Biomedical subjects

J David Jentsch

Publications and source records attributed to J David Jentsch.

At least 19 recordsLinked to original sources

PubMed2006

DeltaFosB in the nucleus accumbens regulates food-reinforced instrumental behavior and motivation.

Alterations in motivation have been implicated in the pathophysiology of several psychiatric disorders, including substance abuse and depression. Repeated exposure to drugs of abuse or stress is known to persistently induce the transcription factor deltaFosB in the nucleus accumbens (NAc) and dorsal striatum, effects hypothesized to contribute to neuroadaptations in dopamine-regulated signaling. Little is known, however, about the specific involvement of deltaFosB in dysregulation of appetitively motivated behaviors. We show here that inducible overexpression of deltaFosB in NAc and dorsal striatum of bitransgenic mice, or specifically in the NAc core of rats by use of viral-mediated gene transfer, enhanced food-reinforced instrumental performance and progressive ratio responding. Very similar behavioral effects were found after previous repeated exposure to cocaine, amphetamine, MDMA [(+)-3,4-methylenedioxymethamphetamine], or nicotine in rats. These results reveal the powerful regulation of motivational processes by deltaFosB, and provide evidence that drug-induced alterations in gene expression via induction of deltaFosB within the NAc core may play a critical role in the impact of motivational influences on instrumental behavior.

Animals↗

PubMed2006

A neurobehavioral systems analysis of adult rats exposed to methylazoxymethanol acetate on E17: implications for the neuropathology of schizophrenia.

BACKGROUND: As a test of plausibility for the hypothesis that schizophrenia can result from abnormal brain, especially cerebral cortical, development, these studies examined whether, in the rat, disruption of brain development initiated on embryonic day (E) 17, using the methylating agent methylazoxymethanol acetate (MAM), leads to a schizophrenia-relevant pattern of neural and behavioral pathology. Specifically, we tested whether this manipulation leads to disruptions of frontal and limbic corticostriatal circuit function, while producing schizophrenia-like, region-dependent reductions in gray matter in cortex and thalamus. METHODS: In offspring of rats administered MAM (22 mg/kg) on E17 or earlier (E15), regional size, neuron number and neuron density were determined in multiple brain regions. Spontaneous synaptic activity at prefrontal cortical (PFC) and ventral striatal (vSTR) neurons was recorded in vivio. Finally, cognitive and sensorimotor processes mediated by frontal and limbic corticostriatal circuits were assessed. RESULTS: Adult MAM-E17-exposed offspring showed selective histopathology: size reductions in mediodorsal thalamus, hippocampus, and parahippocampal, prefrontal, and occipital cortices, but not in sensory midbrain, cerebellum, or sensorimotor cortex. The prefrontal, perirhinal, and occipital cortices showed increased neuron density with no neuron loss. The histopathology was accompanied by a disruption of synaptically-driven "bistable membrane states" in PFC and vSTR neurons, and, at the behavioral level, cognitive inflexibility, orofacial dyskinesias, sensorimotor gating deficits and a post-pubertal-emerging hyper-responsiveness to amphetamine. Earlier embryonic MAM exposure led to microcephaly and a motor phenotype. CONCLUSIONS: The "MAM-E17" rodent models key aspects of neuropathology in circuits that are highly relevant to schizophrenia.

Amphetamine↗

PubMed2005

Haploinsufficiency of the arginine-vasopressin gene is associated with poor spatial working memory performance in rats.

Behavioral pharmacological studies have implicated a role for the neurophysin arginine-vasopressin in learning and memory. Vasopressin, and its analogues, can produce either improvements or impairments in mnemonic functions, effects that depend upon the agent administered, the memory process measured and the task employed. As recent data have implicated vasopressin in regulating the cognitive functions of the prefrontal cortex, we sought to determine whether changes in vasopressinergic tone would affect a form of memory that is dependent upon this brain region. To that end, we used a genetic approach to examine how haploinsufficiency of the vasopressin gene affects working memory performance. Specifically, we tested a naturally occurring null-mutant rat on an operant delayed-non-match-to-position task. Male and female heterozygous and wild-type rats were trained to perform this working memory task, and the effects of varying the delay across which they had to maintain task information were systematically varied. Although vasopressin-deficient rats omitted fewer trials and completed trials more quickly, they exhibited delay-dependent deficits of choice accuracy. The genotype effects were not modified by sex. Collectively, these data indicate that even partial vasopressin deficiency can trigger deficits of spatial working memory performance and add to the growing body of results supporting a regulatory control of neocortical-dependent cognitive functions by this neurohormone.

Analysis of Variance↗

PubMed2005

The HMG-CoA reductase inhibitor lovastatin reverses the learning and attention deficits in a mouse model of neurofibromatosis type 1.

Neurofibromatosis Type 1 (NF1) is a common neurological disorder caused by mutations in the gene encoding Neurofibromin, a p21Ras GTPase Activating Protein (GAP). Importantly, NF1 causes learning disabilities and attention deficits. A previous study showed that the learning and memory deficits of a mouse model of NF1 (nf1+/-) appear to be caused by excessive p21Ras activity leading to impairments in long-term potentiation (LTP), a cellular mechanism of learning and memory. Here, we identify lovastatin as a potent inhibitor of p21Ras/Mitogen Activated Protein Kinase (MAPK) activity in the brain. Lovastatin is a specific inhibitor of three-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, used commonly for the treatment of hypercholesterolemia. We report that lovastatin decreased the enhanced brain p21Ras-MAPK activity of the nf1+/- mice, rescued their LTP deficits, and reversed their spatial learning and attention impairments. Therefore, these results demonstrate that lovastatin may prove useful in the treatment of Neurofibromatosis Type 1.

Analysis of Variance↗

PubMed2005

XXY mice exhibit gonadal and behavioral phenotypes similar to Klinefelter syndrome.

Klinefelter syndrome (XXY males) is the most common sex chromosome aneuploidy. XXY mice were generated by using a four-generation breeding scheme that involves the use of a structurally rearranged Y chromosome, Y*, yielding approximately 50% of the live-born male offspring in the fourth generation with a XXY karyotype. Adult XXY mice have small testes, decreased plasma T levels, and elevated plasma FSH levels. The testes of adult XXY mice contained small seminiferous tubules with intraepithelial vacuolization and absence of germ cells, whereas Leydig cells appeared to be more abundant than their XY littermates. Androgen receptor immunoexpression was localized in Leydig cells and peritubular myoid cells in both XY and XXY mice. Androgen receptor immunoexpression was abundant in the Sertoli cells of XY mice but nearly absent in those of XXY mice. The testicular phenotype was marked by a 23.1% decrease in testis weights in XXY pups beginning at d 7 after birth. Gonocyte numbers were similar in XY and XXY mice at d 1 of age, followed by a 62.6% decrease in the number of gonocytes in the XXY mice on d 3 and further progressive loss in spermatogonia by d 5 and 7. On d 10, only a few spermatogonia remained in the XXY mice. To determine whether the phenotype of XXY mice extended into the neurobehavioral domain, studies were conducted demonstrating impairment of learning and memory function in XXY mice. We conclude that adult XXY mice have testicular failure and learning deficits, similar to its human counterpart, Klinefelter syndrome.

Age Factors↗

PubMed2005

Impaired visuospatial divided attention in the spontaneously hypertensive rat.

The spontaneously hypertensive rat (SHR) is a potential rodent model for the impulsive, inattentive and hyperactive aspects of attention deficit/hyperactivity disorder. Impaired response inhibition and deficits of visual attention are demonstrable phenotypes of SHR (compared with normotensive Wistar-Kyoto rats), and alterations of catecholaminergic transmission in the prefrontal cortex are thought to contribute to aspects of the phenotypic differences. Here, we investigated the attentional performance of SHR and WKY, using a lateralized reaction time task, a behavioral measure of visuospatial divided attention. SHR acquired the conditional rule of the task normally but exhibited deficient accurate performance when stimulus durations were ultimately decreased to less than 1 s. The alpha-2 agonist guanfacine, which is used clinically to treat symptoms of AD/HD, was without effect on the performance of either SHR or Wistar-Kyoto rats. These data indicate that SHR exhibit performance deficits on a test of visual attention but do not resolve the predictive validity this putative model for AD/HD.

Adrenergic alpha-Agonists↗

PubMed2005

Alpha-2 adrenoceptor activation inhibits phencyclidine-induced deficits of spatial working memory in rats.

N-methyl-D-aspartate (NMDA)/glutamate receptor antagonists, such as phencyclidine (PCP), induce behavioral abnormalities (locomotor hyperactivity, sensorimotor gating deficits, impairments of cognition) in animals that are thought to model aspects of schizophrenia. The administration of PCP increases noradrenaline transmission in the rat prefrontal cortex, a brain structure required for normal cognitive processes. Noradrenaline, in turn, works through a set of receptors that have themselves been implicated directly in NMDA antagonist-induced deficits; we recently reported that the alpha-2 agonist, clonidine, is effective at preventing PCP-induced deficits of working memory and visual attention in rats. Here, we further investigated the role for alpha-2 adrenoreceptors in the effects of PCP on spatial working memory performance. The alpha-2 agonist clonidine (0.001-0.01 mg/kg, subcutaneously (s.c.)) produced a significant amelioration of PCP-induced working memory deficits; the effects of PCP (1.0 mg/kg, s.c.), but not clonidine, were reduced in noradrenaline-depleted rats. In addition, the alpha-2A-preferring agonist guanfacine (0.05-1.0 mg/kg, s.c.) dose-dependently prevented the deficits of spatial working memory performance produced by PCP. Although the highly selective alpha-2 receptor antagonist, atipamezole (ATI), failed to affect spatial working memory on its own, at the doses studied (0.1-0.5 mg/kg, s.c.), it dramatically enhanced the working memory deficit produced by PCP. These data indicate that alpha-2 adrenoreceptors tonically inhibit PCP-induced deficits of spatial working memory, suggesting an important role for these receptors in cognitive deficits associated with NMDA receptor hypofunction.

Adrenergic alpha-2 Receptor Agonists↗

PubMed2004

Cannabinoid CB1 receptor-mediated impairment of visuospatial attention in the rat.

RATIONALE: CB1 receptors (CB1Rs) mediate many of the psychoactive effects of cannabinoids, and marijuana intoxication can produce neurocognitive deficits with a similarity to those seen in schizophrenia, including impairments of attention. OBJECTIVES: We thus sought to characterize the effects of a CB1R-selective agonist and antagonist on attention in the rat using a lateralized reaction time task (LRT). We hypothesized that CB1R agonists would impair performance and that CB1R antagonists might improve performance. METHODS: Subjects were trained to perform the LRT, a procedure that measured their ability to attend to and detect brief visual target stimuli. After training, we tested the effects of the CB1R agonist WIN55,212-2 (WIN; 0-2.5 mg/kg) or the CB1R antagonist SR141716A (SR; 0-1.0 mg/kg), administered alone or in combination, on visual attention performance using task conditions in which target stimulus salience was varied systematically across trials. RESULTS: The highest dose of WIN reduced correct choices in well-trained rats, with impairment greatest at the shortest stimulus durations. The highest dose of WIN also increased omissions and slowed response times. By contrast, SR itself did not produce any measurable effects on performance but was able to prevent the impairment produced by WIN. CONCLUSIONS: These results suggest that CB1Rs mediate the attentional performance impairments caused by acute administration of cannabinoid agonists and begin to unravel the possible contribution of cannabinoid systems to the pathophysiological substrates of cognitive dysfunction in schizophrenia.

Animals↗

PubMed2004

A low dose of the alpha2 agonist clonidine ameliorates the visual attention and spatial working memory deficits produced by phencyclidine administration to rats.

RATIONALE: Psychotomimetic N-methyl-D-aspartate/glutamate receptor antagonists, such as phencyclidine (PCP), have been shown to produce a spectrum of behavioral, neurochemical and anatomical changes in rats that are relevant to aspects of schizophrenia, including impairments of working memory and visual attention. The alpha(2) noradrenergic receptor agonist clonidine prevents some of the behavioral effects of NMDA antagonists, suggesting that monoaminergic systems mediate some aspects of these deficits. OBJECTIVES: We sought to determine the ability of clonidine to modify the PCP-induced deficits of visual attention and spatial working memory in rats. RESULTS: In a lateralized reaction time task, a lower dose of clonidine (10 microg/kg) ameliorated the impairment of choice accuracy produced by PCP (2.5 mg/kg, IP), while the higher dose of clonidine (50 microg/kg) slowed response times and induced a deficit of choice accuracy on its own. The high dose of clonidine effectively prevented the motor impulsivity produced by PCP. In addition, clonidine (10 microg/kg) prevented PCP-induced performance deficits in a delayed non-match to sample task. CONCLUSIONS: These data indicate that clonidine may attenuate deficits of attention and working memory produced by PCP, perhaps in part by preventing some of the downstream neurochemical and anatomical effects of this psychotomimetic drug.

Adrenergic alpha-2 Receptor Agonists↗

PubMed2004

Repeated nicotine exposure enhances responding with conditioned reinforcement.

RATIONALE: Stimuli associated with a reinforcer (e.g., an addictive drug) can acquire conditioned reinforcing effects. Clinical observations indicate that smoking depends strongly upon conditioned reinforcement (i.e., cues support smoking behavior); however, little is known about the effects of repeated nicotine exposure on these processes. OBJECTIVE: This study investigated the consequences of prior repeated nicotine exposure on responding with conditioned reinforcement and on the potentiation of conditioned reinforcement by intra-NAc amphetamine infusion. METHODS: Rats received repeated saline or nicotine injections (0.35 mg/kg; 15 days) and were, following 3 days of withdrawal, trained to associate a tone + light stimulus with water reinforcement for 10 days. Animals were subsequently tested on acquisition of a new instrumental response with conditioned reinforcement (i.e., 14 days after the final nicotine injection). In additional experiments, animals received an infusion of amphetamine (10 microg per side) prior to the conditioned reinforcement test. RESULTS: Prior repeated nicotine exposure produced a behaviorally specific enhancement of responding with conditioned reinforcement. Furthermore, repeated nicotine pretreatment also augmented the potentiation of conditioned reinforcement by intra-NAc amphetamine. CONCLUSIONS: These findings demonstrate that prior repeated nicotine exposure augments the control over behavior by a conditioned reinforcer. Such long-lasting alterations in incentive motivational processes produced by repeated nicotine exposure may depend on drug-induced neuroadaptations in dopamine-regulated signaling within limbic-striatal brain regions that could underly persistent and compulsive aspects of addiction.

Adrenergic Uptake Inhibitors↗

PubMed2004

Repeated, intermittent delta(9)-tetrahydrocannabinol administration to rats impairs acquisition and performance of a test of visuospatial divided attention.

The residual neuropsychological effects of marijuana abuse in man indicate a dysfunction of the attentional/executive systems. Moreover, experimental investigations suggest that repeated, intermittent (subchronic) Delta(9)-tetrahydrocannabinol (THC), the main psychoactive ingredient of marijuana, alters neurotransmission in the frontal cortex of rats and humans, a key neural site mediating attention and executive functions. In the present studies, the acquisition and performance of a test of visuospatial attention (the lateralized reaction time task) after subchronic THC administration (10.0 mg/kg twice daily for 14 days) was examined. Rats previously administered THC showed impairments in this self-paced version of the classic multiple-choice serial reaction time task, which persisted 14 days after the final drug administration. Longer time points were not examined. These attentional impairments were transiently reversible with an acute amphetamine (0.5 mg/kg) challenge. These behavioral data demonstrate that chronic THC administration to rats induces an attentional deficit, similar to that observed in humans who abuse marijuana. Finally, amphetamine's ability to reverse the attentional impairments provides indirect evidence that monoaminergic deficits may be linked to the cognitive dysfunction.

Animals↗

PubMed2003

Nicotine enhances responding with conditioned reinforcement.

RATIONALE: The mesolimbic dopamine system has been implicated in the primary reinforcing properties of drugs of abuse as well as in enhanced responding with conditioned reinforcement produced by psychomotor stimulant drugs. Despite clinical observations that nicotine self-administration (i.e. smoking) depends strongly upon conditioned reinforcement (i.e. cues support smoking behavior), little is known about whether nicotine directly affects motivational processes. OBJECTIVE: In these experiments, we investigated whether acute nicotine would influence responding with conditioned reinforcement and the degree to which pretreatment with the nicotinic acetylcholine receptor (nAChR) antagonist mecamylamine would modify any nicotine-induced behavioral effects. METHODS: After subjects had been trained to associate an initially neutral stimulus with water reward, they received acute nicotine (43,25-350 micro g/kg SC; -5 min) or saline injections and were tested on the acquisition of a new response for conditioned reinforcement paradigm. In separate experiments, the effect of pretreatment with the nicotinic acetylcholine receptor antagonist mecamylamine (300 or 1000 micro g/kg SC; -20 min) alone, or in combination with nicotine (350 micro g/kg SC; -5 min), on conditioned reinforcement was also examined. RESULTS: Acute nicotine injection produced a selective enhancement of responding with conditioned reinforcement (i.e. on the CR lever), without producing non-selective increases in overall responding. The effect of nicotine (350 micro g/kg SC; -5 min) was selectively blocked by mecamylamine (300 micro g/kg). CONCLUSIONS: These findings demonstrate that acute exposure to nicotine augments the control over behavior by a conditioned reinforcer, suggesting that nicotine may enhance motivational processes.

Animals↗

PubMed2003

Systemic, but not local, administration of cannabinoid CB1 receptor agonists modulate prefrontal cortical acetylcholine efflux in the rat.

Drugs acting on brain cannabinoid CB(1) receptors exert complex actions on modulatory transmitters that are involved in attention and cognition; however, little is known about the precise pharmacological and anatomical mechanisms that govern these effects. Previously demonstrated effects of cannabinoids on acetylcholine (ACh) in the hippocampus prompted us to evaluate changes in the prefrontal cortex, a site associated with mnemonic and attentional functions. We utilized in vivo microdialysis, coupled with direct reverse perfusion of agents, to study the actions on cannabinoidergic drugs on ACh release within the rat frontal cortex. Systemic administration of the CB(1) receptor agonists Delta(9)-tetrahydrocannabinol (THC) or WIN 55,212-2 (WIN) dose- and time-dependently increased ACh release; these effects were blocked by pretreatment with the selective CB(1) receptor antagonist / partial inverse agonist SR141716A (SR). THC applied by reverse dialysis in the frontal cortex caused no change in ACh release, although intrastriatal infusions of THC decreased ACh efflux. These data indicate that cannabinoid agonists potentiate ACh release in the frontal cortex by activating cannabinoid receptors in brain regions other than the frontal cortex.

Acetylcholine↗

PubMed2003

Null mutation of the arginine-vasopressin gene in rats slows attentional engagement and facilitates response accuracy in a lateralized reaction time task.

The neurophysin vasopressin is thought to play an important role in emotional behavior and aspects of cognition in the rat, and the pathophysiology of this system has been implicated in two neurodevelopmental disorders, namely autism and schizophrenia. Genetic deficiency of vasopressin in rats, resulting from a null mutation of the vasopressin gene, causes alterations of brain development with resulting behavioral and neurochemical phenotypes in adulthood. We previously demonstrated that partial vasopressin deficiency (rats heterozygous for the null mutation) produces enhanced visuospatial attention and motor speeding. Here, the results of studies of homozygous Brattleboro rats that are fully vasopressin deficient are reported. We trained subjects to perform a lateralized reaction time task that measures visuospatial divided attention; in task conditions in which the duration of target stimuli was varied from trial to trial, homozygous Brattleboro rats showed a performance phenotype that consisted of more accurate responding for longer duration, and less accurate responding for briefer duration, target stimuli. No differences in response times were measured. Further experiments revealed that two separate processes produced this complex phenotype: a relatively slowed period of attentional engagement (resulting in compromised detection of fast onset-fast offset stimuli) that only partially masks a generally more accurate pattern of responding. These results, taken with earlier data, indicate that vasopressin plays a critical role in regulating visual attention and cognition, either directly, or via early alterations in neurodevelopment.

Animals↗

PubMed2003

Repeated nicotine exposure enhances reward-related learning in the rat.

Repeated exposure to addictive drugs causes neuroadaptive changes in cortico-limbic-striatal circuits that may underlie alterations in incentive-motivational processes and reward-related learning. Such drug-induced alterations may be relevant to drug addiction because enhanced incentive motivation and increased control over behavior by drug-associated stimuli may contribute to aspects of compulsive drug-seeking and drug-taking behaviors. This study investigated the consequences of repeated nicotine treatment on the acquisition and performance of Pavlovian discriminative approach behavior, a measure of reward-related learning, in male rats. Water-restricted rats were trained to associate a compound conditioned stimulus (tone+light) with the availability of water (the unconditioned stimulus) in 15 consecutive daily sessions. In separate experiments, rats were repeatedly treated with nicotine (0.35 mg/kg, s.c.) either (1) prior to the onset of training, (2) after each daily training session was completed (ie postsession injections), or (3) received nicotine both before the onset of training as well as after each daily training session. In this study, all nicotine treatment schedules increased Pavlovian discriminative approach behavior and, thus, prior repeated exposure to nicotine, repeated postsession nicotine injections, or both, facilitated reward-related learning.

Animals↗

PubMed2003

Genetic vasopressin deficiency facilitates performance of a lateralized reaction-time task: altered attention and motor processes.

Brattleboro rats are a variety of the outbred Long-Evans strain that possess a single nucleotide deletion in the second exon of the arginine vasopressin gene, resulting in the synthesis of an altered protein that does not enter the normal secretory pathway. Rats heterozygous (di/+) for the deletion have a partial vasopressin deficiency and exhibit a variety of behavioral and neurochemical alterations compared with normal wild-type Long-Evans rats, which provide evidence for a CNS function for vasopressin. Here, we examined the acquisition and performance of a test of visuospatial attention by di/+ Brattleboro rats and their wild-type Long-Evans control counterparts. Surprisingly, di/+ rats exhibited superior performance of the task compared with wild-type controls; performance differences included greater accuracy of detection of visual target stimuli, faster overall reaction times, and fewer trial omissions. Di/+ rats also exhibited more approaches to the reinforcer receptacle at nonreinforcement times. These results indicate that alterations of vasopressin signaling result in a clear cognitive phenotype, including faster motor initiations and superior choice accuracy in a test of visual attention.

Animals↗

PubMed2003

Persistent and anatomically selective reduction in prefrontal cortical dopamine metabolism after repeated, intermittent cannabinoid administration to rats.

Long-term abuse of delta-9-tetrahydrocannabinol (THC), the major psychoactive constituent of marijuana, produces behavioral and metabolic signs of frontal cortical dysfunction in humans; these effects persist even after short-term abstinence. Based on a preliminary finding that repeated administration of THC to rats reduces basal frontal cortical dopamine turnover (Jentsch et al. [1998] Neurosci Lett 246:169-172), we further investigated the effects of repeated administrations of THC or WIN 55,212-2 (WIN), a synthetic cannabinoid receptor agonist, on dopamine turnover in the prefrontal cortex, striatum, and nucleus accumbens. THC or WIN (twice daily for 7 or 14 days) caused a persistent and selective reduction in medial prefrontal cortical dopamine turnover; no significant alterations of dopamine metabolism were observed in the nucleus accumbens or striatum. Importantly, these dopaminergic deficits in the prefrontal cortex were observed after a drug-free period of up to 14 days. Thus, the cognitive dysfunction produced by heavy, long-term cannabis use may be subserved, in part, by drug-induced alterations in frontal cortical dopamine turnover.

Analgesics↗

PubMed2003

Sex-related differences in spatial divided attention and motor impulsivity in rats.

The acquisition and performance of a self-paced test of spatial divided attention linked with frontal cortex function were assessed in postpubertal (> 60 days) normal or gonadectomized male and female rats. Males were more accurate at detecting relatively brief visual stimuli than females, but this difference was eliminated by increasing the target stimulus duration, indicating an attentional basis for this effect. Premature errors were, however, greater in males than in females, suggesting greater impulsivity in males. Subsequent experiments in gonadectomized rats suggest that circulating hormones influence attention and impulsivity, but not necessarily sex differences. These results demonstrate a double dissociation between components of impulse control and divided attention in male and female rats and may have implications for sex differences in disorders of attention and cognition.

Animals↗