Krystyna Gołembiowska

Cocaine: Discussion on the Role of Dopamine in the Biochemical Mechanism of Action

The central stimulant effect of cocaine is generally considered related to its potentiating effect on biogenic amines. However, the individual role and significance of the amines involved in various stimulant effects of cocaine are still a controversial topic. Cocaine is a potent inhibitor of noradrenaline uptake (Hertting, Axelrod, and Whitby, 1961; Ross and Renyi, 1967; Langer and Enero, 1974; Azzaro, Ziance, and Rutledge, 1974), dopamine uptake (Fuxe, Hamberger, and Malmfors, 1967; Ross and Renyi, 1967; Harris and Baldessarini, 1973; Heikkila, Orlansky, Mytilineou, and Cohen, 1975), and serotonin uptake (Ross and Renyi, 1969; Friedman, Gershon, and Rotrosen, 1975). High affinity uptake of tryptophan into synaptosomes is also inhibited (Knapp and Mandell, 1972). In vivo studies have shown that cocaine induces a short-lasting uptake inhibition into brain tissues of noradrenaline (Schanberg and Cook, 1972), dopamine (Fuxe, Ham-berger, and Malmfors, 1967), and serotonin (Ross and Renyi, 1969).

MK-801 elevates the etracellular concentration of dopamine in the rat prefrontal cortex and increases the density of striatal dopamine D1 receptors

In the present study we found that MK-801 (dizocilpine), given peripherally in doses (0.2 and 0.4 mg/kg) which evoked locomotor activation in rats, enhanced in a dose-dependent manner the extracellular concentration of dopamine (DA) in the rat prefrontal cortex (PFC). MK-801 used in similar range of doses (0.2, 0.4 mg/kg) failed to alter the DA content in superfusates of the rat striatum (STR). It was also found that single doses of MK-801 enhanced the density of D1 receptors, assessed by the [3H]SCH 23390 binding in the rat STR, but not in the limbic forebrain. An increase in the density of D1 receptors was observed at 24, but not 2, h after MK-801 administration. MK-801 failed to alter the density of D2 receptors in the STR and limbic forebrain. The available data indicate that MK-801 may enhance the dopaminergic neurotransmission by at least two separate mechanisms: a fast one, associated with the release of DA in PFC, and a slow one, resulting from the increase in the D1 receptor density.

Changes in mesolimbic dopamine may explain stress-induced anhedonia

The mesolimbic dopamine projection to the limbic forebrain is known to be critically involved in responsiveness to rewards. In two experiments, the consumption of palatable weak sucrose solutions by rats was reduced by chronic exposure to mild unpredictable stress. Increases in the levels of dopamine and serotonin and their metabolites were found in the limbic forebrain of stressed rats; these changes were not present in the caudate nucleus or septal area, or in the brains of meal-fed control animals. In the first experiment (7 weeks of stress), specific binding to dopamine D2 receptors was decreased in limbic forebrain; this change was not seen in the second experiment (3 weeks of stress). We discuss the possible role of these changes in mesolimbic dopamine function in the reduced sensitivity to reward that follows exposure to chronic mild stress.

Evidence that conditioned stress enhances outflow of dopamine in rat prefrontal cortex: A search for the influence of diazepam and 5-HT1A agonists

We evaluated the impact of conditioned stress on outflow of dopamine in the rat prefrontal cortex. Exposure of rats to an environment associated with aversive stimuli‐foot shock enhanced outflow of dopamine in a similar way as seen during the conditioning session when foot shocks were applied. Diazepam (2.5 and 10 mg/kg) dose‐dependently decreased outflow of dopamine and, when given in a dose of 10 mg/kg, but not 2.5 mg/kg, decreased enhanced dopamine outflow evoked by conditioned stress. On the other hand, ipsapirone (10 mg/kg, but not 2.5 mg/kg) and buspirone (2.5 mg/kg) enhanced basal outflow of dopamine. When ipsapirone (10 mg/kg) and buspirone (2.5 mg/kg) were given to rats exposed to conditioned stress, the stress‐evoked elevation in dopamine outflow was abolished. Ipsapirone in a dose of 2.5 mg/kg was ineffective in the stress paradigm tested. It is concluded that conditioned stress in vivo enhances dopaminergic neurotransmission in the rat prefrontal cortex, this effect being attenuated by diazepam, a classic anxiolytic drug, and by such novel anxiolytics as ipsapirone and buspirone, which operate via serotonergic 5‐HT1A receptors. Although ipsapirone and buspirone blocked stress‐induced enhancement of dopamine outflow, this effect seems to result from their influence on the basal outflow of dopamine. Differential effects of diazepam and 5‐HT1A agonists on basal and stress‐induced alterations in dopamine outflow are discussed in terms of their possible effectiveness in various types of general anxiety disorders.

Involvement of 5-HT1A receptors in the antidepressant-like activity of gepirone in the forced swimming test in rats

The antidepressant-like activity of gepirone, a drug with a high and selective affinity for 5-hydroxytryptamine1A (5-HT1A) receptors, was studied in the forced swimming test in rats. The drug, administered intraperitoneally in single doses of 2.5-20 mg/kg, potently and dose-dependently shortened the immobility time. The anti-immobility effect of gepirone (10 mg/kg) was dose-dependently antagonized by the 5-HT1A receptor and alpha 1-adrenoceptor antagonist, NAN-190 (0.25 and 0.5 mg/kg), the beta-adrenoceptor blocker with the affinity for 5-HT1A and 5-HT1B receptors, pindolol (2 and 4 mg/kg), the 5-HT1A, 5-HT2 and dopamine receptor blocker spiperone (0.01 and 0.03 mg/kg) and by the dopamine receptor antagonist, haloperidol (0.125 and 0.25 mg/kg). On the other hand, the non-selective 5-HT receptor antagonist, metergoline (2 and 4 mg/kg), the selective 5-HT2 receptor antagonist, ketanserin (1 and 2 mg/kg), the selective alpha 1-adrenoceptor blocker, prazosin (0.25 and 0.5 mg/kg) and the beta-blockers with no affinity for 5-HT receptors, betaxolol (4 and 8 mg/kg) and ICI 118,551 (4 and 8 mg/kg), did not affect the anti-immobility effect of gepirone. The effect of gepirone was not modified, either, in animals with a lesion of the 5-HT system, produced by p-chloroamphetamine (PCA, 2 x 10 mg/kg) or p-chlorophenylalanine (PCPA, 3 x 300 mg/kg). The results obtained suggest that the anti-immobility effect of gepirone is mediated by activation of 5-HT1A receptors, most probably located postsynaptically and that dopamine may be involved in this action.

Characterization of the Antinociceptive Actions of Bicifadine in Models of Acute, Persistent, and Chronic Pain

Bicifadine (1-p-tolyl-3-azabicyclo[3.1.0]hexane) inhibits monoamine neurotransmitter uptake by recombinant human transporters in vitro with a relative potency of norepinephrine > serotonin > dopamine (≈1:2:17). This in vitro profile is supported by microdialysis studies in freely moving rats, where bicifadine (20 mg/kg i.p.) increased extrasynaptic norepinephrine and serotonin levels in the prefrontal cortex, norepinephrine levels in the locus coeruleus, and dopamine levels in the striatum. Orally administered bicifadine is an effective antinociceptive in several models of acute, persistent, and chronic pain. Bicifadine potently suppressed pain responses in both the Randall-Selitto and kaolin models of acute inflammatory pain and in the phenyl-p-quinone-induced and colonic distension models of persistent visceral pain. Unlike many transport inhibitors, bicifadine was potent and completely efficacious in both phases of the formalin test in both rats and mice. Bicifadine also normalized the nociceptive threshold in the complete Freunds adjuvant model of persistent inflammatory pain and suppressed mechanical and thermal hyperalgesia and mechanical allodynia in the spinal nerve ligation model of chronic neuropathic pain. Mechanical hyperalgesia was also reduced by bicifadine in the streptozotocin model of neuropathic pain. Administration of the D2 receptor antagonist (-)-sulpiride reduced the effects of bicifadine in the mechanical hyperalgesia assessment in rats with spinal nerve ligations. These results indicate that bicifadine is a functional triple reuptake inhibitor with antinociceptive and antiallodynic activity in acute, persistent, and chronic pain models, with activation of dopaminergic pathways contributing to its antihyperalgesic actions.

Accumbal and pallidal dopamine, glutamate and GABA overflow during cocaine self‐administration and its extinction in rats

We investigated the changes in dopamine (DA), glutamate and γ‐aminobutyric acid (GABA) during cocaine self‐administration in rats implanted with guide cannulae into the nucleus accumbens and ventral pallidum. After stabilized cocaine self‐administration, separate groups of rats underwent extinction (10 days) procedure in which cocaine infusion was replaced by saline injections. With using a ‘yoked’ procedure, the effects of cocaine or its withdrawal on the level of neurotransmitters were evaluated by dual‐probe microdialysis. Repeated cocaine administration reduced basal glutamate levels in the nucleus accumbens and ventral pallidum, whereas it did not affect basal accumbal DA levels. Only rats that self‐administered cocaine had increased basal GABA overflow in both examined brain structures. Active or passive cocaine administration elevated extracellular accumbal DA, however, the extent of cocaine‐evoked DA level was significantly higher in rats that self‐administered cocaine while both groups of animals showed also an attenuation of GABA level in the nucleus accumbens. On day 10 of extinction training, rats previously given cocaine revealed decreases in the basal accumbal concentration of glutamate while the basal GABA levels were significantly enhanced as compared with baseline of saline‐yoked controls. Potassium depolarization delayed the reduction of the accumbal and pallidal extracellular glutamate levels in the active and passive cocaine groups. The present data indicate that changes in DA and GABA neurotransmission during maintenance phase mirror the motivational aspects of cocaine intake. Depending on acute (24 hours) or late (10 days) cocaine withdrawal, different neurotransmitter systems (i.e. glutamate or GABA) seem to be involved.

Differential effects of CGP 37849 and MK-801, competitive and noncompetitive NMDA antagonists, with respect to the modulation of sensorimotor gating and dopamine outflow in the prefrontal cortex of rats

In the present study we compared effects of the competitive and non-competitive NMDA antagonists CGP 37849 and MK-801, respectively, on sensorimotor gating in rats, measured as prepulse-induced inhibition of the acoustic startle response, and the outflow of dopamine in the rat prefrontal cortex. CGP 37849 (10, 20 mg/kg), decreased the amplitude of the acoustic startle response, but was without effect on the prepulse-induced inhibition of the acoustic startle response. MK-801 (0.4 but not 0.2 mg/kg) enhanced the amplitude of the acoustic startle response and its doses of 0.2 and 0.4 mg/kg markedly attenuated the prepulse-induced inhibition of the acoustic startle response. The effects of MK-801 (0.4 mg/kg) on the prepulse-induced inhibition of the acoustic startle response were not antagonized by the selective antagonists of D-2 and D-1 dopaminergic receptors, S(−)sulpiride (25 mg/kg) and SCH 23390 (0.1 mg/kg), respectively. When given alone, S(−)sulpiride attenuated the amplitude of the acoustic startle response and failed to altered the prepulse-induced inhibition of the acoustic startle response. SCH 23390 (0.1 mg/kg) failed to alter the amplitude and prepulse-induced inhibition of the acoustic startle response. The effects of CGP 37849 and MK-801 also differed with respect to dopamine outflow. MK-801 (0.2 and 0.4 mg/kg) enhanced the outflow of dopamine in the rat prefronatl cortex, while CGP 37849 (10 and 20 mg/kg) was without any effect on the extracellular concentration of dopamine. Our data indicate that the blockade of phencyclidine binding sites, exerted by the noncompetitive antagonist MK-801, evoked effects qualitatively different from those induced — via blockade of the NMDA recognition — by the competitive NMDA receptor antagonist CGP 37849. It is postulated that — in contrast to the non-competitive antagonist of NMDA receptors — the competitive NMDA antagonist CGP 37849 is/ should be devoid of psychotomimetic and abusing properties. It is also evident that disruption of sensorimotor gating in rats induced by MK-801 does not involve any dopaminergic mechanisms, since it is not modulated by drugs blocking D-1 and D-2 dopamine receptors.

Striatal adenosine A2A receptor blockade increases extracellular dopamine release following l-DOPA administration in intact and dopamine-denervated rats

The influence of the selective adenosine A(2A) receptor antagonist ZM 241385 on exogenous l-DOPA-derived dopamine (DA) release in intact and dopamine-denervated rats was studied using an in vivo microdialysis in freely moving animals. Local infusion of l-DOPA (2.5 microM) produced a marked increase in striatal extracellular DA level in intact and malonate-lesioned rats. Intrastriatal perfusion of ZM 241385 (50-100 microM) had no effect on basal extracellular DA level, but enhanced dose-dependently the l-DOPA-induced DA release in intact and malonate-lesioned animals. A non-selective adenosine A(2A) receptor antagonist DMPX (100 microM), similarly to ZM 241385, accelerated conversion of l-DOPA in intact and malonate-denervated rats. This effect was not produced by the adenosine A(1) receptor antagonist, CPX (10-50 microM). However, ZM 241385 did not affect the l-DOPA-induced DA release in rats pretreated with reserpine (5 mg/kg i.p.) and alpha-methyl-p-tyrosine (AMPT, 300 mg/kg i.p.). Obtained results indicate that blockade of striatal adenosine A(2A) receptors increases the l-DOPA-derived DA release possibly by indirect mechanism exerted on DA terminals, an effect dependent on striatal tyrosine hydroxylase activity. Selective antagonists of adenosine A(2A) receptors may exert a beneficial effect at early stages of Parkinsons disease by enhancing the therapeutic efficacy of l-DOPA applied exogenously.

Evidence for increased apomorphine-sensitive dopaminergic effects after acute treatment with morphine.

Apomorphine in a very small non-stimulant dose 0.05 mg/kg s.c. antagonized the locomotor stimulant effect of morphine (50 mg/kg) in mice. Apomorphine (0.05 mg/kg) antagonized also the locomotor stimulant effect of a single low dose of morphine (2 mg/kg) in the rat as well as “the late stimulatory effect” seen after a higher dose of morphine (10 or 20 mg/kg). The pretreatment with morphine in increasing doses induced an increasing degree of potentiation of stereotyped behavior induced by high doses of apomorphine (0.5 and 2 mg/kg s.c.) in the rat. The apomorphine stereotyped biting/gnawing activity was found strongly increased by morphine (10–50 mg/kg) during the time interval where morphine given alone induced catalepsy. Our results indicate that the acute treatment with morphine may induce an increase of apomorphine sensitive dopaminergic mechanisms. The inhibitory effect by a very small dose of apomorphine (0.05 mg/kg) of morphine stimulation may be due to a presynaptic dopamine receptor stimulant effect of apomorphine. The antagonism by the serotonin antagonist methergoline of morphine catalepsy and the increase by this drug of “the late morphine excitation” indicate in addition a role of a serotonergic mechanism.