Effect of dietary lipid on locomotor activity and response to psychomotor stimulants

Spontaneous locomotor activity was investigated in developing rats fed diets rich in either saturated fat (coconut oil) or polyunsaturated fat (sunflower oil). The locomotor activity response to amphetamine, methylphenidate, and atropine in the dietary groups was also measured. Rats from dams fed sunflower oil had a late developing (20 days of age) increase in basal locomotor activity when compared to rats from dams fed coconut oil and the standard laboratory diet. The locomotor activity response to d-amphetamine administered IP to 30-day-old animals was potentiated in rats exposed to coconut oil compared to the other two groups. A dose-response analysis of the effect of methylphenidate revealed no differences among the dietary groups. A low dose of atropine (2 mg/kg) decreased 1 h locomotor activity 40% below basal level in rats fed sunflower oil but increased locomotor activity 90% over basal activity in rats fed coconut oil. These results indicate that dietary lipid can have a marked effect on basal locomotor activity as well as on the response to stimulant drugs.     

The effects of 5,7-dihydroxytryptamine lesions of extrapyramidal and mesolimbic sites on spontaneous motor behaviour,and amphetamine-induced stereotypy

Summary 5,7-Dihydroxytryptamine lesions of the nucleus accumbens septi, or substantia nigra, resulted in a twofold increase in spontaneous locomotor activity. Striatal 5HT depletion also raised basal activity levels, as well as increasing rearing behaviour in an open field. The stereotyped responses to all doses of amphetamine tested (2.5–10 mg/kg, i.p.) were enhanced by lesions of the nucleus accumbens or substantia nigra. Striatal lesions only affected the response to the lowest dose of amphetamine. Lesions of the tuberculum olfactorium were without effect on spontaneous or amphetamine induced responses. The results support the concept of a modulatory 5HT influence on nigro-striatal function, and suggest that 5HT in the nucleus accumbens has an antagonistic role with respect to dopamine function in this site.     

Attenuation of amphetamine-induced motor stimulation and stereotypy by 6-hydroxydopamine in the rat

1. In accord with previous reports, intraventricular administration of 6-hydroxydopamine (250 μg) to rats did not influence spontaneous locomotor activity. Neither was the stereotyped behaviour seen after high doses of (+)-amphetamine (5 mg/kg) changed by this treatment. Increases in motor activity induced by (+)-amphetamine (0·5 and 1·0 mg/kg) were significantly reduced after 6-hydroxydopamine.

2. When 6-hydroxydopamine (250 μg) was administered to tranylcypromine (5 mg/kg) pretreated animals, spontaneous activity was significantly reduced. The stimulant effects of (+)-amphetamine (0·5 and 1·0 mg/kg) were completely abolished and amphetamine stereotypy (5·0 mg/kg) was absent or reduced after this treatment.

3. Bilateral injections of 6-hydroxydopamine (10 μg) into the substantia nigra abolished the more pronounced features of amphetamine stereotypy. However, although significantly reduced, amphetamine-induced locomotor stimulation was observed in these animals. Spontaneous activity was also reduced.

4. These observations suggest that dopaminergic nigro-striatal neurones mediate some of the stimulant effects of amphetamine as well as being of critical importance in amphetamine-induced stereotypy. However, other catecholaminergic neurones also appear to be involved in amphetamine motor stimulation. The results are consistent with the view that amphetamine exerts its behavioural effects indirectly through its action on brain catecholamines.

     

Enhanced self-stimulation responding from the substantia nigra after chronic amphetamine treatment: A role for conditioning factors

Rats treated with 2 mg/kg of d-amphetamine and tested for self-stimulation responding supported from the substantia nigra (pre-trial group), showed a progressive augmentation in rates of self-stimulation responding relative to control animals following repeated drug/test pairings for 10 days. A similar behavioral profile was not observed among animals that received behavioral testing followed by drug administration (post-trial group) during the chronic phase. On test day (Day 11), rats that received repeated drug/test pairings during the chronic phase exhibited a facilitated self-stimulation response to a low test dosage of d-amphetamine (0.5 mg/kg) which otherwise had no behavioral effect, whereas rats exposed to chronic test/drug pairings during the chronic phase did not show enhaced self-stimulation rates to the test dosage of d-amphetamine. Animals chronically treated with pre-trial injections of amphetamine also showed facilitated self-stimulation responding when tested with saline, relative to animals that were chronically treated with post-trial injections of amphetamine and tested with saline. These findings were not parallelled by drug-induced changes in locomotor activity. Response sensitization after chronic amphetamine treatment does not appear to involve the accumulation of the drug in adipose tissue. A role for conditioning factors in the development of the response sensitization is discussed.     

Changed eating and locomotor behaviour in the rat after 6-hydroxydopamine lesions to the substantia nigra.

Bilateral 6-hydroxydopamine lesions to the substantia nigra of the rat result in 80–90% loss of striatal dopamine. In such animals, amphetamine does not induce stereotyped behaviour but the running response to lower doses of amphetamine is unaffected. The lesion does, however, produce permanent changes in the spontaneous locomotor behaviour of the rat. Aphagia was observed only in animals with greater striatal dopamine depletion which was associated with additional forebrain noradrenaline loss.     

Effects of (+-)3,4-methylenedioxymethamphetamine (MDMA) on brain dopaminergic activity in rats

Acute treatment with (+-)3,4-methylenedioxymethamphetamine (MDMA) at high doses (10 and 30 mg/kg, IP), but not lower doses increased locomotor activity in male rats. MDMA did not consistently produce any other stereotyped behaviors at any dose. Dopamine (DA) turnover rate as estimated by the ratio of brain tissue levels of 3,4-dihydroxyphenylacetic acid (DOPAC) over DA was decreased in the striatum for up to two hours after acute treatment with 10 mg/kg of MDMA. DA turnover rate was inconsistently decreased in the olfactory tubercle and medial basal hypothalamus, and was unchanged in the medial prefrontal cortex and the substantia nigra/ventral tegmental area. Two hours after a 30 mg/kg injection of MDMA, DA turnover rate was decreased in all brain areas tested. MDMA and d-amphetamine partially reversed a haloperidol-induced elevation of striatal DOPAC levels. In contrast, the nonamphetamine stimulant, amfonelic acid, enhanced haloperidol's effect. In chloral hydrate-anesthesized rats, MDMA injected IV partially inhibited spontaneous firing rate of DA neurons in the substantia nigra (34% decrease at 4 mg/kg of MDMA). Seventeen days after subchronic MDMA treatment (10 or 20 mg/kg, IP, twice per day for four days), DA and DOPAC levels were unchanged in all brain areas tested as compared to levels in control rats. It is concluded that acute treatment with high but not low doses of MDMA has a weak amphetamine-like effect on nigrostriatal as well as mesolimbic/mesocortical and tuberoinfundibular DA neurons in rats. Repeated treatment with MDMA does not appear to be toxic to mesotelencephalic or tuberoinfundibular DA neurons.     

Modification of the behavioural changes induced by amphetamine in the rat by lesions in the caudate nucleus, the caudate-putamen and globus pallidus

Both unilateral and bilateral lesions of the caudate nucleus, caudate putamen and globus pallidus reduced or abolished the stereotypy normally induced by amphetamine 2.5 and 5 mg/kg. These doses of amphetamine induced ipsilateral circling in rats with unilateral lesions of the three areas and periodic cataleptic behaviour in rats with bilateral lesions. No modification of the locomotor stimulant effect of amphetamine was observed in the animals with either unilateral or bilateral lesions of the caudate nucleus and caudate-putamen. Animals with bilateral lesions of the globus pallidus, however, exhibited an increased sensitivity to this effect. The effects of the various lesions on stereotypy and locomotor activity differentiate between these two aspects of behaviour induced by amphetamine and suggest that different anatomical sites of action may be involved.     

The role of monoamines in rotation induced or potentiated by amphetamine after nigral, raphe and mesencephalic reticular lesions in the rat brain

(±)-Amphetamine (2.5 mg/kg i.p.) induced ipsilateral rotation in rats with a lesion in the left substantia nigra, but not in rats with a lesion in the raphé nuclei. Lesions placed in both areas in the same rat reduced the ipsilateral striatal dopamine content and the 5-hydroxytryptamine (5-HT) content of both striata but the response to amphetamine was the same as with a lesion only in the left substantia nigra. A lesion in the left mesencephalic reticular area produced contralateral asymmetry that was potentiated by amphetamine into active rotation.Amphetamine induced (substantia nigra lesion) and potentiated (reticular area lesion) rotation was increased by procyclidine HCl (5 mg/kg i.p.) and prevented by α-methyl-p-tyrosine (250 mg/kg i.p.). FLA-63 (40 mg/kg s.c.) did not inhibit the induced rotation but reduced the potentiated rotation. Haloperidol (5 mg/kg i.p.) caused contralateral rotation in the nigral lesioned rats but did not affect the asymmetry of the rats with a lesion in the reticular area. Chlorpromazine (5 mg/kg i.p.) prevented the induced rotation and reduced the potentiated rotation.The results are discussed in relation to catecholamines and the components of the amphetamine behavioural response. Amphetamine-induced rotation may involve the release of dopamine, without the involvement of striatal 5-HT, and represent amphetamine stereotyped behaviour. Potentiated rotation may represent amphetamine locomotor stimulation and involve the release of noradrenaline but a dopaminergic influence cannot be excluded.     

Exposure to amphetamine in rats during periadolescence establishes behavioural and extrastriatal neural sensitization in adulthood

Drug abuse during adolescence may predispose towards later adult substance abuse and major depressive disorders (Brook et al., 2002). The purpose of the present study was to characterize whether behavioural sensitization to amphetamine occurred in adult rats following adolescent exposure to amphetamine [low (2 mg/kg.d) or high (10 mg/kg.d) i.p. for 10 d] and the pattern of neural activation associated with sensitized behaviour, in male Sprague-Dawley rats. Following initial treatment (post-natal days 33-41) and a subsequent 4-wk period of abstinence, rats initially treated with either amphetamine regime showed a similar sensitized locomotor activity upon re-challenge with amphetamine (1.5 mg/kg i.p.) compared to rats acutely challenged with this dose of amphetamine. Fos-IR expression in the "high" sensitized group was significantly greater than acutely challenged rats in all quadrants of the CPu. Both "low" and "high" sensitized groups demonstrated heightened Fos expression relative to acutely challenged rats in the medial and central amygdala, as well as rostroventrolateral medulla, whereas Fos-IR in the locus coeruleus and substantia nigra pars reticulata was significantly increased only in the "high" sensitized group compared to acute. Double-labelling for tyrosine hydroxylase confirmed an absence of Fos-IR in A9 and A10 regions. The present study has shown a robust and persistent sensitization in adulthood to amphetamine re-challenge following initial adolescent exposure in rats. This manifestation of sensitization apparently results in widespread neural activation in limbic and autonomic structures.     

The effect of previous exposure to amphetamine on drug-induced locomotion and self-administration of a low dose of the drug

Rationale and objectives: In order to assess directly the relationship between locomotor activity and drug self-administration, the present experiment simultaneously measured these two behaviors in rats with different histories of pre-exposure to amphetamine either following or in the absence of priming injections of the drug. Methods: Different groups of rats were exposed to ten daily injections of either saline (1.0 ml/kg, i.p.) or amphetamine (1.5 mg/kg, i.p.) and, in each of 13 daily sessions starting 10 days later, were given the opportunity to lever press for a low dose of amphetamine (10 μg/kg per i.v. infusion) in a two-lever (active versus inactive) continuous reinforcement task. Animals were administered a priming injection of amphetamine (1.0 mg/kg, i.p.) immediately before testing on the first 8 days, a saline injection (1.0 ml/kg, i.p.) on the next 3 days and amphetamine on the final 2 days of testing. Results: Consistent with previous reports, prior exposure to amphetamine led to an enhanced locomotor response to the priming injection of amphetamine on the first day of testing. Little pressing for drug was observed on this day. Following priming injections on the subsequent test days, evidence for enhanced locomotion by amphetamine-pre-exposed rats diminished and both groups showed comparable and progressive increases in active versus inactive lever pressing. When priming injections were not made, however, only animals previously exposed to amphetamine maintained lever pressing for the drug. Under these conditions, these animals emitted more active lever presses and time-out responses and exhibited higher levels of locomotor activation in proximity to the active drug administering lever than did saline-pre-exposed rats. Conclusions: These results are consistent with the view that previous exposure to amphetamine produces a long-lasting enhancement in the behavioral activation animals will direct toward stimuli associated with the drug. This enhancement was displayed initially as a sensitized locomotor response to amphetamine on the first day of testing and was subsequently observed on those test days when no priming injections were given when animals continued to self-administer a low dose of amphetamine under a simple schedule of reinforcement. The implications of these findings for our understanding of the excessive expression of drug-directed behaviors are discussed. Received: 23 November 1998 / Final version: 19 June 1999     

Preexposure to MDMA ("Ecstasy") delays acquisition but facilitates MDMA-induced reinstatement of amphetamine self-administration behavior in rats

The current experiment investigated the effect of 3,4-methylenedioxymethamphetamine (MDMA; 'Ecstasy') preexposure on the acquisition of intravenous amphetamine self-administration and the reinstatement of amphetamine-seeking behavior by either MDMA or amphetamine. Rats were preexposed to a 5-HT depleting regime of MDMA (5 mg/kg every hour for 4 h on two consecutive days) or equivalent vehicle injections. Intravenous self-administration of low dose d-amphetamine (0.03 mg/kg/infusion) on a FR1 schedule was subsequently assessed. The rats were then given 2 weeks of extinction and tested for drug-seeking behavior with priming doses of amphetamine or MDMA. Brains were analysed for monoamine content using high-performance liquid chromatography (HPLC). MDMA-preexposed rats were initially slower to acquire amphetamine self-administration. However, by day 6 of acquisition, there was no difference from controls. Following extinction, amphetamine (1 mg/kg, i.p.) reinstated drug seeking and produced locomotor hyperactivity in both MDMA- and vehicle-pretreated animals. However, MDMA (5 mg/kg, i.p.) was only effective in producing amphetamine seeking and hyperactivity in MDMA-pretreated rats. MDMA pretreatment caused significant decreases in 5-hydroxy-indolacetic acid (5-HIAA) and 5-HT in several brain regions. These results suggest that 5-HT depletion induced by MDMA may initially slow the acquisition of amphetamine self-administration but that MDMA preexposure may also sensitize animals to the locomotor stimulating and priming effects of MDMA on drug-seeking behavior.     

Antagonism of amphetamine locomotor stimulation in rats by single doses of marijuana extract administered orally

The influence of marijuana extract distillate on (+)-amphetamine stimulation of locomotor activity was examined in rats. Marijuana was administered orally and amphetamine was injected intraperitoneally. In rats acclimated to the activity cages, doses of the extract of 5, 10, and 20 mg/kg Δ⁹-THC administered one hour before amphetamine resulted in a significant antagonism of the locomotor stimulation induced by 1 mg/kg (+)-amphetamine; doses of 0·625, 1·25 and 2·5 mg/kg Δ⁹-THC had no effect on the amphetamine response. A dose of 10 mg/kg Δ⁹-THC (as the extract) antagonized the stimulation produced by 0·5,1 and 2 mg/kg (+)-amphetamine in acclimated animals without depressing baseline activity; however, the same dose of marijuana failed to alter significantly the stimulant effect of 1 mg/kg (+)-amphetamine in nonacclimated rats. Although pretreatment with marijuana extract 1 hr before injection of amphetamine resulted in a marked depression of the amphetamine response, when both drugs were administered at the same time only a small and non-significant decrement in the amphetamine response was observed. In conclusion, this study clearly demonstrates that orally administered marijuana antagonizes amphetamine-induced locomotor stimulation in the rat. Mo evidence of enhancement of the amphetamine effect was observed.     

Locomotor activity in morphine-dependent and post-dependent rats

The effects of morphine and naloxone were compared on the locomotor activity of nondependent, morphine-dependent, and post-dependent rats. Dependence was induced and maintained for 30 weeks by scheduled access to 0.05% morphine solution for 10 min every 6 hr. Locomotor activity in nondependent and dependent animals was increased by low doses of morphine and reduced by higher doses. Both components were antagonized by naloxone. Chronic morphine treatment produced marked tolerance to the depressant effect of high morphine doses, but not to the stimulant effect of low doses. Post-dependent animals remained tolerant to the depressant effect of high doses of morphine. The development of tolerance to the depressant but not to the stimulant effect of morphine in dependent and post-dependent animals suggests that different neuronal substrates mediate morphine-induced stimulation and depression of locomotor activity. Abrupt or naloxone-precipitated withdrawal generally disrupted locomotor activity in dependent rats. Naloxone alone also decreased activity in post-dependent animals. Thus, chronic morphine administration produces long-lasting changes in the sensitivity of dependent and post-dependent rats to the effects of morphine and naloxone on locomotor activity.     

Selective alterations in cerebral metabolism within the mesocorticolimbic dopaminergic system produced by acute cocaine administration in rats

The 2-[14C]deoxyglucose method was used to examine the effects of acute intravenous administration of cocaine on local cerebral glucose utilization in rats. These effects were correlated with the effects of cocaine on locomotor activity assessed simultaneously in the same animals. At the lowest dose of cocaine, 0.5 mg/kg (1.47 mumol/kg), alterations in glucose utilization were restricted to the medial prefrontal cortex and nucleus accumbens. Metabolic activity at 1.0 mg/kg (2.9 mumol/kg) was altered in these structures, but in the substantia nigra reticulata and lateral habenula as well. The selectivity of cocaine's effects at low doses demonstrates the particular sensitivity of these structures to cocaine's actions in the brain. In contrast, 5.0 mg/kg (14.7 mumol/kg) produced widespread changes in glucose utilization, particularly in the extrapyramidal system. Only this dose significantly increased locomotor activity above levels in vehicle-treated controls. Rates of glucose utilization were positively correlated with locomotor activity in the globus pallidus, substantia nigra reticulata, and subthalamic nucleus, and negatively correlated in the lateral habenula.     

Predisposition to self-administer amphetamine: the contribution of response to novelty and prior exposure to the drug

 The present experiment examined the contribution of locomotor response to novelty and prior exposure to amphetamine to rats’ predisposition to self-administer a low dose of the drug. Rats were screened for their locomotor response to a novel environment and divided into high (HR) or low (LR) responders based on whether their locomotor scores were above or below the median activity level of the subject sample. Animals were then pre-exposed to nine daily injections of either saline (1 ml/kg, IP) or amphetamine (1.5 mg/kg, IP). Starting 1 week after pre-exposure, animals in the four different groups (HR pre-exposed to saline or amphetamine; LR pre-exposed to saline or amphetamine) were given the opportunity, in each of ten daily sessions, to lever press for a low dose of amphetamine (10 μg/kg per infusion) in a two lever (active versus inactive) continuous reinforcement operant task. Initial lever press performance revealed no difference in active versus inactive lever pressing between amphetamine and saline pre-exposed animals. However, in agreement with previous reports, with successive test sessions amphetamine pre-exposed rats maintained higher levels of active versus inactive lever pressing for drug while saline pre-exposed rats showed a progressive decrease in the pressing of either lever. Interestingly, this enhanced active lever pressing was observed in HR but not LR rats pre-exposed to amphetamine. In addition, HR saline pre-exposed animals showed initial active versus inactive lever pressing equivalent to that of HR amphetamine pretreated rats but this enhanced responding for drug diminished over days and by the last day of self-administration was indistinguishable from that of LR animals having been pre-exposed either to amphetamine or saline. These findings confirm that prior exposure to amphetamine promotes the subsequent self-administration of the drug and suggest that response to novelty may be a predictor more closely linked to an animal’s propensity to become sensitized to the facilitatory effects of the drug rather than to an animal’s current sensitization state and predisposition to self-administer the drug. Received: 6 July 1996 / Final version: 5 October 1996     

Effect of ventral tegmental 6-hydroxydopamine lesions on the locomotor stimulant action of nicotine in rats

Convergent evidence suggests that the locomotor stimulant effect of nicotine is mediated by nicotinic receptors located on mesolimbic dopaminergic neurons. However, 6-hydroxydopamine lesions of the ventral tegmental area, resulting in substantial depletion of nucleus accumbens dopamine, were recently reported to have no effect on nicotine-induced locomotion. The present study sought to re-examine this issue. Rats received bilateral infusions of 6-hydroxydopamine or vehicle into the ventral tegmental area. Starting 3 weeks later, locomotor activity was tested after subcutaneous injection of saline, nicotine (0.4 mg/kg base), amphetamine (0.5 mg/kg) or scopolamine (0.5 mg/kg). In lesioned animals, the locomotor stimulant effects of nicotine and amphetamine were greatly reduced, whereas saline and scopolamine-induced activity was scarcely affected. Dopamine denervation was assessed by autoradiography, using [¹²⁵I]RTI-55 to label plasmalemmal dopamine transporters. Labelling was reduced in nucleus accumbens core and shell and in the ventral tegmental area (by 87, 81 and 70%, respectively), and in nigrostriatal areas (52–77%). The locomotor stimulant effects of nicotine and amphetamine were correlated with residual [¹²⁵I]RTI-55 labelling in mesolimbic and nigrostriatal regions (r=0.6–0.8). The present results provide further evidence that the locomotor stimulant effect of nicotine is dependent on the integrity of ascending dopamine neurons.     

Comparison of changes in locomotor activity with striatal homovanillic acid and 3,4-dihydroxyphenylacetic acid concentrations following the bilateral intranigral injection of dopamine agonist drugs in rats

Bilateral injection of apomorphine (2.5 micrograms) into the substantia nigra zona reticulata of rats reduced both locomotor activity and striatal HVA and DOPAC concentrations. Bilateral injection of dopamine (10 micrograms) did not affect locomotor activity whereas a higher dose of dopamine (50 micrograms) enhanced locomotor activity. Striatal HVA and DOPAC concentrations were unchanged following injection of dopamine. Bilateral injection of (+/-)-3PPP (0.1 or 2.5 micrograms) into the zona reticulata of the substantia nigra did not alter locomotor activity while a higher dose (10 micrograms) enhanced locomotion. Injection of (+/-)-3PPP (0.1-10 micrograms) into the zona reticulata was without effect on striatal HVA or DOPAC concentrations. The bilateral manipulation of nigral dopaminergic neurotransmission alters motor activity and nigrostriatal dopamine turnover in conscious rats. However, the changes in motor activity are not necessarily related to altered nigrostriatal activity, suggesting the involvement of dopamine receptors located at non-dopaminergic sites within the substantia nigra.     

Repeated pre-exposure to tobacco smoke potentiates subsequent locomotor responses to nicotine and tobacco smoke but not amphetamine in adult rats

These studies investigated if pre-exposure to tobacco smoke affects the locomotor response to tobacco smoke, nicotine, and amphetamine in adult rats. The rats were habituated to an open field for 3-4 days and then exposed to tobacco smoke for 2 h/day for 13-14 days. The effect of exposure to tobacco smoke on locomotor activity was investigated after 1, 7, and 14 days of smoke exposure and after one 2-hour exposure session that followed a 3-week off period. The effects of tobacco smoke on the locomotor responses to nicotine (0.04 and 0.4 mg/kg, base) and amphetamine (0.1 and 0.5 mg/kg) were investigated on day 14, one day after the last smoke exposure session. The locomotor response to tobacco smoke was increased after 7 and 14 days of smoke exposure and after one exposure session after the 3-week off-period. The acute administration of the high dose of nicotine (0.4 mg/kg) led to a brief period of hypoactivity that was followed by a period of hyperactivity. Pre-exposure to tobacco smoke attenuated the nicotine-induced hypoactivity and potentiated the nicotine-induced hyperactivity. The low dose of nicotine (0.04 mg/kg) did not affect locomotor activity in the control rats but increased the total distance traveled in the tobacco smoke exposed rats. Exposure to tobacco smoke did not affect the locomotor response to amphetamine. These findings indicate that exposure to tobacco smoke leads to tolerance to the depressant effects of nicotine and potentiates the stimulant effects of nicotine and tobacco smoke.     

Actions of substance P, MIF, TRH and related peptides in the substantia nigra, caudate nucleus and nucleus accumbens

Neurones in the substantia nigra were found to be sensitive to iontophoretically applied substance P, substance P 1-9 methyl ester and substance P 1-9 amide. Substance P 1-2, 4-9 and 5-9 methyl esters, thyrotropin releasing hormone (TRH), Pyroglutamyl-histidyl-2 methyl prolineamide (methyl TRH), Pyroglutamyl-histidyl-2 methyl prolineamide (methyl TRH), histidyl-proline-diketopiperazine (His-Pro) and MSH releasing inhibiting factor (MIF) were without effect on neurones in this area. Thyrotropin releasing hormone (TRH), methyl TRH, His-Pro and MIF were inactive on neurones in the caudate nucleus and nucleus accumbens. Bilateral injections of substance P and substance P 1-9 methyl ester into the ventral tegmental area (VTA) of conscious rats produced locomotor activity, while similar injections of substance P 4-9 and 5-9 methyl esters did not. The locomotor activity produced by amphetamine was prolonged by TRH, while MIF was devoid of such activity. The data suggest that substance P and substance P 1-9 have similar effects in the substantia nigra, although the mechanism of action is unclear. Thyrotropin releasing hormone and MIF probably do not have acute actions in the brain areas tested.     

Effects of the serotonin 5-HT(7) receptor antagonist SB-269970 on the inhibition of dopamine neuronal firing induced by amphetamine

Using extracellular unitary recordings in anaesthetized rats, this study examined the implication of the serotonin 7 (5-HT₇) receptors in the inhibitory effect of amphetamine on ventral tegmental area and substantia nigra pars compacta dopamine neuronal activity. The acute administration of the selective 5-HT₇ receptor antagonist, SB-269970 (0.1, 0.5 and 1 mg/kg, i.p.), did not alter the firing activity of dopamine neurons. Interestingly, this antagonist prevented significantly the inhibition of dopamine neuronal firing activity induced by amphetamine (1 mg/kg, i.v.) in the ventral tegmental area, but not in the substantia nigra pars compacta. The present results suggest that 5-HT₇ receptors modulate the dopamine firing activity in the ventral tegmental area, thus affecting preferentially the mesocorticolimbic pathway.