together, these results are consistent with the presence of large reserves of D~ and O 2 receptors in the preweanling rat pup.

Behav Neurosci, 1997

The kappa-opioid agonist U-50,488 increases the locomotor activity of preweanling rats. The autho... more The kappa-opioid agonist U-50,488 increases the locomotor activity of preweanling rats. The authors attempted to determine whether this effect was modulated by dopamine (DA) system functioning. Surprisingly, U-50,488&amp;amp;amp;amp;amp;amp;amp;#39;s locomotor activating effects were attenuated by both the DA receptor antagonist flupenthixol and the DA receptor agonist R(-)-propylnorapomorphine (NPA). In order to determine those brain areas stimulated by U-50,488, Fos immunoreactivity was assessed in 17- and 80-day-old rats. U-50,488 not only enhanced the locomotor activity of the younger rats, but it also enhanced Fos expression in various brain areas, including the nucleus accumbens and medial striatum. NPA blocked U-50,488-induced Fos expression in the latter region. When considered together, these results indicate that U-50,488 does not increase locomotion by stimulating a DA mechanism. Instead, either agonizing or antagonizing DA receptors is sufficient to disrupt U-50,488&amp;amp;amp;amp;amp;amp;amp;#39;s locomotor activating effects in the preweanling rat.

Pharmacology, biochemistry, and behavior, 2000

The purpose of this study was to determine whether chronic exposure to amphetamine during the pre... more The purpose of this study was to determine whether chronic exposure to amphetamine during the preweanling period causes enduring changes in behavioral and neuronal functioning. In two experiments rats were injected with saline or amphetamine (2.5 or 5.0 mg/kg) on postnatal days (PD) 11-15. Rats then received a challenge injection of saline or 2.5 mg/kg amphetamine on PD 23 or PD 90 and locomotor activity was measured. After behavioral assessment, rats were killed, and their dorsal striata and nucleus accumbens were dissected and later assayed for protein kinase A (PKA) activity. Interestingly, amphetamine treatment during the preweanling period produced an enduring decline in dorsal striatal and accumbal PKA activity that was still apparent in adulthood. These reductions in PKA activity were not related to the occurrence of locomotor sensitization, because rats did not exhibit a sensitized locomotor response when challenged with amphetamine at PD 23 or PD 90.

The Journal of neuroscience : the official journal of the Society for Neuroscience, Jan 17, 2008

The striatum is particularly sensitive to the irreversible inhibitor of succinate dehydrogenase 3... more The striatum is particularly sensitive to the irreversible inhibitor of succinate dehydrogenase 3-nitropropionic acid (3-NP). In the present study, we examined early changes in behavior and dopamine and glutamate synaptic physiology created by a single systemic injection of 3-NP in Fischer 344 rats. Hindlimb dystonia was seen 2 h after 3-NP injections, and rats performed poorly on balance beam and rotarod motor tests 24 h later. Systemic 3-NP increased NMDA receptor-dependent long-term potentiation (LTP) at corticostriatal synapses over the same time period. The 3-NP-induced corticostriatal LTP was not attributable to increased NMDA receptor number or function, because 3-NP did not change MK-801 [(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine] binding or NMDA/AMPA receptor current ratios. The LTP seen 24 h after 3-NP was D(1) receptor dependent and reversed by exogenous addition of dopamine or a D(2) receptor agonist to brain slices. HPLC and fast-scan cyclic volta...

Progress in Neuro-Psychopharmacology and Biological Psychiatry, 1996