The effects on penile erection and yawning
of subcutaneous (SC) injections of the mixed
dopamine D1/D2-like agonist apomorphine
(0.02-0.2 mg/kg) were studied in outbred Roman
High- (RHA) and Low-Avoidance (RLA) male rats,
two lines selectively bred for their
respectively rapid versus poor acquisition of
the active avoidance response in the
shuttle-box, and compared with the effects
observed in male Sprague Dawley (SD) rats.
Apomorphine dose-response curves were
bell-shaped in all rat lines/strains. Notably,
more penile erections and yawns were recorded
mainly in the ascending part of these curves
(e.g., apomorphine 0.02-0.08 mg/kg) in both RLA
and RHA rats compared to SD rats, with RLA rats
showing the higher response (especially for
yawning) with respect to RHA rats. Similar
results were found with PD-168,077 (0.02-0.2
mg/kg SC), a D4 receptor agonist, which induced
penile erection but not yawning. In all rat
lines/strains, apomorphine responses were
markedly reduced by the D2 antagonist L-741,626,
but not by the D3 antagonist, SB277011A, whereas
the D4 antagonists L-745,870 and FAUC213
elicited a partial, yet statistically
significant, inhibitory effect. In contrast, the
pro-erectile effect of PD-168,077 was completely
abolished by L-745,870 and FAUC213, as expected.
The present study confirms and extends
previously reported differences in dopamine
transmission between RLA and RHA rats and
between the SD strain and the Roman lines.
Moreover, it confirms previous studies
supporting the view that dopamine receptors of
the D2 subtype play a predominant role in the
pro-yawning and pro-erectile effect of
apomorphine, and that the selective stimulation
of D4 receptors induces penile erection.
The outbred Roman high- (RHA) and
low-avoidance (RLA) rat lines were
psychogenetically selected from a Wistar stock
for rapid (RHA) versus extremely poor (RLA)
acquisition of active avoidance in a shuttle-box
(Bignami, 1965). Subsequent studies with the
Swiss Roman sublines indicated that emotional
rather than learning proper- ties were
responsible for their divergent performances in
this test (Driscoll and Bättig, 1982;
Steimer and Driscoll, 2003). Accordingly, RLA
rats are hyperemotional and display a
behavioural repertoire characterized by
hypomotility and freezing, whereas the less emo-
tional RHA rats display a proactive coping
behaviour that leads to the rapid acquisition of
the avoidance response (Escorihuela et al.,
1995). RLA rats also show a greater change in
adrenocorticotropin (ACTH) and corticosterone
levels in response to a novel environment when
compared to RHA rats (Carrasco et al., 2008).
Interestingly, the outbred Roman lines also
differ drastically in several behavioural traits
that are strongly influenced by dopamine
transmission (Driscoll et al., 1986; Durcan et
al., 1984; Giorgi et al., 1994, 2003, 2005,
2007; Lecca et al., 2004; Fattore et al., 2009;
Piras et al., 2010). Likewise, the inbred Roman
strains exhibit behavioural patterns closely
resembling those of the outbred Roman lines
fromwhich they derive,when tested in ex-
perimental paradigms that reflect the activity
of central dopaminergic systems (Driscoll et
al., 1998; Escorihuela et al., 1997, 1999;
Fernández-Teruel et al., 1997, 2002;
López-Aumatell et al., 2009; Moreno et
al., 2010).
In keeping with the above mentioned studies,
differential dose- related gradients between the
inbred RLA and RHA strains were found in the
behavioural response patterns (motility,
stereotypy and yawn- ing) induced by the D1/D2
mixed dopamine receptor agonist apomor- phine.
Thus, the inhibition of locomotor activity
induced by low doses of apomorphine as well as
its pro-yawning effect were more pro- nounced in
RLA rats, whereas high doses of apomorphine
increalocomotion and induced stereotyped
behaviour much more effectively in RHA rats
(Giménez-Llort et al., 2005). That study
also showed that in- bred Roman rats display
more intense spontaneous activity than
Sprague&endash;Dawley (SD) rats, with RHA rats
exhibiting the highest re- sponse to novelty. On
the bases of these findings, it was proposed
that the different effects of apomorphine on
yawning, motility and stereo- typed behaviour in
the inbred RHA and RLA strains are dependent on
the differential activation and/or brain
distribution of D1 and D2 recep- tor families at
both pre- and post-synaptic levels
(Giménez-Llort et al., 2005;
Guitart-Masip et al., 2006, 2008). Lowdoses of
apomorphine and other dopamine receptor agonists
induce not only yawning but also penile erection
in laboratory ani- mals and humans. Both these
responses are mediated by dopamine receptors of
the D2 but not of the D1 family. Accordingly,
D2-like but not D1-like receptor agonists induce
these responses in male rats; moreover, only
pre-treatments with D2-like receptor antago-
nists impair the pro-erectile and pro-yawning
effects of D2-like re- ceptor agonists (Melis
and Argiolas, 1995; Argiolas and Melis, 1998 and
references therein).
The characterization of at least three
D2-like receptor subtypes, D2 (with the D2 short
and D2 long splice variants), D3 and D4 (Seeman
and Van Tol, 1994; Sokoloff and Schwartz, 1995;
Missale et al., 1998) allowed the synthesis of
selective agonists and antagonists of these re-
ceptors, which have been and are still being
used to identify dopamine receptor subtypes in
the brain and to investigate their involvement
in mental pathologies (see Lauzon and
Laviolette, 2010; Shioda et al., 2010). The
availability of selective D2, D3 and D4 receptor
agonists and antagonists also allowed studies
aimed at identifying the dopa- mine receptor
subtypes involved in penile erection and
yawning. Whereas several studies revealed a
pro-erectile role of D4 receptors in rats (Hsieh
et al., 2004; Brioni et al., 2004; Melis et al.,
2005, 2006; Enguehard-Gueiffier et al., 2006;
Löber et al., 2009, 2012), other stud- ies
suggested a main role of either D3 (Collins et
al., 2007, 2009) orD2 receptors
(Depoortère et al., 2009) in both penile
erection and yawn- ing, with no role of D4
receptors in these responses. The most recent
studies on this matter confirmed a main role of
D2 receptors in penile erection and yawning, and
also a pro-erectile but not a pro-yawning effect
of D4 receptor activation (Sanna et al., 2011,
2012b). On the bases of the abovementioned
findings, the present studywas designed to
further characterize the differences in
dopaminergic neuro- transmission that
distinguish the outbred RLA and RHA rats. To
this aim, we first compared the effects of
apomorphine and PD 168,077, a selec- tive D4
receptor agonist, on penile erection and yawning
in both Roman rat lines. We then investigated
the relative contribution of D2, D3 and D4
receptors to the responses elicited by the
dopamine receptor ago- nists using currently
available selective D2, D3 and D4 receptor
antago- nists (see Table 1). Finally, we
compared the responses of the Roman lines with
those observed in Sprague&endash;Dawley rats
which were used as a genetically heterogeneous
reference strain.
