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Subchronic cocaine treatment enhances cocaine-induced dopamine efflux, studied by in vivo intracerebral dialysis.

Repeated administration of cocaine in animals results in behavioral sensitization. In order to investigate the neurochemical mechanism underlying such behavioral sensitization, we designed the following two experiments. In both experiments, rats were pretreated with cocaine (20 mg/kg i.p.) or saline, once daily for 14 consecutive days. Exp. 1: 7 days after withdrawal from the drug, the stereotyped behavioral response to a challenge of cocaine (20 mg/kg i.p.) was measured. Exp. 2: 7 days after withdrawal from the drug, we measured extracellular dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) after the challenge administration of cocaine using an in vivo intracerebral dialysis technique. The rats pretreated with cocaine (20 mg/kg i.p.) exhibited behavioral augmentation in response to a challenge of cocaine. The challenge administration of cocaine caused an increase in DA and a decrease in DOPAC. The DA level in the striatal perfusates of the cocaine-pretreated rats was significantly greater than that in the saline-pretreated rats. These results suggest that the increased extracellular DA concentration in the striatum plays an important role in the cocaine-induced behavioral sensitization.

3,4-Dihydroxyphenylacetic Acid↗

Enhancement by the D1 dopamine agonist SKF 38393 of specific components of stereotypy elicited by the D2 agonists LY 171555 and RU 24213.

Dose-effect curves were obtained for five specific components of stereotyped behavior (locomotor hyperactivity, rearing, sniffing, grooming and oral activity) elicited by the nonselective dopamine agonists N-propylnorapomorphine (NPA; 0.001-4.5 mg/kg) and apomorphine (APO; 0.3-10.0 mg/kg), the selective D2 agonists LY 171555 (0.1-18.0 mg/kg) and RU 24213 (0.7-20.0 mg/kg) and the selective D1 agonist SKF 38393 (0.6-40.0 mg/kg) in male Sprague-Dawley rats. All the agonists except SKF 38393 elicited dose-dependent sniffing. Both NPA and APO produced robust oral activity at high doses, with concomitant reductions in other behaviors. Neither RU 24213 nor SKF 38393 elicited dose-dependent oral behavior, whereas LY 171555 induced a maximal level of oral activity which was much less intense than that produced by NPA or APO. SKF 38393 alone induced only dose-dependent grooming. Co-treatment of Sprague-Dawley rats with SKF 38393 (5-40 mg/kg) and either LY 171555 (0.1-1.6 mg/kg) or RU 24213 (6.7 mg/kg) produced significant enhancement of sniffing but not of oral activity. Significant enhancement of both behavioral components was observed in male Wistar rats. Differences in specific components of behavioral response on treatment with combinations of D1 and D2 agonists may reflect use of animal strains with different ratios of D1/D2 innervation and/or different behavioral criteria.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗

Treatment of sex offenders with antiandrogenic medication: conceptualization, review of treatment modalities, and preliminary findings.

Sexual deviation disorders, or paraphilias, are diagnosable psychiatric syndromes manifested by 1) recurrent fantasies about deviant sex, 2) intense associated cravings, and 3) stereotypic behavioral responses. Pedophiles seek out children in response to their erotic thoughts and urges, whereas exhibitionists expose themselves. Paraphiliac syndromes ordinarily follow a chronic course and may be associated with biological pathology, but etiological factors are poorly understood. Treatment becomes a consideration when the well-being or rights of others are compromised. Proposed treatments have included psychotherapy, behavior therapy, surgery, and medication. Medroxyprogesterone acetate, which reduces testosterone, may diminish sexual preoccupation and urges, making self-control easier.

Adolescent↗

Psychotropic activity of angiotensin II and its fragments Val-Tyr-Ile-NH2 and Val-Tyr-Ile-His-NH2.

Angiotensin II (A II) significantly enhanced the motor activity of rats in the open field as measured by forward locomotion, rearings and bar approaches while the tripeptide [A II(3-5)] and the tetrapeptide [A II(3-6)] were ineffective in this test. Also, the stereotyped behavior produced by apomorphine (2 mg/kg) or amphetamine (6.5 mg/kg), both given intraperitoneally, was significantly more intense in rats receiving an icv injection of A II but not A II(3-5) or A II(3-6). A II significantly increased the rate of acquisition of active avoidance while AII(3-5) and AII(3-6) were ineffective. Finally, a remarkable improvement of performance in the passive avoidance situation was caused by AII, and none by AII(3-5) and AII(3-6). These results show that 3-5 and 3-6 fragments of AII are not responsible for the psychotropic activity of their parent octapeptide and suggest that AII(3-7) pentapeptide should be the fragment in question.

Amino Acid Sequence↗

Concomitant sensitization of amphetamine-induced behavioral stimulation and in vivo dopamine release from rat caudate nucleus.

Rats were treated twice daily either with saline or d-amphetamine (5 mg/kg) for 5 days. When challenged approximately 15 days later with an injection of 0.5 mg/kg amphetamine, the chronic amphetamine animals showed (1) an augmented release of dopamine in the caudate nucleus in vivo and (2) an increase in stereotyped behavior compared to the chronic saline animals. These results suggest that an increase in dopamine release from the caudate may contribute to amphetamine-induced behavioral sensitization.

Animals↗

Novelty seeking and stereotypic activation of behavior in mice with disruption of the Dat1 gene.

Disruption of the dopamine (DA) transporter (Dat1) gene in mice leads to a 50% reduction or complete elimination of Dat1 expression in striatum of respective heterozygous (HZ) and knockout (KO) mice. Compared to wild-type (WT) controls, extracellular DA is increased approximately two- and five-fold in the mutants. Although open field (OF) activity is similar for WT and HZ animals, it is enhanced for KO mice. The purpose of the present investigations was to study spontaneously emitted behaviors and to determine the behavioral and neurochemical mechanisms that may contribute to the hyperactivity of KO animals. Heterozygotes are less anxious than other genotypes and they engage in novelty-seeking behaviors that include increased time spent in the center of the OF, enhanced investigation of objects, and augmented free exploration of a novel environment. By comparison, KO mice display neophobia when initially exposed to novel conditions. Over time the anxiety-like response habituates and behaviors become activated and stereotyped; these responses are unrelated to exploration or novelty seeking. No alterations in extracellular DA levels or tissue contents from several brain regions are detected at the time of stereotypic activation of KO mice. By contrast, this behavior is accompanied by changes in serotonin metabolism in basal ganglia. This feature may contribute to the behavioral inflexibility of KO mice in different experimental contexts. Collectively, these findings suggest that disruption of the Dat1 gene in mice leads to two different phenotypes; one related to anxiety-reducing and novelty seeking, while the other has some homology to disorders with a stereotypical-perseverative spectrum.

Animals↗

A behavioral pharmacological study on CCK-8 related peptides in mice.

The effects of CCK-8, ceruletide, their non-sulfated forms and CCK-4 on locomotor activity and rearing in mice were examined. CCK-8 and ceruletide, but not their non-sulfated forms and CCK-4, significantly inhibited the behavioral parameters dose-dependently. The inhibitory effects of CCK-8 and ceruletide were similar, but ceruletide acted more slowly and its inhibitory effect continued much longer than CCK-8, suggesting a difference in stability with the chemical structure. The antagonistic effects of ceruletide on behavioral changes induced by DA agonists were also examined. Peripherally injected ceruletide antagonized both methylphenidate- and methamphetamine-induced hyperactivity in mice dose-dependently, whereas it had no dose-related antagonistic effect on methylphenidate-induced stereotyped behavior. Ceruletide also significantly inhibited apomorphine-induced hyperactivity when injected peripherally. However, no obvious dose-response relationship was observed in either intensity or duration of inhibitory action of ceruletide. These findings suggest that ceruletide does not interfere with dopaminergic transmission due to the blockade of postsynaptic DA receptors in the brain. In conclusion, peripheral injection of CCK-8 and ceruletide may affect directly or indirectly dopamine function producing behavioral changes that resemble those of neuroleptics in some respects.

Animals↗

Typical and atypical repetitive motor behaviors in young children at risk for severe mental retardation.

A sample of children, ages 1 to 3 years, identified as being at risk for severe mental retardation, was observed in a semi-longitudinal study to assess their pattern of typical repetitive movements topographically similar to aberrant, stereotyped behaviors and to determine the prevalence of atypical stereotypies at this age. Frequency scores, collected using a partial-interval time-sampling procedure, were analyzed on three variables (age, time of measurement, and environmental condition) using repeated measures analysis of variance. Results were discussed in light of similar studies of infants without disabilities.

Brain Damage, Chronic↗

Behavioral studies on the enantiomers of butaclamol demonstrating absolute optical specificity for neuroleptic activity.

Butaclamol is a member of a new chemical class for which antipsychotic activity in humans has been demonstrated. Butaclamol, a racemate, has been resolved into its optical isomers and a separation of activities was found to occur between the (+) and (-) enantiomers. The present experiments show that at doses ranging from 0.1 to 0.3 mg/kg the (+) enantiomer abolished amphetamine-induced (a) stereotyped behavior and (b) rotational behavior in rats with unilateral lesions in the substantia nigra. It also inhibited the lever-pressing response in the continuous (Sidman) avoidance procedure, blocked discriminated avoidance behavior, and decreased ambulation and rearing in the open field. In contrast, the (-) enantiomer was devoid of behavioral activity at 100-500 times larger doses. At considerably higher doses (+)-butaclamol antagonized epinephrine-induced mortality. Again, the (-)-butaclamol was devoid of this activity as well. The significance of absolute optical specifity manifested by a neuroleptic drug is discussed in the light of dopaminergic and adrenergic mechanisms.

Animals↗

Observations of novel behaviors as indices of ethanol withdrawal-induced anxiety.

One of the prominent symptoms in alcoholics during withdrawal is an intense feeling of anxiety. Recently new tests have become available which may index anxiety in rodents. We have evaluated two such tests in our model of withdrawal from ethanol (ET) in rats. Rats were given either ET in milk (7-13 g/kg/4 days) or equicaloric dextrin maltose in milk via implanted gastric cannuli. Rats were scored for classical withdrawal symptoms (tremors, convulsions, stereotyped behavior), for stimulus-elicited ultrasonic vocalizations (USVs), and in one study for exploration of novel objects placed in their home cage at various points after the last dose of ET. In Sprague-Dawley rats, classical withdrawal symptoms were highest between 8-12 hours, and disappeared by 36 hours. Latency to explore a novel object was unchanged, but duration was depressed between 10-30 hours, and was recovered by 70 hours. Following a less intense Day 1 treatment regimen in Long-Evans rats, the vocalizations were greatly increased in number, and peak response occurred sooner (6 hours post-infusion) and was of shorter overall duration (50 hours). Pretreatment with diazepam (1.25-5.0 mg/kg) depressed the number of vocalizations during ET withdrawal (ETW), which suggests that this measure could index anxiety in animal models of withdrawal from ET.

Animals↗

Sensory reinforcement in the mentally handicapped and autistic child: a review.

Sensory reinforcement was first studied by learning theorists working with animals in the 1950s. Attempts to examine the phenomenon with children followed in the 1960s, and the studies demonstrated that sensory stimuli could act like any other reinforcers with normal young children. Similar work with the autistic and mentally handicapped child arose in relation to both the study of receptor development and more treatment-oriented research. It now seems that even profoundly handicapped children can learn to operate simple levers when reinforced by sensory stimuli, and some handicapped children have learned quite complex skills through sensory reinforcement. There also appears to be a close relationship between stereotyped behavior and sensory reinforcement. The clinical implications of the studies reviewed are discussed.

Adolescent↗

Effects of intrastriatal injections of atropine and methacholine on the apomorphine-induced gnawing in the rabbit.

To find out the anatomical location of the target point of cholinergic-dopaminergic equilibrium, atropine (40 microng) or methacholine (10 microng) were injected through previously implanted cannulas into various places of caudate nucleus and putamen of the rabbit, and the effect of the injections on stereotype gnawing induced by subcutaneously or intravenously administered apomorphine (1--2 mg/kg) was assessed. The intensity of gnawing was measured using a special apparatus, counting each bite. Atropine inhibited the stereotype, while metacholine potentiated it. The effects were evident with the method used, but difficult to reveal with the classical method of assessing the intensity of stereotyped behavior, based on visual observation. The results suggest that the striatum is not a target point for the cholinergic component of the cholinergic-dopaminergic equilibrium in the central nervous system.

Animals↗

Diurnal differences in rat's motor response to amphetamine.

The dose-response characteristics and time-course of amphetamine's effect on motor activity after a single injection given to rats at four different times of the light/dark cycle was investigated using a computerized infrared motor activity recording system. After 7 days of acclimation and 2 days of baseline activity recording, rats received a single subcutaneous injection of vehicle (saline) or 0.6, 1.25 or 10 mg/kg amphetamine at 08.00, 14.00, 20.00 or 02.00. Recording was then resumed for an additional 36 to 48 h. The locomotor indices analyzed were horizontal activity, total distance, vertical activity, stereotypic activity and number of stereotypic movements. All doses (0.6. 1.25 and 10 mg/kg) significantly elevated (P < 0.01) locomotor activity compared to baseline at all times of administration. At all injection times, the maximum increase over baseline generally occurred following the 1.25 mg/kg dose of amphetamine (P < 0.001). The effect of the lower doses (0.6 and 1.25 mg/kg) on forward locomotion remained the same throughout the light/dark cycle regardless of the large difference in baseline motor activity between the light and dark phases. However, the effects of 10 mg/kg amphetamine on general stereotypic behavior, as well as the ability to cause subsequent depression of nocturnal forward ambulation, were dependent on the time of drug administration. These results showed that the circadian rhythms of locomotor and stereotypic effects of amphetamine are different.

Amphetamine↗

Alterations of accumbens neuronal activity in freely moving rats following methamphetamine.

Multiple unit activity in the nucleus accumbens, locomotor activity, and stereotyped behavior were simultaneously recorded in freely moving rats. An intraperitoneal injection of 1.5 mg/kg methamphetamine produced an increase in the firing rate while a decrease in the discharge rate occurred following an administration of 4.5 mg/kg methamphetamine. In addition, the unit activity was positively correlated with the locomotor activity and negatively correlated with the stereotypy score. These results suggest that accumbens neuronal activation during locomotor hyperactivity may partly depend on the feedback from locomotion.

Animals↗

Hyperactivity and brain catecholamines in lead-exposed developing rats.

Newborn rats that suckled mothers eating a diet containing 4 percent lead carbonate display hyperactivity, aggressiveness, and excessive stereotyped behavior starting at 4 weeks of age. There is an eightfold increase in the concentration of lead in brain, no change in norepinephrine, but a 20 percent decrease in dopamine relative to coetaneous controls. This suggests a relationship between central nervous system dysfunction due to lead and dopamine metabolism in brain.

Aggression↗

The actions of amphetamine on neurotransmitters: a brief review.

The central stimulant actions of d-amphetamine are not altered in animals in which brain stores of catecholamines have been depleted with reserpine, but they are blocked by alpha-methyltyrosine, which inhibits catecholamine synthesis. The results of a variety of experiments suggest that the central actions of amphetamine result primarily from the ability of the drug to facilitate the release of newly synthesized dopamine from nerve terminals in the forebrain. The results of experiments in animals in which dopaminergic nerve terminals in various brain regions have been selectively destroyed by intracranial microinjection of 6-hydroxydopamine reveal that the locomotor stimulant actions of relatively low doses of amphetamine are dependent upon mesolimbic dopaminergic neurons, whereas the stereotyped behaviors induced by relatively larger doses of amphetamine are dependent upon nigrostriatal dopaminergic neurons. The central actions of amphetamine appear to be the primary result of interactions with dopamine neurons, but secondarily the drug also alters the dynamics of other putative neurotransmitters (e.g. acetylcholine, 5-hydroxytryptamine) in the brain.

Amphetamine↗

Effect of brain peptides on hypokinesia produced by anterolateral hypothalamic 6-OHDA lesions in rats.

Intraventricular injections of substance P, TRH and somatostatin were administered to rats rendered hypokinetic by bilateral microinjections of 6-hydroxydopamine into the anterolateral hypothalamus, Only substance P in a dose of 0.30 micrigrams/rat significantly increased motor activity as determined by photocell counts in a 5 min test session immediately after administration of the peptide. Behavioral observations indicated that grooming and not locomotion was mainly responsible for the greater activity scores. None of the three peptides at the doses examined potentiated or reduced the increased activity induced by 1 mg/kg apomorphine. Stereotyped behavior was also not affected by previous injections of substance P and somatostatin but was enhanced in animals which had received 5 micrograms/rat TRH 30 min prior to apomorphine.

Animals↗

Behavioral effects of unilateral dopamine injection into dorsal or ventral striatum.

Dopamine or its vehicle saline was injected unilaterally into dorsal striatum, ventral striatum, or sites outside the striatum in adult male rats. Direction, duration and frequencies of ongoing behaviors were measured. Dopamine injected into any site within the striatum immediately elicited more contralaterally directed behavior than the vehicle injected into the same site. The contralaterally directed behaviors were no longer duration when injected into the dorsal than into the ventral striatum, a result which might reflect regional differences in numbers of dopamine receptors or distribution of efferents. At the doses employed (25 and 100 microgram), dopamine injected unilaterally into the striatum did not induce rotation, stereotyped behavior, or even a significant change in the frequencies of ongoing behaviors; rather, all ongoing behaviors were expressed in a contralateral direction. Thus, the behavioral effects of dopamine in the striatum are best understood as a change in sensory-motor responsiveness.

Animals↗