Biomedical subjects

R Hitzemann

Publications and source records attributed to R Hitzemann.

At least 37 records · Page 2Linked to original sources

PubMed1999

Methylphenidate and cocaine have a similar in vivo potency to block dopamine transporters in the human brain.

The reinforcing effects of cocaine and methylphenidate have been linked to their ability to block dopamine transporters (DAT). Though cocaine and methylphenidate have similar in vitro affinities for DAT the abuse of methylphenidate in humans is substantially lower than of cocaine. To test if differences in in vivo potency at the DAT between these two drugs could account for the differences in their abuse liability we compared the levels of DAT occupancies that we had previously reported separately for intravenous methylphenidate in controls and for intravenous cocaine in cocaine abusers. DAT occupancies were measured with Positron Emission Tomography using [11C]cocaine, as a DAT ligand, in 8 normal controls for the methylphenidate study and in 17 active cocaine abusers for the cocaine study. The ratio of the distribution volume of [11C]cocaine in striatum to that in cerebellum, which corresponds to Bmax/Kd +1, was used as measure of DAT availability. Parallel measures were obtained to assess the cardiovascular effects of these two drugs. Methylphenidate and cocaine produced comparable dose-dependent blockade of DAT with an estimated ED50 (dose required to block 50% of the DAT) for methylphenidate of 0.07 mg/kg and for cocaine of 0.13 mg/kg. Both drugs induced similar increases in heart rate and blood pressure but the duration of the effects were significantly longer for methylphenidate than for cocaine. The similar in vivo potencies at the DAT for methylphenidate than for cocaine are in agreement with their reported relative in vitro affinities (Ki 390 nM and 640 nM respectively), which is likely to reflect the similar degree of uptake (8-10% of the injected dose) and regional distribution of these two drugs in the human brain. Thus, differences in the in vivo potency of these two drugs at the DAT cannot be responsible for the differences in their rate of abuse in humans. Other variables i.e. longer duration of methylphenidate's side effects may counterbalance its reinforcing effects.

Adult↗

PubMed1999

On the relationships of high-frequency hearing loss and cochlear pathology to the acoustic startle response (ASR) and prepulse inhibition of the ASR in the BXD recombinant inbred series.

The measurement of the acoustic startle response (ASR) and prepulse inhibition (PPI) of the ASR in many inbred strains of mice, including C57BL/6 and DBA/2, may be complicated by age-related high-frequency hearing loss (HFHL) and the associated cochlear pathology. Willott and Erway (1998) have recently reported on the age-related changes of the acoustic brain response in the BXD recombinant inbred (RI) series. Based on these data, the RI series was divided into three groups: juvenile-, intermediate-, and adult-onset HFHL. Each of these groups was tested using paradigms which varied the frequency or intensity of the auditory startle and prepulse stimuli. The results obtained in adolescent mice (6-8 weeks) demonstrate that ASR performance is independent of HFHL; there was no group-dependent decline in the ASR amplitudes for high-frequency stimuli. The expected effect of HFHL on PPI is to increase the salience of the still-audible tones. In response to a white-noise prepulse stimulus, the PPI in the juvenile-onset group (which shows marked HFHL at 6 weeks) was similar to that in the adult-onset group. However, when the prepulse stimulus was a pure tone, the juvenile group showed a decrease in salience across all frequencies tested (5-20 kHz). The data point out the need for carefully constructing auditory tasks in the BXD RI series, to avoid the confounding effects of HFHL.

Acoustic Stimulation↗

PubMed1999

Association of methylphenidate-induced craving with changes in right striato-orbitofrontal metabolism in cocaine abusers: implications in addiction.

OBJECTIVE: The authors have shown that decreases in dopamine D2 receptors in cocaine abusers were associated with decreased metabolism in the cingulate and prefrontal and orbitofrontal cortices. To assess whether increasing dopamine would reverse these metabolic decrements, they measured the effects of methylphenidate, a drug that increases dopamine, on brain glucose metabolism in 20 cocaine abusers. METHOD: The subjects underwent two [18F]fluorodeoxyglucose positron emission tomography scans, one after two sequential placebo injections and one after two intravenous doses of methylphenidate. D2 receptors were measured with [11C]raclopride to evaluate their relation to methylphenidate-induced metabolic changes. RESULTS: Methylphenidate induced variable changes in brain metabolism: subjects with the higher D2 measures tended to increase metabolism, whereas those with the lower D2 measures tended to decrease metabolism. Methylphenidate's effects were significant for increases in metabolism in the superior cingulate, right thalamus, and cerebellum. Methylphenidate-induced changes in the right orbitofrontal cortex and right striatum were associated with craving, and those in the prefrontal cortex were associated with mood. CONCLUSIONS: Although methylphenidate increased metabolism in the superior cingulate, it only increased metabolism in orbitofrontal or prefrontal cortices in the subjects in whom it enhanced craving and mood, respectively. This indicates that dopamine enhancement is not sufficient per se to increase metabolism in these frontal regions. Activation of the right orbitofrontal cortex and right striatum (brain regions found to be abnormal in compulsive disorders) in the subjects reporting craving may be one of the mechanisms underlying compulsive drug administration in addicted persons. The predominant correlation of craving with right but not left brain regions suggests laterality of reinforcing and/or conditioned responses.

Adult↗

PubMed1999

Prediction of reinforcing responses to psychostimulants in humans by brain dopamine D2 receptor levels.

OBJECTIVE: This study assessed whether brain dopamine D2 receptor levels, which show significant intersubject variability, predict reinforcing responses to psychostimulants in humans. METHOD: [11C]Raclopride and positron emission tomography were used to measure D2 receptor levels in 23 healthy men (mean age = 34 years, SD = 7) who had no drug abuse histories in order to assess if there were differences between the subjects who liked and those who disliked the effects of intravenous methylphenidate (0.5 mg/kg). RESULTS: Subjects who liked the effects of methylphenidate had significantly lower D2 receptor levels (mean = 2.72 Bmax/Kd, SD = 0.3) than subjects who disliked its effects (mean = 3.16, SD = 0.3). Moreover, the higher the D2 levels found, the more intense were methylphenidate's unpleasant effects. CONCLUSIONS: These results provide preliminary evidence that D2 receptor levels predict response to psychostimulants in humans and that low D2 receptors may contribute to psychostimulant abuse by favoring pleasant response.

Adult↗

PubMed1999

Ethanol-induced expression of c-Fos differentiates the FAST and SLOW selected lines of mice.

The effect of ethanol on the number of Fos-like immunoreactive (Fos-li) neurons was previously studied in the C57BL/6J (B6) and DBA/2J (D2) inbred mouse strains (Hitzemann and Hitzemann, 1997). Data obtained suggested that the locomotor activation response to ethanol found in the D2 but not the B6 strain was associated with an increase in the number of Fos-li neurons (a putative measure of synaptic activity) in the central nucleus of the amygdala (CeA), but not in other brain regions, including the basal ganglia. Supporting results were obtained in B6D2 F2 intercross animals (Demarest et al., 1998) those animals exhibiting a marked locomotor activation response to ethanol also showed a significant increase in the number of Fos-li neurons in the CeA. The current study extends this line of investigation to the FAST and SLOW selected lines of mice (Shen et al., 1995). Twenty-eight SLOW and FAST mice (taken evenly from both replicate lines) were randomly assigned to receive either saline or ethanol (1.5 g/kg). One hour later, the animals were sacrificed, and the number of Fos-li neurons were determined using standard immunocytochemical techniques. Both the FAST and SLOW lines showed a marked increase (>300%) in the number of Fos-li neurons in the lateral aspect of the CeA; however, in the capsular division, only the FAST line showed an increase (>500%). In several brain regions, the basal (saline) response was markedly higher in the SLOW line; these regions included the subthalamic nucleus, the entopeduncular nucleus, the substantia nigra compacta, and the ventral tegmental area. Furthermore, it was found that ethanol decreased the number of Fos-li neurons in the ventral tegmental area of the SLOW but not FAST mice. These data suggest a substantial involvement of the basal ganglia in the segregation of the FAST and SLOW lines.

Amygdala↗

PubMed1999

Chlordiazepoxide-induced expression of c-Fos in the central extended amygdala and other brain regions of the C57BL/6J and DBA/2J inbred mouse strains: relationships to mechanisms of ethanol action.

BACKGROUND: Previous studies have established an association between the ethanol-induced locomotor response and activation of the central nucleus of the amygdala (CeA) as determined by changes in the number of Fos-like immunoreactive (Fos-li) neurons. The purpose of the current study was to determine if the benzodiazepine chlordiazepoxide (CDP) would produce similar effects to ethanol on behavior and the CeA. METHODS: In experiment 1, C57BL/6J (B6) and DBA/2J (D2) mice were administered CDP over a dose range of 3 to 30 mg/kg and the effects on locomotor behavior and the number of Fos-li neurons in the extended CeA determined. For experiment 2, B6D2 F2 intercross animals were phenotyped for their locomotor response to ethanol using a test-retest design. The activity responsive and nonresponsive extreme phenotypes were then tested in the same fashion as the inbred strains. RESULTS: Similar to ethanol, CDP increased locomotor activity in the D2 strain but not the B6 strain; furthermore, the D2 strain was 3 to 10 times more sensitive than the B6 strain in terms of CDP activating the CeA and the associated lateral posterior aspect of the bed nucleus of the stria terminalis (BSTLP). In the shell of the nucleus accumbens (NAc), CDP inhibited the number of Fos-positive neurons in both strains. CDP also discriminated between the responsive and nonresponsive extremes both in terms of behavior and activation of the CeA. CONCLUSIONS: Overall, these data point to the importance of GABA(A) mediated mechanisms in the ethanol-induced locomotor response. It is suggested that both drugs block the feed-forward inhibition in the CeA, resulting in activation of the GABAergic projection neurons. The overall net effect of CDP or ethanol administration on the output from the CeA will be inhibitory, from which it follows that the locomotor activation response must be associated with the selective inhibition of some behavior or ensembles of behaviors that are known to be mediated by the CeA and reduce locomotor activity (i.e., the "freezing" response).

Amygdala↗

PubMed1999

Identification of quantitative trait loci for haloperidol-induced catalepsy on mouse chromosome 14.

Previous studies have established that neuroleptic-induced catalepsy in mice is a highly heritable trait. The current study focuses on the detection of quantitative trait loci (QTL) for haloperidol-induced catalepsy in a BALB/cJ x LP/J F(2) intercross. One thousand thirty-seven F(2) animals were phenotyped and divided into four categories: very responsive (RR), responsive, nonresponsive, and very nonresponsive (NN). The RR and NN phenotypes comprised approximately 18% each of the total and differed in their haloperidol sensitivity by >10-fold. Sex differed significantly between the NN and RR groups (chi(2) = 14.0; p <.0002); females comprised 58% of the RR individuals but only 38% of the NN individuals. The difference between the extreme phenotypes in the number of piebald animals was highly significant (chi(2) = 30, p <. 00001). Eight percent of the RR individuals were piebald compared with 30% of the NN individuals. A genome wide scan confirmed the presence of a QTL (peak LOD = 6.4) on chromosome 14 near the piebald (Ednrb) and 5-hydroxytryptamine(2A) (Htr2a) loci. Although the parental BALB/cJ and LP/J strains differed significantly in striatal 5-hydroxytryptamine(2A) receptor binding, no marked differences were detected between the phenotypic extremes. A second QTL was detected on chromosome 14 (peak LOD = 6.9), which was located more proximally and included the Chat locus. No QTLs were detected on chromosomes 1 and 9, thus differentiating this cross from previous results obtained for a C57BL/6J x DBA/2J intercross.

Animals↗

PubMed1999

Reinforcing effects of psychostimulants in humans are associated with increases in brain dopamine and occupancy of D(2) receptors.

Increases in dopamine concentration in limbic brain regions have been postulated to underlie the reinforcing effects of psychostimulant drugs in laboratory animals. However, neither the qualitative nor the quantitative relationship between drug-induced increases in brain dopamine and the reinforcing effects of psychostimulant drugs have been investigated in humans. Positron emission tomograph and [(11)C]raclopride, a dopamine D(2) receptor radioligand that competes with endogenous dopamine for occupancy of the D(2) receptors, were used to measure changes in brain dopamine after different doses of i.v. methylphenidate in 14 healthy controls. In parallel, measures for self-reports of drug effects were obtained to assess their relationship to methylphenidate-induced changes in brain dopamine. The intensity of the "high" induced by methylphenidate was significantly correlated with the levels of released dopamine (r = 0.78, p <.001); subjects having the greatest increases were those who perceived the most intense high. This relationship remained significant after partialing out for dose and concentration of methylphenidate in plasma. Furthermore, subjects for whom methylphenidate did not increase dopamine did not perceive a high. These results represent the first clear demonstration that stimulant-induced high, a mood descriptor that reflects reinforcing effects of drugs in humans, is associated with increases in brain dopamine, and also that there is a quantitative relationship between levels of D(2) receptor occupancy by dopamine and the intensity of the high.

Adult↗

PubMed1999

Blockade of striatal dopamine transporters by intravenous methylphenidate is not sufficient to induce self-reports of "high".

The reinforcing effects of cocaine and methylphenidate have been linked to their ability to block dopamine transporters (DAT). Using positron emission tomography (PET), we previously showed that intravenous cocaine induced a significant level of DAT blockade, which was associated with the intensity for self-reports of "high" in cocaine abusers. In this study, we measured DAT occupancies after intravenous methylphenidate and assessed whether they also were associated with the "high". Occupation of DAT by intravenous MP was measured with PET using [11C]cocaine, as a DAT ligand, in eight normal control subjects tested with different methylphenidate doses. The ratio of the distribution volume of [11C]cocaine in striatum to that in cerebellum, which corresponds to Bmax/Kd + 1, was used as measure of DAT availability. In parallel, self-reports of "high" were measured. Methylphenidate produced a dose-dependent blockade of DAT with an estimated ED50 of 0.075 mg/kg. DAT occupancies were significantly correlated with the "high" (p <.03). However, four of the eight subjects, despite having significant levels of DAT blockade, did not perceive the "high". Methylphenidate is as effective as cocaine in blocking DAT in the human brain (cocaine ED50 = 0.13 mg/kg), and DAT blockade, as for cocaine, was also associated with the "high". However, the fact that there were subjects who despite significant DAT blockade did not experience the "high" suggests that DAT blockade, although necessary, is not sufficient to produce the "high".

Adult↗

PubMed1998

Differences in regional brain metabolic responses between single and repeated doses of methylphenidate.

Studies investigating the acute effects of drugs of abuse on human brain metabolism have measured single doses whereas these drugs are mostly taken repeatedly. Here we compared the brain metabolic response to intravenous methylphenidate when given after a single dose to that when given after two sequential doses. Methylphenidate-induced changes in metabolism differed; whereas single doses tended to decrease metabolism, repeated doses tended to increase it, and these differences were significant in frontal, parietal and occipital cortices and hippocampus. This indicates that methylphenidate's metabolic effects vary with acute previous exposure and highlights the importance of studying drugs after single and repeated administration.

Adult↗

PubMed1998

Parallel loss of presynaptic and postsynaptic dopamine markers in normal aging.

Aging of the human brain is associated with a decline in dopamine (DA) function, generally interpreted as reflecting DA cell loss. Positron emission tomography studies revealed that in healthy individuals, the age-related losses in DA transporters (presynaptic marker) were associated with losses in D2 receptors (postsynaptic marker) rather than with increases as is known to occur with DA cell loss. This association was specific for DA synaptic markers, because they were not correlated with striatal metabolism. Furthermore, the association was independent of age, suggesting that a common mechanism regulates the expression of receptors and transporters irrespective of age.

Adult↗

PubMed1998

Acoustic startle, prepulse inhibition, locomotion, and latent inhibition in the neuroleptic-responsive (NR) and neuroleptic-nonresponsive (NNR) lines of mice.

The acoustic startle reflex (ASR) is inhibited by low intensity acoustic stimuli (prepulse inhibition; PPI) delivered prior to the startle stimulus. PPI may reflect underlying sensorimotor processes involved in the filtering of exteroceptive stimuli for their cognitive or physiological relevance. Latent inhibition (LI) is a cognitive process in which pre-exposure to the conditioned stimulus (CS) produces pro-active interference with the acquisition of an associative learning task. LI is thought to reflect a selective attention mechanism that contributes to an organism's ability to adjust its behavior to changing contingencies of reinforcement. In the present series of experiments, the ASR, PPI at three prepulse intensities (56, 68, and 80 dB), locomotor activity, and LI using an active avoidance paradigm were assessed in mice bidirectionally selected from a heterogeneous stock for response (NR line) or nonresponse (NNR line) to neuroleptic-induced catalepsy. A randomly selected line was used as the control. Mice from the NNR line displayed weak startle responses and a complete absence of PPI. In contrast, the NR line displayed the largest ASR and the greatest PPI. The control line displayed ASRs and PPI values intermediate to the selected lines. Locomotor activity which is known to affect LI was lowest in the NR line but was similar in the NNR and control lines. In the LI paradigm, acquisition of the avoidance response was impaired in mice from the NR and control lines that were pre-exposed to the auditory CS (normal response). In contrast, the acquisition of the avoidance response in the NNR line was similar in CS pre-exposed and CS non-pre-exposed animals. Overall, the results demonstrate that some of the same genetic factors which regulate neuroleptic response also play a significant role in PPI and LI.

Acoustic Stimulation↗

PubMed1998

Genetics of ethanol-induced locomotor activation: detection of QTLs in a C57BL/6J x DBA/2J F2 intercross.

Moderate doses of ethanol (1-2 g/kg) markedly increase locomotor activity in some inbred mouse strains, for example, the DBA/2J (D2), but have relatively little effect in other strains, for example, the C57BL/6J (B6). In the present study, we conducted a genome-wide search in a B6D2 F2 intercross (N = 925) for quantitative trait loci (QTLs) associated with the locomotor response. A QTL with a LOD score of 8.4 was detected on Chromosome (Chr) 2; this QTL accounted for 11.4% of the phenotypic variance and approximately 30% of the genetic variance. The QTL on Chr 2 is in the same general region as QTLs previously described for ethanol preference/consumption (Rodriguez et al. Alcohol Clin Exp Res 19, 367, 1995; Melo et al. Nat Genet 13, 147, 1996; Phillips et al. Mamm Genome, in press), acute ethanol withdrawal (Buck et al. J. Neurosci 17, 3946, 1997) and nitrous oxide withdrawal severity (Belknap et al. Behav Genet 23, 213, 1993). A logical candidate gene in the region of interest is the enzyme which synthesizes GABA, glutamic acid decarboxylase 1 (GadI).

Animals↗

PubMed1998

Genetics, haloperidol, and the Fos response in the basal ganglia: a comparison of the C57BL/6J and DBA/2J inbred mouse strains.

The haloperidol-induced increase of Fos-like immunoreactive (Fos-li) neurons in the basal ganglia was compared in the C57BL/6J (B6) and DBA/2J (D2) inbred mouse strains. The D2 strain is 10-fold more sensitive than the B6 strain to haloperidol-induced catalepsy, a putative animal model of the extrapyramidal symptoms (EPS) seen after the administration of typical neuroleptics. In contrast, the strains are equally sensitive to the haloperidol facilitation of prepulse inhibition of the acoustic startle response, a measure of drug efficacy on the mesolimbic dopamine system. The haloperidol effects on Fos-li neurons were examined over the range of 0.1 to 6.0 mg/kg; the ED50s for haloperidol-induced catalepsy are 0.4 and 3.8 mg/kg in the D2 and B6 strains, respectively. In neither the core or shell of the nucleus accumbens nor the caudate-putamen (including the dorsolateral aspect) did the D2 strain show a greater Fos response compared to the B6 strain. In fact, in the dorsolateral caudate-putamen, the B6 strain showed a modest but significantly greater Fos response. However, at the output nuclei of the basal ganglia, the entopeduncular nucleus (EP) and the substantia nigra zona reticulata (SNr), the D2 strain consistently showed a greater Fos response. These data suggest that the EP and SNr may be important to understanding the difference in haloperidol-induced catalepsy between the D2 and B6 strains.

Animals↗

PubMed1998

Dopamine transporter occupancies in the human brain induced by therapeutic doses of oral methylphenidate.

OBJECTIVE: The therapeutic effects of methylphenidate in the treatment of attention deficit disorder have been attributed to its ability to increase the synaptic concentration of dopamine by blocking the dopamine transporters. However, the levels of dopamine transporter blockade achieved by therapeutic doses of methylphenidate are not known. This study measured, for the first time, dopamine transporter occupancy by orally administered methylphenidate in the human brain and its rate of uptake in the brain. METHOD: Positron emission tomography (PET) and [11C]cocaine were used to estimate dopamine transporter occupancies after different doses of oral methylphenidate in seven normal subjects (mean age=24 years, SD=7). In addition, the pharmacokinetics of oral methylphenidate were measured in the baboon brain through use of PET and [11C]methylphenidate administered through an orogastric tube. RESULTS: At 120 minutes after administration, oral methylphenidate produced a dose-dependent blockade of dopamine transporter; means=12% (SD= 4%) for 5 mg, 40% (SD=12%) for 10 mg, 54% (SD=5%) for 20 mg, 72% (SD=3%) for 40 mg, and 74% (SD=2%) for 60 mg. The estimated dose of oral methylphenidate required to block 50% of the dopamine transporter corresponded to 0.25 mg/kg. Oral methylphenidate did not reach peak concentration in brain until 60 minutes after its administration. CONCLUSIONS: Oral methylphenidate is very effective in blocking dopamine transporters, and at the weight-adjusted doses used therapeutically (0.3 to 0.6 mg/kg), it is likely to occupy more than 50% of the dopamine transporters. The time to reach peak brain uptake for oral methylphenidate in brain corresponds well with the reported time course to reach peak behavioral effects.

Administration, Oral↗

PubMed1998

Enhanced sensitivity to benzodiazepines in active cocaine-abusing subjects: a PET study.

OBJECTIVE: Because cocaine enhances dopamine brain activity and dopamine signals are transferred through gamma-aminobutyric acid pathways, the authors hypothesized GABA-ergic disruption in cocaine-abusing subjects. This study tests this hypothesis. METHOD: GABA brain function was assessed indirectly by measuring the brain metabolic responses to lorazepam, a drug that facilitates GABA neurotransmission. Thirteen current cocaine-abusing subjects and 14 comparison subjects were scanned twice with positron emission tomography and [18F]fluorodeoxyglucose; the first scan was obtained after placebo administration and the second after lorazepam administration (30 micrograms/kg). RESULTS: Despite significantly higher plasma lorazepam concentrations in comparison subjects than in cocaine-abusing subjects, lorazepam-induced decrements in whole brain metabolism were significantly greater in cocaine-abusing (mean = 21%, SD = 13%) than in comparison (mean = 13%, SD = 7%) subjects. These differences were largest in striatum, thalamus, and parietal cortex. Lorazepam-induced sleepiness in cocaine-abusing subjects was intense and was significantly greater than in comparison subjects, and it was correlated with lorazepam-induced changes in thalamic metabolism. Whereas regional metabolic measures during placebo administration were significantly higher in cocaine-abusing subjects than in comparison subjects, the measures during lorazepam administration were equivalent for both groups. CONCLUSIONS: The enhanced sensitivity to lorazepam in cocaine-abusing subjects suggests disruption of GABA pathways that may reflect, in part, cocaine withdrawal. The intense sleepiness induced by lorazepam in some of the abusers, despite their significantly lower plasma concentrations, should alert clinicians of the potential toxicity from accentuated responses to sedative hypnotics in active cocaine-abusing subjects.

Adult↗

PubMed1998

Association between decline in brain dopamine activity with age and cognitive and motor impairment in healthy individuals.

OBJECTIVE: Although it is documented that brain dopamine activity declines with age, the functional significance of this is not known. This study assessed the relation between measures of brain dopamine activity and indexes of motor and cognitive function in healthy individuals. METHOD: Thirty healthy volunteers aged 24-86 years were studied with positron emission tomography and [11C]raclopride to assess dopamine D2 receptors. All subjects underwent a neuropsychological test battery that included tasks found to be sensitive to dopamine alterations in patients with neurodegenerative disease and control tasks. RESULTS: Transfer of [11C]raclopride from plasma to brain in the striatum and cerebellum was not affected by age. In contrast, D2 receptor availability in the caudate and putamen declined with age. Correlations between D2 receptors and neuropsychological test performance were strongest for the motor task (Finger Tapping Test) and were also significant for most tasks involving frontal brain regions, including measures of abstraction and mental flexibility (Wisconsin Card Sorting Test) and attention and response inhibition (Stroop Color-Word Test, interference score). These relationships remained significant after control for age effects. CONCLUSIONS: Age-related decreases in brain dopamine activity are associated with a decline in motor function and may also contribute to impaired performance on tasks that involve frontal brain regions. Interventions that enhance dopamine activity may improve performance and quality of life for the elderly. The fact that correlations remained significant after age effects were partialed out suggests that dopamine activity may influence motor and cognitive performance irrespective of age.

Adult↗

PubMed1998

Further evidence that the central nucleus of the amygdala is associated with the ethanol-induced locomotor response.

The effect of ethanol on the number of Fos-like immunoreactive (Fos-li) neurons was previously studied in the C57BL/6J (B6) and DBA/2J (D2) inbred mouse strains (Hitzemann and Hitzemann, Alcohol. Clin. Exp. Res. 21:1497-1507, 1997). The data obtained suggested that the locomotor activation response to ethanol found in the D2 but not the B6 strain was associated with an increase in the number of Fos-li neurons (a putative measure of synaptic activity) in the central nucleus of the amygdala (CeA), but not in other brain regions, including the basal ganglia. The current study was performed to obtain data supporting a role for the CeA in the locomotor response. B6D2 F2 intercross animals were phenotyped for their locomotor response to ethanol (1.5 g/kg). The animals from the extreme phenotypes (> 1 SD from the mean) were denoted as very high and very low activity (HH, LL) and differed in their ethanol response by >9,000 cm/15 min (baseline activity was similar in both phenotypes: 5,500 cm/15 min). These extremes especially differed from the parental strains in that the LL group showed a significant ethanol-induced inhibition of activity. After 2 weeks, HH and LL animals were rechallenged with 1.5 g/kg of ethanol or saline and the number of Fos-li neurons determined 1 hr later. In the HH group, ethanol increased the number of Fos-li neurons >600%, whereas in the LL group the increase was 170% (difference: p < 0.001). The increase in the HH group was principally located in the GABA neuron-rich lateral aspect of the CeA and not in the medial posterior-ventral division or the caps division. No significant difference was found between groups in the Fos response for the basolateral or lateral amygdala. Other brain regions were also examined, including the basal ganglia, the hippocampus (CA1, CA3, and dentate gyrus), the bed nucleus of the stria terminalis, and several cortical regions. In some regions (e.g., the bed nucleus), a significant ethanol effect was detected, but it did not differentiate the HH and LL groups. Overall, the data obtained further argue that the CeA has an important role in regulating the acute locomotor response to ethanol.

Amygdala↗