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Biomedical subjects

Paul D Shepard

Publications and source records attributed to Paul D Shepard.

7 recordsLinked to original sources
PubMed2006

Schizophrenia in translation: the presence of absence: habenular regulation of dopamine neurons and the encoding of negative outcomes.

Many patients with schizophrenia have pronounced deficits in the use of negative feedback to guide problem solving and learning, as seen on tasks like the Wisconsin Card Sorting Test. There is now a compelling body of evidence from nonhuman primates that suggests transient decreases in dopamine cell activity may reflect the occurrence of unexpected negative outcomes, such as the absence of an expected reward, and, generalizing to the human, the occurrence of negative feedback or the absence of expected reward. We present preliminary evidence that habenula projections to the midbrain are capable of producing a transient, but nearly complete, inhibition of dopamine neurons at a population level similar to that observed in behaving primates following an unexpected negative outcome. Human functional imaging studies offer further evidence that the habenula is activated following receipt of unexpected negative feedback or the absence of expected positive feedback. We present initial evidence that patients with schizophrenia lack appropriate modulation of habenula activity in response to feedback. Collectively, these data suggest that the habenula may play a critical role in mediating the feedback-processing deficits of schizophrenia.

Cognition Disorders↗
PubMed2005

Prenatal exposure to a repeated variable stress paradigm elicits behavioral and neuroendocrinological changes in the adult offspring: potential relevance to schizophrenia.

Exposure to stress during gestation induces marked changes in the behavior of the affected offspring. Examining the consequences of prenatal stress may prove useful in understanding more about the origins of schizophrenia because a number of clinical investigations have suggested that developmental insults are associated with an increased incidence of schizophrenia. The purpose of these studies is to investigate the effects of stress during gestation on the behaviors of the adult male rat offspring with an emphasis on developing a heuristic animal model of schizophrenia. Pregnant female Sprague-Dawley rats were exposed to a novel variable stress paradigm during either the second or third week of gestation. Behavioral and neuroendocrinological consequences of prenatal stress exposure were evaluated in the male offspring on postnatal day 35 or 56. Prenatal stress exposure during the third week of pregnancy caused adult male rats to exhibit prolonged elevation in plasma glucocorticoid levels following acute exposure to restraint stress indicative of diminished glucocorticoid negative feedback. Similarly, exposure to stress during the third week of pregnancy elicited an enhanced locomotor response to the psychomotor stimulant amphetamine on postnatal day 56 but not on postnatal day 35. In addition, prepulse inhibition of the acoustic startle response was diminished across a range of prepulse stimulus intensities in prenatally stressed adult male rats. Similarly, prenatally stressed rats showed evidence of a disruption in auditory sensory gating as measured by the N40 response. Taken together, these findings suggest that prenatal stress exposure significantly changed many facets of adult rat behavior. Interestingly, the behaviors that are altered have been used to validate animal models of schizophrenia and therefore, suggest that this preparation may be useful to learn more about some aspects of the pathophysiology of schizophrenia.

Age Factors↗
PubMed2004

Cortical spreading depression augments kynurenate levels and reduces malonate toxicity in the rat cortex.

Cortical spreading depression (CSD) is characterized by slowly propagating neuronal and astrocytic depolarization, resulting in transient, heightened resistance to subsequent neuronal injury. This study was designed to examine a possible role of the endogenous neuroprotective agent kynurenate (KYNA) in this phenomenon. Unilateral, consecutive CSDs, induced by topical application of 2 M KCl to the cortical surface of adult male rats, resulted in an ipsilateral increase (201-222% compared to controls) in KYNA levels, which was observed in the frontal, parietal and occipital cortex but not in other brain areas. This effect peaked on day 3 after CSD, and KYNA levels returned to normal on day 7. In separate rats, the lesion caused by an intracortical microinjection of the indirect excitotoxin malonate (500 nmol/0.5 microl) on days 1, 3 or 7 after CSD was reduced by 56-75% in the ipsilateral hemisphere. In normal rats, single or multiple injections of the kynurenine 3-hydroxylase inhibitor 4,5-dichlorobenzoylalanine (PNU 156561; 50 mg/kg, i.p.), which results in selective increases in brain KYNA levels, failed to protect cortical neurons against a focal malonate injection. Taken together, these findings indicate that the observed increase in brain KYNA is not responsible for CSD-induced tolerance to malonate-induced neuronal damage.

Animals↗
PubMed2004

Regional distribution of SK3 mRNA-containing neurons in the adult and adolescent rat ventral midbrain and their relationship to dopamine-containing cells.

SK3 small conductance, calcium-activated potassium channels play an important role in regulating the activity of mesencephalic dopamine (DA) neurons. In the present series of experiments, in situ hybridization techniques were used to compare SK3 and tyrosine hydroxylase (TH) mRNA expression throughout the rostrocaudal extent of the ventral midbrain in juvenile and adult rats. SK3 mRNA was found exclusively in areas that also contained large numbers of DA neurons including the substantia nigra (SN), the ventral tegmental area, and related cell groups (VTA-A10). An anteroposterior and mediolateral gradient in SK3 mRNA hybridization was apparent in the VTA-A10 but not in the SN. Younger rats appeared to possess higher levels and less regional variation in TH and SK3 transcripts. These results are consistent with previous studies reporting differential expression of SK3 protein within the midbrain and suggest that variations in SK3 channel distribution could contribute to differences in dopamine-related functions in the rat.

Age Factors↗
PubMed2004

Effects of acute and chronic clozapine on D-amphetamine-induced disruption of auditory gating in the rat.

RATIONALE: Auditory gating deficits observed in patients with schizophrenia have been modeled in animals administered the indirect-acting monoaminergic agonist, D-amphetamine (AMPH). The atypical antipsychotic drug clozapine (CLOZ) reverses the disruption of auditory gating in schizophrenic patients. However, its effects on psychostimulant-induced deficits in animals have yet to be assessed. OBJECTIVES: In the present series of experiments, an auditory evoked potential paradigm was used to: (a) confirm the ability of AMPH to alter auditory gating in the anesthetized rat, (b) specify the nature of the accompanying change(s) in evoked potential waveforms and (c) determine the effects of CLOZ administration on AMPH-induced alterations in auditory gating. METHODS: We compared the effects of acute (5 mg/kg, i.p.) and chronic (28 days, 0.5 mg/ml in drinking water) CLOZ on AMPH-induced (1.8 mg/kg, i.p.) alterations in evoked potentials recorded in the hippocampus of anesthetized rats during presentation of a pair of identical tones. Gating was assessed by comparing the amplitude of conditioning and test responses in CLOZ and AMPH-treated rats. RESULTS: The ratio of test to conditioning response amplitude (T/C ratio) was not altered by vehicle or CLOZ alone. However, T/C ratio was significantly increased following AMPH due to suppression of the conditioning response. Acute but not chronic CLOZ attenuated but did not prevent the increase in T/C ratio. CONCLUSIONS: Qualitative differences between the idiopathic gating deficits observed in schizophrenic patients and AMPH-induced increases in T/C ratio in animals limit this models utility as a means of evaluating the ability of atypical antipsychotic drugs to restore normal sensory gating.

Amphetamine↗
PubMed2003

Micromolar brain levels of kynurenic acid are associated with a disruption of auditory sensory gating in the rat.

Brain levels of kynurenic acid (KYNA), an endogenous antagonist of glycine(B)/NMDA and alpha-7 nicotinic acetylcholine receptors, are elevated in individuals with schizophrenia. Both receptors are broadly implicated in the pathophysiology of this disease, particularly in the deficits many patients show in filtering the sensorium. In the present study, we sought to determine whether elevated brain levels of KYNA disrupt auditory gating in anesthetized rats. A mid-latency evoked potential was recorded from the hippocampus in response to a pair of auditory tones. Gating was assessed by determining the ratio of the amplitude of test and conditioning responses (T/C ratio) in rats that had received KYNA's precursor L-kynurenine (KYN; 150 mg/kg, i.p.) together with probenecid (PBCD; 200 mg/kg, i.p.) 2 h prior to the start of the recording session. KYNA levels in the hippocampus of KYN+PBCD-treated rats were increased 500-fold, and accompanied by a significant increase in T/C ratio consistent with a disruption in sensory gating. PBCD alone increased hippocampal KYNA 12-fold, but did not significantly elevate T/C ratio. L-701,324 (3-30 mg/kg, i.v.), a centrally acting glycine(B) site antagonist, also failed to disrupt gating; however, large quantities of the competitive NMDA receptor antagonist DL-2-amino-5-phosphopentanoate (200 nmol, i.c.v.) markedly increased T/C ratio. Thus, while total blockade of NMDA receptors disrupts auditory gating, partial blockade achieved by antagonism of its glycine coagonist binding site does not. These observations indicate that the disruption in auditory processing in rats with greatly elevated KYNA levels is not attributable to the compound's antagonist actions at the glycine(B) receptor.

Acoustic Stimulation↗