Locomotor Stimulant Effects Of D-amphetamine Research Articles

Drug reward and intake in lines of mice selectively bred for divergent exploration of a hole board apparatus

Individuals characterized as high-novelty seekers are more likely to abuse drugs than are low-novelty seekers, and it is possible that the biological substrates underlying novelty seeking and drug abuse are similar. We selectively bred replicate lines of mice from a B6D2 F3 hybrid stock for high exploratory behavior (HEB) or low exploratory behavior (LEB) as measured by the number of head dips on a hole board. To determine whether common genes might influence exploratory behavior and behaviors relevant to drug abuse, we tested HEB and LEB mice for conditioned place preference produced by ethanol and d-amphetamine and also examined oral methamphetamine intake. After four generations of selection, HEB and LEB mice did not differ in the magnitude of place preference for ethanol, but LEB mice showed a greater place preference for an amphetamine-paired location than did HEB mice. However, this difference did not replicate in mice tested from the fifth generation of selection. The selected lines also did not differ in sensitization to the locomotor stimulant effects of d-amphetamine that developed across the conditioning trials. Finally, HEB and LEB mice consumed equivalently low amounts of methamphetamine. These results suggest that common genes do not influence head dipping and several behaviors potentially relevant to drug abuse.

Behavioural sensitisation to repeated d-amphetamine: effects of excitotoxic lesions of the pedunculopontine tegmental nucleus

The pedunculopontine tegmental nucleus (PPTg) interacts with anatomical systems thought to be involved in mediating sensitisation of the locomotor response to repeated d-amphetamine. The PPTg has direct and indirect connections with the nucleus accumbens and prefrontal cortex, and also influences midbrain dopamine activity through direct projections to substantia nigra and ventral tegmental area. In this experiment, the development of behavioural sensitisation to the locomotor stimulant effects of repeated d-amphetamine was examined in rats bearing excitotoxic lesions of the PPTg, and sham-lesioned controls. Rats were given repeated d-amphetamine (1.5 mg/kg i.p.) treatment in an on–off procedure, with saline and d-amphetamine given on alternate days, such that rats received a total of seven d-amphetamine and seven saline treatments. Locomotor responses were measured in photocell cages. On the first day of d-amphetamine treatment, there was no difference between excitotoxin and sham-lesioned rats. Development of sensitisation to the locomotor stimulant effects of d-amphetamine was delayed in PPTg-lesioned rats, relative to the sham-lesioned control rats. However, there was no difference between lesion and control groups in the locomotion seen on saline-treatment days. These data suggest that the PPTg is involved in the development of behavioural sensitisation to the locomotor stimulant effects of repeated d-amphetamine, and indicate that traditional striatal circuitry models of the mechanisms underlying sensitisation should be extended to include the PPTg.

Lack of sensitization to the effects of d-amphetamine and apomorphine on sensorimotor gating in rats.

This study assessed whether repeated injections of d-amphetamine or apomorphine could induce sensitization to the disruptive effects of these psychomotor stimulants on sensorimotor gating in rats. In the first experiment, rats were given six pre-exposures to either 2.0 mg/kg d-amphetamine or saline before being tested for the effects of d-amphetamine (0.0, 0.5, 1.0, 2.0 or 4.0 mg/kg, i.p.) on prepulse inhibition of acoustic startle (PPI) and locomotor activity. The tests for PPI confirmed that sensorimotor gating could be disrupted by a high dose of d-amphetamine (4.0 mg/kg). However, comparison of the dose-response curves for the drug and saline pre-exposed groups did not reveal evidence for sensitization to this d-amphetamine effect in drug-pre-exposed rats, despite indications that sensitization had developed to the locomotor stimulant effects of d-amphetamine. A similar pattern of results was obtained in a second experiment that examined the effects of apomorphine (0.0, 0.1, 0.2, 0.4 and 0.8 mg/kg, s.c.) on PPI and locomotion in rats pre-exposed to 2.0 mg/kg of this drug or its vehicle. These findings demonstrate that treatments which induce sensitization to the behavioral activating effects of psychomotor stimulants do not necessarily produce sensitization to the disruptive effects of stimulants on sensorimotor gating. The implications of these results for hypotheses linking sensitization-like processes to the etiology of schizophrenia are discussed.

Hyperactivity and altered amphetamine sensitivity in premature juvenile rats

‘Premature’ rats that were delivered by cesarean section on day 21 of gestation and ‘normal’ rats that were delivered spontaneously on day 22 of gestation were tested for basal locomotor activity and locomotor stimulation in response to d-amphetamine at 19–21 days of age. Compared to normal rats, premature rats had increased basal levels of locomotor activity and showed enhanced sensitivity to the locomotor stimulant effects of d-amphetamine. Cesarean-delivered premature rats may be a useful animal model for investigating mechanisms of neurobehavioral deficits associated with premature birth in humans.

Effects of chronic electroconvulsive shock on interstitial concentrations of dopamine in the nucleus accumbens

There is accumulating evidence that chronic electroconvulsive shock (ECS) can increase the functional output of central dopaminergic systems. The present experiments investigated the effects of acute and chronic ECS on interstitial concentrations of dopamine (DA) in the nucleus accumbens (NAC) using in vivo microdialysis in awake freely moving rats. ECS (150 V, 0.75 s) increased interstitial concentrations of DA, DOPAC and HVA to approximately 130% of baseline values. The magnitude of the ECS-induced increase in DA was not affected by chronic ECS. In contrast, the response of the DA metabolites was attenuated in the chronic ECS group. Chronic ECS did not influence apomorphine (25 micrograms/kg, SC)-induced decreases in extracellular concentrations of DA or its metabolites in the NAC, thus providing no support for the hypothesis that chronic ECS produces subsensitivity of DA autoreceptors. d-Amphetamine (1.5 mg/kg SC)-induced increases in extracellular DA were significantly prolonged in the NAC of the chronic ECS group. In accordance with previous reports, the locomotor stimulant effects of d-amphetamine were also enhanced in the chronic ECS group. These data provide further evidence that chronic ECS can increase certain behavioral and neurochemical indices of meso-accumbens DA function.

Chronic desipramine enhances aniphetamine-induced increases in interstitial concentrations of dopamine in the nucleus accumbens

There is accumulating evidence that some antidepressant treatments can increase the functional output of the meso-aecumbens dopanunergic system. For example, chronic administration of tricyclic antidepressant drugs such as imipramme and desipramine (DMI) enhances the locomotor stimulant effects of d-amphetamine Subsensitivity of inhibitory dopamine (DA) autoreceptors and supersensitivity of postsynaptic DA receptor mechanisms are among the mechanisms that have been suggested to underlie these observations. The present experiments investigated the effects of acute and chronic DMI treatment on interstitial DA concentrations in the nucleus accumbens and striatum using in vivo microdialysis in awake freely moving rats (48 h following implantation of a microdialysis probe). Neither acute (5 mg/kg b.i.d. for 2 days followed by 72 h withdrawal) nor chronic (5 mg/kg b.i.d. for 21 days followed by 72 h withdrawal) DMI influenced the ability of apomorphine (25 μtg/kg s.c.) to decrease extracellular concentrations of DA or its metabolites 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) in the nucleus accumbens. In contrast, d-amphetamine (1.5 mg/kg s.c.)-induced increases in extracellular DA were significantly enhanced in the nucleus accumbens of the chronic but not the acute DMI group. This effect was at least partially regionally selective, as significant effects were not observed in the striatum. In accordance with previous reports, the locomotor stimulant effects of d-amphetamine were also enhanced in the chronic DMI groups. DMI itself failed to alter the interstitial concentrations of DA and its metabolites in the nucleus accumbens of the control and chronic DMI groups. These results provide in vivo neurochemical confirmation that chronically administered DMI does not produce DA autoreceptor subsensitivity. They also demonstrate that chronic DMI-induced increases in the locomotor stimulant effects of d-amphetamine are accompanied by a selective potentiation of the effects of this stimulant on interstitial DA concentrations in the nucleus accumbens.

Dopamine D-2 receptor agonist-induced behavioural depression: critical dependence upon postsynaptic dopamine D-1 function

The dopamine (DA) D-2 receptor agonists quinpirole (threshold dose, 0.01 mg/kg IP), pergolide (0.025 mg/kg), B-HT 920 (0.003 mg/kg) and (-)-3-PPP (4 mg/kg) produced dose-dependent locomotor depression (immobility) in mice as assessed by a subjective scoring system, with the immobility being characterized by a frozen posture. The animals were still but had their eyes open. The immobility was accompanied by reductions in sniffing, rearing and grooming. The depression (and the associated reduction in the various behaviours) produced by quinpirole (0.1 mg/kg), pergolide (0.1 mg/kg) and B-HT 920 (0.1 mg/kg) was substantially (but not always completely) reversed by the selective D-1 receptor agonist SKF38393 (up to 12 mg/kg) and the non-selective D-1 receptor agonist CY208243 (up to 3 mg/kg). The immobility induced by (-)-3-PPP (16 mg/kg) was also reversed by CY208243 and SKF38393, but the reversal was due to an increase in grooming behaviour in mice challenged with the D-1 receptor agonists, whether or not the animals had also received (-)-3-PPP. There was no reversal of the depression of rearing or sniffing. In contrast, CY208243 and SKF38393 also antagonized the immobility induced by B-HT 920, but the reversal was accompanied by at least partial reversals of the depression of sniffing, rearing and grooming. The reversal of quinpirole-induced immobility by SKF38393 and CY208243 was antagonized by SCH23390 (0.1 mg/kg). The selective D-2 receptor antagonist raclopride (0.025 to 0.4 mg/kg) could not reverse quinpirole-induced immobility. High doses of either raclopride (0.4 mg/kg) or SCH23390 (greater than 0.1 mg/kg) significantly increased immobility. Although raclopride itself (0.2 mg/kg) produced a substantial increase in DOPAC and homovanillic acid (HVA) levels in the striatum, it did not antagonize the autoreceptor mediated effects of quinpirole (0.1 mg/kg) in reducing the striatal dihydroxyphenylacetic acid (DOPAC) to DA ratio. However, the same dose of raclopride was partly effective in reducing the effects of lower doses of quinpirole (0.01 and 0.03 mg/kg) on the striatal DOPAC to DA ratio. Raclopride (0.2 mg/kg) also partially but significantly reduced the locomotor stimulant effects of d-amphetamine in reserpinized mice. Biochemical analyses in the striata indicated that CY208243 slightly retarded DA turnover (as assessed by the DOPAC/DA ratio). SKF38393 itself also slightly reduced DA turnover. In automated activity cages, using mice depleted of DA with reserpine and alpha-methyltyrosine, all the D-2 receptor agonists tested, in combination with SKF38393, produced an increase in activity.(ABSTRACT TRUNCATED AT 400 WORDS)

Differences in amphetamine and morphine sensitivity in lateralized and non-lateralized rats: Locomotor activity and drug self-administration

Morphine and d-amphetamine were tested for their effects on locomotor activity and for their propensities to be intravenously self-administered in rats that had been screened for their tendencies to rotate (turn in circles) spontaneously at night; noctural rotation was used as a behavioral index of asymmetry in the dopaminergic nigrostriatal system. Lateralized (rotating) rats were more sensitive to the locomotor stimulant effects of d-amphetamine than non-lateralized (non-rotating) rats. The stimulant effects of low doses of morphine were also greater in lateralized rats, whereas the depressant effects of high doses of morphine were greater in non-lateralized rats. Lateralized rats self-administered more d-amphetamine than non-lateralized rats whereas non-lateralized rats self-administered more morphine than lateralized rats. The data indicate that the degree of lateralization in some brain pathways is a source of interindividual variation in drug sensitivity--this may in part be responsible for the individual tendencies of humans to selectively abuse particular types of drugs.

A behavioural study of the changes in the central nervous system of mice after subchronic treatment with the selective dopamine autoreceptor agonist 3-PPP (dl-3-[3-hydroxyphenyl]-N-n-propylpiperidine).

In naive mice the selective dopamine (DA) autoreceptor agonist 3-PPP (dl-3-[3-hydroxyphenyl]-N-n-propylpiperidine) produced a dose-dependent depression of locomotor activity. The duration of action of the depression was short, with no significant depression being noted one or more hours after a dose of 23.47 mg/kg (expressed as the base). Mice, administered the drug twice daily (23.47 mg/kg, in the morning and the evening, i.p.) for 5 days, were, 15 to 25 hours after the last dose, marginally less sensitive to the locomotor depressant effects of a challenge with the same drug. There was no change in the sensitivity of postsynaptic DA and alpha-adrenergic receptors, as assessed by the locomotor stimulant effects of apomorphine and apomorphine plus clonidine, respectively, in reserpine and alpha-methyltyrosine pretreated animals. However, 3-PPP-pretreated mice were most sensitive to the activating effects of d-amphetamine, and this increased sensitivity was blocked by pretreatment with reserpine. In naive mice, a low, DA autoreceptor selective dose of haloperidol (25 micrograms/kg) potentiated the locomotor stimulant effects of d-amphetamine. One explanation for the data obtained is that subchronic pretreatment with 3-PPP produced DA autoreceptor subsensitivity with no concomitant change in postsynaptic DA or alpha-adrenergic receptor sensitivity. The increased sensitivity to d-amphetamine in the 3-PPP pretreated mice may be due to a reduction in the feedback control exerted by the DA released by the d-amphetamine due to the DA autoreceptors having become subsensitive.

Comparison of tyrosine hydroxylase and dopamine-?-hydroxylase inhibition with the effects of various 6-hydroxydopamine treatments on d-amphetamine induced motor activity

The significance of central noradrenergic and dopaminergic neural systems for the locomotor stimulant effects of d-amphetamine were investigated in rats with depletions of norepinephrine, dopamine, or both catecholamines produced by treatment with either reserpine, L-α-methyl-tyrosine (α-MPT), 6-hydroxydopamine (6-OHDA), or the dopamine-Β-hydroxylase inhibitor 1-phenyl-3-(2-thiazolyl)-2-thiourea (U-14,624). In animals pretreated with reserpine, amphetamine-stimulated locomotor activity was blocked by Β-MPT but not by U-14,624 when amphetamine was given l h after these catecholamine synthesis inhibitors. In rats with chronic depletions of brain norepinephrine, dopamine, or both catecholamines produced by different 6-OHDA treatments, both amphetamine-stimulated motor activity and stereotyped behavior were antagonized by treatments reducing dopamine or both catecholamines but not in animals in which brain norepinephrine was reduced. Results are consistent with the view that the locomotor stimulation and stereotyped behaviors produced by d-amphetamine are dependent upon functional dopaminergic neural systems in brain.

Antagonism of d-amphetamine by alpha-methyl- l-tyrosine: Behavioral evidence for the participation of catecholamine stores and synthesis in the amphetamine stimulant response

The ability of α-methyl- l-tyrosine to antagonize the locomotor stimulant effects of d-amphetamine was tested in rats pretreated with saline pheniprazine or reserpine. Dose α-methyl- l-tyrosine-antagonism curves in saline-pretreated rats were shown to be dependent upon the challenging dose of amphetamine employed. After 1 mg kg of the stimulant no antagonism of the evoked locomotor stimulation was observed at doses of the amino acid below 25 mg kg . Stimulation to 2 and 4 mg kg amphetamine on the other hand was significantly antagonized by much lower doses of α-methyltyrosine. Pheniprazine-pretreated rats were more sensitive to the effects of amphetamine but less prone to antagonism by the amino acid. The locomotor stimulation to the sympathomimetic amine in the reserpine-pretreated rats was inhibited by very low doses of α-methyl- l-tyrosine. These data are interpreted to reveal a participation of both endogenous catecholamine stores and biosynthesis in the amphetamine response in saline-pretreated rats. Pheniprazine increases the relative importance of stores whereas reserpine pretreatment leaves the animals completely dependent upon catecholamine biosynthesis for realization of amphetamine-induced locomotor stimulation.