The yohimbine-induced anticonflict effect in the rat, part II. Neurochemical findings

Abstract

In a companion paper the alpha 2-adrenoceptor antagonist yohimbine was found to produce a dose-dependent anticonflict effect in a modified Vogel's conflict test. The behavioral data further indicated that noradrenergic and serotonergic neurons as well as the benzodiazepine (BDZ) receptor may be involved in the anticonflict effect of yohimbine. In the present study the effects on rat brain monoamine neurochemistry and GABAA/BDZ receptor function (36Cl-uptake in corticohippocampal synaptoneurosomes) of a maximally anticonflict producing dose of yohimbine (4.0 mg/kg, i.p.) were studied. The levels of rat brain catecholamines and indoleamines were measured ex vivo using high performance liquid chromatography with electrochemical detection (HPLC-ED). Yohimbine decreased noradrenaline levels both in the hippocampus and the hemispheres but instead increased DOPAC levels in these brain regions as well as in the limbic forebrain. Yohimbine also markedly enhanced DOPA accumulation in the hippocampus and the hemispheres after inhibition of 1-aromatic amino acid decarboxylase by means of NSD 1015, whereas in the limbic system only a modest increase was obtained. The yohimbine-induced effects on the catecholamine synthesis rate were largely abolished in animals severely depleted of NA by means of 6-hydroxy-dopamine (6-OH-DA) pretreatment. Yohimbine decreased both the 5-HIAA/5-HT quotient (an indicator of 5-HT turnover) and 5-HTP accumulation after NSD 1015 in the hemispheres, whereas in the hippocampus and the limbic system only 5-HTP accumulation was decreased. The yohimbine-induced effect on the indoleamine synthesis rate was not influenced by 6-OH-DA pretreatment, whereas this effect and that on the catecholamine synthesis rate were both abolished by reserpine pretreatment. Neither in vivo nor in vitro administration of yohimbine significantly altered baseline or GABA-induced accumulation of 36Cl- in corticohippocampal synaptoneurosomes. In conclusion, the present study provides neurochemical support for the suggestion that yohimbine may exert its anticonflict effect in a modified Vogel's conflict test by increasing and decreasing NA and 5-HT neurotransmission, respectively, whereas no evidence was obtained for a direct interaction of yohimbine with GABAA/BDZ receptor function.

Agonist and antagonist actions of yohimbine as compared to fluparoxan at ?2-adrenergic receptors (AR)s, serotonin (5-HT)1A, 5-HT1B, 5-HT1D and dopamine D2 and D3 receptors. Significance for the modulation of frontocortical monoaminergic transmission and depressive states

“…Yohimbine, however, in line with its agonist actions at 5-HT 1A autoreceptors (Figs. 6 and 7;Söderpalm et al, 1995b), decreased dialysate levels of 5-HT in FCX, an action blocked by WAY100,635. Yohimbine may, then, by virtue of its marked agonist actions at 5-HT 1A sites be differentiated from fluparoxan as concerns its inhibitory influence upon serotonergic transmission in the rat.…”

“…12; Gobert et al, 1997a and, it is curious that yohimbine was previously reported (Cheng et al, 1993) to increase extracellular levels of 5-HT in rat FCX. However, this action was attributed to its ''anxiogenic'' actions, a property exercised independently of 5-HT 1A receptors and ␣ 2 -ARs by an, as yet, unclear mechanism (Charney et al, 1983;Cole et al, 1995;Redfern and Williams, 1995;Söderpalm et al, 1995b).…”

Anti-stress neuropharmacological mechanisms and targets for addiction treatment: A translational framework

“…Yohimbine (YOH) is an α 2 -adrenoceptor antagonist that increases NA neurotransmission by blocking feedback at presynaptic autoreceptors ( Doxey et al, 1984 ; Goldberg and Robertson, 1983 ) and has become an important tool for investigating stress-related drug seeking/use. YOH-mediated increases in NA release and synaptic levels regulate HPA axis activity ( Armario, 2010 ; Banihashemi and Rinaman, 2006 ; Grunhaus et al, 1989 ; Leri et al, 2002 ; Smythe et al, 1983 ), as well as 5-HT and DA neurotransmission ( Brannan et al, 1991 ; Cheng et al, 1993 ; Hopwood and Stamford, 2001 ; Maura et al, 1982 ; McCall et al, 1991 ; Millan et al, 2000 ; Mongeau et al, 1993 ; Raiteri et al, 1990 ; Söderpalm et al, 1995a , b ; Winter and Rabin, 1992 ). In a PET neuroimaging study of rhesus monkeys, YOH increased [ 11 C]-flumazenil binding potential ( Matsunaga et al, 2001 ) indicating YOH actions at GABA-A receptors that might correlate with its anxiogenic (negative-hedonic, arousing) and/or disinhibiting motivational effects ( Fig.…”