AAS SO Primary Responses
Graduate Category: Physical and Life Sciences Degree Level: PhD Abstract ID# 700
Microiontophoretic application of arginine vasopressin, serotonin, and eticlopride affect the electrophysiological activity of LAH neurons in aggressive adolescent AAS-treated hamsters. *T.R. Morrison, **R.W. Sikes, *R.H. Melloni Jr. **Physical Therapy Program -- *Behavioral Neuroscience Program
53% (n=16)
45% (n=23)
40% (n=12)
18% (n=9)
13% (n=4)
43% (n=22)
43% (n=13)
39% (n=20)
43% (n=13)
11% (n=6)
3% (n=1)
39% (n=20)
40% (n=12)
49% (n=25)
56% (n=17)
p = 0.9
p = 0.45
AVP Interactions If.. 5HT
ETIC
AAS 45% (n=10) 14% (n=3) 41% (n=9)
SO 8% (n=1) 62% (n=8) 30% (n=9)
AVP 0.2 M @ 60 nA
(n=16/30)
AVP
% Baseline
16% (n=8)
*** p = 0.0003
(n=20/51)
5HT3
Decreasers (n=13/30)
5HT 5HT 50 mM @ 80 nA
30% (n=6) 25% (n=5) 45% (n=9)
0% (n=0) 58% (n=7) 42% (n=5)
M p = 0.07
39% (n=9) 13% (n=3) 48% (n=11)
13% (n=2) 50% (n=6) 58% (n=7)
M p = 0.09
SO
M p = 0.07
5HT 50 mM @ 80 nA
AVP 0.2 M @ 60 nA
mSON/NC
AAS
5HT 50 mM @ 80 nA
(n=7/14) 5HT 50 mM @ 80 nA
mSON/NC
AAS
5HT
GABA
GLU
RN 5HT
SO
mSON/NC
AAS
+AVP
+AVP
AVP
RN
GLU
+5HT
GLU
RN
AVP
GABA
AVP 0.2 M @ 60 nA
GABA
AVP
AVP
GABA
Decreasers
5HT + AVP
AVP
+5HT
mSON/NC
(n=8/16)
GABA
5HT
5HT
Increasers
5HT
RN
mSON/NC (n=22/51)
GABAA
GLU
5HT
Decreasers
AVPV1A
AVP
GABA
** p = 0.007
8% (n=1) 25% (n=3) 67% (n=8)
AVP
Molecules
AVP 0.2 M @ 60 nA
Fisher’s Exact Test
35% (n=7) 5% (n=1) 60% (n=12)
SO
RN
% Baseline
ETIC
7% (n=2)
of responses of cells a$er microiontophore+c applica+on of vasopressin (AVP), serotonin (5HT) or e+cilopride (ETIC) to the latero-‐ anterior hypothalamus of hamsters chronically treated throughout development with anabolic steroids (AAS) or vehicle (SO). (BoKom) Propor+ons of cell responses to AVP in the context of their response to either 5HT or E+clopride
Decreasers
% Baseline
5HT
39% (n=20)
(Le$) Propor+ons
% Baseline
AVP
SO
Increasers
% Baseline
AAS
Fisher’s Exact Test
5HT1A/1B
mSON/NC
% Baseline
Single Drugs Response Proportions
Behavioral pharmacology and neuroanatomical studies indicate that the serotonin (5HT), vasopressin (AVP) and dopamine (DA) neural systems interact to modulate adolescent anabolic steroid (AAS)enhanced aggressive behavior. In untreated animals, AVP microinjection into the anterior hypothalamus (AH) has been shown to enhance aggressive/dominant behaviors in the male hamster [Ferris, 1997]. AVP-enhanced aggressive behavior can be reversed by both systemic fluoxetine and local 5HT1A (but not 5HT1B) agonist microinjection [Delville,1996]. Like 5HT and AVP, DA has also been implicated in rodent aggressive behavior. For example aggressive male rats show increased limbic concentrations of DA prior to an aggressive encounter and dominant mice show increased concentrations of tyrosine-hydroxylase and DA transporter expression in aggression neural loci [Ferrari, 2003; Filipenko, 2001]. In AAS treated hamsters, AVP release and binding are enhanced within the latero-anterior [Melloni, 2010] and ventro-lateral hypothalamic regions [DeLeon, 2002], respectively. Moreover, AAS exposure throughout adolescence reduces putative aggression-inhibiting 5HT afferent fibers while increasing the presence of putative aggression-enhancing AVP afferent fibers [Grimes, 2002; 2006]. More recently we have shown that LAH D2 antagonist microinjection reduces AAS-induced aggressive behavior [Morrison, 2014]. This reduction is reversed by both the exogenous application of AVP or D2 agonist microinjection [Morrison, 2014]. These DA-ligand alterations of AAS aggression are underscored by increased DA production in the AH and (accordingly) an increased density of TH-containing neurons in LAH efferent regions (i.e., the nucleus circularis (NC) and medial supraoptic nucleus (mSON) [Ricci, 2009]. Despite numerous studies from our lab showing behavioral and anatomical alterations induced by adolescent AAS, we have little physiological data showing how aggressive neural substrates interact to produce the AAS-induced aggressive phenotype. Recently we have collected pilot data showing that systemic fluoxetine reduces the firing rate of LAH neurons in AAS- but not vehicle treated hamsters, suggesting that AAS exposure alters tonic inhibition of LAH neuronal activity [Sikes, 2013]. Based on previous localization and behavioral pharmacology studies, here we present findings that further our understanding of the electrophysiological profile of LAH neurons by microiontrophoretically applying selective and non-selective ligands that target the AVP, 5HT, and DA systems within the LAH region of the adolescent AAS-exposed male hamster.
Neuronal Responses
Response Proportions
Introduction/Abstract
Primary Responses AAS SO
Receptors
GLU
GABA
GLU
RN 5HT
(Top Left) In normal hamsters, 5HT afferents inhibit putative aggression-stimulating glutamate (GLU) neurons within the LAH. (Top Right) AAS exposure: reduces 5HT afferents (Grimes, 2002), increases AVP afferents [Harrison, 2000], increases AVP binding [Deleon, 2002], reduces somatic 5HT1A receptors [Ricci, 2006], and reduces punctate 5HT1B receptors while enhancing somatic 1B receptors [Grimes, 2005]; summing to increased aggression. (Middle Left) Exogenous (X) 5HT reduces activity of LAH neurons (putative GABA) by acting on 5HT1A receptors. (Middle Right) X-5HT reduces LAH activity by acting on GLU neurons that have lost their 1A receptors, potentially accounting for the difference in Decreased activity (i.e., 1A vs 1B regulated) observed between AAS and SO animals (time series -- Middle). Indeed, 5HT1B receptor agonists are effective in reducing aggression in AAS- but not normal AVP-injected animals [Delville,2006; Grimes, 2005]. (Bottom Left) In SO treated animals, AVP decreases activity by inhibiting GABA neuronal activity, thereby disinhibiting AVP release and activating AVPaggression. (Bottom Right) AVP increases activity of AASdisinhibiting GLU neurons by amplifying the effect of endogenous AVP. GABA neuronal activity is not affected due to AAS-induced reductions of somatic 5HT1A receptors [Ricci, 2006].
Microiontophoretic application of arginine vasopressin, serotonin, and eticlopride affect the electrophysiological activity of LAH neurons in aggressive adolescent AAS-treated hamsters. *T.R. Morrison, **R.W. Sikes, *R.H. Melloni Jr. **Physical Therapy Program -- *Behavioral Neuroscience Program
53% (n=16)
45% (n=23)
40% (n=12)
18% (n=9)
13% (n=4)
43% (n=22)
43% (n=13)
39% (n=20)
43% (n=13)
11% (n=6)
3% (n=1)
39% (n=20)
40% (n=12)
49% (n=25)
56% (n=17)
p = 0.9
p = 0.45
AVP Interactions If.. 5HT
ETIC
AAS 45% (n=10) 14% (n=3) 41% (n=9)
SO 8% (n=1) 62% (n=8) 30% (n=9)
AVP 0.2 M @ 60 nA
(n=16/30)
AVP
% Baseline
16% (n=8)
*** p = 0.0003
(n=20/51)
5HT3
Decreasers (n=13/30)
5HT 5HT 50 mM @ 80 nA
30% (n=6) 25% (n=5) 45% (n=9)
0% (n=0) 58% (n=7) 42% (n=5)
M p = 0.07
39% (n=9) 13% (n=3) 48% (n=11)
13% (n=2) 50% (n=6) 58% (n=7)
M p = 0.09
SO
M p = 0.07
5HT 50 mM @ 80 nA
AVP 0.2 M @ 60 nA
mSON/NC
AAS
5HT 50 mM @ 80 nA
(n=7/14) 5HT 50 mM @ 80 nA
mSON/NC
AAS
5HT
GABA
GLU
RN 5HT
SO
mSON/NC
AAS
+AVP
+AVP
AVP
RN
GLU
+5HT
GLU
RN
AVP
GABA
AVP 0.2 M @ 60 nA
GABA
AVP
AVP
GABA
Decreasers
5HT + AVP
AVP
+5HT
mSON/NC
(n=8/16)
GABA
5HT
5HT
Increasers
5HT
RN
mSON/NC (n=22/51)
GABAA
GLU
5HT
Decreasers
AVPV1A
AVP
GABA
** p = 0.007
8% (n=1) 25% (n=3) 67% (n=8)
AVP
Molecules
AVP 0.2 M @ 60 nA
Fisher’s Exact Test
35% (n=7) 5% (n=1) 60% (n=12)
SO
RN
% Baseline
ETIC
7% (n=2)
of responses of cells a$er microiontophore+c applica+on of vasopressin (AVP), serotonin (5HT) or e+cilopride (ETIC) to the latero-‐ anterior hypothalamus of hamsters chronically treated throughout development with anabolic steroids (AAS) or vehicle (SO). (BoKom) Propor+ons of cell responses to AVP in the context of their response to either 5HT or E+clopride
Decreasers
% Baseline
5HT
39% (n=20)
(Le$) Propor+ons
% Baseline
AVP
SO
Increasers
% Baseline
AAS
Fisher’s Exact Test
5HT1A/1B
mSON/NC
% Baseline
Single Drugs Response Proportions
Behavioral pharmacology and neuroanatomical studies indicate that the serotonin (5HT), vasopressin (AVP) and dopamine (DA) neural systems interact to modulate adolescent anabolic steroid (AAS)enhanced aggressive behavior. In untreated animals, AVP microinjection into the anterior hypothalamus (AH) has been shown to enhance aggressive/dominant behaviors in the male hamster [Ferris, 1997]. AVP-enhanced aggressive behavior can be reversed by both systemic fluoxetine and local 5HT1A (but not 5HT1B) agonist microinjection [Delville,1996]. Like 5HT and AVP, DA has also been implicated in rodent aggressive behavior. For example aggressive male rats show increased limbic concentrations of DA prior to an aggressive encounter and dominant mice show increased concentrations of tyrosine-hydroxylase and DA transporter expression in aggression neural loci [Ferrari, 2003; Filipenko, 2001]. In AAS treated hamsters, AVP release and binding are enhanced within the latero-anterior [Melloni, 2010] and ventro-lateral hypothalamic regions [DeLeon, 2002], respectively. Moreover, AAS exposure throughout adolescence reduces putative aggression-inhibiting 5HT afferent fibers while increasing the presence of putative aggression-enhancing AVP afferent fibers [Grimes, 2002; 2006]. More recently we have shown that LAH D2 antagonist microinjection reduces AAS-induced aggressive behavior [Morrison, 2014]. This reduction is reversed by both the exogenous application of AVP or D2 agonist microinjection [Morrison, 2014]. These DA-ligand alterations of AAS aggression are underscored by increased DA production in the AH and (accordingly) an increased density of TH-containing neurons in LAH efferent regions (i.e., the nucleus circularis (NC) and medial supraoptic nucleus (mSON) [Ricci, 2009]. Despite numerous studies from our lab showing behavioral and anatomical alterations induced by adolescent AAS, we have little physiological data showing how aggressive neural substrates interact to produce the AAS-induced aggressive phenotype. Recently we have collected pilot data showing that systemic fluoxetine reduces the firing rate of LAH neurons in AAS- but not vehicle treated hamsters, suggesting that AAS exposure alters tonic inhibition of LAH neuronal activity [Sikes, 2013]. Based on previous localization and behavioral pharmacology studies, here we present findings that further our understanding of the electrophysiological profile of LAH neurons by microiontrophoretically applying selective and non-selective ligands that target the AVP, 5HT, and DA systems within the LAH region of the adolescent AAS-exposed male hamster.
Neuronal Responses
Response Proportions
Introduction/Abstract
Primary Responses AAS SO
Receptors
GLU
GABA
GLU
RN 5HT
(Top Left) In normal hamsters, 5HT afferents inhibit putative aggression-stimulating glutamate (GLU) neurons within the LAH. (Top Right) AAS exposure: reduces 5HT afferents (Grimes, 2002), increases AVP afferents [Harrison, 2000], increases AVP binding [Deleon, 2002], reduces somatic 5HT1A receptors [Ricci, 2006], and reduces punctate 5HT1B receptors while enhancing somatic 1B receptors [Grimes, 2005]; summing to increased aggression. (Middle Left) Exogenous (X) 5HT reduces activity of LAH neurons (putative GABA) by acting on 5HT1A receptors. (Middle Right) X-5HT reduces LAH activity by acting on GLU neurons that have lost their 1A receptors, potentially accounting for the difference in Decreased activity (i.e., 1A vs 1B regulated) observed between AAS and SO animals (time series -- Middle). Indeed, 5HT1B receptor agonists are effective in reducing aggression in AAS- but not normal AVP-injected animals [Delville,2006; Grimes, 2005]. (Bottom Left) In SO treated animals, AVP decreases activity by inhibiting GABA neuronal activity, thereby disinhibiting AVP release and activating AVPaggression. (Bottom Right) AVP increases activity of AASdisinhibiting GLU neurons by amplifying the effect of endogenous AVP. GABA neuronal activity is not affected due to AAS-induced reductions of somatic 5HT1A receptors [Ricci, 2006].
